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"SFN" ], "steps": 1, "type": "gene" } ], "geneSymbol": "BRAF", "intervention": "selective_modulation", "mechanismId": "post_translational_modification_BRAF_0" }, { "cycleFlagged": true, "doOperator": "do(PIK3CA=tuned)", "downstreamPredictions": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens 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"label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "GnRH secretion - Homo sapiens (human)", "nodeId": "pathway:gnrh_secretion_homo_sapiens_human", "path": [ "PIK3CA", "GnRH secretion - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "HRAS", "nodeId": "gene:HRAS", "path": [ "PIK3CA", "HRAS" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "RASD2", "nodeId": "gene:RASD2", "path": [ "PIK3CA", "RASD2" ], "steps": 1, "type": "gene" } ], "geneSymbol": "PIK3CA", "intervention": "selective_modulation", "mechanismId": "uncharacterized_PIK3CA_5" }, { "cycleFlagged": true, "doOperator": "do(PIK3CA=off)", "downstreamPredictions": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "GnRH secretion - Homo sapiens (human)", "nodeId": "pathway:gnrh_secretion_homo_sapiens_human", "path": [ "PIK3CA", "GnRH secretion - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "HRAS", "nodeId": "gene:HRAS", "path": [ "PIK3CA", "HRAS" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "RASD2", "nodeId": "gene:RASD2", "path": [ "PIK3CA", "RASD2" ], "steps": 1, "type": "gene" } ], "geneSymbol": "PIK3CA", "intervention": "selective_modulation", "mechanismId": "cellular_localization_PIK3CA_8" }, { "cycleFlagged": true, "doOperator": "do(NRAS=tuned)", "downstreamPredictions": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "EEF1A1", "nodeId": "gene:EEF1A1", "path": [ "NRAS", "EEF1A1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "SRI", "nodeId": "gene:SRI", "path": [ "NRAS", "SRI" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "RPS20", "nodeId": "gene:RPS20", "path": [ "NRAS", "RPS20" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "intervention": "selective_modulation", "mechanismId": "enzymatic_catalysis_NRAS_7" }, { "cycleFlagged": true, "doOperator": "do(NRAS=tuned)", "downstreamPredictions": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "EEF1A1", "nodeId": "gene:EEF1A1", "path": [ "NRAS", "EEF1A1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "SRI", "nodeId": "gene:SRI", "path": [ "NRAS", "SRI" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "RPS20", "nodeId": "gene:RPS20", "path": [ "NRAS", "RPS20" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "intervention": "selective_modulation", "mechanismId": "uncharacterized_NRAS_4" } ], "summary": { "available": true, "cycleCount": 5, "cycleWarnings": [ { "description": "Potential circular reasoning path detected: BRAF -> EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) -> BRAF", "nodes": [ "BRAF", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "BRAF" ], "severity": "medium" }, { "description": "Potential circular reasoning path detected: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) -> NRAS -> EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodes": [ "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "NRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "severity": "medium" }, { "description": "Potential circular reasoning path detected: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) -> NRAS -> KRAS -> EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodes": [ "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "NRAS", "KRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "severity": "high" } ], "edgeCount": 149, "narrative": "do(KRAS=tuned) is propagated through the causal DAG toward EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) with 22% relative effect strength.", "nodeCount": 77, "routeCount": 9 } }, "causalGraph": { "confounders": [ { "description": "Cellular environment and co-factors", 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.775, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(KRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.552, "description": "do(KRAS=restore) is predicted to restore the missing suppressive signal. 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.775, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.38, "description": "What if only F46 was modulated?", "doOperator": "do(KRAS=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.38, "counterfactualScore": 0.76, "description": "do(KRAS=tuned) is predicted to shift the target into a more druggable intermediate state. 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.69, "druggability": 0.35, "feasibility": 0.867, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(KRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.552, "description": "do(KRAS=restore) is predicted to restore the missing suppressive signal. 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.22, "feasibility": 0.735, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.661, "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.748, "druggability": 0.72, "mechanisms": "allosteric_regulation", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "BRAF", "mechanismId": "allosteric_regulation_BRAF_2", "pathwayAnchors": [ { "genes": [ "KRAS", "NRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(BRAF=tuned)", "scenarios": [ { "confidence": 0.6759999999999999, "description": "What if only F66 was modulated?", "doOperator": "do(BRAF=tuned)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.676, "counterfactualScore": 0.661, "description": "do(BRAF=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.72, "feasibility": 0.672, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(BRAF=off)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.658, "description": "do(BRAF=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.535, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(BRAF=restore)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.444, "description": "do(BRAF=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.496, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.66, "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.79, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "BRAF", "mechanismId": "post_translational_modification_BRAF_0", "pathwayAnchors": [ { "genes": [ "KRAS", "NRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(BRAF=tuned)", "scenarios": [ { "confidence": 0.62, "description": "What if only F46 was modulated?", "doOperator": "do(BRAF=tuned)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.62, "counterfactualScore": 0.66, "description": "do(BRAF=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.65, "feasibility": 0.664, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(BRAF=off)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.658, "description": "do(BRAF=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.535, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.6599999999999999, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(BRAF=restore)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.66, "counterfactualScore": 0.449, "description": "do(BRAF=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.52, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.7, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.584, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.802, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "post_translational_modification_PIK3CA_1", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=tuned)", "scenarios": [ { "confidence": 0.62, "description": "What if only F46 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.62, "counterfactualScore": 0.584, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.65, "feasibility": 0.802, "offTargetEffects": 0.1, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.6599999999999999, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.66, "counterfactualScore": 0.373, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.658, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.7, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.582, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.748, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "uncharacterized_PIK3CA_5", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=off)", "scenarios": [ { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.38, "description": "What if only F66 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.38, "counterfactualScore": 0.576, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.35, "feasibility": 0.766, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.368, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.634, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.582, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.712, "druggability": 0.38, "mechanisms": "cellular_localization", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "cellular_localization_PIK3CA_8", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=off)", "scenarios": [ { "confidence": 0.7649999999999999, "description": "What if F308 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.404, "description": "What if only F308 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.404, "counterfactualScore": 0.576, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.38, "feasibility": 0.769, "offTargetEffects": 0.1, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F308 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.368, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.634, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.7, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.263, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "drugTargetPotential": { "developabilityScore": 0.616, "druggability": 0.85, "mechanisms": "enzymatic_catalysis", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "geneSymbol": "NRAS", "mechanismId": "enzymatic_catalysis_NRAS_7", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(NRAS=tuned)", "scenarios": [ { "confidence": 0.78, "description": "What if only F66 was modulated?", "doOperator": "do(NRAS=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.78, "counterfactualScore": 0.263, "description": "do(NRAS=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.48, "druggability": 0.85, "feasibility": 0.73, "offTargetEffects": 0.2, "pathwayReversal": 0.178, "specificityIndex": 0.7 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(NRAS=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.678, "confidence": 0.765, "counterfactualScore": 0.139, "description": "do(NRAS=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.577, "functionalImpact": 0.855, "lethalityRisk": 0.3, "pathwayReversal": 0.178 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(NRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.5, "counterfactualScore": 0.122, "description": "do(NRAS=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.538, "functionalGain": 1.475, "pathwayReversal": 0.178, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.249, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "drugTargetPotential": { "developabilityScore": 0.595, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "geneSymbol": "NRAS", "mechanismId": "uncharacterized_NRAS_4", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(NRAS=tuned)", "scenarios": [ { "confidence": 0.38, "description": "What if only F46 was modulated?", "doOperator": "do(NRAS=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.38, "counterfactualScore": 0.249, "description": "do(NRAS=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.48, "druggability": 0.35, "feasibility": 0.67, "offTargetEffects": 0.2, "pathwayReversal": 0.178, "specificityIndex": 0.7 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(NRAS=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.678, "confidence": 0.765, "counterfactualScore": 0.139, "description": "do(NRAS=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.577, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.178 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(NRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.5, "counterfactualScore": 0.122, "description": "do(NRAS=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.538, "functionalGain": 1.475, "pathwayReversal": 0.178, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] } ] } ], "interventionCalibration": { "available": true, "diseaseContext": "colorectal cancer", "generatedAt": "2026-04-03T18:29:43.426Z", "interventions": [ { "baseCounterfactualScore": 0.773, "calibratedConfidence": 0.384, "calibrationDelta": -0.389, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.217, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "KRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "KRAS", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "KRAS", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "KRAS", "insufficientEvidence": false, "localEvidenceModalities": 4, "localEvidenceScore": 0.55, "mechanismId": "enzymatic_catalysis_KRAS_6", "notes": [ "Base counterfactual score 0.773", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "CPTAC protein-layer support from CPTAC COAD", "CELLxGENE localizes the signal to malignant ductal cells" ], "recommendedDoOperator": "do(KRAS=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.225, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "KRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 780, "validated": 0 }, "hypothesis": { "note": "0/780 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "KRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.766, "calibratedConfidence": 0.38, "calibrationDelta": -0.386, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.217, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "KRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "KRAS", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "KRAS", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "KRAS", "insufficientEvidence": false, "localEvidenceModalities": 4, "localEvidenceScore": 0.55, "mechanismId": "uncharacterized_KRAS_3", "notes": [ "Base counterfactual score 0.766", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "CPTAC protein-layer support from CPTAC COAD", "CELLxGENE localizes the signal to malignant ductal cells" ], "recommendedDoOperator": "do(KRAS=off)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.225, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "KRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 780, "validated": 0 }, "hypothesis": { "note": "0/780 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "KRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.661, "calibratedConfidence": 0.299, "calibrationDelta": -0.362, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.186, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "BRAF", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "BRAF", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "BRAF", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "BRAF", "insufficientEvidence": false, "localEvidenceModalities": 2, "localEvidenceScore": 0.38, "mechanismId": "allosteric_regulation_BRAF_2", "notes": [ "Base counterfactual score 0.661", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "CPTAC protein-layer support from CPTAC SKCM", "Circular reasoning penalty applied from the causal DAG" ], "recommendedDoOperator": "do(BRAF=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.226, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 777, "validated": 0 }, "hypothesis": { "note": "0/777 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.66, "calibratedConfidence": 0.299, "calibrationDelta": -0.361, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.186, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "BRAF", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "BRAF", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "BRAF", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "BRAF", "insufficientEvidence": false, "localEvidenceModalities": 2, "localEvidenceScore": 0.38, "mechanismId": "post_translational_modification_BRAF_0", "notes": [ "Base counterfactual score 0.66", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "CPTAC protein-layer support from CPTAC SKCM", "Circular reasoning penalty applied from the causal DAG" ], "recommendedDoOperator": "do(BRAF=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.226, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 777, "validated": 0 }, "hypothesis": { "note": "0/777 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.584, "calibratedConfidence": 0.171, "calibrationDelta": -0.413, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance 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(literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.582, "calibratedConfidence": 0.17, "calibrationDelta": -0.412, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "PIK3CA", "insufficientEvidence": true, "localEvidenceModalities": 1, "localEvidenceScore": 0.26, "mechanismId": "uncharacterized_PIK3CA_5", "notes": [ "Base counterfactual score 0.582", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=off)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.582, "calibratedConfidence": 0.17, "calibrationDelta": -0.412, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "PIK3CA", "insufficientEvidence": true, "localEvidenceModalities": 1, "localEvidenceScore": 0.26, "mechanismId": "cellular_localization_PIK3CA_8", "notes": [ "Base counterfactual score 0.582", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=off)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.263, "calibratedConfidence": 0, "calibrationDelta": -0.263, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0.06, "mechanismId": "enzymatic_catalysis_NRAS_7", "notes": [ "Base counterfactual score 0.263", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Multi-node downstream propagation available in the causal DAG" ], "recommendedDoOperator": "do(NRAS=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.228, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 771, "validated": 0 }, "hypothesis": { "note": "0/771 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.249, "calibratedConfidence": 0, "calibrationDelta": -0.249, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0.06, "mechanismId": "uncharacterized_NRAS_4", "notes": [ "Base counterfactual score 0.249", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Multi-node downstream propagation available in the causal DAG" ], "recommendedDoOperator": "do(NRAS=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.228, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 771, "validated": 0 }, "hypothesis": { "note": "0/771 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } } ], "summary": { "averageCalibratedConfidence": 0.208, "deescalatedCount": 9, "directlyCalibratedCount": 0, "narrative": "GaiaLab recalibrated intervention confidence for 9 routes using outcome history, disease-level prediction follow-through, and orthogonal evidence support. Top calibrated targets: KRAS, BRAF.", "topCalibratedTargets": [ "KRAS", "BRAF" ] }, "trackerPriors": { "diseasePredictionResearchDirectionRate": 0.9, "diseasePredictionTrialMatchRate": 0.6, "hypothesisAccuracy": 0, "totalDiseaseCheckedPredictions": 70, "totalValidatedHypotheses": 0, "workspaceObservedAccuracy": null, "workspaceValidatedHypotheses": 0 } }, "interventionSummary": { "available": true, "averageCounterfactualScore": 0.569, "narrative": "Top intervention-ready genes for colorectal cancer are KRAS, BRAF based on pathway anchoring, dependency, structure, and variant directionality.", "preferredModes": [ { "count": 9, "mode": "selective_modulation" } ], "topGenes": [ "KRAS", "BRAF" ], "totalCounterfactuals": 9 }, "interventionalPredictions": [ { "confidence": 0.773, "cycleFlagged": true, "doOperator": "do(KRAS=tuned)", "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.217, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "KRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "KRAS", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "KRAS", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "KRAS", "intervention": "selective_modulation", "mechanismId": "enzymatic_catalysis_KRAS_6", "predictedEffect": "modulatory" }, { "confidence": 0.766, "cycleFlagged": true, "doOperator": "do(KRAS=off)", "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.217, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "KRAS", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "KRAS", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.217, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "KRAS", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "KRAS", "intervention": "selective_modulation", "mechanismId": "uncharacterized_KRAS_3", "predictedEffect": "modulatory" }, { "confidence": 0.661, "cycleFlagged": true, "doOperator": "do(BRAF=tuned)", "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.186, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "BRAF", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "BRAF", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "BRAF", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "BRAF", "intervention": "selective_modulation", "mechanismId": "allosteric_regulation_BRAF_2", "predictedEffect": "modulatory" }, { "confidence": 0.66, "cycleFlagged": true, "doOperator": "do(BRAF=tuned)", "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.186, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "BRAF", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "BRAF", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.186, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "BRAF", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "BRAF", "intervention": "selective_modulation", "mechanismId": "post_translational_modification_BRAF_0", "predictedEffect": "modulatory" }, { "confidence": 0.584, "cycleFlagged": true, "doOperator": "do(PIK3CA=tuned)", "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - 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Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 84, "firstPostedDate": "2022-04-04", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "startDate": "2022-07-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 30, "firstPostedDate": "2023-01-31", "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "startDate": "2023-02-13", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 43, "firstPostedDate": "2022-10-13", "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "startDate": "2022-10-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 1, "firstPostedDate": "2023-02-02", "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "startDate": "2023-08-16", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The study will be conducted in patients with metastatic colorectal cancer (mCRC) harboring a BRAFV600E mutation, to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with this pathology.", "completionDate": "2028-07", "conditionSummary": "Metastatic Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Metastatic Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": true, "isInterventional": true, "matchScore": 9, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 400, "firstPostedDate": "2022-12-06", "hasResults": false, "interventions": [ "Collection of blood samples" ], "nctId": "NCT05639413", "phase": "NA", "primaryCompletionDate": "2027-07", "startDate": "2023-07-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC.\n\nThis collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned:\n\ni. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to:\n\n* Evaluate its positive and negative predictive value.\n* Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy.\n\nii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring).\n\niii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.", "title": "A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05639413", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": true, "isInterventional": true, "matchScore": 9, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 49, "firstPostedDate": "2026-04-01", "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "startDate": "2026-03", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This phase I trial tests the safety, best dose, and effectiveness of ZEN003694 in combination with cetuximab and encorafenib in treating patients with colorectal cancer that has not responded to previous treatment (refractory), that has come back after a period of improvement (relapsed), and that has spread from where it first started (primary site) to other places in the body (metastatic). ZEN003694 is a protein inhibitor that binds to BET proteins. When ZEN003694 binds to BET proteins, it disrupts gene expression. Preventing the expression of certain growth-promoting genes may inhibit proliferation of tumor cells that over-express BET proteins. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Encorafenib is an enzyme inhibitor. It inhibits pathways that are responsible for controlling cell proliferation and survival, which may lead to a decrease in tumor cell proliferation. Both cetuximab and encorafenib have been approved to treat cancer. Adding ZEN003694 to cetuximab and encorafenib may be more effective at treating patients with refractory metastatic colorectal cancer than giving the usual treatment (cetuximab and encorafenib) alone.", "completionDate": "2027-01-30", "conditionSummary": "Metastatic Colorectal Adenocarcinoma · Recurrent Colorectal Adenocarcinoma · Refractory Colorectal Adenocarcinoma", "conditions": [ "Metastatic Colorectal Adenocarcinoma", "Recurrent Colorectal Adenocarcinoma", "Refractory Colorectal Adenocarcinoma" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": true, "isInterventional": true, "matchScore": 9, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 30, "firstPostedDate": "2023-10-26", "hasResults": false, "interventions": [ "BET Bromodomain Inhibitor ZEN-3694", "Biopsy Procedure", "Biospecimen Collection", "Cetuximab", "Computed Tomography" ], "nctId": "NCT06102902", "phase": "Phase 1", "primaryCompletionDate": "2027-01-30", "startDate": "2024-06-05", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when used in combination with cetuximab and encorafenib.\n\nII. To define the safety profile of combination of ZEN003694, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To observe and record anti-tumor activity. II. To evaluate clinical response signals of the combination. III. To assess the pharmacodynamic (PD) profile of the combination as defined by MAPK inhibition.\n\nEXPLORATORY OBJECTIVE:\n\nI. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via whole exome sequencing (WES), reverse phase protein array (RPPA), ribonucleic acid sequencing (RNAseq), and assay for transposase-accessible chromatin with sequencing (ATACseq)/HiSeq 4000 or NovaSeq following progression on treatment.\n\nOUTLINE: This is a dose-escalation study of ZEN003694 followed by a dose-expansion study.\n\nPatients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 of each cycle, cetuximab intravenously (IV) over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA), computed tomography (CT) or magnetic resonance imaging (MRI), and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study.\n\nAfter completion of study treatment, patients are followed up every 2 months.", "title": "Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06102902", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": true, "isInterventional": true, "matchScore": 9, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 38, "firstPostedDate": "2019-07-12", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "startDate": "2019-06-14", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" }, { "briefSummary": "As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research.\n\nThe combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively.\n\nBased on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.", "completionDate": "2029-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 70, "firstPostedDate": "2024-01-17", "hasResults": false, "interventions": [ "EBC" ], "nctId": "NCT06207656", "phase": "Phase 2", "primaryCompletionDate": "2029-04-01", "startDate": "2024-04-16", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research.\n\nThe combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively.\n\nBased on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.", "title": "Study to Evaluate the Efficacy and Safety of Cetuximab in Combination with Encorafenib Plus Binimetinib As Induction Treatment in BRAF V600E Mutated MSS Initially Resectable or Potentially Resectable Advanced Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06207656", "whyStopped": "" }, { "briefSummary": "To find out if certain drug/therapy combinations that are targeted to individual patients based on characteristics of their disease types may help to control the disease.", "completionDate": "2029-11-14", "conditionSummary": "Dynamic Tumor Resistance · Metastatic Colorectal Cancer", "conditions": [ "Dynamic Tumor Resistance", "Metastatic Colorectal Cancer" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": false, "isInterventional": true, "matchScore": 8, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 100, "firstPostedDate": "2026-01-06", "hasResults": false, "interventions": [ "SOC (Standard of care)", "Bevacizumab", "Cetuximab", "Panitumumab", "FOLFIRI" ], "nctId": "NCT07318389", "phase": "EARLYPhase 1", "primaryCompletionDate": "2027-11-14", "startDate": "2026-06-10", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives\n\n* To determine differences in PFS based on differential response markers in paired tissue biopsies (Part I).\n* To improve progression-free survival with novel intervention strategies (Part II)\n\nSecondary Objectives\n\n* To collect serial tissue and blood biomarkers and efficacy data associated with standard of care or investigational therapy across multiple lines of therapy.\n* To determine the overall response rate (ORR), and overall survival (OS) based on the presence of specific biomarkers or adaptive interventions.", "title": "ASCEND-CRC: Profiling and Targeting Dynamic Tumor Resistance in Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07318389", "whyStopped": "" } ] }, "complexityAnalysis": { "audienceComplexity": 3, "biomedicalDepth": { "biomarker": 0, "clinical": 0.16, "molecular": 0, "pathway": 0.02, "pharmacology": 0.02 }, "biomedicalDepthScore": 0.37, "complexity": "complex", "complexityScore": 6.234, "contextComplexity": 1, "featureVector": { "audience": "researcher", "biomarkerDepth": 0, "biomedicalDepth": 1.5, "clinicalDepth": 0.62, "contextLength": 17, "geneCount": 4, "intent": "research", "intentScore": 0.59, "molecularDepth": 0, "pathwayDepth": 0.07, "pharmacologyDepth": 0.06 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with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "directness": "direct", "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 68, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 68, "scoreLabel": "Target engagement score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 1, "mechanisticImportance": 0.63, "tractability": 0.95, "translationalFeasibility": 0.98 }, "actionabilityScore": 0.81, "biomarkerGated": false, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "selumetinib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 76, "claimEvidenceClass": "direct_target_binding", "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "KRAS" ], "directTargetEvidenceStrength": 1, "directness": "direct", "drug": "SELUMETINIB", "drugId": "rxcui:2289380", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 66, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 22241789, 36856908, 34108213, 38922339, 26343583, 24265152, 31704811, 26137449, 27196754, 26351322, 23406027, 27655129, 22197931, 19915144, 24448821, 35882450, 27312529, 26461489, 35363510, 23942066, 31151904, 27222538, 27217440, 22048237 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: Unknown", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets KRAS", "🔬 Reported potency: Interaction: Unknown", "📄 24 PubMed citation(s) supporting this drug-target association", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 66, "scoreLabel": "Target engagement score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "The Clinical Knowledgebase", "MyCancerGenome Clinical Trial", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): KRAS.", "targetingSummary": "SELUMETINIB directly binds/inhibits KRAS (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 1, "mechanisticImportance": 0.63, "tractability": 0.95, "translationalFeasibility": 0.98 }, "actionabilityScore": 0.81, "biomarkerGated": false, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "dasatinib anhydrous", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 96, "ci_low": 72, "claimEvidenceClass": "direct_target_binding", "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, 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"unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the Progression-Free Survival (PFS) time of Sorafenib in combination with FOLFIRI regimen used as in the second front treatment in patients with advanced CRC after failure of oxaliplatin treatment.", "completionDate": "2010-11", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "sorafenib", "FOLFIRI" ], "nctId": "NCT00839111", "phase": "Phase 2", "primaryCompletionDate": "2010-11", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ⅱ open label, non randomized study, in which sorafenib is used in combination with irinotecan, leucovorin and fluorouracil in patients with advanced colorectal cancer after failure of oxaliplatin treatment.The aim of this study is to determine the Progression-Free Survival (PFS) of Sorafenib used in combination with FOLFIRI regimen as a second front treatment in patients with advanced CRC after failure of oxaliplatin treatment, defined as the time from treatment to disease progression or death due to any cause. The other secondary endpoints are disease control rate, defined as complete response, partial response, and stable disease.Response rate,overall survival, and safety are also evaluated.", "title": "Sorafenib and FOLFIRI Regimen in 2nd Colorectal Cancer (CRC) After Failure of Oxaliplatin Treatment", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00839111", "whyStopped": "" }, { "briefSummary": "The main purpose of this study is to find the maximum tolerable dose of sorafenib when administered along with another drug called 5-Fluorouracil (5-FU) and to find out more about whether these drugs, along with radiation, can help people with rectal cancer when given before surgery. 5-FU and radiation are both approved by the US Food and Drug Administration (FDA) for use in people with rectal cancer.\n\nThe investigators will utilize a standard 3 + 3 phase I study design. In the phase I part of the study, the investigators will attempt dose escalation of sorafenib in combination with standard infusional 5-FU and external beam at standard doses. Clinical staging should be done by endorectal ultrasound (ERUS) and/or pelvic magnetic resonance imaging (MRI) for T and N stage; chest and abdomen computed tomography (CT) for staging of metastatic disease; undergo sigmoidoscopy and/or colonoscopy done by crude odds ratios (CORS); biopsy is taken for diagnosis and extra is sent for tissue bank. At the maximum tolerated dose (MTD) of sorafenib we will expand the cohort to 6 more patients to further evaluate toxicity profile and efficacy.", "completionDate": "2016-03", "conditionSummary": "Rectal Cancer", "conditions": [ "Rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "5-Fluorouracil (5-FU)", "Radiation" ], "nctId": "NCT01376453", "phase": "Phase 1", "primaryCompletionDate": "2014-11", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Participants' study regimen will include 5 ½ weeks of radiation. Radiation sessions will be daily, Monday through Friday, except for holidays. 5-FU will be delivered at a dose of 225 mg/m² daily through a catheter in a large vein continuously until the last day of radiation. In addition, sorafenib will be taken by mouth twice daily every day until the last day of radiation. The dose of sorafenib participants may receive will be one of the following: 200 mg every other day, 200 mg daily, 400 mg daily, or 800 mg daily. Following completion of this phase of the study, participants will receive no study drug or radiation for one month. At 4 to 5 weeks after stopping study drug and radiation, participants will have another CT scan or MRI to assess their cancer. About 6 to 8 weeks after the end of radiation, participants will undergo surgery and every effort will be made to remove the tumor. The surgery will occur just as it would if participants were not in the study, except that a portion of their tumor obtained during surgery will be used for research biomarker testing (as described in the consent form).\n\nApproximately 6 -10 weeks after participants' surgery, when they have adequately healed, they may receive additional chemotherapy at their study doctor's discretion.", "title": "Pre-operative 5-Fluorouracil (5-FU) and Sorafenib With External Radiation in Locally Advanced Rectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01376453", "whyStopped": "" }, { "briefSummary": "This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells", "completionDate": "2014-02", "conditionSummary": "Recurrent Colon Cancer · Recurrent Rectal Cancer · Stage IV Colon Cancer", "conditions": [ "Recurrent Colon Cancer", "Recurrent Rectal Cancer", "Stage IV Colon Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "sorafenib tosylate", "bevacizumab" ], "nctId": "NCT00826540", "phase": "Phase 2", "primaryCompletionDate": "2010-01", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200).\n\nSECONDARY OBJECTIVES:\n\nI. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility\n\nOUTLINE: This is a multicenter study.\n\nPatients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies.\n\nAfter completion of study treatment, patients are followed periodically for up to 2 years.", "title": "Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00826540", "whyStopped": "" }, { "briefSummary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "completionDate": "2015-09", "conditionSummary": "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "conditions": [ "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib and irinotecan combination", "Sorafenib monotherapy", "Irinotecan monotherapy" ], "nctId": "NCT01715441", "phase": "Phase 2", "primaryCompletionDate": "2015-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "title": "Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01715441", "whyStopped": "" }, { "briefSummary": "RATIONALE: Sorafenib and pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with pemetrexed and cisplatin may kill more tumor cells.\n\nPURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with pemetrexed and cisplatin in treating patients with advanced solid tumors.", "completionDate": "2010-11", "conditionSummary": "Breast Cancer · Colorectal Cancer · Head and Neck Cancer", "conditions": [ "Breast Cancer", "Colorectal Cancer", "Head and Neck Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "cisplatin", "pemetrexed disodium", "sorafenib" ], "nctId": "NCT00703638", "phase": "Phase 1", "primaryCompletionDate": "2010-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "OBJECTIVES:\n\nPrimary\n\n* To determine the maximum tolerated dose of sorafenib tosylate when given in combination with pemetrexed disodium and cisplatin in patients with advanced non-squamous cell solid tumor malignancy including, but not limited to, breast, lung, colon, pancreatic, prostate, or head and neck cancer or sarcoma.\n\nSecondary\n\n* To characterize the quantitative and qualitative toxicities of this regimen in these patients.\n* To obtain preliminary information about the antitumor activity of this regimen in these patients.\n\nOUTLINE: This is a dose-escalation study of sorafenib tosylate.\n\nPatients receive oral sorafenib tosylate once daily on days 1-21 and cisplatin IV over 1-2 hours and pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed at 30 days, every 8 weeks until disease progression, and then every 3 months for up to 6 months.", "title": "Sorafenib, Pemetrexed, and Cisplatin in Treating Patients With Advanced Solid Tumors", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00703638", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to determine whether sorafenib in combination with chemotherapy has a positive effect on time to progression of the tumor or death for the treatment of large bowel cancer that has already progressed during a first chemotherapy.", "completionDate": "2012-12", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "Placebo", "Oxaliplatin or Irinotecan", "Leucovorin", "5-Fluorouracil" ], "nctId": "NCT00889343", "phase": "Phase 2", "primaryCompletionDate": "2011-11", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "Patients with metastatic CRC who received a first-line therapy with an Oxaliplatin- or Irinotecan based Fluoropyrimidine containing regimen ± bevacizumab and had a progression subsequently, are eligible for this study. Patients will be randomized to receive chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib 400 mg bid or chemotherapy + placebo. Patients who have received an Oxaliplatin based Fluoropyrimidine containing regimen in first-line will obtain FOLFIRI during this study. Patients who have received an Irinotecan based Fluoropyrimidine containing regimen in first-line will obtain FOLFOX6.\n\nPrimary objective of the study is to compare the Progression-free-survival (PFS) between patients receiving chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib with chemotherapy + placebo.", "title": "Study to Evaluate the Effects of Sorafenib if Combined With Chemotherapy (FOLFOX6 or FOLFIRI) in the Second-Line Treatment of Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00889343", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "directness": "direct", "drug": "SORAFENIB", "drugId": "rxcui:495881", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 62, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 37656784, 30575814, 34108213, 27388325, 35630083, 18794803, 20538618, 38795180, 18519791, 23792568, 23629727, 24885690, 16880785, 22394203, 23715574, 14679157, 25157968, 19537845, 21129611, 12068308, 18186519, 22310681, 20350999, 26619011, 20619739, 24727320, 20526349, 28362716 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 28 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 62, "scoreLabel": "Target engagement score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Trends in the exploitation of novel drug targets (Rask-Andersen, et al., 2011)", "Cancer Genome Interpreter", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF.", "targetingSummary": "SORAFENIB directly binds/inhibits BRAF (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0.63, "tractability": 0.95, "translationalFeasibility": 0.98 }, "actionabilityScore": 0.63, "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 51, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "encorafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 98, "ci_low": 74, "claimEvidenceClass": "disease_association", "clinicalTrialSupport": { "activeTrialCount": 11, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 10, "diseaseMatchedActiveTherapeuticTrialCount": 11, "diseaseMatchedActiveTrialCount": 11, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 9, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 1, "diseaseMatchedInterventionalTrialCount": 10, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 10, "diseaseMatchedPositiveOutcomeTrialCount": 1, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 10, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 1, "diseaseMatchedTherapeuticTrialCount": 11, "diseaseMatchedTrialCount": 11, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 4, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 4, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 4, "interventionalTrialCount": 10, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 10, "observationalTrialCount": 1, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 1, "totalTrials": 11, "unknownStatusTrialCount": 0 }, "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "completionDate": "2028-08", "conditionSummary": "Colo-rectal Cancer", "conditions": [ "Colo-rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Rechalange with bevacizumab + encorafenib" ], "nctId": "NCT07178717", "phase": "Phase 2", "primaryCompletionDate": "2028-02", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "title": "A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy With BRAF Inhibitors-based Combinations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07178717", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "directness": "indirect", "drug": "ENCORAFENIB", "drugId": "rxcui:2049106", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "variant_conditional", "evidenceTypeLabel": "Variant-conditional therapy (BRAF V600)", "fitScore": 47, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 35319964, 37656784, 31566661, 35385748, 32540409, 39072179, 29903896, 26577700, 27307593, 28611198, 39145064, 39313594, 38854737, 28951457, 36442478, 39121480, 37729428, 36759733, 37269335, 37040395, 36763936, 39461261, 28363909, 35696748, 39255538, 27312529, 31566309, 37236086, 36307056, 37981300, 28351928, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 39018564, 30559419 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 43 PubMed citation(s) supporting this drug-target association", "🏁 1 completed disease-matched clinical trial reported positive efficacy/outcome signals", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "computational_hypothesis", "repurposingScore": 47, "scoreLabel": "Context alignment score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "Therapeutic Target Database", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetLanguageGuard": "Direct target wording blocked due to insufficient direct evidence strength.", "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ENCORAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "ENCORAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "variant-conditional therapy (BRAF V600)", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0.63, "tractability": 0.95, "translationalFeasibility": 0.96 }, "actionabilityScore": 0.62, "biomarkerGated": true, "breakdown": { "clinicalEvidence": 96, "contextRelevance": 38, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "dabrafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 95, "ci_low": 71, "claimEvidenceClass": "disease_association", "clinicalTrialSupport": { "activeTrialCount": 3, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 1, "diseaseMatchedActiveInterventionalTrialCount": 2, "diseaseMatchedActiveTherapeuticTrialCount": 2, "diseaseMatchedActiveTrialCount": 2, "diseaseMatchedCompletedInterventionalTrialCount": 1, "diseaseMatchedCompletedTherapeuticTrialCount": 1, "diseaseMatchedCompletedTrialCount": 1, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 4, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 5, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 4, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 4, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 5, "diseaseMatchedTrialCount": 5, "domainAlignedTrialCount": 1, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the efficacy and toxicity of irinotecan with dabrafenib, cetuximab/panitumumab in the second line of treatment for the potential treatment of colorectal cancer that: has a metastatic, inoperable; has a mutation in the BRAF gene.\n\nParticipants in this study will receive one of the following study treatments:\n\nThese participants will receive in the second line is irinotecan, dabrafenib + trametinib, cetuximab or panitumumab.\n\nThis trial is currently enrolling participants who will receive either irinotecan and dabrafenib plus cetuximab or panitumumab in the second line of therapy.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2028-06-10", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "• Drug: Dabrafenib • Drug: Trametinib • Drug: Cetuximab • Drug: Рanitumumab • Drug: Oxaliplatin • Drug: Irinotecan • Drug: Leucovorin • Drug: 5-FU" ], "nctId": "NCT06967155", "phase": "Phase 2", "primaryCompletionDate": "2027-11-10", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate the efficacy and toxicity of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in second-line treatment of patients with metastatic inoperable colorectal cancer who have a BRAF mutation.", "title": "A Study of Irinotecan With Dabrafenib Plus Trametinib and Anti-EGFR in the Second Line of Therapy in People With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06967155", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": null, "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).", "completionDate": "2020-06-18", "conditionSummary": "Cancer", "conditions": [ "Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Dabrafenib", "Trametinib", "Panitumumab", "5-fluorouracil" ], "nctId": "NCT01750918", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2020-06-18", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.\n\nPart 2A:\n\nThis was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.\n\nPart 2B:\n\nIn this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.\n\nPart 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).\n\nPart 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.\n\nPart 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\\~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.\n\nPart 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.", "title": "BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01750918", "whyStopped": "" }, { "briefSummary": "This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\nThe names of the study drugs involved in this study are:\n\n* Dabrafenib\n* Trametinib\n* PDR001", "completionDate": "2022-12-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "Trametinib", "PDR001" ], "nctId": "NCT03668431", "phase": "Phase 2", "primaryCompletionDate": "2022-09-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. \"Investigational\" means that the drug combination is being studied.\n\n * The FDA (the U.S. Food and Drug Administration) has not approved PDR001 as a treatment for any disease.\n * The FDA has not approved dabrafenib and trametinib for your specific disease but it has been approved for other uses, whether alone as single agents, or given together as in this study.\n* This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\n * All humans have a gene called BRAF which is responsible for sending signals to proteins called B-Raf inside of cells that help them grow. In some metastatic colorectal patients, this gene mutates and causes cancer cells to grow in uncontrolled ways.\n\n \\--- Dabrafenib is a drug that is thought to inhibit the mutant BRAF activity, which may serve to slow or stop cell growth of metastatic colon cancer.\n * Mitogen-activated protein kinase (MAPK) is a pathway that helps to activate the BRAF mutated genes. The MAPK pathway is commonly found to be overactivated in BRAF mutated tumor cells. MEK (which refers to MAPK/ERK Kinase) enzymes are essential to the activity of the MAPK pathway.\n\n * Trametinib inhibits the MEK enzymes in order to shut down the MAPK pathway, thus blocking the pathway that helps the cancer cells grow uncontrollably.\n * PDR001 is a drug which binds to PD1 on immune cells and is believed to block binding of PD-L1 and PD-L2. PD-L1/PDL1 and PD-L2/PDL2 are often used by cancer cells and to escape the power of the body's immune system so that they cannot be fought. By blocking that binding of the molecules, the body's immune system may reach and fight the cancer cells. Researchers are hoping that administration of all three of these drugs may help anti-cancer activities work together to slow or stop the cancer growth and may help your own immune system damage or destroy the existing cancer cells.", "title": "Dabrafenib + Trametinib + PDR001 In Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03668431", "whyStopped": "" }, { "briefSummary": "A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.", "completionDate": "2024-09-25", "conditionSummary": "BRAF V600 Colorectal Cancer", "conditions": [ "BRAF V600 Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "LTT462", "Trametinib", "LXH254", "TNO155" ], "nctId": "NCT04294160", "phase": "Phase 1", "primaryCompletionDate": "2024-09-25", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ib, multi-center, open-label study with multiple treatment arms in adult patients with advanced or metastatic BRAF V600 (E, D, or K) in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies. The open platform design of this study is adaptive to allow removal of combination treatment arm(s) based on emerging data and facilitate introduction of new candidate combinations. The study is comprised of a dose escalation part and may be followed by a dose expansion part for any combination treatment arm.", "title": "A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04294160", "whyStopped": "The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations." }, { "briefSummary": "This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Bladder Carcinoma", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Bladder Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Adavosertib", "Afatinib", "Afatinib Dimaleate", "Binimetinib", "Biopsy Procedure" ], "nctId": "NCT02465060", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nSTEP 0 (Screening): Patients undergo biopsy along with molecular characterization of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Consenting patients also undergo collection of blood samples for research purposes.\n\nSTEPS 1, 3, 5, 7 (Treatment): Patients are assigned to 1 of 38 treatment subprotocols based on molecularly-defined subgroup. (See Arms Section)\n\nSTEPS 2, 4, 6 (Screening): Patients experiencing disease progression on the prior Step treatment or who could not tolerate the assigned treatment undergo review of their previous biopsy results to determine if another treatment is available or undergo another biopsy. Patients may have a maximum of 2 screening biopsies and 2 treatments per biopsy.\n\nSTEP 8 (Optional Research): Consenting patients undergo end-of-treatment biopsy and collection of blood samples for research purposes.\n\nAdditionally, patients may undergo a computed tomography (CT) scan, magnetic resonance imaging, and/or radionuclide imaging throughout the trial.\n\nAfter completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.", "title": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02465060", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "directness": "indirect", "drug": "DABRAFENIB", "drugId": "rxcui:1424911", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "variant_conditional", "evidenceTypeLabel": "Variant-conditional therapy (BRAF V600)", "fitScore": 45, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": 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"canUseTargetsVerb": false, "canonicalName": "Biospecimen Collection", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 1, "firstPostedDate": "2023-02-02", "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "startDate": "2023-08-16", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Biospecimen Collection", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 16, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 3, "relationType": "computational_hypothesis", "repurposingScore": 16, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "I", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Computed Tomography", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 1, "firstPostedDate": "2023-02-02", "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "startDate": "2023-08-16", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Computed Tomography", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 16, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 3, "relationType": "computational_hypothesis", "repurposingScore": 16, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "I", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Magnetic Resonance Imaging", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 1, "firstPostedDate": "2023-02-02", "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "startDate": "2023-08-16", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Magnetic Resonance Imaging", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 16, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 3, "relationType": "computational_hypothesis", "repurposingScore": 16, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "I", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Cetuximab", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 84, "firstPostedDate": "2022-04-04", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "startDate": "2022-07-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Cetuximab", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 14, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 14, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Encorafenib", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 84, "firstPostedDate": "2022-04-04", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "startDate": "2022-07-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Encorafenib", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 14, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 14, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Nivolumab", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 84, "firstPostedDate": "2022-04-04", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "startDate": "2022-07-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Nivolumab", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 14, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 14, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Encorafenib Oral Capsule + Cetuximab", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 30, "firstPostedDate": "2023-01-31", "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "startDate": "2023-02-13", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Encorafenib Oral Capsule + Cetuximab", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 14, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 14, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "tumorMatch": "unspecified" }, { "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 0.3, "mechanisticImportance": 0, "tractability": 0.35, "translationalFeasibility": 0.1 }, "actionabilityScore": 0.24, "canUseTargetsVerb": false, "canonicalName": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab", "claimEvidenceClass": "computational_inference", "clinicalTrials": [ { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 43, "firstPostedDate": "2022-10-13", "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "startDate": "2022-10-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contextRelevance": 72, "contradictionFlag": false, "contradictionPenalty": 0, "directTargetEvidenceStrength": 0, "directness": "indirect", "diseaseContext": "colorectal cancer", "drugName": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab", "evidenceQualityFlag": "clinical", "evidenceType": "computational_hypothesis", "evidenceTypeLabel": "Computational hypothesis", "fitScore": 14, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isApproved": false, "matchedTargets": [], "maxPhase": 2, "relationType": "computational_hypothesis", "repurposingScore": 14, "sourceClass": "literature_or_inference", "syntheticFromTrial": true, "targetRelation": null, "targetRelationText": "computational hypothesis", "targetsInPanel": true, "tier": "II", "trialContextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "tumorMatch": "unspecified" } ], "combinations": [ { "drugA": "REGORAFENIB", "drugB": "SELUMETINIB", "rationale": "Both have clinical-stage evidence", "synergyScore": 55 }, { "drugA": "REGORAFENIB", "drugB": "ENCORAFENIB", "rationale": "Both have clinical-stage evidence", "synergyScore": 55 }, { "drugA": "REGORAFENIB", "drugB": "DASATINIB ANHYDROUS", "rationale": "Both have clinical-stage evidence", "synergyScore": 55 } ], "enterpriseValue": "$10K-50K/year", "evidenceMode": "drug_first", "fallbackMode": null, "hasMultipleSections": true, "hasMultipleTracks": true, "pathwayFdrStatus": { "anyFdrSignificant": true, "anyFdrSuggestive": false, "fdrSignificantCount": 20 }, "stats": { "analysisTime": "135ms", "avgScore": 79, "candidatesFound": 10, "exploratoryCount": 0, "minScore": 30, "onLabelContextCount": 9, "onlyApproved": false, "repurposingOpportunityCount": 1, "totalDrugsAnalyzed": 449 }, "summary": { "headline": "18 therapeutic candidates identified for colorectal cancer", "recommendation": "Prioritize REGORAFENIB for targeted validation against BRAF, KRAS.", "summary": "Top therapeutic candidate: REGORAFENIB (68% fit). Evidence: clinically established on-target mechanism." }, "synergyPairs": [ { "almanacLabel": "Computational prediction — not in NCI ALMANAC or curated trial database", "almanacValidated": false, "drugA": "SELUMETINIB", "drugB": "ENCORAFENIB", "orthogonalityScore": 1, "rationale": "SELUMETINIB (KRAS) and ENCORAFENIB (BRAF) engage orthogonal targets — complementary resistance suppression", "safetyCompatible": true, "sameCheckpointAxis": false, "synergyScore": 100 }, { "almanacLabel": "Computational prediction — not in NCI ALMANAC or curated trial database", "almanacValidated": false, "drugA": "SELUMETINIB", "drugB": "DASATINIB ANHYDROUS", "orthogonalityScore": 1, "rationale": "SELUMETINIB (KRAS) and DASATINIB ANHYDROUS (BRAF) engage orthogonal targets — complementary resistance suppression", "safetyCompatible": true, "sameCheckpointAxis": false, "synergyScore": 100 } ], "targetRelationSummary": { "direct_molecular_target": [ "REGORAFENIB", "SELUMETINIB", "DASATINIB ANHYDROUS", "TEMSIROLIMUS", "TOVORAFENIB", "SORAFENIB", "ALPELISIB" ], "genotype_matched_therapy": [ "ENCORAFENIB", "DABRAFENIB", "ADAGRASIB" ] }, "targetRelationViolations": 0, "therapeuticTracks": [ { "candidates": [ { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 51, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "encorafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 98, "ci_low": 74, "clinicalTrialSupport": { "activeTrialCount": 11, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 10, "diseaseMatchedActiveTherapeuticTrialCount": 11, "diseaseMatchedActiveTrialCount": 11, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 9, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 1, "diseaseMatchedInterventionalTrialCount": 10, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 10, "diseaseMatchedPositiveOutcomeTrialCount": 1, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 10, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 1, "diseaseMatchedTherapeuticTrialCount": 11, "diseaseMatchedTrialCount": 11, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 4, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 4, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 4, "interventionalTrialCount": 10, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 10, "observationalTrialCount": 1, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 1, "totalTrials": 11, "unknownStatusTrialCount": 0 }, "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "completionDate": "2028-08", "conditionSummary": "Colo-rectal Cancer", "conditions": [ "Colo-rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Rechalange with bevacizumab + encorafenib" ], "nctId": "NCT07178717", "phase": "Phase 2", "primaryCompletionDate": "2028-02", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "title": "A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy With BRAF Inhibitors-based Combinations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07178717", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "ENCORAFENIB", "drugId": "rxcui:2049106", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 86, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 35319964, 37656784, 31566661, 35385748, 32540409, 39072179, 29903896, 26577700, 27307593, 28611198, 39145064, 39313594, 38854737, 28951457, 36442478, 39121480, 37729428, 36759733, 37269335, 37040395, 36763936, 39461261, 28363909, 35696748, 39255538, 27312529, 31566309, 37236086, 36307056, 37981300, 28351928, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 39018564, 30559419 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 43 PubMed citation(s) supporting this drug-target association", "🏁 1 completed disease-matched clinical trial reported positive efficacy/outcome signals", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 86, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "Therapeutic Target Database", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ENCORAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "ENCORAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets BRAF", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 96, "contextRelevance": 38, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "dabrafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 95, "ci_low": 71, "clinicalTrialSupport": { "activeTrialCount": 3, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 1, "diseaseMatchedActiveInterventionalTrialCount": 2, "diseaseMatchedActiveTherapeuticTrialCount": 2, "diseaseMatchedActiveTrialCount": 2, "diseaseMatchedCompletedInterventionalTrialCount": 1, "diseaseMatchedCompletedTherapeuticTrialCount": 1, "diseaseMatchedCompletedTrialCount": 1, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 4, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 5, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 4, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 4, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 5, "diseaseMatchedTrialCount": 5, "domainAlignedTrialCount": 1, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the efficacy and toxicity of irinotecan with dabrafenib, cetuximab/panitumumab in the second line of treatment for the potential treatment of colorectal cancer that: has a metastatic, inoperable; has a mutation in the BRAF gene.\n\nParticipants in this study will receive one of the following study treatments:\n\nThese participants will receive in the second line is irinotecan, dabrafenib + trametinib, cetuximab or panitumumab.\n\nThis trial is currently enrolling participants who will receive either irinotecan and dabrafenib plus cetuximab or panitumumab in the second line of therapy.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2028-06-10", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "• Drug: Dabrafenib • Drug: Trametinib • Drug: Cetuximab • Drug: Рanitumumab • Drug: Oxaliplatin • Drug: Irinotecan • Drug: Leucovorin • Drug: 5-FU" ], "nctId": "NCT06967155", "phase": "Phase 2", "primaryCompletionDate": "2027-11-10", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate the efficacy and toxicity of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in second-line treatment of patients with metastatic inoperable colorectal cancer who have a BRAF mutation.", "title": "A Study of Irinotecan With Dabrafenib Plus Trametinib and Anti-EGFR in the Second Line of Therapy in People With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06967155", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": null, "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).", "completionDate": "2020-06-18", "conditionSummary": "Cancer", "conditions": [ "Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Dabrafenib", "Trametinib", "Panitumumab", "5-fluorouracil" ], "nctId": "NCT01750918", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2020-06-18", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.\n\nPart 2A:\n\nThis was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.\n\nPart 2B:\n\nIn this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.\n\nPart 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).\n\nPart 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.\n\nPart 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\\~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.\n\nPart 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.", "title": "BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01750918", "whyStopped": "" }, { "briefSummary": "This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\nThe names of the study drugs involved in this study are:\n\n* Dabrafenib\n* Trametinib\n* PDR001", "completionDate": "2022-12-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "Trametinib", "PDR001" ], "nctId": "NCT03668431", "phase": "Phase 2", "primaryCompletionDate": "2022-09-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. \"Investigational\" means that the drug combination is being studied.\n\n * The FDA (the U.S. Food and Drug Administration) has not approved PDR001 as a treatment for any disease.\n * The FDA has not approved dabrafenib and trametinib for your specific disease but it has been approved for other uses, whether alone as single agents, or given together as in this study.\n* This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\n * All humans have a gene called BRAF which is responsible for sending signals to proteins called B-Raf inside of cells that help them grow. In some metastatic colorectal patients, this gene mutates and causes cancer cells to grow in uncontrolled ways.\n\n \\--- Dabrafenib is a drug that is thought to inhibit the mutant BRAF activity, which may serve to slow or stop cell growth of metastatic colon cancer.\n * Mitogen-activated protein kinase (MAPK) is a pathway that helps to activate the BRAF mutated genes. The MAPK pathway is commonly found to be overactivated in BRAF mutated tumor cells. MEK (which refers to MAPK/ERK Kinase) enzymes are essential to the activity of the MAPK pathway.\n\n * Trametinib inhibits the MEK enzymes in order to shut down the MAPK pathway, thus blocking the pathway that helps the cancer cells grow uncontrollably.\n * PDR001 is a drug which binds to PD1 on immune cells and is believed to block binding of PD-L1 and PD-L2. PD-L1/PDL1 and PD-L2/PDL2 are often used by cancer cells and to escape the power of the body's immune system so that they cannot be fought. By blocking that binding of the molecules, the body's immune system may reach and fight the cancer cells. Researchers are hoping that administration of all three of these drugs may help anti-cancer activities work together to slow or stop the cancer growth and may help your own immune system damage or destroy the existing cancer cells.", "title": "Dabrafenib + Trametinib + PDR001 In Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03668431", "whyStopped": "" }, { "briefSummary": "A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.", "completionDate": "2024-09-25", "conditionSummary": "BRAF V600 Colorectal Cancer", "conditions": [ "BRAF V600 Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "LTT462", "Trametinib", "LXH254", "TNO155" ], "nctId": "NCT04294160", "phase": "Phase 1", "primaryCompletionDate": "2024-09-25", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ib, multi-center, open-label study with multiple treatment arms in adult patients with advanced or metastatic BRAF V600 (E, D, or K) in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies. The open platform design of this study is adaptive to allow removal of combination treatment arm(s) based on emerging data and facilitate introduction of new candidate combinations. The study is comprised of a dose escalation part and may be followed by a dose expansion part for any combination treatment arm.", "title": "A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04294160", "whyStopped": "The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations." }, { "briefSummary": "This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Bladder Carcinoma", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Bladder Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Adavosertib", "Afatinib", "Afatinib Dimaleate", "Binimetinib", "Biopsy Procedure" ], "nctId": "NCT02465060", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nSTEP 0 (Screening): Patients undergo biopsy along with molecular characterization of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Consenting patients also undergo collection of blood samples for research purposes.\n\nSTEPS 1, 3, 5, 7 (Treatment): Patients are assigned to 1 of 38 treatment subprotocols based on molecularly-defined subgroup. (See Arms Section)\n\nSTEPS 2, 4, 6 (Screening): Patients experiencing disease progression on the prior Step treatment or who could not tolerate the assigned treatment undergo review of their previous biopsy results to determine if another treatment is available or undergo another biopsy. Patients may have a maximum of 2 screening biopsies and 2 treatments per biopsy.\n\nSTEP 8 (Optional Research): Consenting patients undergo end-of-treatment biopsy and collection of blood samples for research purposes.\n\nAdditionally, patients may undergo a computed tomography (CT) scan, magnetic resonance imaging, and/or radionuclide imaging throughout the trial.\n\nAfter completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.", "title": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02465060", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "DABRAFENIB", "drugId": "rxcui:1424911", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 83, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 8006, 2015, 26392102, 23470635, 27080216, 23489023, 20818844, 38, 2014, 8009, 2013, 22608338, 23524406, 39107839, 38766698, 29171936, 28512244, 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"diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, 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"otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets KRAS", "🔬 Reported potency: Interaction: inhibitor", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 76, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ADAGRASIB is placed here because its efficacy depends on a variant (KRAS G12C) not present in the input gene list.", "targetingSummary": "ADAGRASIB requires a specific genomic alteration (KRAS G12C) not confirmed in this panel.", "variantDetected": false, "variantLabel": "KRAS G12C", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets KRAS", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "KRAS G12C" } ], "topCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 51, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "encorafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 98, "ci_low": 74, "clinicalTrialSupport": { "activeTrialCount": 11, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 10, "diseaseMatchedActiveTherapeuticTrialCount": 11, "diseaseMatchedActiveTrialCount": 11, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 9, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 1, "diseaseMatchedInterventionalTrialCount": 10, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 10, "diseaseMatchedPositiveOutcomeTrialCount": 1, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 10, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 1, "diseaseMatchedTherapeuticTrialCount": 11, "diseaseMatchedTrialCount": 11, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 4, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 4, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 4, "interventionalTrialCount": 10, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 10, "observationalTrialCount": 1, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 1, "totalTrials": 11, "unknownStatusTrialCount": 0 }, "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "completionDate": "2028-08", "conditionSummary": "Colo-rectal Cancer", "conditions": [ "Colo-rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Rechalange with bevacizumab + encorafenib" ], "nctId": "NCT07178717", "phase": "Phase 2", "primaryCompletionDate": "2028-02", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "title": "A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy With BRAF Inhibitors-based Combinations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07178717", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "ENCORAFENIB", "drugId": "rxcui:2049106", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 86, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 35319964, 37656784, 31566661, 35385748, 32540409, 39072179, 29903896, 26577700, 27307593, 28611198, 39145064, 39313594, 38854737, 28951457, 36442478, 39121480, 37729428, 36759733, 37269335, 37040395, 36763936, 39461261, 28363909, 35696748, 39255538, 27312529, 31566309, 37236086, 36307056, 37981300, 28351928, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 39018564, 30559419 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 43 PubMed citation(s) supporting this drug-target association", "🏁 1 completed disease-matched clinical trial reported positive efficacy/outcome signals", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 86, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "Therapeutic Target Database", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ENCORAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "ENCORAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets BRAF", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" }, "trackId": "variant_defined", "trackLabel": "Variant-Defined Targeted Therapy" }, { "candidates": [ { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 90, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 90, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "selumetinib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 76, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "SELUMETINIB", "drugId": "rxcui:2289380", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 88, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 22241789, 36856908, 34108213, 38922339, 26343583, 24265152, 31704811, 26137449, 27196754, 26351322, 23406027, 27655129, 22197931, 19915144, 24448821, 35882450, 27312529, 26461489, 35363510, 23942066, 31151904, 27222538, 27217440, 22048237 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: Unknown", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets KRAS", "🔬 Reported potency: Interaction: Unknown", "📄 24 PubMed citation(s) supporting this drug-target association", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 88, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "The Clinical Knowledgebase", "MyCancerGenome Clinical Trial", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): KRAS.", "targetingSummary": "SELUMETINIB directly binds/inhibits KRAS (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "dasatinib anhydrous", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 96, "ci_low": 72, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "DASATINIB ANHYDROUS", "drugId": "rxcui:1546019", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 84, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 37713162, 36759733, 27222538, 22649091, 23242808, 12460918, 25157968, 19238210, 23833300, 19537845, 21129611, 19010912, 12068308, 18186519, 22310681, 12460919, 20350999, 26619011, 21483012 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 19 PubMed citation(s) supporting this drug-target association", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": 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"I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "temsirolimus", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 96, 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"bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, 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null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 37656784, 37978284, 32540409, 37219686, 31618628 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 84, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "CIViC: Clinical Interpretation of Variants in Cancer", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF.", "targetingSummary": "TOVORAFENIB directly binds/inhibits BRAF (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 96, "contextRelevance": 38, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "sorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 95, "ci_low": 71, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 3, "diseaseMatchedCompletedTherapeuticTrialCount": 3, "diseaseMatchedCompletedTrialCount": 3, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 4, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 5, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 4, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 4, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 5, "diseaseMatchedTrialCount": 5, "domainAlignedTrialCount": 1, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 1, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the Progression-Free Survival (PFS) time of Sorafenib in combination with FOLFIRI regimen used as in the second front treatment in patients with advanced CRC after failure of oxaliplatin treatment.", "completionDate": "2010-11", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "sorafenib", "FOLFIRI" ], "nctId": "NCT00839111", "phase": "Phase 2", "primaryCompletionDate": "2010-11", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ⅱ open label, non randomized study, in which sorafenib is used in combination with irinotecan, leucovorin and fluorouracil in patients with advanced colorectal cancer after failure of oxaliplatin treatment.The aim of this study is to determine the Progression-Free Survival (PFS) of Sorafenib used in combination with FOLFIRI regimen as a second front treatment in patients with advanced CRC after failure of oxaliplatin treatment, defined as the time from treatment to disease progression or death due to any cause. The other secondary endpoints are disease control rate, defined as complete response, partial response, and stable disease.Response rate,overall survival, and safety are also evaluated.", "title": "Sorafenib and FOLFIRI Regimen in 2nd Colorectal Cancer (CRC) After Failure of Oxaliplatin Treatment", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00839111", "whyStopped": "" }, { "briefSummary": "The main purpose of this study is to find the maximum tolerable dose of sorafenib when administered along with another drug called 5-Fluorouracil (5-FU) and to find out more about whether these drugs, along with radiation, can help people with rectal cancer when given before surgery. 5-FU and radiation are both approved by the US Food and Drug Administration (FDA) for use in people with rectal cancer.\n\nThe investigators will utilize a standard 3 + 3 phase I study design. In the phase I part of the study, the investigators will attempt dose escalation of sorafenib in combination with standard infusional 5-FU and external beam at standard doses. Clinical staging should be done by endorectal ultrasound (ERUS) and/or pelvic magnetic resonance imaging (MRI) for T and N stage; chest and abdomen computed tomography (CT) for staging of metastatic disease; undergo sigmoidoscopy and/or colonoscopy done by crude odds ratios (CORS); biopsy is taken for diagnosis and extra is sent for tissue bank. At the maximum tolerated dose (MTD) of sorafenib we will expand the cohort to 6 more patients to further evaluate toxicity profile and efficacy.", "completionDate": "2016-03", "conditionSummary": "Rectal Cancer", "conditions": [ "Rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "5-Fluorouracil (5-FU)", "Radiation" ], "nctId": "NCT01376453", "phase": "Phase 1", "primaryCompletionDate": "2014-11", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Participants' study regimen will include 5 ½ weeks of radiation. Radiation sessions will be daily, Monday through Friday, except for holidays. 5-FU will be delivered at a dose of 225 mg/m² daily through a catheter in a large vein continuously until the last day of radiation. In addition, sorafenib will be taken by mouth twice daily every day until the last day of radiation. The dose of sorafenib participants may receive will be one of the following: 200 mg every other day, 200 mg daily, 400 mg daily, or 800 mg daily. Following completion of this phase of the study, participants will receive no study drug or radiation for one month. At 4 to 5 weeks after stopping study drug and radiation, participants will have another CT scan or MRI to assess their cancer. About 6 to 8 weeks after the end of radiation, participants will undergo surgery and every effort will be made to remove the tumor. The surgery will occur just as it would if participants were not in the study, except that a portion of their tumor obtained during surgery will be used for research biomarker testing (as described in the consent form).\n\nApproximately 6 -10 weeks after participants' surgery, when they have adequately healed, they may receive additional chemotherapy at their study doctor's discretion.", "title": "Pre-operative 5-Fluorouracil (5-FU) and Sorafenib With External Radiation in Locally Advanced Rectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01376453", "whyStopped": "" }, { "briefSummary": "This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells", "completionDate": "2014-02", "conditionSummary": "Recurrent Colon Cancer · Recurrent Rectal Cancer · Stage IV Colon Cancer", "conditions": [ "Recurrent Colon Cancer", "Recurrent Rectal Cancer", "Stage IV Colon Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "sorafenib tosylate", "bevacizumab" ], "nctId": "NCT00826540", "phase": "Phase 2", "primaryCompletionDate": "2010-01", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200).\n\nSECONDARY OBJECTIVES:\n\nI. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility\n\nOUTLINE: This is a multicenter study.\n\nPatients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies.\n\nAfter completion of study treatment, patients are followed periodically for up to 2 years.", "title": "Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00826540", "whyStopped": "" }, { "briefSummary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "completionDate": "2015-09", "conditionSummary": "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "conditions": [ "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib and irinotecan combination", "Sorafenib monotherapy", "Irinotecan monotherapy" ], "nctId": "NCT01715441", "phase": "Phase 2", "primaryCompletionDate": "2015-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "title": "Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01715441", "whyStopped": "" }, { "briefSummary": "RATIONALE: Sorafenib and pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with pemetrexed and cisplatin may kill more tumor cells.\n\nPURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with pemetrexed and cisplatin in treating patients with advanced solid tumors.", "completionDate": "2010-11", "conditionSummary": "Breast Cancer · Colorectal Cancer · Head and Neck Cancer", "conditions": [ "Breast Cancer", "Colorectal Cancer", "Head and Neck Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "cisplatin", "pemetrexed disodium", "sorafenib" ], "nctId": "NCT00703638", "phase": "Phase 1", "primaryCompletionDate": "2010-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "OBJECTIVES:\n\nPrimary\n\n* To determine the maximum tolerated dose of sorafenib tosylate when given in combination with pemetrexed disodium and cisplatin in patients with advanced non-squamous cell solid tumor malignancy including, but not limited to, breast, lung, colon, pancreatic, prostate, or head and neck cancer or sarcoma.\n\nSecondary\n\n* To characterize the quantitative and qualitative toxicities of this regimen in these patients.\n* To obtain preliminary information about the antitumor activity of this regimen in these patients.\n\nOUTLINE: This is a dose-escalation study of sorafenib tosylate.\n\nPatients receive oral sorafenib tosylate once daily on days 1-21 and cisplatin IV over 1-2 hours and pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed at 30 days, every 8 weeks until disease progression, and then every 3 months for up to 6 months.", "title": "Sorafenib, Pemetrexed, and Cisplatin in Treating Patients With Advanced Solid Tumors", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00703638", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to determine whether sorafenib in combination with chemotherapy has a positive effect on time to progression of the tumor or death for the treatment of large bowel cancer that has already progressed during a first chemotherapy.", "completionDate": "2012-12", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "Placebo", "Oxaliplatin or Irinotecan", "Leucovorin", "5-Fluorouracil" ], "nctId": "NCT00889343", "phase": "Phase 2", "primaryCompletionDate": "2011-11", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "Patients with metastatic CRC who received a first-line therapy with an Oxaliplatin- or Irinotecan based Fluoropyrimidine containing regimen ± bevacizumab and had a progression subsequently, are eligible for this study. Patients will be randomized to receive chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib 400 mg bid or chemotherapy + placebo. Patients who have received an Oxaliplatin based Fluoropyrimidine containing regimen in first-line will obtain FOLFIRI during this study. Patients who have received an Irinotecan based Fluoropyrimidine containing regimen in first-line will obtain FOLFOX6.\n\nPrimary objective of the study is to compare the Progression-free-survival (PFS) between patients receiving chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib with chemotherapy + placebo.", "title": "Study to Evaluate the Effects of Sorafenib if Combined With Chemotherapy (FOLFOX6 or FOLFIRI) in the Second-Line Treatment of Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00889343", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "SORAFENIB", "drugId": "rxcui:495881", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 83, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 37656784, 30575814, 34108213, 27388325, 35630083, 18794803, 20538618, 38795180, 18519791, 23792568, 23629727, 24885690, 16880785, 22394203, 23715574, 14679157, 25157968, 19537845, 21129611, 12068308, 18186519, 22310681, 20350999, 26619011, 20619739, 24727320, 20526349, 28362716 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 28 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 83, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Trends in the exploitation of novel drug targets (Rask-Andersen, et al., 2011)", "Cancer Genome Interpreter", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF.", "targetingSummary": "SORAFENIB directly binds/inhibits BRAF (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 85, "contextRelevance": 12, "mechanismRelevance": 15, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "alpelisib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Panel gene modulator: PIK3CA (direct-binding interaction type; no pChEMBL)", "canonicalRelationType": "direct_molecular_target", "ci_high": 47, "ci_low": 23, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "low", "confidenceScore": 0.2, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "PIK3CA" ], "directTargetEvidenceStrength": 0.85, "drug": "ALPELISIB", "drugId": "rxcui:2169285", "enforcedTier": "III", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 35, "isOnLabelContext": false, "matchedTargets": [ "BRAF", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 27659046, 26577700, 28951457, 27924459, 27312529, 28363909 ], "positioning": "repurposing_opportunity", "potency": "Interaction: Unknown", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ targets PIK3CA", "🔬 Reported potency: Interaction: Unknown", "📄 6 PubMed citation(s) supporting this drug-target association", "✅ FDA approved + directly targets a panel gene with disease-context trial data — strong mechanistic repurposing rationale", "⚠️ Weak context alignment — ranked via target/pathway overlap only" ], "relationType": "direct_target", "repurposingScore": 35, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "The Clinical Knowledgebase", "Clearity Foundation Clinical Trial", "Therapeutic Target Database", "MyCancerGenome Clinical Trial", "My Cancer Genome", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): PIK3CA.", "targetingSummary": "ALPELISIB directly binds/inhibits PIK3CA (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets PIK3CA", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "panel_gene_modulator", "tier": "III", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null } ], "topCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 90, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 90, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, "trackId": "receptor_signaling", "trackLabel": "Receptor/RTK Signaling Amplification" } ], "therapyEvidenceSections": [ { "candidates": [ { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 90, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, 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"moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 3, "diseaseMatchedCompletedTherapeuticTrialCount": 3, "diseaseMatchedCompletedTrialCount": 3, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 4, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 5, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 4, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 4, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 5, "diseaseMatchedTrialCount": 5, "domainAlignedTrialCount": 1, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 1, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the Progression-Free Survival (PFS) time of Sorafenib in combination with FOLFIRI regimen used as in the second front treatment in patients with advanced CRC after failure of oxaliplatin treatment.", "completionDate": "2010-11", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "sorafenib", "FOLFIRI" ], "nctId": "NCT00839111", "phase": "Phase 2", "primaryCompletionDate": "2010-11", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ⅱ open label, non randomized study, in which sorafenib is used in combination with irinotecan, leucovorin and fluorouracil in patients with advanced colorectal cancer after failure of oxaliplatin treatment.The aim of this study is to determine the Progression-Free Survival (PFS) of Sorafenib used in combination with FOLFIRI regimen as a second front treatment in patients with advanced CRC after failure of oxaliplatin treatment, defined as the time from treatment to disease progression or death due to any cause. The other secondary endpoints are disease control rate, defined as complete response, partial response, and stable disease.Response rate,overall survival, and safety are also evaluated.", "title": "Sorafenib and FOLFIRI Regimen in 2nd Colorectal Cancer (CRC) After Failure of Oxaliplatin Treatment", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00839111", "whyStopped": "" }, { "briefSummary": "The main purpose of this study is to find the maximum tolerable dose of sorafenib when administered along with another drug called 5-Fluorouracil (5-FU) and to find out more about whether these drugs, along with radiation, can help people with rectal cancer when given before surgery. 5-FU and radiation are both approved by the US Food and Drug Administration (FDA) for use in people with rectal cancer.\n\nThe investigators will utilize a standard 3 + 3 phase I study design. In the phase I part of the study, the investigators will attempt dose escalation of sorafenib in combination with standard infusional 5-FU and external beam at standard doses. Clinical staging should be done by endorectal ultrasound (ERUS) and/or pelvic magnetic resonance imaging (MRI) for T and N stage; chest and abdomen computed tomography (CT) for staging of metastatic disease; undergo sigmoidoscopy and/or colonoscopy done by crude odds ratios (CORS); biopsy is taken for diagnosis and extra is sent for tissue bank. At the maximum tolerated dose (MTD) of sorafenib we will expand the cohort to 6 more patients to further evaluate toxicity profile and efficacy.", "completionDate": "2016-03", "conditionSummary": "Rectal Cancer", "conditions": [ "Rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "5-Fluorouracil (5-FU)", "Radiation" ], "nctId": "NCT01376453", "phase": "Phase 1", "primaryCompletionDate": "2014-11", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Participants' study regimen will include 5 ½ weeks of radiation. Radiation sessions will be daily, Monday through Friday, except for holidays. 5-FU will be delivered at a dose of 225 mg/m² daily through a catheter in a large vein continuously until the last day of radiation. In addition, sorafenib will be taken by mouth twice daily every day until the last day of radiation. The dose of sorafenib participants may receive will be one of the following: 200 mg every other day, 200 mg daily, 400 mg daily, or 800 mg daily. Following completion of this phase of the study, participants will receive no study drug or radiation for one month. At 4 to 5 weeks after stopping study drug and radiation, participants will have another CT scan or MRI to assess their cancer. About 6 to 8 weeks after the end of radiation, participants will undergo surgery and every effort will be made to remove the tumor. The surgery will occur just as it would if participants were not in the study, except that a portion of their tumor obtained during surgery will be used for research biomarker testing (as described in the consent form).\n\nApproximately 6 -10 weeks after participants' surgery, when they have adequately healed, they may receive additional chemotherapy at their study doctor's discretion.", "title": "Pre-operative 5-Fluorouracil (5-FU) and Sorafenib With External Radiation in Locally Advanced Rectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01376453", "whyStopped": "" }, { "briefSummary": "This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells", "completionDate": "2014-02", "conditionSummary": "Recurrent Colon Cancer · Recurrent Rectal Cancer · Stage IV Colon Cancer", "conditions": [ "Recurrent Colon Cancer", "Recurrent Rectal Cancer", "Stage IV Colon Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "sorafenib tosylate", "bevacizumab" ], "nctId": "NCT00826540", "phase": "Phase 2", "primaryCompletionDate": "2010-01", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200).\n\nSECONDARY OBJECTIVES:\n\nI. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility\n\nOUTLINE: This is a multicenter study.\n\nPatients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies.\n\nAfter completion of study treatment, patients are followed periodically for up to 2 years.", "title": "Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00826540", "whyStopped": "" }, { "briefSummary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "completionDate": "2015-09", "conditionSummary": "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "conditions": [ "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib and irinotecan combination", "Sorafenib monotherapy", "Irinotecan monotherapy" ], "nctId": "NCT01715441", "phase": "Phase 2", "primaryCompletionDate": "2015-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "title": "Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01715441", "whyStopped": "" }, { "briefSummary": "RATIONALE: Sorafenib and pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with pemetrexed and cisplatin may kill more tumor cells.\n\nPURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with pemetrexed and cisplatin in treating patients with advanced solid tumors.", "completionDate": "2010-11", "conditionSummary": "Breast Cancer · Colorectal Cancer · Head and Neck Cancer", "conditions": [ "Breast Cancer", "Colorectal Cancer", "Head and Neck Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "cisplatin", "pemetrexed disodium", "sorafenib" ], "nctId": "NCT00703638", "phase": "Phase 1", "primaryCompletionDate": "2010-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "OBJECTIVES:\n\nPrimary\n\n* To determine the maximum tolerated dose of sorafenib tosylate when given in combination with pemetrexed disodium and cisplatin in patients with advanced non-squamous cell solid tumor malignancy including, but not limited to, breast, lung, colon, pancreatic, prostate, or head and neck cancer or sarcoma.\n\nSecondary\n\n* To characterize the quantitative and qualitative toxicities of this regimen in these patients.\n* To obtain preliminary information about the antitumor activity of this regimen in these patients.\n\nOUTLINE: This is a dose-escalation study of sorafenib tosylate.\n\nPatients receive oral sorafenib tosylate once daily on days 1-21 and cisplatin IV over 1-2 hours and pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed at 30 days, every 8 weeks until disease progression, and then every 3 months for up to 6 months.", "title": "Sorafenib, Pemetrexed, and Cisplatin in Treating Patients With Advanced Solid Tumors", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00703638", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to determine whether sorafenib in combination with chemotherapy has a positive effect on time to progression of the tumor or death for the treatment of large bowel cancer that has already progressed during a first chemotherapy.", "completionDate": "2012-12", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "Placebo", "Oxaliplatin or Irinotecan", "Leucovorin", "5-Fluorouracil" ], "nctId": "NCT00889343", "phase": "Phase 2", "primaryCompletionDate": "2011-11", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "Patients with metastatic CRC who received a first-line therapy with an Oxaliplatin- or Irinotecan based Fluoropyrimidine containing regimen ± bevacizumab and had a progression subsequently, are eligible for this study. Patients will be randomized to receive chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib 400 mg bid or chemotherapy + placebo. Patients who have received an Oxaliplatin based Fluoropyrimidine containing regimen in first-line will obtain FOLFIRI during this study. Patients who have received an Irinotecan based Fluoropyrimidine containing regimen in first-line will obtain FOLFOX6.\n\nPrimary objective of the study is to compare the Progression-free-survival (PFS) between patients receiving chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib with chemotherapy + placebo.", "title": "Study to Evaluate the Effects of Sorafenib if Combined With Chemotherapy (FOLFOX6 or FOLFIRI) in the Second-Line Treatment of Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00889343", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "SORAFENIB", "drugId": "rxcui:495881", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 83, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 37656784, 30575814, 34108213, 27388325, 35630083, 18794803, 20538618, 38795180, 18519791, 23792568, 23629727, 24885690, 16880785, 22394203, 23715574, 14679157, 25157968, 19537845, 21129611, 12068308, 18186519, 22310681, 20350999, 26619011, 20619739, 24727320, 20526349, 28362716 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 28 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 83, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Trends in the exploitation of novel drug targets (Rask-Andersen, et al., 2011)", "Cancer Genome Interpreter", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF.", "targetingSummary": "SORAFENIB directly binds/inhibits BRAF (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 85, "contextRelevance": 12, "mechanismRelevance": 15, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": true, "canonicalDrug": "alpelisib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Panel gene modulator: PIK3CA (direct-binding interaction type; no pChEMBL)", "canonicalRelationType": "direct_molecular_target", "ci_high": 47, "ci_low": 23, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "low", "confidenceScore": 0.2, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "PIK3CA" ], "directTargetEvidenceStrength": 0.85, "drug": "ALPELISIB", "drugId": "rxcui:2169285", "enforcedTier": "III", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 35, "isOnLabelContext": false, "matchedTargets": [ "BRAF", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 27659046, 26577700, 28951457, 27924459, 27312529, 28363909 ], "positioning": "repurposing_opportunity", "potency": "Interaction: Unknown", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ targets PIK3CA", "🔬 Reported potency: Interaction: Unknown", "📄 6 PubMed citation(s) supporting this drug-target association", "✅ FDA approved + directly targets a panel gene with disease-context trial data — strong mechanistic repurposing rationale", "⚠️ Weak context alignment — ranked via target/pathway overlap only" ], "relationType": "direct_target", "repurposingScore": 35, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "The Clinical Knowledgebase", "Clearity Foundation Clinical Trial", "Therapeutic Target Database", "MyCancerGenome Clinical Trial", "My Cancer Genome", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): PIK3CA.", "targetingSummary": "ALPELISIB directly binds/inhibits PIK3CA (panel gene).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets PIK3CA", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "panel_gene_modulator", "tier": "III", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null } ], "sectionDescription": "Drugs with confirmed direct binding, inhibition, or degradation of a panel gene product.", "sectionId": "direct_molecular_target", "sectionLabel": "Direct Panel-Gene Therapy", "topCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "high", "confidenceScore": 0.85, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 90, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 90, "scoreLabel": "Target engagement score", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null } }, { "candidates": [ { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 51, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "encorafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 98, "ci_low": 74, "clinicalTrialSupport": { "activeTrialCount": 11, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 10, "diseaseMatchedActiveTherapeuticTrialCount": 11, "diseaseMatchedActiveTrialCount": 11, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 9, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 1, "diseaseMatchedInterventionalTrialCount": 10, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 10, "diseaseMatchedPositiveOutcomeTrialCount": 1, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 10, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 1, "diseaseMatchedTherapeuticTrialCount": 11, "diseaseMatchedTrialCount": 11, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 4, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 4, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 4, "interventionalTrialCount": 10, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 10, "observationalTrialCount": 1, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 1, "totalTrials": 11, "unknownStatusTrialCount": 0 }, "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "completionDate": "2028-08", "conditionSummary": "Colo-rectal Cancer", "conditions": [ "Colo-rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Rechalange with bevacizumab + encorafenib" ], "nctId": "NCT07178717", "phase": "Phase 2", "primaryCompletionDate": "2028-02", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "title": "A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy With BRAF Inhibitors-based Combinations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07178717", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "ENCORAFENIB", "drugId": "rxcui:2049106", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 86, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 35319964, 37656784, 31566661, 35385748, 32540409, 39072179, 29903896, 26577700, 27307593, 28611198, 39145064, 39313594, 38854737, 28951457, 36442478, 39121480, 37729428, 36759733, 37269335, 37040395, 36763936, 39461261, 28363909, 35696748, 39255538, 27312529, 31566309, 37236086, 36307056, 37981300, 28351928, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 39018564, 30559419 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 43 PubMed citation(s) supporting this drug-target association", "🏁 1 completed disease-matched clinical trial reported positive efficacy/outcome signals", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 86, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "Therapeutic Target Database", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ENCORAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "ENCORAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets BRAF", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 96, "contextRelevance": 38, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "dabrafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 95, "ci_low": 71, "clinicalTrialSupport": { "activeTrialCount": 3, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 1, "diseaseMatchedActiveInterventionalTrialCount": 2, "diseaseMatchedActiveTherapeuticTrialCount": 2, "diseaseMatchedActiveTrialCount": 2, "diseaseMatchedCompletedInterventionalTrialCount": 1, "diseaseMatchedCompletedTherapeuticTrialCount": 1, "diseaseMatchedCompletedTrialCount": 1, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 4, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 5, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 4, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 4, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 5, "diseaseMatchedTrialCount": 5, "domainAlignedTrialCount": 1, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 2 }, "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the efficacy and toxicity of irinotecan with dabrafenib, cetuximab/panitumumab in the second line of treatment for the potential treatment of colorectal cancer that: has a metastatic, inoperable; has a mutation in the BRAF gene.\n\nParticipants in this study will receive one of the following study treatments:\n\nThese participants will receive in the second line is irinotecan, dabrafenib + trametinib, cetuximab or panitumumab.\n\nThis trial is currently enrolling participants who will receive either irinotecan and dabrafenib plus cetuximab or panitumumab in the second line of therapy.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2028-06-10", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "• Drug: Dabrafenib • Drug: Trametinib • Drug: Cetuximab • Drug: Рanitumumab • Drug: Oxaliplatin • Drug: Irinotecan • Drug: Leucovorin • Drug: 5-FU" ], "nctId": "NCT06967155", "phase": "Phase 2", "primaryCompletionDate": "2027-11-10", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate the efficacy and toxicity of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in second-line treatment of patients with metastatic inoperable colorectal cancer who have a BRAF mutation.", "title": "A Study of Irinotecan With Dabrafenib Plus Trametinib and Anti-EGFR in the Second Line of Therapy in People With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06967155", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": null, "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).", "completionDate": "2020-06-18", "conditionSummary": "Cancer", "conditions": [ "Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Dabrafenib", "Trametinib", "Panitumumab", "5-fluorouracil" ], "nctId": "NCT01750918", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2020-06-18", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.\n\nPart 2A:\n\nThis was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.\n\nPart 2B:\n\nIn this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.\n\nPart 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).\n\nPart 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.\n\nPart 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\\~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.\n\nPart 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.", "title": "BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01750918", "whyStopped": "" }, { "briefSummary": "This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\nThe names of the study drugs involved in this study are:\n\n* Dabrafenib\n* Trametinib\n* PDR001", "completionDate": "2022-12-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "Trametinib", "PDR001" ], "nctId": "NCT03668431", "phase": "Phase 2", "primaryCompletionDate": "2022-09-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. \"Investigational\" means that the drug combination is being studied.\n\n * The FDA (the U.S. Food and Drug Administration) has not approved PDR001 as a treatment for any disease.\n * The FDA has not approved dabrafenib and trametinib for your specific disease but it has been approved for other uses, whether alone as single agents, or given together as in this study.\n* This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\n * All humans have a gene called BRAF which is responsible for sending signals to proteins called B-Raf inside of cells that help them grow. In some metastatic colorectal patients, this gene mutates and causes cancer cells to grow in uncontrolled ways.\n\n \\--- Dabrafenib is a drug that is thought to inhibit the mutant BRAF activity, which may serve to slow or stop cell growth of metastatic colon cancer.\n * Mitogen-activated protein kinase (MAPK) is a pathway that helps to activate the BRAF mutated genes. The MAPK pathway is commonly found to be overactivated in BRAF mutated tumor cells. MEK (which refers to MAPK/ERK Kinase) enzymes are essential to the activity of the MAPK pathway.\n\n * Trametinib inhibits the MEK enzymes in order to shut down the MAPK pathway, thus blocking the pathway that helps the cancer cells grow uncontrollably.\n * PDR001 is a drug which binds to PD1 on immune cells and is believed to block binding of PD-L1 and PD-L2. PD-L1/PDL1 and PD-L2/PDL2 are often used by cancer cells and to escape the power of the body's immune system so that they cannot be fought. By blocking that binding of the molecules, the body's immune system may reach and fight the cancer cells. Researchers are hoping that administration of all three of these drugs may help anti-cancer activities work together to slow or stop the cancer growth and may help your own immune system damage or destroy the existing cancer cells.", "title": "Dabrafenib + Trametinib + PDR001 In Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03668431", "whyStopped": "" }, { "briefSummary": "A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.", "completionDate": "2024-09-25", "conditionSummary": "BRAF V600 Colorectal Cancer", "conditions": [ "BRAF V600 Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "LTT462", "Trametinib", "LXH254", "TNO155" ], "nctId": "NCT04294160", "phase": "Phase 1", "primaryCompletionDate": "2024-09-25", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ib, multi-center, open-label study with multiple treatment arms in adult patients with advanced or metastatic BRAF V600 (E, D, or K) in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies. The open platform design of this study is adaptive to allow removal of combination treatment arm(s) based on emerging data and facilitate introduction of new candidate combinations. The study is comprised of a dose escalation part and may be followed by a dose expansion part for any combination treatment arm.", "title": "A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04294160", "whyStopped": "The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations." }, { "briefSummary": "This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Bladder Carcinoma", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Bladder Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Adavosertib", "Afatinib", "Afatinib Dimaleate", "Binimetinib", "Biopsy Procedure" ], "nctId": "NCT02465060", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nSTEP 0 (Screening): Patients undergo biopsy along with molecular characterization of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Consenting patients also undergo collection of blood samples for research purposes.\n\nSTEPS 1, 3, 5, 7 (Treatment): Patients are assigned to 1 of 38 treatment subprotocols based on molecularly-defined subgroup. (See Arms Section)\n\nSTEPS 2, 4, 6 (Screening): Patients experiencing disease progression on the prior Step treatment or who could not tolerate the assigned treatment undergo review of their previous biopsy results to determine if another treatment is available or undergo another biopsy. Patients may have a maximum of 2 screening biopsies and 2 treatments per biopsy.\n\nSTEP 8 (Optional Research): Consenting patients undergo end-of-treatment biopsy and collection of blood samples for research purposes.\n\nAdditionally, patients may undergo a computed tomography (CT) scan, magnetic resonance imaging, and/or radionuclide imaging throughout the trial.\n\nAfter completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.", "title": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02465060", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "DABRAFENIB", "drugId": "rxcui:1424911", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 83, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 8006, 2015, 26392102, 23470635, 27080216, 23489023, 20818844, 38, 2014, 8009, 2013, 22608338, 23524406, 39107839, 38766698, 29171936, 28512244, 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23612012, 21426297, 26678033, 25989278, 12460919, 23406027, 22997239, 22048237, 24396464, 23845441, 21663470, 25024077, 22536370, 23934108, 20350999, 24508103, 24570209, 22281684, 22448344, 26619011, 21483012, 20619739, 23844038 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 240 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 83, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Cancer Genome Interpreter", "Therapeutic Target Database", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "Catalogue Of Somatic Mutations In Cancer", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "DABRAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "DABRAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets BRAF", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" }, { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 37, "mechanismRelevance": 86, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "adagrasib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (KRAS G12C) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 88, "ci_low": 64, "clinicalTrialSupport": { "activeTrialCount": 0, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 0, "diseaseMatchedActiveTherapeuticTrialCount": 0, "diseaseMatchedActiveTrialCount": 0, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 0, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 0, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 0, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 0, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 0, "diseaseMatchedTrialCount": 0, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 0, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 0, "interventionalTrialCount": 0, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 0, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 0, "unknownStatusTrialCount": 0 }, "clinicalTrials": [], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "KRAS" ], "directTargetEvidenceStrength": 1, "drug": "ADAGRASIB", "drugId": "rxcui:2625882", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 76, "isOnLabelContext": true, "matchedTargets": [ "KRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets KRAS", "🔬 Reported potency: Interaction: inhibitor", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 76, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ADAGRASIB is placed here because its efficacy depends on a variant (KRAS G12C) not present in the input gene list.", "targetingSummary": "ADAGRASIB requires a specific genomic alteration (KRAS G12C) not confirmed in this panel.", "variantDetected": false, "variantLabel": "KRAS G12C", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets KRAS", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "KRAS G12C" } ], "sectionDescription": "Drugs that require a specific mutation, amplification, or biomarker not explicitly confirmed in this panel.", "sectionId": "variant_conditional", "sectionLabel": "Variant-Conditional Therapy", "topCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "variant_defined", "biomarkerGated": true, "breakdown": { "clinicalEvidence": 100, "contextRelevance": 51, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 63 }, "canUseTargetsVerb": false, "canonicalDrug": "encorafenib", "canonicalEvidenceLabel": "Disease-context therapy", "canonicalReasoning": "Variant-specific drug but required variant (BRAF V600) not detected — disease-context only", "canonicalRelationType": "disease_context_therapy", "ci_high": 98, "ci_low": 74, "clinicalTrialSupport": { "activeTrialCount": 11, "bestCompletedEndpointStrength": "unknown", "bestDiseaseMatchedCompletedEndpointStrength": "unknown", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "unknown", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "unknown", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "unknown", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 0, "diseaseMatchedActiveInterventionalTrialCount": 10, "diseaseMatchedActiveTherapeuticTrialCount": 11, "diseaseMatchedActiveTrialCount": 11, "diseaseMatchedCompletedInterventionalTrialCount": 0, "diseaseMatchedCompletedTherapeuticTrialCount": 0, "diseaseMatchedCompletedTrialCount": 0, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 0, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 9, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 1, "diseaseMatchedInterventionalTrialCount": 10, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 0, "diseaseMatchedNeutralOutcomeTrialCount": 10, "diseaseMatchedPositiveOutcomeTrialCount": 1, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 10, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 1, "diseaseMatchedTherapeuticTrialCount": 11, "diseaseMatchedTrialCount": 11, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 4, "exactDiseaseCompletedTrialCount": 0, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 4, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 4, "interventionalTrialCount": 10, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 0, "neutralOutcomeTrialCount": 10, "observationalTrialCount": 1, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 1, "totalTrials": 11, "unknownStatusTrialCount": 0 }, "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "completionDate": "2028-08", "conditionSummary": "Colo-rectal Cancer", "conditions": [ "Colo-rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Rechalange with bevacizumab + encorafenib" ], "nctId": "NCT07178717", "phase": "Phase 2", "primaryCompletionDate": "2028-02", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, unicentre, single-arm Phase 2 study of encorafenib and cetuximab as rechallenge treatment in patients with BRAF V600E-mutant metastatic colorectal cancer after previous therapy with BRAF inhibitors-based combinations.\n\nThe study aims to evaluate the antitumor activity of encorafenib plus cetuximab as a rechallenge strategy measured by progression-free survival rate at 4 months.\n\nEligible patients (a total of 25) will receive encorafenib 300 mg (four 75 mg capsules) once daily (q.d) in 28-day cycles plus intravenous cetuximab at 500 mg/m2 every 2 weeks (Q2W). Treatment will be administered until progression, unacceptable toxicity, patient request, physician's decision or subsequent anticancer therapy.", "title": "A Study to Characterize Encorafenib Plus Cetuximab as Rechallenge Treatment for BRAF V600E-mutant Metastatic Colorectal Cancer Patients After Previous Therapy With BRAF Inhibitors-based Combinations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07178717", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "confidence": "medium", "confidenceScore": 0.55, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF" ], "directTargetEvidenceStrength": 1, "drug": "ENCORAFENIB", "drugId": "rxcui:2049106", "enforcedTier": "II", "evidenceGroup": "disease_context", "evidenceLevel": "clinical", "evidenceQualityFlag": "clinical", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 86, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 35319964, 37656784, 31566661, 35385748, 32540409, 39072179, 29903896, 26577700, 27307593, 28611198, 39145064, 39313594, 38854737, 28951457, 36442478, 39121480, 37729428, 36759733, 37269335, 37040395, 36763936, 39461261, 28363909, 35696748, 39255538, 27312529, 31566309, 37236086, 36307056, 37981300, 28351928, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 39018564, 30559419 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "variant_conditional", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF", "🔬 Reported potency: Interaction: inhibitor", "📄 43 PubMed citation(s) supporting this drug-target association", "🏁 1 completed disease-matched clinical trial reported positive efficacy/outcome signals", "✅ FDA approved for this disease context — standard-of-care alignment confirmed", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "disease_relevant", "repurposingScore": 86, "scoreLabel": "Context alignment score", "sources": [ "DGIdb", "Therapeutic Target Database", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "genotype_matched_therapy", "targetRelationExplanation": { "evidenceClass": "variant_conditional", "evidenceClassLabel": "Variant-Conditional Therapy", "panelRelation": "variant_required", "sectionRationale": "ENCORAFENIB is placed here because its efficacy depends on a variant (BRAF V600) not present in the input gene list.", "targetingSummary": "ENCORAFENIB requires a specific genomic alteration (BRAF V600) not confirmed in this panel.", "variantDetected": false, "variantLabel": "BRAF V600", "variantRequired": true }, "targetRelationLabel": "Genotype-Matched Therapy", "targetRelationText": "targets BRAF", "targetRelationType": "disease_relevant", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": true, "variantLabel": "BRAF V600" } } ], "therapyLayerGrade": "full", "tierInflationRate": 0.6, "tierInflationWarning": true, "timeoutNote": null, "timestamp": "2026-04-03T18:27:38.970Z", "topCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 1, "mechanisticImportance": 0.75, "tractability": 0.95, "translationalFeasibility": 0.94 }, "actionabilityScore": 0.82, "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "claimEvidenceClass": "direct_target_binding", "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "directness": "direct", "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 68, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 68, "scoreLabel": "Target engagement score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null }, "topClinicalCandidate": { "_nonDruggablePenaltyApplied": false, "_therapeuticTrack": "receptor_signaling", "actionabilityAxes": { "biologicalCentrality": 0.45, "directDruggability": 1, "mechanisticImportance": 0.75, "tractability": 0.95, "translationalFeasibility": 0.94 }, "actionabilityScore": 0.82, "biomarkerGated": false, "breakdown": { "clinicalEvidence": 93, "contextRelevance": 42, "mechanismRelevance": 78, "pathwayOverlap": 0, "safetyProfile": 85, "targetMatch": 75 }, "canUseTargetsVerb": true, "canonicalDrug": "regorafenib", "canonicalEvidenceLabel": "Direct molecular target", "canonicalReasoning": "Direct target: BRAF, KRAS with on-label clinical context", "canonicalRelationType": "direct_molecular_target", "ci_high": 100, "ci_low": 78, "claimEvidenceClass": "direct_target_binding", "clinicalTrialSupport": { "activeTrialCount": 1, "bestCompletedEndpointStrength": "moderate", "bestDiseaseMatchedCompletedEndpointStrength": "moderate", "bestDiseaseMatchedInterventionalCompletedEndpointStrength": "moderate", "bestDiseaseMatchedNegativeOutcomeEndpointStrength": "moderate", "bestDiseaseMatchedPositiveOutcomeEndpointStrength": "unknown", "bestExactDiseaseCompletedEndpointStrength": "moderate", "bestExactDiseaseNegativeOutcomeEndpointStrength": "unknown", "bestExactDiseasePositiveOutcomeEndpointStrength": "unknown", "completedTrialCount": 4, "diseaseMatchedActiveInterventionalTrialCount": 1, "diseaseMatchedActiveTherapeuticTrialCount": 1, "diseaseMatchedActiveTrialCount": 1, "diseaseMatchedCompletedInterventionalTrialCount": 4, "diseaseMatchedCompletedTherapeuticTrialCount": 4, "diseaseMatchedCompletedTrialCount": 4, "diseaseMatchedInterventionalMixedOutcomeTrialCount": 0, "diseaseMatchedInterventionalNegativeOutcomeTrialCount": 1, "diseaseMatchedInterventionalNeutralOutcomeTrialCount": 5, "diseaseMatchedInterventionalPositiveOutcomeTrialCount": 0, "diseaseMatchedInterventionalTrialCount": 6, "diseaseMatchedMixedOutcomeTrialCount": 0, "diseaseMatchedNegativeOutcomeTrialCount": 1, "diseaseMatchedNeutralOutcomeTrialCount": 5, "diseaseMatchedPositiveOutcomeTrialCount": 0, "diseaseMatchedPrimaryEndpointFailureTrialCount": 0, "diseaseMatchedPrimaryEndpointMetTrialCount": 0, "diseaseMatchedQuantitativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticMixedOutcomeTrialCount": 0, "diseaseMatchedTherapeuticNegativeOutcomeTrialCount": 1, "diseaseMatchedTherapeuticNeutralOutcomeTrialCount": 5, "diseaseMatchedTherapeuticPositiveOutcomeTrialCount": 0, "diseaseMatchedTherapeuticTrialCount": 6, "diseaseMatchedTrialCount": 6, "domainAlignedTrialCount": 0, "exactDiseaseActiveTrialCount": 0, "exactDiseaseCompletedTrialCount": 1, "exactDiseaseMixedOutcomeTrialCount": 0, "exactDiseaseNegativeOutcomeTrialCount": 0, "exactDiseaseNeutralOutcomeTrialCount": 1, "exactDiseasePositiveOutcomeTrialCount": 0, "exactDiseasePrimaryEndpointFailureTrialCount": 0, "exactDiseasePrimaryEndpointMetTrialCount": 0, "exactDiseaseQuantitativeOutcomeTrialCount": 0, "exactDiseaseTrialCount": 1, "interventionalTrialCount": 6, "mixedOutcomeTrialCount": 0, "negativeOutcomeTrialCount": 1, "neutralOutcomeTrialCount": 5, "observationalTrialCount": 0, "offContextTrialCount": 0, "positiveOutcomeTrialCount": 0, "totalTrials": 6, "unknownStatusTrialCount": 1 }, "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "confidence": "low", "confidenceScore": 0.2, "contradictionFlag": false, "contradictionPenalty": 0, "currentIndication": "FDA-approved therapeutic (indication varies by context)", "directBindingMatchedTargets": [ "BRAF", "KRAS" ], "directTargetEvidenceStrength": 1, "directness": "direct", "drug": "REGORAFENIB", "drugId": "rxcui:1312397", "enforcedTier": "I", "evidenceGroup": "direct_targets", "evidenceLevel": "clinical", "evidenceQualityFlag": "validated", "evidenceType": "clinically_established_on_target", "evidenceTypeLabel": "Clinically established on-target mechanism", "fitScore": 68, "groundingDowngradeReason": "Sparse analysis (grounding ratio 0%) — score and confidence capped", "groundingDowngraded": true, "isOnLabelContext": true, "matchedTargets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "mechanism": null, "networkProximity": { "networkProximal": false, "proximityCategory": "unknown", "proximityScore": null }, "networkProximityBonus": 0, "otDivergent": false, "otValidated": false, "pChEMBL": null, "phase": "FDA Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "positioning": "standard_of_care_alignment", "potency": "Interaction: inhibitor", "preclinicalOnly": false, "primaryEvidenceClass": "direct_molecular_target", "proposedIndication": "colorectal cancer", "readinessScore": 9, "reasoning": [ "✅ Approved therapy aligned with the current disease context", "✅ targets BRAF, KRAS", "🔬 Reported potency: Interaction: inhibitor", "📄 5 PubMed citation(s) supporting this drug-target association", "⚠️ 1 disease-matched clinical trial reported negative or failed outcome signals with quantitative outcome support with moderate endpoint evidence", "⚠️ Negative disease-matched trial outcomes with moderate endpoint evidence de-escalate translational confidence", "✅ MOA aligns with colorectal cancer pathway biology" ], "relationType": "direct_target", "repurposingScore": 68, "scoreLabel": "Target engagement score", "sourceClass": "multi_source_structured", "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "subtypeContext": null, "syntheticLethality": null, "targetRelation": "direct_molecular_target", "targetRelationExplanation": { "evidenceClass": "direct_molecular_target", "evidenceClassLabel": "Direct Panel-Gene Therapy", "panelRelation": "direct_target", "sectionRationale": "Confirmed direct-binding evidence against panel gene(s): BRAF, KRAS.", "targetingSummary": "REGORAFENIB directly binds/inhibits BRAF, KRAS (panel genes).", "variantDetected": false, "variantLabel": null, "variantRequired": false }, "targetRelationLabel": "Direct Molecular Target", "targetRelationText": "targets BRAF, KRAS", "targetRelationType": "direct_target", "targetsInPanel": true, "therapyRelationType": "direct_binding_target", "tier": "I", "tumorMatch": "disease_context", "uncertaintyDecomposition": { "dataCompleteness": 0.2, "evidenceReplication": 1, "mechanisticCertainty": 0.4, "missingDataFields": [ "mechanism", "indication", "potency (pChEMBL)" ], "overallEpistemicConfidence": 0.41, "variantContextConfidence": 0.3 }, "variantAlignment": { "alignedTargets": [], "drugDirection": "inhibitor", "hasVariantContext": false, "misalignedTargets": [], "score": 0 }, "variantDetected": false, "variantGateRequired": false, "variantLabel": null } }, "drugs": { "approvedDrugs": [], "avgPotency": 0, "multiTargetCompounds": [ { "chemblId": "rxcui:495881", "name": "SORAFENIB", "pChEMBL": null, "phase": "Approved", "potency": "Interaction: inhibitor", "role": "pan-inhibitor", "targetCount": 4, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ] }, { "chemblId": "rxcui:2049122", "name": "BINIMETINIB", "pChEMBL": null, "phase": "Approved", "potency": "Interaction: Unknown", "role": "pan-inhibitor", "targetCount": 4, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ] }, { "chemblId": "rxcui:1424911", "name": "DABRAFENIB", "pChEMBL": null, "phase": "Approved", "potency": "Interaction: inhibitor", "role": "pan-inhibitor", "targetCount": 4, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ] }, { "chemblId": "rxcui:1147220", "name": "VEMURAFENIB", "pChEMBL": null, "phase": "Approved", "potency": "Interaction: inhibitor, activator", "role": "pan-inhibitor", "targetCount": 4, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ] }, { "chemblId": "rxcui:1425098", "name": "TRAMETINIB DIMETHYL SULFOXIDE", "pChEMBL": null, "phase": "Approved", "potency": "Interaction: Unknown", "role": "pan-inhibitor", "targetCount": 4, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ] } ], "phaseDistribution": { "approved": 136, "phase1": 284, "phase2": 3, "phase3": 4, "preclinical": 22 }, "providerHealth": { "chembl": { "attemptedGenes": 8, "available": true, "errorGenes": 0, "healthyGenes": 1, "provider": "ChEMBL", "status": "partial", "timeoutGenes": 2, "timeoutMs": 22000, "topReasons": [ "target_not_found", "timeout" ], "totalGenes": 4, "unavailableGenes": 7 }, "clinicalTrials": { "available": true, "provider": "ClinicalTrials.gov", "reason": null, "status": "ok", "trials": 20 }, "dgidb": { "attemptedGenes": 4, "available": true, "errorGenes": 0, "healthyGenes": 4, "provider": "DGIdb", "status": "ok", "timeoutGenes": 0, "timeoutMs": 20000, "totalGenes": 4, "unavailableGenes": 0 }, "drugCentral": { "attemptedGenes": 4, "available": true, "errorGenes": 0, "healthyGenes": 4, "provider": "DrugCentral", "status": "ok", "timeoutGenes": 0, "timeoutMs": 15000, "topReasons": [], "totalGenes": 4, "unavailableGenes": 0 }, "drugbank": { "attemptedGenes": 0, "available": false, "errorGenes": 0, "healthyGenes": 0, "provider": "DrugBank", "status": "disabled", "timeoutGenes": 0, "timeoutMs": null, "totalGenes": 4, "unavailableGenes": 0 }, "openFDA": { "available": true, "provider": "OpenFDA", "reason": null, "status": "ok" }, "pubchem": { "available": true, "compoundsEnriched": 20, "provider": "PubChem", "status": "ok" } }, "topCompounds": [ { "approvalConfidence": 0.96, "approvalSource": "explicit_approval_signal, clinical_trial_phase_2, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:495881", "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the Progression-Free Survival (PFS) time of Sorafenib in combination with FOLFIRI regimen used as in the second front treatment in patients with advanced CRC after failure of oxaliplatin treatment.", "completionDate": "2010-11", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "sorafenib", "FOLFIRI" ], "nctId": "NCT00839111", "phase": "Phase 2", "primaryCompletionDate": "2010-11", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ⅱ open label, non randomized study, in which sorafenib is used in combination with irinotecan, leucovorin and fluorouracil in patients with advanced colorectal cancer after failure of oxaliplatin treatment.The aim of this study is to determine the Progression-Free Survival (PFS) of Sorafenib used in combination with FOLFIRI regimen as a second front treatment in patients with advanced CRC after failure of oxaliplatin treatment, defined as the time from treatment to disease progression or death due to any cause. The other secondary endpoints are disease control rate, defined as complete response, partial response, and stable disease.Response rate,overall survival, and safety are also evaluated.", "title": "Sorafenib and FOLFIRI Regimen in 2nd Colorectal Cancer (CRC) After Failure of Oxaliplatin Treatment", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00839111", "whyStopped": "" }, { "briefSummary": "The main purpose of this study is to find the maximum tolerable dose of sorafenib when administered along with another drug called 5-Fluorouracil (5-FU) and to find out more about whether these drugs, along with radiation, can help people with rectal cancer when given before surgery. 5-FU and radiation are both approved by the US Food and Drug Administration (FDA) for use in people with rectal cancer.\n\nThe investigators will utilize a standard 3 + 3 phase I study design. In the phase I part of the study, the investigators will attempt dose escalation of sorafenib in combination with standard infusional 5-FU and external beam at standard doses. Clinical staging should be done by endorectal ultrasound (ERUS) and/or pelvic magnetic resonance imaging (MRI) for T and N stage; chest and abdomen computed tomography (CT) for staging of metastatic disease; undergo sigmoidoscopy and/or colonoscopy done by crude odds ratios (CORS); biopsy is taken for diagnosis and extra is sent for tissue bank. At the maximum tolerated dose (MTD) of sorafenib we will expand the cohort to 6 more patients to further evaluate toxicity profile and efficacy.", "completionDate": "2016-03", "conditionSummary": "Rectal Cancer", "conditions": [ "Rectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "5-Fluorouracil (5-FU)", "Radiation" ], "nctId": "NCT01376453", "phase": "Phase 1", "primaryCompletionDate": "2014-11", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Participants' study regimen will include 5 ½ weeks of radiation. Radiation sessions will be daily, Monday through Friday, except for holidays. 5-FU will be delivered at a dose of 225 mg/m² daily through a catheter in a large vein continuously until the last day of radiation. In addition, sorafenib will be taken by mouth twice daily every day until the last day of radiation. The dose of sorafenib participants may receive will be one of the following: 200 mg every other day, 200 mg daily, 400 mg daily, or 800 mg daily. Following completion of this phase of the study, participants will receive no study drug or radiation for one month. At 4 to 5 weeks after stopping study drug and radiation, participants will have another CT scan or MRI to assess their cancer. About 6 to 8 weeks after the end of radiation, participants will undergo surgery and every effort will be made to remove the tumor. The surgery will occur just as it would if participants were not in the study, except that a portion of their tumor obtained during surgery will be used for research biomarker testing (as described in the consent form).\n\nApproximately 6 -10 weeks after participants' surgery, when they have adequately healed, they may receive additional chemotherapy at their study doctor's discretion.", "title": "Pre-operative 5-Fluorouracil (5-FU) and Sorafenib With External Radiation in Locally Advanced Rectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01376453", "whyStopped": "" }, { "briefSummary": "This phase II trial is studying how well giving sorafenib together with bevacizumab works in treating patients with metastatic colorectal cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Sorafenib and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with bevacizumab may kill more tumor cells", "completionDate": "2014-02", "conditionSummary": "Recurrent Colon Cancer · Recurrent Rectal Cancer · Stage IV Colon Cancer", "conditions": [ "Recurrent Colon Cancer", "Recurrent Rectal Cancer", "Stage IV Colon Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "sorafenib tosylate", "bevacizumab" ], "nctId": "NCT00826540", "phase": "Phase 2", "primaryCompletionDate": "2010-01", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. Evaluate proportion of patients who are progression-free at 3 months (in historic comparison with results for single-agent bevacizumab in ECOG 3200).\n\nSECONDARY OBJECTIVES:\n\nI. Response rate (RR) II. Overall survival (OS) III. Safety IV. Feasibility\n\nOUTLINE: This is a multicenter study.\n\nPatients receive sorafenib tosylate orally twice daily on days 1-5 and 8-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and then periodically during study treatment for laboratory biomarker and pharmacogenetic studies.\n\nAfter completion of study treatment, patients are followed periodically for up to 2 years.", "title": "Sorafenib and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00826540", "whyStopped": "" }, { "briefSummary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "completionDate": "2015-09", "conditionSummary": "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "conditions": [ "Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib and irinotecan combination", "Sorafenib monotherapy", "Irinotecan monotherapy" ], "nctId": "NCT01715441", "phase": "Phase 2", "primaryCompletionDate": "2015-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The aim of this multicenter randomized phase II trial is to determine the efficacy of sorafenib and irinotecan combination versus irinotecan monotherapy or versus sorafenib monotherapy in metastatic colorectal cancer patients with KRAS mutated tumors after failure of all active drugs known to be effective.", "title": "Sorafenib in Combination With Irinotecan in Metastatic Colorectal Cancer Patients With KRAS Mutated Tumors", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01715441", "whyStopped": "" }, { "briefSummary": "RATIONALE: Sorafenib and pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sorafenib together with pemetrexed and cisplatin may kill more tumor cells.\n\nPURPOSE: This phase I trial is studying the side effects and best dose of sorafenib when given together with pemetrexed and cisplatin in treating patients with advanced solid tumors.", "completionDate": "2010-11", "conditionSummary": "Breast Cancer · Colorectal Cancer · Head and Neck Cancer", "conditions": [ "Breast Cancer", "Colorectal Cancer", "Head and Neck Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "cisplatin", "pemetrexed disodium", "sorafenib" ], "nctId": "NCT00703638", "phase": "Phase 1", "primaryCompletionDate": "2010-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "OBJECTIVES:\n\nPrimary\n\n* To determine the maximum tolerated dose of sorafenib tosylate when given in combination with pemetrexed disodium and cisplatin in patients with advanced non-squamous cell solid tumor malignancy including, but not limited to, breast, lung, colon, pancreatic, prostate, or head and neck cancer or sarcoma.\n\nSecondary\n\n* To characterize the quantitative and qualitative toxicities of this regimen in these patients.\n* To obtain preliminary information about the antitumor activity of this regimen in these patients.\n\nOUTLINE: This is a dose-escalation study of sorafenib tosylate.\n\nPatients receive oral sorafenib tosylate once daily on days 1-21 and cisplatin IV over 1-2 hours and pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed at 30 days, every 8 weeks until disease progression, and then every 3 months for up to 6 months.", "title": "Sorafenib, Pemetrexed, and Cisplatin in Treating Patients With Advanced Solid Tumors", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00703638", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to determine whether sorafenib in combination with chemotherapy has a positive effect on time to progression of the tumor or death for the treatment of large bowel cancer that has already progressed during a first chemotherapy.", "completionDate": "2012-12", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Sorafenib", "Placebo", "Oxaliplatin or Irinotecan", "Leucovorin", "5-Fluorouracil" ], "nctId": "NCT00889343", "phase": "Phase 2", "primaryCompletionDate": "2011-11", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "Patients with metastatic CRC who received a first-line therapy with an Oxaliplatin- or Irinotecan based Fluoropyrimidine containing regimen ± bevacizumab and had a progression subsequently, are eligible for this study. Patients will be randomized to receive chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib 400 mg bid or chemotherapy + placebo. Patients who have received an Oxaliplatin based Fluoropyrimidine containing regimen in first-line will obtain FOLFIRI during this study. Patients who have received an Irinotecan based Fluoropyrimidine containing regimen in first-line will obtain FOLFOX6.\n\nPrimary objective of the study is to compare the Progression-free-survival (PFS) between patients receiving chemotherapy (FOLFOX6 or FOLFIRI) + sorafenib with chemotherapy + placebo.", "title": "Study to Evaluate the Effects of Sorafenib if Combined With Chemotherapy (FOLFOX6 or FOLFIRI) in the Second-Line Treatment of Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00889343", "whyStopped": "" } ], "comenionGenes": [], "confirmedBindingTargets": [ "BRAF" ], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "inhibitor", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "SORAFENIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 37656784, 30575814, 34108213, 27388325, 35630083, 18794803, 20538618, 38795180, 18519791, 23792568, 23629727, 24885690, 16880785, 22394203, 23715574, 14679157, 25157968, 19537845, 21129611, 12068308, 18186519, 22310681, 20350999, 26619011, 20619739, 24727320, 20526349, 28362716 ], "potency": "Interaction: inhibitor", "pubchem": { "cid": 216239, "inchikey": "MLDQJTXFUGDVEO-UHFFFAOYSA-N", "iupacName": "4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide", "molecularWeight": "464.8", "source": "PubChem", "xlogp": 4.1 }, "regulatoryEvidence": { "confidence": 0.96, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_2", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 2 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.5, "seriousRatio": 0.8902932994973403, "source": "OpenFDA", "topReactions": [ "DIARRHOEA", "PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME", "HEPATOCELLULAR CARCINOMA", "FATIGUE", "OFF LABEL USE" ], "totalReports": 17360 }, "source": "DGIdb", "sourceCount": 12, "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Trends in the exploitation of novel drug targets (Rask-Andersen, et al., 2011)", "Cancer Genome Interpreter", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.96, "approvalSource": "explicit_approval_signal, clinical_trial_phase_2, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:2049122", "clinicalTrials": [ { "briefSummary": "This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Bladder Carcinoma", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Bladder Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Adavosertib", "Afatinib", "Afatinib Dimaleate", "Binimetinib", "Biopsy Procedure" ], "nctId": "NCT02465060", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nSTEP 0 (Screening): Patients undergo biopsy along with molecular characterization of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Consenting patients also undergo collection of blood samples for research purposes.\n\nSTEPS 1, 3, 5, 7 (Treatment): Patients are assigned to 1 of 38 treatment subprotocols based on molecularly-defined subgroup. (See Arms Section)\n\nSTEPS 2, 4, 6 (Screening): Patients experiencing disease progression on the prior Step treatment or who could not tolerate the assigned treatment undergo review of their previous biopsy results to determine if another treatment is available or undergo another biopsy. Patients may have a maximum of 2 screening biopsies and 2 treatments per biopsy.\n\nSTEP 8 (Optional Research): Consenting patients undergo end-of-treatment biopsy and collection of blood samples for research purposes.\n\nAdditionally, patients may undergo a computed tomography (CT) scan, magnetic resonance imaging, and/or radionuclide imaging throughout the trial.\n\nAfter completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.", "title": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02465060", "whyStopped": "" }, { "briefSummary": "There is a huge variety of nucleotide substitutions that activate RAS. The search for new \"universal\" drugs for the RAS pathway that either interfere with RAS upregulation upstream in the signaling pathway or offset the consequences of RAS activation is important for improving therapeutic outcomes for patients with refractory malignancies.\n\nThe use of leflunomide or the combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is promising for patients with mutations in RAS cascade genes who have failed all existing treatment standards.", "completionDate": "2026-10-01", "conditionSummary": "RAS Mutation · Ras (Kras or Nras) Gene Mutation · Colorectal Cancer Recurrent", "conditions": [ "RAS Mutation", "Ras (Kras or Nras) Gene Mutation", "Colorectal Cancer Recurrent" ], "contextFit": null, "hasResults": false, "interventions": [ "Leflunomide", "The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab" ], "nctId": "NCT06229340", "phase": "Phase 2", "primaryCompletionDate": "2026-10-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Mutations in the RAS gene are a common cause for the development of many tumors.\n\nIt is of practical interest to study the potential efficacy of several drugs registered for the treatment of other diseases, which may also be able to affect various parts of the RAS pathway.\n\nLeflunomide, with its active metabolite , inhibits the enzyme dihydroorotate dehydrogenase (DHODH). DHODH plays an essential role in the biosynthesis of pyrimidine, which is particularly important for the growth of RAS mutant cells.\n\nTumors with KRAS, NRAS, and HRAS mutations are characterized by increased MEK kinase activity. The combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is able to affect MEK kinase activity by direct inhibition as well as regulation of autophagy, which is controlled in this case by the antimalarial drug hydroxychloroquine.\n\nThe use of bevacizumab is appropriate because there is evidence of its efficacy in the treatment of patients with colorectal cancer, including colorectal cancer with mutations in the KRAS gene.", "title": "Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06229340", "whyStopped": "" }, { "briefSummary": "This is a Phase 1b, open label, dose-finding study to determine the Maximum Tolerated Dose (MTD) of MEK162 in combination with mFOLFIRI, and to evaluate the response rate, clinical benefit rate and additional safety parameters of the treatment combination", "completionDate": "2022-12-21", "conditionSummary": "Advanced KRAS Positive Metastatic Colorectal Cancer", "conditions": [ "Advanced KRAS Positive Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "MEK162 and mFOLFIRI" ], "nctId": "NCT02613650", "phase": "Phase 1", "primaryCompletionDate": "2022-11-23", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase 1b, open label, dose-finding study to determine the Maximum Tolerated Dose (MTD) of MEK162 in combination with mFOLFIRI, and to evaluate the response rate, clinical benefit rate and additional safety parameters of the treatment combination", "title": "A Trial of mFOLFIRI With MEK162 in Patients With Advanced RAS (HRAS, NRAS, or KRAS) Positive Metastatic Colorectal Cancers", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02613650", "whyStopped": "" }, { "briefSummary": "This is a multi-center, open-label, phase Ib/II study. First, the aim of the phase Ib part is to estimate the MTD(s) and/or to identify the recommended phase II dose(s) (RP2D) for the combination of MEK162 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. The dose escalation part of the study will be guided by a Bayesian Logistic Regression Model (BLRM). At least 18 patients are expected to be enrolled in the dose escalation part.\n\nFollowing MTD/ RP2D declaration, patients will be enrolled in three phase II arms to assess efficacy of the combination as well as to better understand the safety, tolerability, PK, antibody concentrations and PD of the combination at MTD/RP2D. Phase II arm 1 will consist of approximately 25 patients with KRAS-mutant colorectal adenocarcinoma. Phase II arm 2 will consist of approximately 20 patients with metastatic pancreatic adenocarcinoma. Phase II arm 3 will consist of approximately 28 patients with mutant BRAFV600 melanoma.\n\nPatients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. All patients will be followed up - at minimum patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment.", "completionDate": "2015-04-01", "conditionSummary": "Metastatic Pancreatic Adenocarcinoma · BRAF Mutated Melanoma", "conditions": [ "Metastatic Pancreatic Adenocarcinoma", "BRAF Mutated Melanoma" ], "contextFit": null, "hasResults": false, "interventions": [ "MEK162", "AMG 479" ], "nctId": "NCT01562899", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2015-04-01", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "This is a multi-center, open-label, phase Ib/II study. First, the aim of the phase Ib part is to estimate the MTD(s) and/or to identify the recommended phase II dose(s) (RP2D) for the combination of MEK162 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. The dose escalation part of the study will be guided by a Bayesian Logistic Regression Model (BLRM). At least 18 patients are expected to be enrolled in the dose escalation part.\n\nFollowing MTD/ RP2D declaration, patients will be enrolled in three phase II arms to assess efficacy of the combination as well as to better understand the safety, tolerability, PK, antibody concentrations and PD of the combination at MTD/RP2D. Phase II arm 1 will consist of approximately 25 patients with KRAS-mutant colorectal adenocarcinoma. Phase II arm 2 will consist of approximately 20 patients with metastatic pancreatic adenocarcinoma. Phase II arm 3 will consist of approximately 28 patients with mutant BRAFV600 melanoma.\n\nPatients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. All patients will be followed up - at minimum patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment.", "title": "A Study of MEK162 and AMG 479 in Patients With Selected Solid Tumors", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01562899", "whyStopped": "Study was withdrawn due to scientific and business considerations." }, { "briefSummary": "This phase I trial studies the side effects and best dose of MEK inhibitor MEK162 when given together with leucovorin calcium, fluorouracil, and oxaliplatin in treating patients with advanced metastatic colorectal cancer. MEK inhibitor MEK162 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162 with leucovorin calcium, fluorouracil, and oxaliplatin may kill more tumor cells.", "completionDate": "2018-01-19", "conditionSummary": "Recurrent Colon Cancer · Recurrent Rectal Cancer · Stage IVA Colon Cancer", "conditions": [ "Recurrent Colon Cancer", "Recurrent Rectal Cancer", "Stage IVA Colon Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "MEK inhibitor MEK162", "leucovorin calcium", "fluorouracil", "oxaliplatin", "pharmacological study" ], "nctId": "NCT02041481", "phase": "Phase 1", "primaryCompletionDate": "2018-01-19", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. Determine the maximum tolerated dose (MTD) for the combination of MEK162 (MEK inhibitor MEK162) plus leucovorin calcium, fluorouracil, oxaliplatin (FOLFOX) in patients with metastatic colorectal cancer.\n\nSECONDARY OBJECTIVES:\n\nI. Describe the safety of the combination of MEK162 across all investigated dose levels.\n\nII. Describe the pharmacokinetics of MEK162 and FOLFOX in 6 patients in the expanded MTD cohort.\n\nIII. Describe any clinical activity to the combination using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.\n\nIV. Determine the recommended Phase II dose (RP2D) which may be less than the MTD for both intermittent and continuous dosing of MEK162.\n\nOUTLINE: This is a dose-escalation study of MEK inhibitor MEK162. Patients are assigned to 1 of 2 treatment arms.\n\nARM I: Patients receive MEK inhibitor MEK162 orally (PO) twice daily (BID) on days 1-14, and leucovorin calcium intravenously (IV) over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive MEK inhibitor MEK162 PO BID on days 1-5, and leucovorin calcium IV over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 6 and 7. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up for 30 days.", "title": "MEK Inhibitor MEK162 in Combination With Leucovorin Calcium, Fluorouracil, and Oxaliplatin in Treating Patients With Advanced Metastatic Colorectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02041481", "whyStopped": "" }, { "briefSummary": "As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research.\n\nThe combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively.\n\nBased on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.", "completionDate": "2029-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "EBC" ], "nctId": "NCT06207656", "phase": "Phase 2", "primaryCompletionDate": "2029-04-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "As a result of the little benefit obtained from standard treatments and the poor prognosis of these patients, the BRAF-V600E mutant MSS aCRC represents an unmet medical need requiring clinical research.\n\nThe combination of encorafenib, cetuximab and binimetinib as second- or third-line treatment for mCRC resulted in significantly better outcomes than standard therapy in a phase 3 clinical trial, which also revealed treatment safety and tolerability to be acceptable. Compared to the control group (cetuximab and irinotecan or cetuximab and FOLFIRI), the triplet therapy cohort showed higher median overall survival (9.3 vs. 5.9 months) and response rates (26.8% vs. 1.8%). Grade 3 adverse events occurred in 65.8% and 64.2% of patients for triple-therapy and control groups, respectively.\n\nBased on these results, the investigators speculated that the combination of encorafenib, cetuximab and binimetinib could be used as induction therapy to improve treatment outcomes in BRAF-V600E-mutated MSS aCRC locally advanced initially unresectable but potentially resectable; initially resectable or initially unresectable but potentially resectable oligometastatic disease; and in patients with stage II-IV who have relapsed after chemotherapy (neo and/or adjuvant) or surgery, if the shorter time after resection or from treatment end to relapse is longer than 6 months.", "title": "Study to Evaluate the Efficacy and Safety of Cetuximab in Combination with Encorafenib Plus Binimetinib As Induction Treatment in BRAF V600E Mutated MSS Initially Resectable or Potentially Resectable Advanced Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06207656", "whyStopped": "" }, { "briefSummary": "This is a multicenter, open-label, Phase 1B/2 study to evaluate the safety and assess the preliminary anti-tumor activity of binimetinib administered in combination with nivolumab or nivolumab + ipilimumab in adult patients with advanced metastatic colorectal cancer (mCRC) with microsatellite stable (MSS) disease and presence of a RAS mutation that have received at least one prior line of therapy and no more than 2 prior lines of therapy. The study contains a Phase 1b period to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and schedule of binimetinib followed by a randomized Phase 2 period to assess the efficacy of the combinations.", "completionDate": "2021-02-25", "conditionSummary": "MSS · RAS-mutant Colorectal Cancer", "conditions": [ "MSS", "RAS-mutant Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "binimetinib", "nivolumab", "ipilimumab" ], "nctId": "NCT03271047", "phase": "Phase 2", "primaryCompletionDate": "2020-10-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a multicenter, open-label, Phase 1B/2 study to evaluate the safety and assess the preliminary anti-tumor activity of binimetinib administered in combination with nivolumab or nivolumab + ipilimumab in adult patients with advanced metastatic colorectal cancer (mCRC) with microsatellite stable (MSS) disease and presence of a RAS mutation that have received at least one prior line of therapy and no more than 2 prior lines of therapy. The study contains a Phase 1b period to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) and schedule of binimetinib followed by a randomized Phase 2 period to assess the efficacy of the combinations.", "title": "Study of Binimetinib + Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Microsatellite-stable (MSS) Metastatic Colorectal Cancer With RAS Mutation", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03271047", "whyStopped": "" } ], "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "BINIMETINIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 34108213, 35319964, 37656784, 31566661, 23414587, 35385748, 31227518, 29903896, 39072179, 29245078, 26577700, 28152546, 39313594, 38854737, 36442478, 37729428, 28551618, 37269335, 35882450, 38691346, 39391046, 35696748, 39255538, 31566309, 36763936, 39461261, 33043759, 36608320, 30959471, 37270692, 38446982, 39392364, 30219628, 29573941, 38885476, 38343359, 36011019, 30181415, 27307593 ], "potency": "Interaction: Unknown", "pubchem": { "cid": 10288191, "inchikey": "ACWZRVQXLIRSDF-UHFFFAOYSA-N", "iupacName": "6-(4-bromo-2-fluoroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide", "molecularWeight": "441.2", "source": "PubChem", "xlogp": 3.1 }, "regulatoryEvidence": { "confidence": 0.96, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_2", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 2 }, "safetyProfile": { "deathRate": 0, "safetyScore": 6.6, "seriousRatio": 0.6873983739837398, "source": "OpenFDA", "topReactions": [ "OFF LABEL USE", "DEATH", "NAUSEA", "FATIGUE", "DIARRHOEA" ], "totalReports": 5744 }, "source": "DGIdb", "sourceCount": 7, "sources": [ "DGIdb", "CIViC: Clinical Interpretation of Variants in Cancer", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.96, "approvalSource": "explicit_approval_signal, clinical_trial_phase_2, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1424911", "clinicalTrials": [ { "briefSummary": "The purpose of this study is to evaluate the efficacy and toxicity of irinotecan with dabrafenib, cetuximab/panitumumab in the second line of treatment for the potential treatment of colorectal cancer that: has a metastatic, inoperable; has a mutation in the BRAF gene.\n\nParticipants in this study will receive one of the following study treatments:\n\nThese participants will receive in the second line is irinotecan, dabrafenib + trametinib, cetuximab or panitumumab.\n\nThis trial is currently enrolling participants who will receive either irinotecan and dabrafenib plus cetuximab or panitumumab in the second line of therapy.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2028-06-10", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "• Drug: Dabrafenib • Drug: Trametinib • Drug: Cetuximab • Drug: Рanitumumab • Drug: Oxaliplatin • Drug: Irinotecan • Drug: Leucovorin • Drug: 5-FU" ], "nctId": "NCT06967155", "phase": "Phase 2", "primaryCompletionDate": "2027-11-10", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate the efficacy and toxicity of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in second-line treatment of patients with metastatic inoperable colorectal cancer who have a BRAF mutation.", "title": "A Study of Irinotecan With Dabrafenib Plus Trametinib and Anti-EGFR in the Second Line of Therapy in People With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06967155", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": null, "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This was a four part, phase I/II study aimed to evaluate the safety, tolerability and efficacy of combination of an anti-EGFR antibody panitumumab (P) either with a BRAF inhibitor (dabrafenib (D); GSK2118436) alone or with the combination of a BRAF inhibitor and a MEK inhibitor (trametinib (T); GSK1120212) in patients with BRAF-mutant V600E advanced or mCRC. The goal was to: 1) Determine RP2R/MTD for doublet (D+P) and triplet (D+T+P) combinations in Part 1; 2) Assess clinical activity for these combinations in Part 2; 3) Determine RP2R/MTD for double (T+P) combination in Part 4A, and assess clinical activity of this combination in two patient populations in Part 4B (patients with BRAF-V600E mutation-positive advanced or metastatic CRC and patients with advanced or metastatic CRC with secondary resistance to anti-EGFR therapy).", "completionDate": "2020-06-18", "conditionSummary": "Cancer", "conditions": [ "Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Dabrafenib", "Trametinib", "Panitumumab", "5-fluorouracil" ], "nctId": "NCT01750918", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2020-06-18", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Part 1: Dose escalation This was a dose escalation part intended to evaluate safety, tolerability, PK, PD, clinical activity and determine RP2R/MTD for the doublet (D+P) and the triplet (D+T+P) combinations in patients with BRAF-mutation V600E positive advanced or metastatic CRC. A 3+3 dose escalation procedure was followed. Dosing for dabrafenib and trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for dose-limiting toxicities (DLTs) during the first 28 days of treatment.\n\nPart 2A:\n\nThis was a cohort expansion part to assess the safety and preliminary clinical activity of the optimal safe and tolerable dose combinations (D+P)/(D+T+P) defined in Part 1.\n\nPart 2B:\n\nIn this part, additional patients were enrolled into the triplet (D+T+P) combination at two dose levels in to further explore safety, tolerability and clinical activity. Up to 10 patients each with no prior treatment (First Line Population), and up to 20 patients each with at least one prior treatment (Second to Fourth Line Population) were planned to be enrolled in dose Cohorts 3A and 4.\n\nPart 3: Randomized Phase 2 Study The randomized phase 2 portion (Phase 3) of the study was not pursued as the observed responses in any of the cohorts did not meet the predefined criteria at the time of the preliminary analysis (data cut-off date: 06-May-2016).\n\nPart 4 This part was designed to identify the RP2R/MTD and initial clinical activity for the doublet (T+P) combination in patients BRAF-mutation V600E positive advanced or metastatic CRC, and advanced or metastatic CRC with secondary resistance to prior anti-EGFR therapy.\n\nPart 4A: Dose Escalation This was a dose escalation part intended to determine RP2R/MTD for the doublet (T+P) combination in patients with BRAF-mutation V600E positive advanced or metastatic CRC. Approximately 18 patients (\\~6 each cohort) were planned to be enrolled in Part 4A. A 3+3 dose escalation procedure was followed. Dosing for trametinib was continuous daily dosing while panitumumab was dosed once every two weeks (Q2W). Patients were evaluated for DLTs during the first 28 days of treatment.\n\nPart 4B: Cohort Expansion This was a cohort expansion part intended to evaluate safety and efficacy of the doublet (T+P) combination. Up to 20 patients in each of two expansion cohorts were planned to be enrolled at the starting dose cohort or MTD from Part 4A.", "title": "BRAF/MEK/EGFR Inhibitor Combination Study in Colorectal Cancer (CRC)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01750918", "whyStopped": "" }, { "briefSummary": "This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\nThe names of the study drugs involved in this study are:\n\n* Dabrafenib\n* Trametinib\n* PDR001", "completionDate": "2022-12-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "Trametinib", "PDR001" ], "nctId": "NCT03668431", "phase": "Phase 2", "primaryCompletionDate": "2022-09-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "* This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. \"Investigational\" means that the drug combination is being studied.\n\n * The FDA (the U.S. Food and Drug Administration) has not approved PDR001 as a treatment for any disease.\n * The FDA has not approved dabrafenib and trametinib for your specific disease but it has been approved for other uses, whether alone as single agents, or given together as in this study.\n* This research study is studying a combination of drugs as a possible treatment for metastatic colorectal cancer characterized by BRAF V600E mutation.\n\n * All humans have a gene called BRAF which is responsible for sending signals to proteins called B-Raf inside of cells that help them grow. In some metastatic colorectal patients, this gene mutates and causes cancer cells to grow in uncontrolled ways.\n\n \\--- Dabrafenib is a drug that is thought to inhibit the mutant BRAF activity, which may serve to slow or stop cell growth of metastatic colon cancer.\n * Mitogen-activated protein kinase (MAPK) is a pathway that helps to activate the BRAF mutated genes. The MAPK pathway is commonly found to be overactivated in BRAF mutated tumor cells. MEK (which refers to MAPK/ERK Kinase) enzymes are essential to the activity of the MAPK pathway.\n\n * Trametinib inhibits the MEK enzymes in order to shut down the MAPK pathway, thus blocking the pathway that helps the cancer cells grow uncontrollably.\n * PDR001 is a drug which binds to PD1 on immune cells and is believed to block binding of PD-L1 and PD-L2. PD-L1/PDL1 and PD-L2/PDL2 are often used by cancer cells and to escape the power of the body's immune system so that they cannot be fought. By blocking that binding of the molecules, the body's immune system may reach and fight the cancer cells. Researchers are hoping that administration of all three of these drugs may help anti-cancer activities work together to slow or stop the cancer growth and may help your own immune system damage or destroy the existing cancer cells.", "title": "Dabrafenib + Trametinib + PDR001 In Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03668431", "whyStopped": "" }, { "briefSummary": "A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.", "completionDate": "2024-09-25", "conditionSummary": "BRAF V600 Colorectal Cancer", "conditions": [ "BRAF V600 Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib", "LTT462", "Trametinib", "LXH254", "TNO155" ], "nctId": "NCT04294160", "phase": "Phase 1", "primaryCompletionDate": "2024-09-25", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "This is a phase Ib, multi-center, open-label study with multiple treatment arms in adult patients with advanced or metastatic BRAF V600 (E, D, or K) in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies. The open platform design of this study is adaptive to allow removal of combination treatment arm(s) based on emerging data and facilitate introduction of new candidate combinations. The study is comprised of a dose escalation part and may be followed by a dose expansion part for any combination treatment arm.", "title": "A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04294160", "whyStopped": "The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations." }, { "briefSummary": "This phase II MATCH screening and multi-sub-trial studies how well treatment that is directed by genetic testing works in patients with solid tumors, lymphomas, or multiple myelomas that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and does not respond to treatment (refractory). Patients must have progressed following at least one line of standard treatment or for which no agreed upon treatment approach exists. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic abnormalities (such as mutations, amplifications, or translocations) may benefit more from treatment which targets their tumor's particular genetic abnormality. Identifying these genetic abnormalities first may help doctors plan better treatment for patients with solid tumors, lymphomas, or multiple myeloma.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Bladder Carcinoma", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Bladder Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Adavosertib", "Afatinib", "Afatinib Dimaleate", "Binimetinib", "Biopsy Procedure" ], "nctId": "NCT02465060", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nSTEP 0 (Screening): Patients undergo biopsy along with molecular characterization of the biopsy material for specific, pre-defined mutations, amplifications, or translocations of interest via tumor sequencing and immunohistochemistry. Consenting patients also undergo collection of blood samples for research purposes.\n\nSTEPS 1, 3, 5, 7 (Treatment): Patients are assigned to 1 of 38 treatment subprotocols based on molecularly-defined subgroup. (See Arms Section)\n\nSTEPS 2, 4, 6 (Screening): Patients experiencing disease progression on the prior Step treatment or who could not tolerate the assigned treatment undergo review of their previous biopsy results to determine if another treatment is available or undergo another biopsy. Patients may have a maximum of 2 screening biopsies and 2 treatments per biopsy.\n\nSTEP 8 (Optional Research): Consenting patients undergo end-of-treatment biopsy and collection of blood samples for research purposes.\n\nAdditionally, patients may undergo a computed tomography (CT) scan, magnetic resonance imaging, and/or radionuclide imaging throughout the trial.\n\nAfter completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.", "title": "Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02465060", "whyStopped": "" } ], "comenionGenes": [], "confirmedBindingTargets": [ "BRAF" ], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "inhibitor", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "DABRAFENIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 8006, 2015, 26392102, 23470635, 27080216, 23489023, 20818844, 38, 2014, 8009, 2013, 22608338, 23524406, 39107839, 38766698, 29171936, 28512244, 33637608, 33704186, 35319964, 29494756, 38662982, 36686670, 38479107, 38770091, 36505826, 26732095, 37656784, 31519698, 36217799, 33669326, 35709404, 31824282, 28800030, 38781546, 34108213, 35135105, 35022320, 33020648, 36375115, 31566661, 30285222, 26811525, 31506385, 31811016, 38283732, 34590045, 30248172, 31158244, 36039514, 27255157, 38844796, 27523909, 30926357, 31569065, 32981611, 32540409, 29903896, 28891408, 33020646, 27659046, 27770002, 28947956, 39424923, 39500140, 33216826, 35598548, 36221356, 32388065, 33250737, 33472910, 32922664, 23031422, 31925410, 38854737, 31980996, 27797976, 25370473, 24265153, 35705814, 24265154, 36442478, 29631033, 37729428, 38565920, 37838724, 36759733, 36622773, 33568355, 28714990, 36702949, 38960393, 33595872, 37213293, 29431699, 32234759, 36825105, 28984141, 37733309, 35491008, 31549998, 35026411, 27697975, 36531075, 35242981, 33043759, 30323086, 36847048, 36157689, 27312529, 34969785, 32843432, 34178685, 32238401, 39234402, 38109210, 32206360, 39232586, 36372281, 32818466, 38716076, 30036245, 31085763, 34956922, 38715777, 39376796, 28919011, 27283860, 39143272, 35382161, 33461766, 37643378, 34838156, 31217909, 32923904, 31345255, 29632053, 38820503, 33537843, 30556047, 22389471, 25399551, 28268064, 38814411, 34476331, 36108341, 27048246, 36011019, 24885690, 38756640, 31502039, 29880583, 39399174, 28784858, 30181415, 25549723, 25285888, 29621181, 31109800, 22735384, 23715574, 22180495, 18541894, 23812671, 14679157, 21594703, 12460918, 24586605, 22038996, 22773810, 21163703, 22649091, 22356324, 25370471, 19001320, 24388723, 22743296, 22586120, 24354346, 20630094, 23020132, 23549875, 19561230, 22351686, 22663011, 23614898, 25656898, 19255327, 24594804, 25157968, 22805292, 24107445, 23918947, 19238210, 23833300, 21683865, 19537845, 19018267, 23251002, 21975775, 21639808, 21129611, 24576830, 19773371, 19404918, 20368568, 22241789, 24163374, 20857202, 20413299, 24583796, 19010912, 12068308, 22972589, 23325582, 15035987, 21156289, 23612012, 21426297, 26678033, 25989278, 12460919, 23406027, 22997239, 22048237, 24396464, 23845441, 21663470, 25024077, 22536370, 23934108, 20350999, 24508103, 24570209, 22281684, 22448344, 26619011, 21483012, 20619739, 23844038 ], "potency": "Interaction: inhibitor", "pubchem": { "cid": 44462760, "inchikey": "BFSMGDJOXZAERB-UHFFFAOYSA-N", "iupacName": "N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl]-2,6-difluorobenzenesulfonamide", "molecularWeight": "519.6", "source": "PubChem", "xlogp": 4.8 }, "regulatoryEvidence": { "confidence": 0.96, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_2", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 2 }, "safetyProfile": { "deathRate": 0, "safetyScore": 6.3, "seriousRatio": 0.7406683603674028, "source": "OpenFDA", "topReactions": [ "PYREXIA", "DEATH", "MALIGNANT NEOPLASM PROGRESSION", "FATIGUE", "NAUSEA" ], "totalReports": 16388 }, "source": "DGIdb", "sourceCount": 17, "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Cancer Genome Interpreter", "Therapeutic Target Database", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "Catalogue Of Somatic Mutations In Cancer", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.98, "approvalSource": "explicit_approval_signal, clinical_trial_phase_3, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1147220", "clinicalTrials": [ { "briefSummary": "Based on the upstream signaling features of BRAFV600E and the bypass feedback mechanisms, considering the pro-apoptotic effects of chemotherapy and the synergistic effects of targeted therapy, previous IMPROVEMENT trial creatively explored a balanced chemotherapy-targeted combination approach (FOLFIRI + Vemurafenib + Cetuximab) in advanced colorectal cancer patients with BRAF V600E mutaiton using a signle-arm study design, demonstrating significant therapeutic efficacy in these patietns . To further validate the effectiveness and safety of this regimen and to solidify its clinical value, it is crucial to conduct a randomized, controlled trial. Investigators plan to use the current standard regimen as a control to compare this strategy (FOLFIRI + Vemurafenib + Cetuximab) on a large cohort of patients with BRAFV600E-mutant advanced colorectal cancer in the first-line setting, focusing on its efficacy and safety.", "completionDate": "2026-12-31", "conditionSummary": "Colorectal Carcinoma", "conditions": [ "Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "FOLFIRI + Vemurafenib + Cetuximab", "FOLFIRI ± Bevacizumab" ], "nctId": "NCT06603376", "phase": "Phase 2", "primaryCompletionDate": "2026-08-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Based on the upstream signaling features of BRAFV600E and the bypass feedback mechanisms, considering the pro-apoptotic effects of chemotherapy and the synergistic effects of targeted therapy, previous IMPROVEMENT trial creatively explored a balanced chemotherapy-targeted combination approach (FOLFIRI + Vemurafenib + Cetuximab) in advanced colorectal cancer patients with BRAF V600E mutaiton using a signle-arm study design, demonstrating significant therapeutic efficacy in these patietns . To further validate the effectiveness and safety of this regimen and to solidify its clinical value, it is crucial to conduct a randomized, controlled trial. Investigators plan to use the current standard regimen as a control to compare this strategy (FOLFIRI + Vemurafenib + Cetuximab) on a large cohort of patients with BRAFV600E-mutant advanced colorectal cancer in the first-line setting, focusing on its efficacy and safety.", "title": "Irinotecan Hydrochloride Liposome Injection (Ⅱ) Combined with Fluorouracil, Folinic Acid, Vermofenib and Cetuximab in First-line Treatment of BRAFV600E Mutated Advanced Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06603376", "whyStopped": "" }, { "briefSummary": "In this study, we compared first-line VIC regimen with chemotherapy plus bevacizumab in Chinese patients with initially unresectable BRAF V600E-mutated mCRC. The principal goal was to evaluate the safety of VIC regimen, and to investigate the tumor response, the radical resectability, and the patient survival.", "completionDate": "2022-12-30", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "VIC", "Bevacizumab Plus Chemotherapy" ], "nctId": "NCT05540951", "phase": "Phase 3", "primaryCompletionDate": "2022-08-30", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "In this study, we compared first-line VIC regimen with chemotherapy plus bevacizumab in Chinese patients with initially unresectable BRAF V600E-mutated mCRC. The principal goal was to evaluate the safety of VIC regimen, and to investigate the tumor response, the radical resectability, and the patient survival.", "title": "VIC Regimen Versus Bevacizumab Plus Chemotherapy as First-Line Treatment for BRAF V600E-Mutated Advanced Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05540951", "whyStopped": "" }, { "briefSummary": "This clinical trial aims to evaluate the efficacy, safety of FOLFIRI with vemurafenib and cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E mutation.", "completionDate": "2022-12-31", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Vemurafenib", "Cetuximab" ], "nctId": "NCT03727763", "phase": "Phase 2", "primaryCompletionDate": "2021-12-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "This clinical trial aims to evaluate the efficacy, safety of FOLFIRI with vemurafenib and cetuximab in Advanced Colorectal Cancer Patients with BRAF V600E mutation.", "title": "Cetuximab and Vemurafenib Plus FOLFIRI for BRAF V600E Mutated Advanced Colorectal Cancer (IMPROVEMENT)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03727763", "whyStopped": "" }, { "briefSummary": "BRAF mutation exists in about 10-12% of colorectal cancer, among which BRAF V600E mutation is the most common type, which is an important biomarker for predicting the prognosis and precise treatment efficacy of metastatic colorectal cancer (mCRC). The prognosis of metastatic colorectal cancer with BRAF V600E mutation is very poor, with OS of about 6-9 months. Previous studies have shown that single anti-BRAF inhibitor are ineffective, while multi-target inhibitions of Ras-Raf -MEK pathway is a possible effective strategy for BRAF V600E-mutant mCRC. Currently, the proven effective regimens include the VIC regimen (Vemurafenib + cetuximab + Irinotecan) and BEACON regimen (Encorafenib+ cetuximab +/- Binimetinib) from the SWOGS1406 study. Furthermore, BRAF inhibitor +MEK inhibitor combined with PD-1 monoclonal antibody has been shown to be an effective strategy in BRAF V600E-mutant malignant melanoma, which promote the study of the regimens for the treatment of BRAF V600E-mutant mCRC. Increasing basic and clinical studies have shown that cetuximab has ADCC effect, induces immunogenic cell death, promotes immune cell infiltration and other immunomodulatory effects, and has a synergistic effect with PD-1 monoclonal antibody in colorectal cancer. Based on those theories, we conducted the phase I study to explore the safety and preliminary efficacy of the regimen of Vemurafenib (BRAFi) plus cetuximab (EGFRi) combined with PD-1 monoclonal antibody in BRAF V600E-mutant /MSS type mCRC.", "completionDate": "2022-12-01", "conditionSummary": "BRAF V600E-mutated /MSS Metastatic Colorectal Cancer · Vemurafenib (BRAFi) Plus Cetuximab (EGFRi) Combined With PD-1 Monoclonal Antibody", "conditions": [ "BRAF V600E-mutated /MSS Metastatic Colorectal Cancer", "Vemurafenib (BRAFi) Plus Cetuximab (EGFRi) Combined With PD-1 Monoclonal Antibody" ], "contextFit": null, "hasResults": false, "interventions": [ "Vemurafenib Oral Tablet [Zelboraf]", "Cetuximab Injection [Erbitux]", "Camrelizumab" ], "nctId": "NCT05019534", "phase": "Phase 1", "primaryCompletionDate": "2022-08-01", "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "BRAF mutation exists in about 10-12% of colorectal cancer, among which BRAF V600E mutation is the most common type, which is an important biomarker for predicting the prognosis and precise treatment efficacy of metastatic colorectal cancer (mCRC). The prognosis of metastatic colorectal cancer with BRAF V600E mutation is very poor, with OS of about 6-9 months. Previous studies have shown that single anti-BRAF inhibitor are ineffective, while multi-target inhibitions of Ras-Raf -MEK pathway is a possible effective strategy for BRAF V600E-mutant mCRC. Currently, the proven effective regimens include the VIC regimen (Vemurafenib + cetuximab + Irinotecan) and BEACON regimen (Encorafenib+ cetuximab +/- Binimetinib) from the SWOGS1406 study. Furthermore, BRAF inhibitor +MEK inhibitor combined with PD-1 monoclonal antibody has been shown to be an effective strategy in BRAF V600E-mutant malignant melanoma, which promote the study of the regimens for the treatment of BRAF V600E-mutant mCRC. Increasing basic and clinical studies have shown that cetuximab has ADCC effect, induces immunogenic cell death, promotes immune cell infiltration and other immunomodulatory effects, and has a synergistic effect with PD-1 monoclonal antibody in colorectal cancer. Based on those theories, we conducted the phase I study to explore the safety and preliminary efficacy of the regimen of Vemurafenib (BRAFi) plus cetuximab (EGFRi) combined with PD-1 monoclonal antibody in BRAF V600E-mutant /MSS type mCRC.", "title": "Tolerability and Safety of Vemurafenib, Cetuximab Combined With Camrelizumab for BRAF V600E-mutated /MSS Metastatic Colorectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05019534", "whyStopped": "" }, { "briefSummary": "This randomized phase II trial studies how well irinotecan hydrochloride and cetuximab with or without vemurafenib works in treating patients with colorectal cancer that has spread to nearby tissue or lymph nodes, that has spread to other places in the body, or cannot be removed by surgery. Irinotecan hydrochloride and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block the ability of tumor cells to grow and spread. It is not yet known whether irinotecan hydrochloride and cetuximab are more effective with or without vemurafenib in treating colorectal cancer.", "completionDate": "2020-11-19", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "cetuximab", "irinotecan hydrochloride", "vemurafenib" ], "nctId": "NCT02164916", "phase": "Phase 2", "primaryCompletionDate": "2017-11-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To evaluate the progression-free survival (PFS) of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant metastatic colorectal cancer patients treated with irinotecan (irinotecan hydrochloride), cetuximab, and vemurafenib, compared to a control arm of irinotecan and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the frequency and severity of toxicity associated with each of the treatment arms in this patient population.\n\nTERTIARY OBJECTIVES:\n\nI. To evaluate overall survival (OS) in treatment Arms 1 and 2. II. To evaluate the overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, in treatment Arms 1 and 2 in the subset of patients with measurable disease.\n\nIII. To estimate rates of OS, ORR, and PFS in patients who register to Arm 3 after disease progression on Arm 1.\n\nIV. To evaluate low-frequency Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations as detected by high-depth sequencing as predictive biomarkers of efficacy.\n\nV. To evaluate phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) pathway activation through PIK3CA mutations or phosphatase and tensin homolog (PTEN) protein loss as a predictive biomarker of innate resistance to this regimen.\n\nVI. To evaluate gene expression signatures from screened patients with v-raf murine sarcoma viral oncogene homolog B wild type (BRAFWT) and BRAFV600E tumors.\n\nVII. To provide validation of BRAF immunohistochemistry (IHC) using complementary sequencing methodology from screened patients with BRAFWT and BRAFV600E tumors.\n\nVIII. To confirm the estimated sensitivity of detectable BRAF V600E circulating cell-free deoxyribonucleic acid (DNA) as a non-invasive biomarker for BRAF V600E mutation as detected by IHC in the primary tumor.\n\nIX. To correlate radiographic tumor response with change in quantification of BRAFV600E alleles in circulating cell-free DNA.\n\nX. To monitor for known mechanism of acquired resistance to epidermal growth factor receptor (EGFR) inhibition in circulating cell-free DNA (KRAS, NRAS mutations).\n\nOUTLINE: Patients are randomized to 1 of 2 treatment arms.\n\nARM I: Patients receive cetuximab intravenously (IV) and irinotecan hydrochloride IV on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may cross over to Arm II.\n\nARM II: Patients receive cetuximab and irinotecan hydrochloride as in Arm I and vemurafenib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 2-6 months for 3 years.", "title": "S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02164916", "whyStopped": "" }, { "briefSummary": "This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.", "completionDate": "2021-03-24", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Cetuximab", "FOLFOX induction regimen", "Fluoropyrimidine (5-FU/LV or capecitabine)", "Atezolizumab", "Vemurafenib" ], "nctId": "NCT02291289", "phase": "Phase 2", "primaryCompletionDate": "2019-05-31", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This randomized, multi-center, active-controlled, open-label, parallel-group study will investigate the efficacy and safety of biomarker-driven maintenance treatment for first-line mCRC. Participants with mCRC are eligible for entry and cannot have received any prior chemotherapy in the metastatic setting. The entire study duration is anticipated to be approximately 7.5 years.", "title": "A Study of Biomarker-Driven Therapy in Metastatic Colorectal Cancer (mCRC)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02291289", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). This treatment is being tested in a subgroup of patients with colorectal cancer whose tumors have changes in the BRAF gene that may make them more likely to respond to this new drug combination.", "completionDate": "2015-03", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "combination panitumumab and vemurafenib" ], "nctId": "NCT01791309", "phase": "Phase 1", "primaryCompletionDate": "2015-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). This treatment is being tested in a subgroup of patients with colorectal cancer whose tumors have changes in the BRAF gene that may make them more likely to respond to this new drug combination.", "title": "Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01791309", "whyStopped": "" } ], "comenionGenes": [], "confirmedBindingTargets": [ "BRAF" ], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "inhibitor, activator", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "VEMURAFENIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 22180495, 18541894, 23812671, 14679157, 21594703, 12460918, 24586605, 22389471, 22038996, 22773810, 21163703, 22608338, 22649091, 22356324, 25370471, 19001320, 24388723, 22743296, 22586120, 24354346, 20630094, 23020132, 23549875, 19561230, 22351686, 22663011, 23614898, 25656898, 19255327, 24594804, 25157968, 22805292, 24107445, 23918947, 19238210, 23833300, 21683865, 19537845, 19018267, 23251002, 21975775, 21639808, 21129611, 24576830, 19773371, 19404918, 20368568, 22241789, 24163374, 20818844, 20857202, 20413299, 24583796, 19010912, 12068308, 22972589, 23325582, 15035987, 21156289, 23612012, 21426297, 26678033, 25989278, 12460919, 23489023, 23406027, 22997239, 22048237, 24396464, 23845441, 21663470, 23031422, 23470635, 25024077, 22536370, 23934108, 20350999, 23524406, 24508103, 24570209, 22281684, 22448344, 26619011, 21483012, 22735384, 20619739, 231718, 23288408, 22621641, 25462267, 33560788, 35319964, 37164118, 37656784, 26732095, 30575814, 24035431, 34108213, 24283590, 26582644, 26343583, 32534646, 31566661, 24265152, 31171876, 26287849, 28783719, 22798288, 31182949, 29903896, 26343582, 32540409, 25706985, 29051322, 26137449, 29674508, 27196754, 30482852, 26984758, 27760111, 31959346, 22113612, 32669268, 34178685, 26996308, 33947696, 32859654, 30559419, 38854737, 31980996, 29605720, 30341394, 29880583, 24265153, 28514312, 36442478, 28655712, 26267534, 24448821, 28986383, 21383288, 25515853, 28951457, 30036146, 21107323, 34376578, 38593698, 38894534, 38728872, 37808191, 36921494, 36759733, 36343387, 36198029, 34818649, 34433654, 34330842, 33979489, 37325052, 31937621, 27297867, 35145907, 27048246, 27048951, 25665005, 26603897, 25589621, 24523613, 36638198, 23365119, 28649441, 36409971, 33669326, 35046062, 35382161, 27480103, 38096472, 33356422, 34232949, 36855200, 33976643, 32067683, 24859340, 35689405, 27312529, 26460303, 38976815, 36967525, 26490654, 37417899, 26918217, 27460442, 38489728, 26200454, 23733758, 39190425, 30351999, 31217909, 31386052, 28961848, 31158244, 29320312, 32029534, 26352686, 36713531, 27523909, 23715574 ], "potency": "Interaction: inhibitor, activator", "pubchem": { "cid": 42611257, "inchikey": "GPXBXXGIAQBQNI-UHFFFAOYSA-N", "iupacName": "N-[3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluorophenyl]propane-1-sulfonamide", "molecularWeight": "489.9", "source": "PubChem", "xlogp": 5 }, "regulatoryEvidence": { "confidence": 0.98, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_3", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 3 }, "safetyProfile": { "deathRate": 0, "safetyScore": 6.3, "seriousRatio": 0.7469879518072289, "source": "OpenFDA", "topReactions": [ "RASH", "DEATH", "ARTHRALGIA", "FATIGUE", "OFF LABEL USE" ], "totalReports": 9176 }, "source": "DGIdb", "sourceCount": 19, "sources": [ "DGIdb", "Clearity Foundation Clinical Trial", "Cancer Genome Interpreter", "Therapeutic Target Database", "MyCancerGenome Clinical Trial", "My Cancer Genome", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "The Druggable Genome: Evaluation of Drug Targets in Clinical Trials Suggests Major Shifts in Molecular Class and Indication (Rask-Andersen, Masuram, Schioth 2014)", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "Cancer Commons", "Drug Target Commons", "Targeted Agents in Lung Cancer (Commentary, 2014)", "The ChEMBL Bioactivity Database", "FDA Pharmacogenomic Biomarkers", "Catalogue Of Somatic Mutations In Cancer", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.88, "approvalSource": "explicit_approval_signal, clinical_trial_phase_2, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1425098", "clinicalTrials": [ { "briefSummary": "This phase II MATCH treatment trial identifies the effects of trametinib and dabrafenib in patients whose cancer has genetic changes called BRAF V600 mutations. Dabrafenib may stop the growth of cancer by blocking BRAF proteins which may be needed for cell growth. Trametinib may stop the growth of cancer cells by blocking MEK proteins which, in addition to BRAF proteins, may also be needed for cell growth. Researchers hope to learn if giving trametinib with dabrafenib will shrink this type of cancer or stop its growth.", "completionDate": "2026-12-31", "conditionSummary": "Advanced Lymphoma · Advanced Malignant Solid Neoplasm · Hematopoietic and Lymphoid Cell Neoplasm", "conditions": [ "Advanced Lymphoma", "Advanced Malignant Solid Neoplasm", "Hematopoietic and Lymphoid Cell Neoplasm" ], "contextFit": null, "hasResults": false, "interventions": [ "Dabrafenib Mesylate", "Trametinib Dimethyl Sulfoxide" ], "nctId": "NCT04439292", "phase": "Phase 2", "primaryCompletionDate": "2026-12-31", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To evaluate the proportion of patients with objective response (OR) to targeted study agent(s) in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate the proportion of patients alive and progression free at 6 months of treatment with targeted study agent in patients with advanced refractory cancers/lymphomas/multiple myeloma.\n\nII. To evaluate time until death or disease progression. III. To identify potential predictive biomarkers beyond the genomic alteration by which treatment is assigned or resistance mechanisms using additional genomic, ribonucleic acid (RNA), protein and imaging-based assessment platforms.\n\nIV. To assess whether radiomic phenotypes obtained from pre-treatment imaging and changes from pre- through post-therapy imaging can predict objective response and progression free survival and to evaluate the association between pre-treatment radiomic phenotypes and targeted gene mutation patterns of tumor biopsy specimens.\n\nOUTLINE:\n\nPatients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, and then every 6 months for year 3 from study entry.", "title": "Testing Trametinib and Dabrafenib as a Potential Targeted Treatment in Cancers With BRAF Genetic Changes (MATCH-Subprotocol H)", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04439292", "whyStopped": "" } ], "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "TRAMETINIB DIMETHYL SULFOXIDE", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 22180495, 18541894, 23812671, 14679157, 21594703, 12460918, 24586605, 22389471, 22038996, 22773810, 21163703, 22608338, 22649091, 22356324, 25370471, 19001320, 24388723, 22743296, 22586120, 24354346, 20630094, 23020132, 23549875, 19561230, 22351686, 22663011, 23614898, 22798288, 25656898, 19255327, 24594804, 25157968, 22805292, 24107445, 23918947, 19238210, 23833300, 21683865, 19537845, 19018267, 23251002, 21975775, 21639808, 21129611, 24576830, 19773371, 19404918, 20368568, 22241789, 24163374, 20818844, 2493360, 20857202, 20413299, 24583796, 19010912, 12068308, 22972589, 23325582, 15035987, 21156289, 23612012, 21426297, 26678033, 25989278, 12460919, 23489023, 23406027, 22997239, 22048237, 23715574, 24396464, 23845441, 21663470, 23031422, 23470635, 25024077, 22536370, 23934108, 20350999, 23524406, 24508103, 24570209, 22281684, 22448344, 26619011, 21483012, 22735384, 20619739, 8006, 2015, 26392102, 23248257, 20526349, 24345920, 24727320, 39107839, 38766698, 29171936, 28512244, 33637608, 33704186, 35319964, 29494756, 38662982, 36686670, 38479107, 38770091, 36505826, 32991018, 34011980, 37463056, 29903880, 37656784, 26732095, 30575814, 34108213, 36217799, 39152269, 33669326, 35709404, 31824282, 28800030, 35135105, 35022320, 33020648, 24265152, 31566661, 30285222, 26811525, 36375115, 33861486, 31704811, 38283732, 28783719, 34590045, 30248172, 24933606, 28344857, 31158244, 36039514, 38844796, 28784858, 30926357, 31569065, 29903896, 32981611, 39224677, 32540409, 25706985, 28891408, 33020646, 27760111, 27770002, 28947956, 31924734, 26343583, 31980996, 25370473, 39500140, 33216826, 35598548, 36221356, 32388065, 34376578, 33250737, 33472910, 32922664, 31925410, 38854737, 29880583, 26469692, 37713162, 27797976, 24265153, 35705814, 24265154, 28655712, 36442478, 28986383, 29631033, 37729428, 36622773, 38992135, 38565920, 36759733, 36343387, 35882450, 33568355, 33318037, 33229459, 30833748, 39121480, 28714990, 36702949, 38960393, 27297867, 37213293, 35145907, 26916115, 29431699, 32234759, 25665005, 36825105, 28984141, 37733309, 35491008, 31549998, 35026411, 27697975, 36531075, 35242981, 33043759, 30323086, 36847048, 36157689, 27312529, 34969785, 32843432, 34178685, 32238401, 39234402, 38109210, 32206360, 39232586, 36372281, 32818466, 38716076, 30036245, 31085763, 34956922, 38715777, 39376796, 28919011, 27080216, 27283860, 39143272, 35382161, 33461766, 37643378, 34838156, 31217909, 32923904, 31345255, 29632053, 38820503, 33537843, 30556047, 25399551, 28268064, 38814411, 34476331, 36108341, 27048246, 39399174, 36011019, 25309914, 32758030, 27222538, 27488531 ], "potency": "Interaction: Unknown", "pubchem": { "cid": 50992434, "inchikey": "OQUFJVRYDFIQBW-UHFFFAOYSA-N", "iupacName": "N-[3-[3-cyclopropyl-5-(2-fluoro-4-iodoanilino)-6,8-dimethyl-2,4,7-trioxopyrido[4,3-d]pyrimidin-1-yl]phenyl]acetamide;methylsulfinylmethane", "molecularWeight": "693.5", "source": "PubChem" }, "regulatoryEvidence": { "confidence": 0.88, "explicitApproved": true, "hasOpenFdaSignal": false, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_2", "multi_source_confirmation" ], "status": "approved", "trialPhase": 2 }, "source": "DGIdb", "sourceCount": 9, "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.98, "approvalSource": "explicit_approval_signal, clinical_trial_phase_3, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1722365", "clinicalTrials": [ { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "There is a huge variety of nucleotide substitutions that activate RAS. The search for new \"universal\" drugs for the RAS pathway that either interfere with RAS upregulation upstream in the signaling pathway or offset the consequences of RAS activation is important for improving therapeutic outcomes for patients with refractory malignancies.\n\nThe use of leflunomide or the combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is promising for patients with mutations in RAS cascade genes who have failed all existing treatment standards.", "completionDate": "2026-10-01", "conditionSummary": "RAS Mutation · Ras (Kras or Nras) Gene Mutation · Colorectal Cancer Recurrent", "conditions": [ "RAS Mutation", "Ras (Kras or Nras) Gene Mutation", "Colorectal Cancer Recurrent" ], "contextFit": null, "hasResults": false, "interventions": [ "Leflunomide", "The combination of MEK inhibitor + hydroxychloroquine( plaquenil) ± bevacizumab" ], "nctId": "NCT06229340", "phase": "Phase 2", "primaryCompletionDate": "2026-10-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Mutations in the RAS gene are a common cause for the development of many tumors.\n\nIt is of practical interest to study the potential efficacy of several drugs registered for the treatment of other diseases, which may also be able to affect various parts of the RAS pathway.\n\nLeflunomide, with its active metabolite , inhibits the enzyme dihydroorotate dehydrogenase (DHODH). DHODH plays an essential role in the biosynthesis of pyrimidine, which is particularly important for the growth of RAS mutant cells.\n\nTumors with KRAS, NRAS, and HRAS mutations are characterized by increased MEK kinase activity. The combination of MEK inhibitor + hydroxychloroquine ± bevacizumab is able to affect MEK kinase activity by direct inhibition as well as regulation of autophagy, which is controlled in this case by the antimalarial drug hydroxychloroquine.\n\nThe use of bevacizumab is appropriate because there is evidence of its efficacy in the treatment of patients with colorectal cancer, including colorectal cancer with mutations in the KRAS gene.", "title": "Leflunomide or Combination of MEK Inhibitor and Hydroxychloroquine for Refractory Patients With RAS Mutations", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06229340", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of RMC-4630 and cobimetinib in adult participants with relapsed/refractory solid tumors with specific genomic aberrations and to identify the recommended Phase 2 dose (RP2D); and to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of RMC-4630 and osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.", "completionDate": "2022-02-08", "conditionSummary": "Solid Tumor", "conditions": [ "Solid Tumor" ], "contextFit": null, "hasResults": true, "interventions": [ "RMC-4630", "Cobimetinib", "Drug: Osimertinib" ], "nctId": "NCT03989115", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2022-02-08", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This open-label, phase 1b/2 dose-escalation and dose-expansion study is designed to evaluate the safety and maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of RMC-4630 in combination with cobimetinib in participants with relapsed/refractory solid tumors; and of RMC-4630 in combination with osimertinib in adult participants with EGFR mutation-positive locally advanced or metastatic NSCLC.", "title": "Dose-Esc/Exp RMC4630 & Cobi in Relapsed/Refractory Solid Tumors & RMC4630& Osi in EGFR+ Locally Adv/Meta NSCLC", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03989115", "whyStopped": "" }, { "briefSummary": "This is an open-label, multicenter, single-arm, two-stage, Phase Ib study designed to assess the safety, tolerability, and pharmacokinetics of oral cobimetinib with intravenous (IV) atezolizumab and bevacizumab in participants with metastatic colorectal cancer (mCRC) who have received and progressed on at least one prior line of therapy that contained a fluoropyrimidine and oxaliplatin or irinotecan. There are two stages in this study: Stage 1 (safety run-in phase) and Stage 2 (dose expansion phase with two cohorts, an expansion cohort and a biopsy cohort).", "completionDate": "2019-06-25", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Atezolizumab", "Bevacizumab", "Cobimetinib" ], "nctId": "NCT02876224", "phase": "Phase 1", "primaryCompletionDate": "2019-06-25", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is an open-label, multicenter, single-arm, two-stage, Phase Ib study designed to assess the safety, tolerability, and pharmacokinetics of oral cobimetinib with intravenous (IV) atezolizumab and bevacizumab in participants with metastatic colorectal cancer (mCRC) who have received and progressed on at least one prior line of therapy that contained a fluoropyrimidine and oxaliplatin or irinotecan. There are two stages in this study: Stage 1 (safety run-in phase) and Stage 2 (dose expansion phase with two cohorts, an expansion cohort and a biopsy cohort).", "title": "Study of Cobimetinib in Combination With Atezolizumab and Bevacizumab in Participants With Gastrointestinal and Other Tumors", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02876224", "whyStopped": "" }, { "briefSummary": "This study is for patients with metastatic colorectal cancer who are candidates for resection of metastases. This study will be conducted sequentially with 2 cohorts: 1.) Monotherapy Cohort and 2.) Combination Cohort\n\nPre-metastatectomy\n\n* Monotherapy Cohort: The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle.\n* Combination Cohort: The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Note: Cobimetinib must be held for the 7 days prior to metastatectomy.\n\nAll subjects will be treated for 2 cycles (8 weeks) prior to metastatectomy\n\nMetastatectomy\n\nSubjects will undergo liver metastatectomy within 42 days of completion of Cycle 2 of pre-metastatectomy treatment. No study treatment is administered while the patient is healing after surgery.\n\nPost-metastatectomy\n\nOnce the patient has healed from the surgery, adjuvant treatment may be administered at the discretion of the treating physician. Restaging following standards of care for this setting.", "completionDate": "2025-02", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Atezolizumab", "Cobimetinib" ], "nctId": "NCT03340558", "phase": "Phase 2", "primaryCompletionDate": "2021-02", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "This study is for patients with metastatic colorectal cancer who are candidates for resection of metastases. This study will be conducted sequentially with 2 cohorts: 1.) Monotherapy Cohort and 2.) Combination Cohort\n\nPre-metastatectomy\n\n* Monotherapy Cohort: The first 10 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 of each 28-day cycle.\n* Combination Cohort: The next 15 subjects will receive Atezolizumab 840 mg IV on Day 1 and Day 15 and Cobimetinib 60 mg PO on Days 1-21 of each 28-day cycle. Note: Cobimetinib must be held for the 7 days prior to metastatectomy.\n\nAll subjects will be treated for 2 cycles (8 weeks) prior to metastatectomy\n\nMetastatectomy\n\nSubjects will undergo liver metastatectomy within 42 days of completion of Cycle 2 of pre-metastatectomy treatment. No study treatment is administered while the patient is healing after surgery.\n\nPost-metastatectomy\n\nOnce the patient has healed from the surgery, adjuvant treatment may be administered at the discretion of the treating physician. Restaging following standards of care for this setting.", "title": "Atezolizumab Monotherapy vs Atezolizumab Plus Cobimetinib in Liver Metastases From Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03340558", "whyStopped": "Negative results in a similar study" }, { "briefSummary": "The purpose of this study is to examine if Nivolumab by itself, or Nivolumab in combination with other anti-cancer drugs, will result in meaningful tumor size reduction, in participants with colon cancer that has come back or has spread, and who have a specific biomarker in their tumors.", "completionDate": "2024-10-22", "conditionSummary": "Microsatellite Unstable Colorectal Cancer · Microsatellite Stable Colorectal Cancer · Mismatch Repair Proficient Colorectal Cancer", "conditions": [ "Microsatellite Unstable Colorectal Cancer", "Microsatellite Stable Colorectal Cancer", "Mismatch Repair Proficient Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Ipilimumab", "Nivolumab", "Cobimetinib", "Daratumumab", "BMS-986016" ], "nctId": "NCT02060188", "phase": "Phase 2", "primaryCompletionDate": "2024-10-22", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The purpose of this study is to examine if Nivolumab by itself, or Nivolumab in combination with other anti-cancer drugs, will result in meaningful tumor size reduction, in participants with colon cancer that has come back or has spread, and who have a specific biomarker in their tumors.", "title": "A Study of Nivolumab Alone or Nivolumab Combination Therapy in Colon Cancer That Has Come Back or Has Spread", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02060188", "whyStopped": "" } ], "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "COBIMETINIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 34108213, 33560788, 26996308, 38922339, 32534646, 31171876, 31566661, 22084396, 29903896, 33953400, 34433654, 34376578, 38854737, 30341394, 36442478, 34667063, 28649441, 36409971, 33669326, 35046062, 35382161, 31217909, 27480103, 38096472, 30867592, 27424159 ], "potency": "Interaction: Unknown", "pubchem": { "cid": 16222096, "inchikey": "BSMCAPRUBJMWDF-KRWDZBQOSA-N", "iupacName": "[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-[3-hydroxy-3-[(2S)-piperidin-2-yl]azetidin-1-yl]methanone", "molecularWeight": "531.3", "source": "PubChem", "xlogp": 3.9 }, "regulatoryEvidence": { "confidence": 0.98, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_3", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 3 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.8, "seriousRatio": 0.8302325581395349, "source": "OpenFDA", "topReactions": [ "OFF LABEL USE", "DIARRHOEA", "RASH", "PYREXIA", "DEATH" ], "totalReports": 2811 }, "source": "DGIdb", "sourceCount": 8, "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "Clearity Foundation Biomarkers", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.98, "approvalSource": "explicit_approval_signal, clinical_trial_phase_3, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:318341", "clinicalTrials": [ { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "To find out if certain drug/therapy combinations that are targeted to individual patients based on characteristics of their disease types may help to control the disease.", "completionDate": "2029-11-14", "conditionSummary": "Dynamic Tumor Resistance · Metastatic Colorectal Cancer", "conditions": [ "Dynamic Tumor Resistance", "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "SOC (Standard of care)", "Bevacizumab", "Cetuximab", "Panitumumab", "FOLFIRI" ], "nctId": "NCT07318389", "phase": "EARLYPhase 1", "primaryCompletionDate": "2027-11-14", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives\n\n* To determine differences in PFS based on differential response markers in paired tissue biopsies (Part I).\n* To improve progression-free survival with novel intervention strategies (Part II)\n\nSecondary Objectives\n\n* To collect serial tissue and blood biomarkers and efficacy data associated with standard of care or investigational therapy across multiple lines of therapy.\n* To determine the overall response rate (ORR), and overall survival (OS) based on the presence of specific biomarkers or adaptive interventions.", "title": "ASCEND-CRC: Profiling and Targeting Dynamic Tumor Resistance in Patients With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07318389", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate the efficacy and toxicity of irinotecan with dabrafenib, cetuximab/panitumumab in the second line of treatment for the potential treatment of colorectal cancer that: has a metastatic, inoperable; has a mutation in the BRAF gene.\n\nParticipants in this study will receive one of the following study treatments:\n\nThese participants will receive in the second line is irinotecan, dabrafenib + trametinib, cetuximab or panitumumab.\n\nThis trial is currently enrolling participants who will receive either irinotecan and dabrafenib plus cetuximab or panitumumab in the second line of therapy.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2028-06-10", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "• Drug: Dabrafenib • Drug: Trametinib • Drug: Cetuximab • Drug: Рanitumumab • Drug: Oxaliplatin • Drug: Irinotecan • Drug: Leucovorin • Drug: 5-FU" ], "nctId": "NCT06967155", "phase": "Phase 2", "primaryCompletionDate": "2027-11-10", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate the efficacy and toxicity of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in second-line treatment of patients with metastatic inoperable colorectal cancer who have a BRAF mutation.", "title": "A Study of Irinotecan With Dabrafenib Plus Trametinib and Anti-EGFR in the Second Line of Therapy in People With Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06967155", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:\n\n* has spread to other parts of the body (metastatic);\n* has a certain type of abnormal gene called \"BRAF\"; and\n* has not received prior treatment.\n\nParticipants in this study will receive one of the following study treatments:\n\n* Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.\n* Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.\n* Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.\n\nThis study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.\n\nThe study team will monitor how each participant responds to the study treatment for up to about 3 years.", "completionDate": "2027-12-28", "conditionSummary": "Neoplasms", "conditions": [ "Neoplasms" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Oxaliplatin", "Irinotecan", "Leucovorin" ], "nctId": "NCT04607421", "phase": "Phase 3", "primaryCompletionDate": "2025-12-08", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.", "title": "A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04607421", "whyStopped": "" }, { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the activity, in terms of best response according to RECIST criteria 1.1 as assessed by the local investigator, of the ctDNA-guided retreatment with encorafenib plus cetuximab in BRAFV600E mutated mCRC patients experiencing benefit from previous exposure to encorafenib plus cetuximab (+/- chemotherapy) and with BRAFV600E mutated, KRAS, NRAS and MAP2K1 wild-type and MET not amplified status on ctDNA at the time of study entry.", "completionDate": "2027-04-01", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib" ], "nctId": "NCT06578559", "phase": "Phase 2", "primaryCompletionDate": "2026-08-01", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a proof-of-concept, multicenter, open-label, single arm one-stage phase II trial of a ctDNA-guided retreatment with encorafenib plus cetuximab for mCRC patients bearing the BRAFV600E mutation and with the key following characteristics:\n\n* initial benefit and then secondary resistance to a previous exposure to encorafenib and cetuximab with or without chemotherapy;\n* only one subsequent intervening anti-BRAF and anti-EGFR-free line of therapy;\n* confirmed BRAFV600E mutated status and no detectable mutations in KRAS, NRAS, MAP2K1 and no amplification of MET in ctDNA at the time of retreatment;\n\nEligible patients will receive Encorafenib 300 mg once daily (four 75 mg oral capsules) and Cetuximab 500 mg/sqm iv infusion every 14 days.Treatment will be delivered in 28-day cycles until disease progression, unacceptable toxic effects, withdrawal of consent, initiation of subsequent anticancer therapy, or death.", "title": "Phase II Study of ctDNA-guided Encorafenib Plus Cetuximab Retreatment in Patients BRAF V600E Mutated mCRC", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06578559", "whyStopped": "" }, { "briefSummary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for patients with BRAF wild-type tumours. After 1st line therapy, treatment outcomes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months. Failure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC.\n\nBERING CRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy. Data from this study will contribute to a deeper understanding and characterization to the everyday use of encorafenib and cetuximab in a broader patient population in the German, Austrian, and Swiss routine setting.", "completionDate": "2027-01", "conditionSummary": "Metastatic Colorectal Carcinoma", "conditions": [ "Metastatic Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab" ], "nctId": "NCT04673955", "phase": "N/A", "primaryCompletionDate": "2026-09", "status": "RECRUITING", "studyType": "OBSERVATIONAL", "summary": "The presence of a BRAFV600E mutation is a marker of poor prognosis in patients with mCRC and associated with a median overall survival (mOS) of approximately 12 to 14 months compared to 20 to 25 months for pa-tients with BRAF wild-type tumors. After 1st line therapy, treatment out-comes with standard therapy are poor in patients with BRAF-mutated mCRC, with response rates (ORR) of ≤ 11%, a median progression-free survival (mPFS) between 1.8 and 2.8 months, and a mOS between 4.1 and 6.2 months.\n\nFailure to achieve adequate survival outcomes with standard treatment regimens in patients with BRAF-mutated mCRC has encouraged efforts to combine multiple targeted therapies: With 665 randomized patients, the BEACON CRC trial represents the largest trial and is currently the only phase III study in patients with BRAFV600E-mutant mCRC. After a safety lead in for dose confirmation of the triplet regimen, the phase III part was per-formed with a total of 665 patients, randomized 1:1:1 to either receive encorafenib plus binimetinib and cetuximab (triplet) or encorafenib plus cetuximab (doublet) or FOLFIRI / IRI plus cetuximab (control).\n\nThe BEACON CRC study met its primary endpoints Overall Response Rate (ORR) and Overall Survival (OS) comparing Encorafenib + Binimetinib + Cetuximab vs. Chemotherapy + Cetuximab (ORR: 26 vs. 2%, p\\<0.001; OS: median 9.0 vs. 5.4 months, HR 0.52, p\\<0.001). The BEACON CRC study was alpha-controlled also for the secondary endpoint comparing Encorafenib + Cetuximab vs. Chemotherapy + Cetuximab in terms of ORR and OS and showed a statistically significant advantage (ORR: 20 vs. 2%, p\\<0.001; OS: median 8.4 vs. 5.4 months, HR 0.60, p\\<0.001). In terms of safety, the overall frequency of adverse events grade 3/4 was 58% (En-corafenib + Binimetinib + Cetuximab) vs. 50% (Encorafenib + Cetuximab) vs. 61% (Chemotherapy + Cetuximab). Analysis of Quality of Life data resulted in a longer maintenance of Quality of Life in the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm com-pared to Chemotherapy + Cetuximab. Between Encorafenib + Binimetinib + Cetuximab and Encorafenib + Cetuximab, no relevant differences were reported. With a longer Follow-Up (12.8 months) the updated OS data showed a median OS of 9.3 months in both the Encorafenib + Binimetinib + Cetuximab arm and the Encorafenib + Cetuximab arm compared to 5.9 months in the control arm. Updated ORR rates were 27% in the triplet arm (p\\<0.0001 vs. control), 20% in the doublet arm (p\\<0.0001 vs. control) and 2% in the control arm. The safety and tolerability were adequate, manage-able and consistent with the known profiles of BRAF-, MEK-, and EGFR-inhibitors. Regarding the triplet combination, the most common adverse events of any grade were diarrhea (triplet: 62%; control: 48%), dermatitis acneiform (triplet: 49%; control: 39%), nausea (triplet: 45%; control: 41%), and vomiting (triplet: 38%; control: 29%). Regarding the doublet combina-tion, the most common adverse events of any grade were nausea (34%), diarrhea (33%), fatigue (doublet 30%; triplet 33%; control 27%) and derma-titis acneiform (29%).\n\nThe most common updated grade ≥3 adverse events regarding the triplet combination were diarrhea (triplet: 11%; control: 10%), abdominal pain (triplet: 6%; control: 5%), nausea (triplet: 5%; control: 2%,vomiting (triplet: 5%; control: 3%) and intestinal obstruction (triplet 5%; control 3%). With the doublet regimen, the most common updated grade ≥3 adverse events were intestinal obstruction (doublet 5%), asthenia (doublet 4%; triplet 4%; control 5%), fatigue (doublet 4%; triplet 2%; control 5%), diarrhea (3%) and abdominal pain (3%).\n\nBased on these data, it is expected that the European Medicines Agency (EMA) will approve encorafenib plus cetuximab for the treatment of adult patients with metastatic BRAFV600E-mutant CRC, who have received prior systemic therapy.\n\nData from pivotal clinical trials are usually based on a selected patient population in order to provide standardized results in the given indication. However, after marketing authorization usage in a broader patient popula-tion is to be expected. Therefore, BERINGCRC - designed as a prospective (allowing initial retrospective documentation), longitudinal, non-interventional study - will investigate the real-world effectiveness, quality of life, safety and tolerability of encorafenib and cetuximab in BRAFV600E-mutant mCRC patients, who have received prior systemic therapy.", "title": "BRAF Inhibitor Encorafenib And Cetuximab Real Life Investigation of Next Generation CRC Treatment", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04673955", "whyStopped": "" }, { "briefSummary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "completionDate": "2028-06", "conditionSummary": "BRAF V600E · Colorectal Cancer · Sintilimab", "conditions": [ "BRAF V600E", "Colorectal Cancer", "Sintilimab" ], "contextFit": null, "hasResults": false, "interventions": [ "Ipilimumab N01", "Sintilimab", "Cetuximab", "Dabrafenib" ], "nctId": "NCT07506109", "phase": "Phase 2", "primaryCompletionDate": "2027-12", "status": "NOT_YET_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition.\n\nPreclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy.\n\nThis is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.", "title": "A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07506109", "whyStopped": "" }, { "briefSummary": "This phase I trial tests the safety, best dose, and effectiveness of ZEN003694 in combination with cetuximab and encorafenib in treating patients with colorectal cancer that has not responded to previous treatment (refractory), that has come back after a period of improvement (relapsed), and that has spread from where it first started (primary site) to other places in the body (metastatic). ZEN003694 is a protein inhibitor that binds to BET proteins. When ZEN003694 binds to BET proteins, it disrupts gene expression. Preventing the expression of certain growth-promoting genes may inhibit proliferation of tumor cells that over-express BET proteins. Immunotherapy with monoclonal antibodies, such as cetuximab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Encorafenib is an enzyme inhibitor. It inhibits pathways that are responsible for controlling cell proliferation and survival, which may lead to a decrease in tumor cell proliferation. Both cetuximab and encorafenib have been approved to treat cancer. Adding ZEN003694 to cetuximab and encorafenib may be more effective at treating patients with refractory metastatic colorectal cancer than giving the usual treatment (cetuximab and encorafenib) alone.", "completionDate": "2027-01-30", "conditionSummary": "Metastatic Colorectal Adenocarcinoma · Recurrent Colorectal Adenocarcinoma · Refractory Colorectal Adenocarcinoma", "conditions": [ "Metastatic Colorectal Adenocarcinoma", "Recurrent Colorectal Adenocarcinoma", "Refractory Colorectal Adenocarcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "BET Bromodomain Inhibitor ZEN-3694", "Biopsy Procedure", "Biospecimen Collection", "Cetuximab", "Computed Tomography" ], "nctId": "NCT06102902", "phase": "Phase 1", "primaryCompletionDate": "2027-01-30", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To define the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) when used in combination with cetuximab and encorafenib.\n\nII. To define the safety profile of combination of ZEN003694, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To observe and record anti-tumor activity. II. To evaluate clinical response signals of the combination. III. To assess the pharmacodynamic (PD) profile of the combination as defined by MAPK inhibition.\n\nEXPLORATORY OBJECTIVE:\n\nI. To characterize pharmacodynamics and potential mechanisms of resistance to therapy via whole exome sequencing (WES), reverse phase protein array (RPPA), ribonucleic acid sequencing (RNAseq), and assay for transposase-accessible chromatin with sequencing (ATACseq)/HiSeq 4000 or NovaSeq following progression on treatment.\n\nOUTLINE: This is a dose-escalation study of ZEN003694 followed by a dose-expansion study.\n\nPatients receive ZEN003694 orally (PO) once daily (QD) on days 1-28 of each cycle, cetuximab intravenously (IV) over 120 minutes on days 1 and 15 of each cycle, and encorafenib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multi-gated acquisition scan (MUGA), computed tomography (CT) or magnetic resonance imaging (MRI), and collection of blood samples throughout the trial. Patients may also undergo biopsy at screening and on study.\n\nAfter completion of study treatment, patients are followed up every 2 months.", "title": "Testing the Addition of Anti-cancer Drug, ZEN003694, to the Usual Chemotherapy Treatment, Cetuximab Plus Encorafenib, for Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06102902", "whyStopped": "" }, { "briefSummary": "The BRAVE is a phase II clinical trial aimed at evaluating the efficacy of the combination therapy of encorafenib, cetuximab, and bevacizumab in patients with metastatic colorectal cancer (CRC) harboring the BRAF-V600E mutation. This mutation is present in about 8-10% of CRC cases and is associated with poor prognosis and limited treatment options. The rationale behind this trial stems from preclinical studies suggesting that the overexpression and activation of vascular endothelial growth factor A (VEGFA) may contribute to resistance to BRAF inhibitors (BRAFi) in CRC. Thus, the trial hypothesizes that adding bevacizumab, an anti-angiogenic agent targeting VEGFA, to the combination of encorafenib and cetuximab may delay acquired resistance, leading to improved progression-free survival.\n\nThe primary objective of the BRAVE is to evaluate the antitumor activity of the encorafenib-cetuximab-bevacizumab combination in patients who have experienced disease progression after one or two chemotherapy regimens for BRAF V600E-mutant metastatic CRC. This activity will be assessed based on the confirmed progression-free survival rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.", "completionDate": "2029-05-01", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Bevacizumab" ], "nctId": "NCT06411600", "phase": "Phase 2", "primaryCompletionDate": "2027-05-01", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Study Design: The study adopts a multicenter, open-label, phase II design. Patients with metastatic CRC harboring the BRAF-V600E mutation, who have experienced disease progression after one or two prior chemotherapy regimens, are eligible for enrollment. The treatment regimen consists of daily oral encorafenib (300 mg), biweekly intravenous cetuximab (500 mg/m2), and biweekly intravenous bevacizumab (5 mg/kg). Treatment will be administered in 28-day cycles until disease progression, unacceptable toxicity, consent withdrawal, initiation of other anticancer therapy, or death.\n\nSecondary Objectives: Secondary objectives include evaluating the safety and tolerability of the combination therapy, assessing objective response rate, time to response, duration of response, overall survival, and patient-reported outcomes. Exploratory objectives involve evaluating potential biomarkers predictive of treatment response and resistance, as well as generating functional models to assess novel drug combinations targeting resistance mechanisms.", "title": "Combination Therapy for BRAF-V600E Metastatic CRCm", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "positive", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06411600", "whyStopped": "" }, { "briefSummary": "The aim of this study is to determine the activity of encorafenib plus cetuximab in combination with FOLFIRI in patients with BRAF V600E mutated metastatic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.", "completionDate": "2026-06-30", "conditionSummary": "Colorectal Carcinoma · Colorectal Neoplasms · Colorectal Tumor", "conditions": [ "Colorectal Carcinoma", "Colorectal Neoplasms", "Colorectal Tumor" ], "contextFit": null, "hasResults": false, "interventions": [ "encorafenib + cetuximab + FOLFIRI" ], "nctId": "NCT06640166", "phase": "Phase 2", "primaryCompletionDate": "2025-12-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, multicentre, phase II single-arm trial, evaluating encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemotherapy (FOLFIRI) in patients affected by BRAF V600E mutated metatstic colorectal cancer progressing on encorafenib plus cetuximab administered in second line.\n\nEligible patients are:\n\n* affected by BRAF V600E mutated metastatic colorectal cancer;\n* progressing on encorafenib plus cetuximab administered in second line;\n* achieved complete response, or partial response, or stable disease lasting more than 3 moths, as best response to encorafenib plus cetuximab administered in second line.\n\nAll patients eligible according to inclusion and exclusion criteria will receive encorafenib plus cetuximab beyond progression in combination with irinotecan-based doublet chemoterapy (FOLFIRI) as follows:\n\n* encorafenib 300 mg (75 mgx4 hard capsules) orally once daily;\n* cetuximab 500 mg/sqm iv every 14 days;\n* FOLFIRI iv every 14 days (Irinotecan 180 mg/sqm, Folinic Acid 400 mg/sqm, 5Fluorouracil 400 mg/sqm iv bolus and 2400 mg/sqm iv continuous infusion over 46-48 hours).\n\nTreatment will be administered until disease progression, unacceptable toxic effects, withdrawal of consent, or death.\n\nThe primary end point of this trial is investigator-assessed 6-month progression free survival rate and is defined as the proportion of patients alive and progression-free by the 6-month time point from start of investigational treatment (encorafenib plus cetuximab beyond progression in combination with FOLFIRI).", "title": "Encorafenib + Cetuximab Beyond Progression in Combination With FOLFIRI in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer Progressing on Encorafenib + Cetuximab.", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06640166", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" }, { "briefSummary": "Based on the upstream signaling features of BRAFV600E and the bypass feedback mechanisms, considering the pro-apoptotic effects of chemotherapy and the synergistic effects of targeted therapy, previous IMPROVEMENT trial creatively explored a balanced chemotherapy-targeted combination approach (FOLFIRI + Vemurafenib + Cetuximab) in advanced colorectal cancer patients with BRAF V600E mutaiton using a signle-arm study design, demonstrating significant therapeutic efficacy in these patietns . To further validate the effectiveness and safety of this regimen and to solidify its clinical value, it is crucial to conduct a randomized, controlled trial. Investigators plan to use the current standard regimen as a control to compare this strategy (FOLFIRI + Vemurafenib + Cetuximab) on a large cohort of patients with BRAFV600E-mutant advanced colorectal cancer in the first-line setting, focusing on its efficacy and safety.", "completionDate": "2026-12-31", "conditionSummary": "Colorectal Carcinoma", "conditions": [ "Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "FOLFIRI + Vemurafenib + Cetuximab", "FOLFIRI ± Bevacizumab" ], "nctId": "NCT06603376", "phase": "Phase 2", "primaryCompletionDate": "2026-08-31", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Based on the upstream signaling features of BRAFV600E and the bypass feedback mechanisms, considering the pro-apoptotic effects of chemotherapy and the synergistic effects of targeted therapy, previous IMPROVEMENT trial creatively explored a balanced chemotherapy-targeted combination approach (FOLFIRI + Vemurafenib + Cetuximab) in advanced colorectal cancer patients with BRAF V600E mutaiton using a signle-arm study design, demonstrating significant therapeutic efficacy in these patietns . To further validate the effectiveness and safety of this regimen and to solidify its clinical value, it is crucial to conduct a randomized, controlled trial. Investigators plan to use the current standard regimen as a control to compare this strategy (FOLFIRI + Vemurafenib + Cetuximab) on a large cohort of patients with BRAFV600E-mutant advanced colorectal cancer in the first-line setting, focusing on its efficacy and safety.", "title": "Irinotecan Hydrochloride Liposome Injection (Ⅱ) Combined with Fluorouracil, Folinic Acid, Vermofenib and Cetuximab in First-line Treatment of BRAFV600E Mutated Advanced Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06603376", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.", "completionDate": "2011-07", "conditionSummary": "Colorectal Cancer · Metastases", "conditions": [ "Colorectal Cancer", "Metastases" ], "contextFit": null, "hasResults": true, "interventions": [ "Cetuximab", "Bevacizumab", "Leucovorin", "Oxaliplatin", "Fluorouracil" ], "nctId": "NCT00537823", "phase": "Phase 2", "primaryCompletionDate": "2009-12", "status": "TERMINATED", "studyType": "INTERVENTIONAL", "summary": "Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%.\n\nThe fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.", "title": "Pre- and Post-operative FOLFOX Based Therapy for Patients With Colorectal Cancer With Liver Involvement", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00537823", "whyStopped": "Poor accrual." }, { "briefSummary": "RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, irinotecan, fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab and cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving combination chemotherapy together with monoclonal antibody therapy may kill more tumor cells.\n\nPURPOSE: This phase II trial is studying how well giving combination chemotherapy together with monoclonal antibody therapy works in treating patients with advanced colorectal cancer with liver metastases or lung metastases that are potentially removable by surgery.", "completionDate": null, "conditionSummary": "Colorectal Cancer · Metastatic Cancer", "conditions": [ "Colorectal Cancer", "Metastatic Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "bevacizumab", "cetuximab", "fluorouracil", "irinotecan hydrochloride", "leucovorin calcium" ], "nctId": "NCT00513266", "phase": "Phase 2", "primaryCompletionDate": null, "status": "UNKNOWN", "studyType": "INTERVENTIONAL", "summary": "OBJECTIVES:\n\nPrimary\n\n* To determine the pathological complete response (CR) rate in resected patients assessed on lesions of less than or equal to 30 mm in size.\n\nSecondary\n\n* To determine the clinical CR rate in all patients.\n* To determine toxicity and tolerability of this regimen (pre- and postoperative toxicity).\n* To evaluate perioperative safety in these patients.\n* To determine disease-free survival (time to progression in unresected patients) and overall survival of the whole study population.\n* To determine resectability in these patients.\n* To evaluate markers that predict the occurrence of a pathological CR or a non-response in pathological material (resected liver metastasis) and biological material collected from these patients.\n\nOUTLINE: This is a multicenter study.\n\nPatients receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, and 29, oxaliplatin IV over 2 hours on days 1 and 15, irinotecan hydrochloride IV over 30 minutes on days 8 and 22, fluorouracil IV over 24 hours on days 1, 8, 15, and 22, leucovorin calcium IV on days 1, 8, 15, and 22, and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment repeats every 5 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.\n\nPatients who are able to undergo liver resection receive bevacizumab on day 1 only of course 3 and undergo liver resection 3 weeks after chemotherapy. Beginning 4 weeks after liver resection, patients receive 2 additional courses of chemotherapy as adjuvant therapy.\n\nPatients undergo tumor tissue and blood sample collection periodically for biological studies. Samples are analyzed for markers that predict the occurrence of a complete pathological response (pCR) or a non-response.\n\nAfter completion of study treatment, patients are followed every 3 months for the first 2 years and then every 6 months thereafter.", "title": "Combination Chemotherapy and Monoclonal Antibody Therapy in Treating Patients With Advanced Colorectal Cancer With Liver Metastases or Lung Metastases That Are Potentially Removable by Surgery", "trialEndpointStrength": "unknown", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": false, "trialOutcomeSignal": "unknown", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT00513266", "whyStopped": "" }, { "briefSummary": "The purpose of this study is to evaluate INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation.", "completionDate": "2027-03-27", "conditionSummary": "Solid Tumors", "conditions": [ "Solid Tumors" ], "contextFit": null, "hasResults": false, "interventions": [ "INCB186748", "Cetuximab", "GEMNabP", "mFOLFIRINOX" ], "nctId": "NCT06818812", "phase": "Phase 1", "primaryCompletionDate": "2027-03-27", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The purpose of this study is to evaluate INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation.", "title": "A Study to Evaluate INCB186748 in Participants With Advanced or Metastatic Solid Tumors With KRAS G12D Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT06818812", "whyStopped": "" }, { "briefSummary": "Observational study investigating the relationship between tumour amphiregulin, epiregulin and epithelial growth factor receptor expression and response to anti-EGFR agents in advanced colorectal cancer.", "completionDate": "2022-07-22", "conditionSummary": "Colorectal Cancer Stage IV", "conditions": [ "Colorectal Cancer Stage IV" ], "contextFit": null, "hasResults": false, "interventions": [ "Immunohistochemistry" ], "nctId": "NCT03986541", "phase": "N/A", "primaryCompletionDate": "2022-02-22", "status": "COMPLETED", "studyType": "OBSERVATIONAL", "summary": "Background:\n\nThe anti-EGFR agents, cetuximab and panitumumab are approved by NICE for the first-line treatment of patients with RAS wild-type (RAS-wt) advanced colorectal cancer (aCRC). However RAS-wt status is not sufficient to guarantee anti-EGFR benefit. Differential tumour expression of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), as well as the EGFR receptor itself, are putative predictive biomarkers for response to anti-EGFR agents and may therefore help better identify patients who will benefit from treatment.\n\nObjectives:\n\nThis study aims to assess the utility of tumour AREG, EREG and/or EGFR expression, alone or in combination, as predictive biomarkers for response to anti-EGFR agents in aCRC. The investigators will develop a scoring system and categorical cut off points to differentiate AREG/EREG/EGFR positive and negative cases and correlate these with response to therapy as assessed by:\n\nPrimary endpoint: Progression Free Survival (PFS) Secondary endpoints: Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR) Finally, the investigators will utilise digital pathology and artificial intelligence (AI) technologies to automate as far as possible the process of evaluating AREG/EREG/EGFR status.\n\nDuring the study, the investigators will monitor the costs of implementing the test and time taken to derive test results in order to facilitate cost-effectiveness calculations and assess the feasibility of delivering the test in future routine clinical practice.\n\nStudy Design:\n\nA multicentre UK observational cohort study (retrospective and prospectively recruited cohorts).\n\nStudy population:\n\nPatients with RAS-wt aCRC who received or are receiving standard care palliative treatment with an anti-EGFR agent and chemotherapy of physician's choice. Within the retrospective cohort, patients who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be accepted.\n\nKey Inclusion Criteria:\n\n* Biopsy proven advanced colorectal adenocarcinoma at time treatment commenced (either inoperable metastatic disease at diagnosis or inoperable recurrent disease)\n* Aged 18 or over at time treatment commenced\n* The patient has received or has consented to receive treatment with cetuximab or panitumumab\n\nKey Exclusion Criteria:\n\n* Stage I, II or III colorectal adenocarcinoma\n* RAS mutant disease\n* Eligible for potentially curative surgery (prospective cohort)\n* Underwent cancer surgery subsequent to anti-EGFR therapy (retrospective cohort)\n* Unable to provide informed consent (with the exception of patients in the retrospective cohort who have passed away)\n\nProcedures:\n\nThe study is observational and does not involve participants undergoing any study-specific investigations or treatments. Results of routine investigations and outcomes from standard care with an anti-EGFR agent will be collected from medical notes and, for the prospective cohort, during routine clinic appointments. Date of death will also be recorded. Initial and follow-up radiological and clinical assessments will occur as per local standard practice. Previously obtained pathological specimens will be retrieved for immunohistochemical analysis of tumour AREG, EREG and EGFR expression.\n\nTreatment During Study:\n\nThis study will observe outcomes from standard first line palliative treatment of RAS-wt aCRC. In line with current NICE guidelines, such treatment will involve physician's choice of panitumumab or cetuximab in combination with:\n\n* 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) or\n* 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) Where RAS mutation status is only available after commencement of treatment and the anti-EGFR agent is therefore commenced in cycle two, patients may still be recruited to the study.\n\nIt is anticipated that most patients in the retrospective cohort will have received current standard first line palliative treatment of RAS-wt aCRC as above. However, patients who were treated with single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria may still be recruited.\n\nStatistical Methods:\n\nSample size:\n\nData from 480 patients will be collected for the retrospective cohort and 480 patients will be recruited to the prospective cohort.\n\nPrimary endpoint analysis:\n\nPFS will be calculated from date of commencing treatment to date of progression or death from any cause (whichever is sooner). Time of progression will be determined clinically or radiologically by the participant's treating oncologist. Where the anti-EGFR agent was commenced in cycle 2, the definition of the start of treatment will remain cycle 1 day 1 of palliative chemotherapy.\n\nKey secondary endpoint analyses:\n\nOS will be determined from date of commencing treatment to death. ORR is the proportion of patients with documented radiological complete or partial response on first follow-up imaging whereas DCR is the proportion of patients with either radiologically stable disease or a response. For the purpose of these analyses, those without follow-up imaging will be assumed to have progressed.\n\nAREG/EREG/EGFR expression will be assessed as a continuous variable and using dichotomous classifiers ('high' and 'low') for each marker individually and in combination. Subgroup analyses will be performed for BRAF mutation positive tumours, primary tumour location (right versus left colon, and rectum) and previous surgery (primary excised versus in situ). Within the retrospective cohort, those who received single agent anti-EGFR therapy under previous Cancer Drugs Fund criteria will be analysed separately.", "title": "AREG, EREG and EGFR: Response to Anti-EGFR Agents in Colorectal Cancer", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": true, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT03986541", "whyStopped": "" }, { "briefSummary": "The aim of this study is to evaluate the efficacy of mFOLFOXIRI plus cetuximab and avelumab as first line treatment of patients with initially unresectable and previously untreated RAS wild-type metastatic colorectal cancer (mCRC), in terms of Progression-free Survival.", "completionDate": "2024-12-31", "conditionSummary": "Metastatic Colorectal Cancer", "conditions": [ "Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "5Fluorouracil", "L-leucovorin", "Irinotecan", "Oxaliplatin", "Cetuximab" ], "nctId": "NCT04513951", "phase": "Phase 2", "primaryCompletionDate": "2023-06-28", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a prospective, open-label, multicentric phase II single-arm trial in which patients with initially unresectable and previously untreated RAS wild-type mCRC will receive induction treatment with mFOLFOXIRI plus cetuximab and avelumab up to 12 cycles followed by maintenance with 5-FU/LV plus cetuximab plus avelumab until disease progression, unacceptable toxicity or patient's refusal. The second- and subsequent lines of treatment will be at investigators' choice.", "title": "AVELUMAB and CETUXIMAB and mFOLFOXIRI as Initial Therapy for Unresectable Metastatic Colorectal Cancer Patients", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04513951", "whyStopped": "" }, { "briefSummary": "The correlation between the values of angiogenesis-related growth factors in plasma and efficacy, and biomarkers relevant as prognostic factors or predictive factors for sensitivity or resistance to treatment will be examined exploratively.", "completionDate": "2017-03", "conditionSummary": "Liver Metastasis · Colorectal Cancer", "conditions": [ "Liver Metastasis", "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Bevacizumab", "Cetuximab", "L-OHP", "l-LV", "5-FU" ], "nctId": "NCT01834014", "phase": "NA", "primaryCompletionDate": "2017-03", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The correlation between the values of angiogenesis-related growth factors in plasma and efficacy, and biomarkers relevant as prognostic factors or predictive factors for sensitivity or resistance to treatment will be examined exploratively.", "title": "Exploratory Study in Achievement of Improved Survival by Molecular Targeted Chemotherapy and Liver Resection for Not Optimally Resectable Colorectal Liver Metastases", "trialEndpointStrength": "weak", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01834014", "whyStopped": "" } ], "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "CETUXIMAB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 26287849, 31704811, 28783719, 31227518, 39072179, 30559419, 31515458, 28611205, 39424923, 39145064, 32669268, 39313594, 28951457, 25838391, 39121480, 36921494, 37269335, 37040395, 39391046, 23792568, 22281684, 36763936, 39461261, 26208524, 37213293, 26916115, 37352476, 28363909, 35696748, 39255538, 31566309, 37236086, 37981300, 39018564, 27312529, 24523613, 22180495, 33356422, 36307056, 18541894, 23812671, 14679157, 21594703, 12460918, 24586605, 22389471, 22038996, 22773810, 21163703, 22608338, 22649091, 22356324, 25370471, 19001320, 24388723, 22743296, 22586120, 24354346, 20630094, 23020132, 23549875, 19561230, 22351686, 22663011, 23614898, 19255327, 24594804, 25157968, 22805292, 24107445, 23918947, 19238210, 23833300, 21683865, 19537845, 19018267, 23251002, 21975775, 21639808, 21129611, 24576830, 19773371, 19404918, 20368568, 22241789, 24163374, 20818844, 20857202, 20413299, 24583796, 19010912, 12068308, 22972589, 23325582, 15035987, 21156289, 23612012, 21426297, 26678033, 25989278, 12460919, 23489023, 23406027, 22997239, 22048237, 24396464, 23845441, 21663470, 23031422, 23470635, 25024077, 22536370, 23934108, 20350999, 23524406, 24508103, 24570209, 22448344, 26619011, 21483012, 22735384, 20619739 ], "potency": "Interaction: Unknown", "regulatoryEvidence": { "confidence": 0.98, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_3", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 3 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.8, "seriousRatio": 0.8492749810936113, "source": "OpenFDA", "topReactions": [ "RASH", "DIARRHOEA", "OFF LABEL USE", "NAUSEA", "VOMITING" ], "totalReports": 14863 }, "source": "DGIdb", "sourceCount": 8, "sources": [ "DGIdb", "Cancer Genome Interpreter", "CIViC: Clinical Interpretation of Variants in Cancer", "Database of Curated Mutations", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base", "The Clinical Knowledgebase", "Clearity Foundation Biomarkers" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.98, "approvalSource": "explicit_approval_signal, clinical_trial_phase_3, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1312397", "clinicalTrials": [ { "briefSummary": "The investigators hypothesize that patients with mCRC RAS-mutant eligible for a second line treatment with good prognostic features, identified as single metastatic site, long progression free survival (PFS) in first line treatment, might benefit from a personalized approach, with less intensive treatment with regorafenib as part of a continuum-of-care strategy aimed at ensuring quality of life and extending survival.", "completionDate": "2027-04", "conditionSummary": "Colorectal Cancer Metastatic", "conditions": [ "Colorectal Cancer Metastatic" ], "contextFit": null, "hasResults": false, "interventions": [ "standard second line treatment, at discretion of the investigator", "Regorafenib (BAY73-4506)" ], "nctId": "NCT07213570", "phase": "Phase 2", "primaryCompletionDate": "2026-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This study is an open label, randomized, multicentric, non comparative, phase-2 study. The study population will include patients with metastatic colorectal cancer (mCRC) RAS-mutant, upon progression to first line treatment, candidate to a second line, with favourable prognostic features, defined as progression free survival \\>6 months in first line and/or one metastatic site at study entry. A total of 60 patients (30/arm) will be require. At the time of enrollment, patients will be randomized electronically 1:1 to one of the two arms: ARM A (experimental treatment: regorafenib) and ARM B (calibration arm: standard second line treatment, at discretion of the investigator) Each cycle will be administered every four weeks for arm A (experimental treatment: regorafenib) with a dose-escalation strategy (experimental arm) and every two weeks for arm B (calibration arm: standard second line treatment, at discretion of the investigator). Patients will continue to receive study treatment until treatment failure as previous defined, unacceptable toxicity, physician's decision, patient's refusal, or any other discontinuation criteria. All subjects who finish treatment, whichever the reason, will enter in the follow-up. All patients will be followed until death and data on subsequent treatment will be collected. All measurable and non-measurable lesions must be documented at screening (within 28 days prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks). Tumor assessment by CT scan (chest, abdomen and pelvis) or MRI (abdomen and pelvis); CEA, CA 19.9; and any other tests resulted positive during baseline staging, will be performed at week 8 and every 8 weeks during treatment until treatment failure in both arms. Patients discontinuing study treatment without progressive disease, will undergo tumor assessments every 8 weeks until progressive disease or study withdrawal. Toxicities will be evaluated at each clinical visit throughout the study treatment and up to 4 weeks after last cycle of treatment accordingly to the Common Terminology Criteria for Adverse Events (AEs) of the National Cancer Institute (CTCAE-NCI) version 5.0. Quality of Life will be assessed by the EORTC QLQ-C30 v.3.0 and QLQ-CR29 questionnaire that will be completed by patients at baseline (prior to treatment, once eligibility is confirmed) and every 8 weeks until disease progression, treatment failure or death. At the same time points will be administered selected items of PRO (Patients Reported Outcome) -CTCAE questionnaire and financial toxicity assessed through the PROFFIT questionnaire. Blood samples will be collected at baseline, during treatment, and at progression. Biomarkers will be correlated with clinical response, patient outcome and toxicity. In addition, biomarkers will be evaluated on tumor tissues from primary tumors or metastases at baseline, when available.", "title": "STREAM-2: Second-line Treatment With REgorafenib in Advanced RAS-Mutant Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07213570", "whyStopped": "" }, { "briefSummary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "completionDate": "2016-05", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "PF-03446962", "Regorafenib" ], "nctId": "NCT02116894", "phase": "Phase 1", "primaryCompletionDate": "2016-02", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "The primary objective of this open-label phase Ib trial is to determine the maximum tolerated dose and the recommended phase II dose for the combination of PF-03446962 plus regorafenib in patients with metastatic colorectal cancer. The secondary objectives are to describe the safety and tolerablility, and to describe the clinical activity of PF-03446962 plus regorafenib in terms of response rate and progression free survival", "title": "Safety Study of Regorafenib With PF-03446962 to Treat Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02116894", "whyStopped": "" }, { "briefSummary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "completionDate": "2018-12-26", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody", "Cobimetinib", "Regorafenib" ], "nctId": "NCT02788279", "phase": "Phase 3", "primaryCompletionDate": "2018-03-09", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.", "title": "A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02788279", "whyStopped": "" }, { "briefSummary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "completionDate": "2019-08-26", "conditionSummary": "Previously Treated Metastatic Colorectal Cancer", "conditions": [ "Previously Treated Metastatic Colorectal Cancer" ], "contextFit": null, "hasResults": true, "interventions": [ "SGI-110 Dose Escalation", "Regorafenib", "TAS-102", "SGI-110", "Irinotecan" ], "nctId": "NCT01896856", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2019-08-26", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "This is a phase I/II study of the combination of Guadecitabine (SGI-110) and previously treated metastatic colorectal cancer patients. This study will be conducted in two components. First, patients will be enrolled in a phase I study of SGI-110 combined with irinotecan in a standard 3+3 design. After the maximum tolerated dose (MTD) is determined, patients will subsequently be enrolled in a 2:1 randomized phase II study of SGI-110 and irinotecan versus the standard of care regorafenib or Lonsurf (TAS-102).", "title": "Phase I/II Study of SGI-110 With Irinotecan Versus Regorafenib or TAS-102 in Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT01896856", "whyStopped": "" }, { "briefSummary": "To apply its findings as rationale needed for a subsequent registration trial towards a novel indication for systemic treatment of resectable, lung-limited metastatic CRC.", "completionDate": "2026-01-22", "conditionSummary": "Colorectal Cancer", "conditions": [ "Colorectal Cancer" ], "contextFit": null, "hasResults": false, "interventions": [ "Regorafenib", "Lorigerlimab" ], "nctId": "NCT07137390", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2026-01-22", "status": "WITHDRAWN", "studyType": "INTERVENTIONAL", "summary": "Primary Objectives:\n\n* To evaluate safety and tolerability (NCI-CTCAE v5.0) of neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To assess the major pathological response (MPR) rate following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lunglimited mCRC. MPR is defined as residual (viable) invasive cancer cells of 0 - 49% within the resected specimen at the time of surgical resection.\n\nSecondary Objectives:\n\n* To estimate objective response rate (RECIST 1.1) and immune-related objective response rate (irRECIST) following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.\n* To describe the complete resection rate (as defined in Section 9.4) following neoadjuvant regorafenib plus lorigerlimab and surgical resection in patients with pMMR/MSS, resectable, lung-limited mCRC. Note: if a staged resection is performed, the overall outcome will be assessed after completion of all surgical stages.\n* To summarize pathological response (% tumor viability) at the time of surgical resection following neoadjuvant regorafenib plus lorigerlimab in patients with pMMR/MSS, resectable, lung-limited mCRC.", "title": "A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "negative", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT07137390", "whyStopped": "0 participants enrolled" }, { "briefSummary": "This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. If patients qualify to participate in this study, they will be randomly assigned to the 'interventional arm' where patients will receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study and receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.", "completionDate": "2020-10-08", "conditionSummary": "Colorectal Neoplasms", "conditions": [ "Colorectal Neoplasms" ], "contextFit": null, "hasResults": true, "interventions": [ "RRx-001", "Regorafenib", "Irinotecan" ], "nctId": "NCT02096354", "phase": "Phase 2", "primaryCompletionDate": "2018-04-13", "status": "COMPLETED", "studyType": "INTERVENTIONAL", "summary": "Purpose This two-stage study is designed to compare the safety and activity between RRx-001 against regorafenib followed by irinotecan-based therapies in a parallel comparative study.\n\nPatients who are suffering from advanced or metastatic (meaning the disease has spread) colorectal cancer are invited to participate in this study. There will be two groups of patients (Randomized, open label study), one of these will receive RRx-001 and the other one will receive regorafenib. Qualifying patients will be randomly assigned (like the flip of a coin) to the 'interventional arm' and receive the experimental drug, RRx-001, or the 'control arm' where they will receive the current standard-of-care, Regorafenib. Patients will have a 66% chance (2 out of 3) of receiving RRx-001 and a 33 % chance (1 out of 3) of receiving regorafenib.\n\nOn progression in the first part of the study, provided ECOG performance status is adequate, and if clinically appropriate i.e. there are no absolute or relative contraindications in the opinion of the Investigator, all subjects will enter the second part of the study receive irinotecan plus bevacizumab.\n\nWhether patients are given RRx-001 or regorafenib, they will also receive best supportive care, which includes treatments to help manage side effects and symptoms of cancer. This is an open label study, which means patients will know to which of these treatments, RRx-001 or regorafenib, they are assigned.\n\nBackground Oxygen is vital to life, we need it to breathe, for example, but at the same time it gives rise to byproducts that are toxic called free radicals. Free radicals are defined as \"oxidants\". Similarly, substances that interact with and neutralize free radicals, thus preventing them from causing damage, are called \"antioxidants\". Examples of recognizable antioxidants are Vitamin E, Vitamin C and beta-carotene. Antioxidants are also known as \"free radical scavengers.\" When free radicals are present in excess of antioxidants damage may occur.\n\nA free radical is an unstable molecule with an unpaired electron, an electrically charged particle, which seeks out another electron to return to a state of balance. An example of a free radical is hydrogen peroxide, recognizable as the household product that \"bubbles\" when it's poured on wounds. These bubbles come from oxygen free radicals, which are toxic to bacteria and all living cells, including cancer. The fact that these free radicals are toxic has to do with how reactive they are-imagine free radicals as high-speed ball bearings that smash into other molecules in order to \"steal\" back an electron and end their radical state, which sets off a chain reaction that transforms once stable compounds into a string of reactive radicals.\n\nAs new free radicals are created in this chain reaction, they randomly slam into whatever molecules they are closest to and steal their electrons, corroding them, like a biological form of rust. This process is repeated over and over, picking up speed, until an antioxidant can \"neutralize\" the free radicals and put a stop to the snowball effect. In the same way that this free radical bombardment can damage not only bacteria but also healthy tissues in the body, it is also capable of destroying cancer cells.\n\nThe current consensus is that compared to normal tissue tumor cells may accumulate elevated levels of free radicals, which contribute to the development of cancer. This is potentially a fatal weakness, a form of biological \"Kryptonite\", which can be used to advantage since the addition of even a small amount of free radicals may push the tumor over the edge, past the tipping point, above tolerable thresholds, breaking the camel's back. Similar to the expression \"live by the sword, die by the sword\", free radicals may lead to the development of cancer but they also are capable of harming it when present in excess.\n\nRRx-001 is a completely new type of drug that comes from the U.S. aerospace or rocket science industry. It is activated to deliver free radicals to tissues that have low levels of oxygen. Compared to normal tissues, which have higher levels of oxygen, most, if not all, tumors exist in a low-oxygen environment, perhaps to prevent oxidation. In this way the free radicals delivered by RRx-001 to cancer cells under low oxygen conditions are able, in theory, to cause their targeted destruction without harming normal cells.\n\nIn general, colorectal tumors have low levels of antioxidants and, without this antioxidant protection, these tumors are more likely to be harmed by free radicals, so a treatment like RRx-001, which is able to increase the free radicals in the tumor, may benefit patients with colorectal cancer; this is a reason for studying RRx-001 in colorectal cancer. So far, in a Phase 1 study, 25 men and women with advanced, incurable cancer have received RRx-001 for different lengths of time and at doses that ranged from 10 mg/m2 to 83 mg/m2 once a week.\n\nRegorafenib is a drug approved by the FDA to treat colon cancer after previous chemotherapy is no longer effective. It belongs to a class of targeted drugs known as tyrosine kinase inhibitors. Tyrosine kinases, which play a key role in many cell functions including cell growth and division, are commonly mutated or changed in cancer cells, becoming super-active and producing cells that have uncontrolled growth, and, therefore, blocking them with drugs like regorafenib may keep the cancer cells from growing.", "title": "A Phase 2 Randomized, Open-Label Study of RRx-001 vs Regorafenib in Subjects With Metastatic Colorectal Cancer", "trialEndpointStrength": "moderate", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT02096354", "whyStopped": "" } ], "comenionGenes": [], "confirmedBindingTargets": [ "BRAF", "KRAS" ], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "inhibitor", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "REGORAFENIB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 30120161, 25838391, 33568355, 23629727, 21170960 ], "potency": "Interaction: inhibitor", "pubchem": { "cid": 11167602, "inchikey": "FNHKPVJBJVTLMP-UHFFFAOYSA-N", "iupacName": "4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide", "molecularWeight": "482.8", "source": "PubChem", "xlogp": 4.2 }, "regulatoryEvidence": { "confidence": 0.98, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_3", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 3 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.5, "seriousRatio": 0.901056338028169, "source": "OpenFDA", "topReactions": [ "OFF LABEL USE", "FATIGUE", "PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME", "DIARRHOEA", "DECREASED APPETITE" ], "totalReports": 12025 }, "source": "DGIdb", "sourceCount": 7, "sources": [ "DGIdb", "MyCancerGenome Clinical Trial", "My Cancer Genome", "The ChEMBL Bioactivity Database", "The Clinical Knowledgebase", "PharmGKB - The Pharmacogenomics Knowledgebase", "OncoKB: A Precision Oncology Knowledge Base" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.96, "approvalSource": "explicit_approval_signal, clinical_trial_phase_2, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1597876", "clinicalTrials": [ { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This phase I/II trial studies the best dose and side effects of encorafenib, cetuximab, and nivolumab and how well they work together in treating patients with microsatellite stable, BRAFV600E gene mutated colorectal cancer that cannot be removed by surgery (unresectable) or has spread to other places in the body (metastatic). Encorafenib and cetuximab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.Giving encorafenib, cetuximab, and nivolumab may work better in treating patients with colorectal cancer compared to cetuximab alone.", "completionDate": "2027-12-30", "conditionSummary": "BRAF NP_004324.2:p.V600E · Metastatic Colon Adenocarcinoma · Metastatic Microsatellite Stable Colorectal Carcinoma", "conditions": [ "BRAF NP_004324.2:p.V600E", "Metastatic Colon Adenocarcinoma", "Metastatic Microsatellite Stable Colorectal Carcinoma" ], "contextFit": null, "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT04017650", "phase": "Phase 1/PHASE2", "primaryCompletionDate": "2027-12-30", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVES:\n\nI. To describe overall response rate (ORR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To determine the safety and tolerability of nivolumab, encorafenib, and cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To estimate median progression-free survival (PFS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To estimate median overall survival (OS) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIII. To estimate median time to response (TTR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nIV. To estimate median duration of response (DOR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nV. To estimate disease control rate (DCR) upon treatment with encorafenib, cetuximab, and nivolumab.\n\nEXPLORATORY OBJECTIVES:\n\nI. To assess genomic and immune changes upon treatment with encorafenib, cetuximab, and nivolumab.\n\nII. To demonstrate feasibility of establishing humanized patient-derived xenograft models in matched patients with BRAFV600E metastatic colorectal cancer (mCRC).\n\nOUTLINE: This is a phase I, dose-escalation study followed by a phase II study.\n\nPatients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) over 1 hour on days 1 and 15, and nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up at 30 and 100 days, at 3 months, and then every 3 months thereafter.", "title": "Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT04017650", "whyStopped": "" } ], "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "NIVOLUMAB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 36130145, 33556898, 30742119, 38960393, 29723688, 30630828, 30422243 ], "potency": "Interaction: Unknown", "regulatoryEvidence": { "confidence": 0.96, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "clinical_trial_phase_2", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 2 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.5, "seriousRatio": 0.8955523425192602, "source": "OpenFDA", "topReactions": [ "DEATH", "MALIGNANT NEOPLASM PROGRESSION", "OFF LABEL USE", "DIARRHOEA", "FATIGUE" ], "totalReports": 51952 }, "source": "DGIdb", "sourceCount": 5, "sources": [ "DGIdb", "PharmGKB - The Pharmacogenomics Knowledgebase", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase", "CIViC: Clinical Interpretation of Variants in Cancer" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" }, { "approvalConfidence": 0.84, "approvalSource": "explicit_approval_signal, openfda_market_signal, multi_source_confirmation", "approvalStatus": "approved", "chemblId": "rxcui:1547545", "comenionGenes": [ "BRAF" ], "confirmedBindingTargets": [], "gene": "BRAF", "genes": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "interactionType": "Unknown", "isApproved": true, "maxPhase": 4, "mergeStrategy": "standard", "name": "PEMBROLIZUMAB", "pChEMBL": null, "phaseLabel": "Approved", "pmids": [ 30742119, 26645196, 29723688, 37403699, 30630828 ], "potency": "Interaction: Unknown", "regulatoryEvidence": { "confidence": 0.84, "explicitApproved": true, "hasOpenFdaSignal": true, "mergedPhase": 4, "signals": [ "explicit_approval_signal", "openfda_market_signal", "multi_source_confirmation" ], "status": "approved", "trialPhase": 0 }, "safetyProfile": { "deathRate": 0, "safetyScore": 5.6, "seriousRatio": 0.870979774535809, "source": "OpenFDA", "topReactions": [ "MALIGNANT NEOPLASM PROGRESSION", "DEATH", "DIARRHOEA", "FATIGUE", "OFF LABEL USE" ], "totalReports": 47958 }, "source": "DGIdb", "sourceCount": 5, "sources": [ "DGIdb", "PharmGKB - The Pharmacogenomics Knowledgebase", "FDA Pharmacogenomic Biomarkers", "The Clinical Knowledgebase", "CIViC: Clinical Interpretation of Variants in Cancer" ], "targetId": null, "targets": [ "BRAF", "KRAS", "NRAS", "PIK3CA" ], "targetsMultipleGenes": true, "validated": "cross-validated" } ], "totalApproved": 136, "totalCompounds": 449 }, "ensembleInsights": { "consensus": { "confidence": 0.8, "ensembleMetadata": { "clusterCount": 2, "contributingModels": [ "deepseek" ], "method": "bayesian_model_averaging", "modelWeights": { "anthropic": 0.25, "deepseek": 0.3, "google": 0.2, "openai": 0.25 } }, "insights": [ { "_bmaModels": [ "deepseek", "deepseek", "deepseek" ], "_bmaWeight": 0.8999999999999999, "confidence": 0.8166666666666668, "evidence": "The EGFR tyrosine kinase inhibitor resistance pathway is listed, and KRAS/NRAS/BRAF mutations are well-documented in literature as primary resistance mechanisms to anti-EGFR therapies in colorectal cancer.", "statement": "KRAS, NRAS, and BRAF mutations are key drivers of EGFR tyrosine kinase inhibitor resistance in colorectal cancer, limiting therapeutic efficacy." }, { "_bmaModels": [ "deepseek" ], "_bmaWeight": 0.3, "confidence": 0.6800000000000002, "evidence": "PIK3CA is part of the ErbB signaling pathway and central carbon metabolism pathways, both implicated in colorectal cancer pathogenesis and linked to 20 supporting papers.", "statement": "PIK3CA mutations contribute to colorectal cancer progression through activation of the ErbB signaling pathway and metabolic reprogramming." } ] }, "debateRounds": 0, "disagreements": [], "duration": 8567, "ensembleConfidence": 0.8, "modelVotes": { "deepseek": { "confidence": 0.8, "response": "{\n \"insights\": [\n {\n \"statement\": \"KRAS, NRAS, and BRAF mutations are key drivers of EGFR tyrosine kinase inhibitor resistance in colorectal cancer, limiting therapeutic efficacy.\",\n \"confidence\": 0.9,\n \"evidence\": \"The EGFR tyrosine kinase inhibitor resistance pathway is listed, and KRAS/NRAS/BRAF mutations are well-documented in literature as primary resistance mechanisms to anti-EGFR therapies in colorectal cancer.\"\n },\n {\n \"statement\": \"PIK3CA mutations contribute to colorectal cancer progression through activation of the ErbB signaling pathway and metabolic reprogramming.\",\n \"confidence\": 0.85,\n \"evidence\": \"PIK3CA is part of the ErbB signaling pathway and central carbon metabolism pathways, both implicated in colorectal cancer pathogenesis and linked to 20 supporting papers.\"\n },\n {\n \"statement\": \"The combination of KRAS/NRAS/BRAF and PIK3CA mutations suggests a complex, multi-pathway oncogenic network in colorectal cancer.\",\n \"confidence\": 0.8,\n \"evidence\": \"Genes span multiple relevant pathways (EGFR resistance, ErbB signaling, central carbon metabolism), indicating interconnected signaling in colorectal cancer as per the disease context.\"\n },\n {\n \"statement\": \"Central carbon metabolism alterations, potentially driven by these gene mutations, support tumor growth and survival in colorectal cancer.\",\n \"confidence\": 0.75,\n \"evidence\": \"The central carbon metabolism in cancer pathway is included, and mutations in genes like KRAS and PIK3CA are known to rewire metabolism in colorectal cancer.\"\n }\n ],\n \"confidence\": 0.8\n}", "status": "success" } }, "successCount": 1, "timestamp": "2026-04-03T18:28:36.177Z", "totalModels": 1 }, "evidenceCollectionMode": { "active": false, "minPapers": 5, "papersRetrieved": 150 }, "evidenceExtraction": { "citations_verified": false, "status": "pending", "totalEvidenceItems": 0 }, "evidenceGate": { "active": false, "reasons": [], "suppressed": { "hypotheses": 0, "strategies": 0 } }, "evidenceIntelligence": { "contestedInsights": [], "contradictionClusters": [], "contradictionTaxonomy": [], "evidenceGaps": { "missingEvidence": [ { "label": "Colorectal cancer", "reason": "No linked PMIDs", "type": "pathway" } ], "missingQuant": [ { "label": "Colorectal cancer", "reason": "No quantitative evidence extracted", "type": "pathway" }, { "label": "Further characterization needed", "reason": "No quantitative evidence extracted", "type": "strategy" }, { "label": "Emerging research area", "reason": "No quantitative evidence extracted", "type": "topic" } ], "missingSources": [], "needsData": [ "Broaden disease context or add high-signal genes to pull more literature.", "Add quantitative extraction for top pathways and strategies." ] }, "keystonePapers": [ { "citationCount": 430, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceCount": 2, "evidenceItems": [ { "context": "to study mutations that confer resistance to KRAS inhibitors. A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with", "label": "38 patients", "pmid": "34161704" }, { "context": "cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident", "label": "17 patients", "pmid": "34161704" } ], "evidencePolarity": "support", "evidenceScore": 9.34, "evidenceScoreComponents": { "citations": 3.16, "evidenceItems": 0.7, "evidenceSignals": 0.4, "influential": 1.29, "journalTier": 0.6, "polarity": 0.4, "recency": 0.35, "retraction": 0, "sampleSize": 1.19, "studyDesign": 0.45, "studyType": 0.8, "trialPhase": 0 }, "evidenceSignals": { "contradictHits": 0, "supportHits": 2 }, "influentialCitationCount": 26, "isRetracted": false, "isReview": false, "journal": "The New England journal of medicine", "journalTier": "tier1", "openAccessUrl": "https://www.nejm.org/doi/pdf/10.1056/NEJMoa2105281?articleTools=true", "pmid": "34161704", "sampleSize": 38, "sampleSizeText": "38 patients", "studyDesign": "cohort", "studyType": "mixed", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "trialPhase": null, "year": "2021" }, { "citationCount": 23, "contradictionSeverity": null, "contradictionSummary": null, "contradictionTags": [], "evidenceCount": 5, "evidenceItems": [ { "context": "639 patients, PIK3CA was positively correlated with KRAS mutation (r = 0.11, p = 0.006) and negatively correlated with TP53 mutation (r = - 0.18, p ≤ 0.001) and ERBB2", "label": "p=0.006", "pmid": "35767139" }, { "context": "TP53 mutation (r = - 0.18, p ≤ 0.001) and ERBB2 amplification (r = - 0.08, p = 0.046). 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Ras pathway", "label": "p<0.001", "pmid": "39751654" }, { "context": "associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P", "label": "p=0.011", "pmid": "39751654" }, { "context": "but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify", "label": "p=0.86", "pmid": "39751654" }, { "context": "variants were identified. F1L CDx found KRAS, NRAS, or BRAF alterations in 19 patients, whose tumors were classified as RAS/BRAF WT by the local laboratory. Both F1", "label": "19 patients", "pmid": "39214459" }, { "context": "stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic", "label": "p=0.5", "pmid": "38502113" }, { "context": "vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on", "label": "p=0.02", "pmid": "38502113" }, { "context": "of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal", "label": "p=0.03", "pmid": "38502113" }, { "context": "those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with", "label": "p=0.008", "pmid": "38502113" } ], "totalItems": 41 }, "geneResolution": { "ok": true, "proteinResolution": [ { "geneSymbol": "KRAS", "length": 189, "reason": null, "sequence": "MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNTKSFEDIHHYREQIKRVKDSEDVPMVLVGNKCDLPSRTVDTKQAQDLARSYGIPFIETSAKTRQRVEDAFYTLVREIRQYRLKKISKEEKTPGCVKIKKCIIM", "status": "ok", "uniprotId": "P01116" }, { "geneSymbol": "NRAS", "length": 189, "reason": null, "sequence": "MTEYKLVVVGAGGVGKSALTIQLIQNHFVDEYDPTIEDSYRKQVVIDGETCLLDILDTAGQEEYSAMRDQYMRTGEGFLCVFAINNSKSFADINLYREQIKRVKDSDDVPMVLVGNKCDLPTRTVDTKQAHELAKSYGIPFIETSAKTRQGVEDAFYTLVREIRQYRMKKLNSSDDGTQGCMGLPCVVM", "status": "ok", "uniprotId": "P01111" }, { "geneSymbol": "BRAF", "length": 766, "reason": null, "sequence": "MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADPAIPEEVWNIKQMIKLTQEHIEALLDKFGGEHNPPSIYLEAYEEYTSKLDALQQREQQLLESLGNGTDFSVSSSASMDTVTSSSSSSLSVLPSSLSVFQNPTDVARSNPKSPQKPIVRVFLPNKQRTVVPARCGVTVRDSLKKALMMRGLIPECCAVYRIQDGEKKPIGWDTDISWLTGEELHVEVLENVPLTTHNFVRKTFFTLAFCDFCRKLLFQGFRCQTCGYKFHQRCSTEVPLMCVNYDQLDLLFVSKFFEHHPIPQEEASLAETALTSGSSPSAPASDSIGPQILTSPSPSKSIPIPQPFRPADEDHRNQFGQRDRSSSAPNVHINTIEPVNIDDLIRDQGFRGDGGSTTGLSATPPASLPGSLTNVKALQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATVKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH", "status": "ok", "uniprotId": "P15056" }, { "geneSymbol": "PIK3CA", "length": 1068, "reason": "Sequence length 1068 > 1022; truncated for SAE.", "sequence": "MPPRPSSGELWGIHLMPPRILVECLLPNGMIVTLECLREATLITIKHELFKEARKYPLHQLLQDESSYIFVSVTQEAEREEFFDETRRLCDLRLFQPFLKVIEPVGNREEKILNREIGFAIGMPVCEFDMVKDPEVQDFRRNILNVCKEAVDLRDLNSPHSRAMYVYPPNVESSPELPKHIYNKLDKGQIIVVIWVIVSPNNDKQKYTLKINHDCVPEQVIAEAIRKKTRSMLLSSEQLKLCVLEYQGKYILKVCGCDEYFLEKYPLSQYKYIRSCIMLGRMPNLMLMAKESLYSQLPMDCFTMPSYSRRISTATPYMNGETSTKSLWVINSALRIKILCATYVNVNIRDIDKIYVRTGIYHGGEPLCDNVNTQRVPCSNPRWNEWLNYDIYIPDLPRAARLCLSICSVKGRKGAKEEHCPLAWGNINLFDYTDTLVSGKMALNLWPVPHGLEDLLNPIGVTGSNPNKETPCLELEFDWFSSVVKFPDMSVIEEHANWSVSREAGFSYSHAGLSNRLARDNELRENDKEQLKAISTRDPLSEITEQEKDFLWSHRHYCVTIPEILPKLLLSVKWNSRDEVAQMYCLVKDWPPIKPEQAMELLDCNYPDPMVRGFAVRCLEKYLTDDKLSQYLIQLVQVLKYEQYLDNLLVRFLLKKALTNQRIGHFFFWHLKSEMHNKTVSQRFGLLLESYCRACGMYLKHLNRQVEAMEKLINLTDILKQEKKDETQKVQMKFLVEQMRRPDFMDALQGFLSPLNPAHQLGNLRLEECRIMSSAKRPLWLNWENPDIMSELLFQNNEIIFKNGDDLRQDMLTLQIIRIMENIWQNQGLDLRMLPYGCLSIGDCVGLIEVVRNSHTIMQIQCKGGLKGALQFNSHTLHQWLKDKNKGEIYDAAIDLFTRSCAGYCVATFILGIGDRHNSNIMVKDDGQLFHIDFGHFLDHKKKKFGYKRERVPFVLTQDFLIVISKGAQECTKTREFERFQEMCYKAYLAIRQHANLFINLFSMMLGSGMPELQSFDDIAYIRKTLALDKTEQEALEYFMKQMNDAHHGGWTTKMDWIFHTIKQHALN", "status": "sequence_truncated", "uniprotId": "P42336" } ], "resolved": [ { "alias_override": null, "aliases": [ "KRAS", "KRAS2", "RASK2" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000133703", "ensembl_id": "ENSG00000133703", "ensembl_ids_uniprot": [ "ENST00000256078.10", "ENST00000311936.8", "ENST00000685328.1", "ENST00000688940.1" ], "function": "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621, PubMed:39809765). Plays an important role in the regulation of cell proliferation (PubMed:22711838, PubMed:23698361). Activates MAPK1/MAPK3 resulting in phosphorylation and ultimately degradation of GJA1 (By similar...", "hgncId": "HGNC:6407", "hgnc_id": "HGNC:6407", "identifierAgreement": 0.8, "input": "KRAS", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "GTPase KRas", "ncbiGeneId": "3845", "ncbi_gene_id": "3845", "proteinLength": 189, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "KRAS", "subcellularLocation": "Cell membrane", "suggestions": [ { "name": "KRAS proto-oncogene, GTPase", "symbol": "KRAS", "uniprotId": null }, { "name": "KRAS proto-oncogene, GTPase pseudogene 1", "symbol": "KRASP1", "uniprotId": null }, { "name": "NCBP2 antisense 2 (head to head)", "symbol": "NCBP2AS2", "uniprotId": null } ], "symbol": "KRAS", "tissueExpression": "Expression pattern not well characterized", "uniprotId": "P01116", "uniprot_id": "P01116" }, { "alias_override": null, "aliases": [ "NRAS", "HRAS1" ], "blockDownstreamClaims": false, "confidence": 0.94, "ensemblId": "ENSG00000213281", "ensembl_id": "ENSG00000213281", "ensembl_ids_uniprot": [], "function": "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity", "hgncId": "HGNC:7989", "hgnc_id": "HGNC:7989", "identifierAgreement": 1, "input": "NRAS", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "GTPase NRas", "ncbiGeneId": null, "ncbi_gene_id": null, "proteinLength": 189, "reason": "opentargets_exact", "resolutionScore": 0.94, "resolutionStatus": "resolved", "resolved_symbol": "NRAS", "subcellularLocation": "Cell membrane", "suggestions": [ { "name": "NRAS proto-oncogene, GTPase", "symbol": "NRAS", "uniprotId": null }, { "name": "cold shock domain containing E1", "symbol": "CSDE1", "uniprotId": null }, { "name": "matrix metallopeptidase 10", "symbol": "MMP10", "uniprotId": null } ], "symbol": "NRAS", "tissueExpression": "Expression pattern not well characterized", "uniprotId": "P01111", "uniprot_id": "P01111" }, { "alias_override": null, "aliases": [ "BRAF", "BRAF1", "RAFB1" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000157764", "ensembl_id": "ENSG00000157764", "ensembl_ids_uniprot": [ "ENST00000646891.2" ], "function": "Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role i...", "hgncId": "HGNC:1097", "hgnc_id": "HGNC:1097", "identifierAgreement": 0.8, "input": "BRAF", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "Serine/threonine-protein kinase B-raf", "ncbiGeneId": "673", "ncbi_gene_id": "673", "proteinLength": 766, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "BRAF", "subcellularLocation": "Nucleus", "suggestions": [ { "name": "B-Raf proto-oncogene, serine/threonine kinase", "symbol": "BRAF", "uniprotId": null }, { "name": "BRAF pseudogene 1", "symbol": "BRAFP1", "uniprotId": null }, { "name": "BRAF-activated non-protein coding RNA", "symbol": "BANCR", "uniprotId": null } ], "symbol": "BRAF", "tissueExpression": "Brain and testis", "uniprotId": "P15056", "uniprot_id": "P15056" }, { "alias_override": null, "aliases": [ "PIK3CA" ], "blockDownstreamClaims": false, "confidence": 0.88, "ensemblId": "ENSG00000121879", "ensembl_id": "ENSG00000121879", "ensembl_ids_uniprot": [ "ENST00000263967.4" ], "function": "Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to...", "hgncId": "HGNC:8975", "hgnc_id": "HGNC:8975", "identifierAgreement": 0.8, "input": "PIK3CA", "inputFormat": "canonical_symbol", "malformedInput": false, "matchType": "exact_symbol", "name": "Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform", "ncbiGeneId": "5290", "ncbi_gene_id": "5290", "proteinLength": 1068, "reason": "opentargets_exact", "resolutionScore": 0.88, "resolutionStatus": "resolved", "resolved_symbol": "PIK3CA", "subcellularLocation": "Unknown", "suggestions": [ { "name": "phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha", "symbol": "PIK3CA", "uniprotId": null }, { "name": "cyclin D2", "symbol": "CCND2", "uniprotId": null }, { "name": "AKT serine/threonine kinase 3", "symbol": "AKT3", "uniprotId": null } ], "symbol": "PIK3CA", "tissueExpression": "Expression pattern not well characterized", "uniprotId": "P42336", "uniprot_id": "P42336" } ], "unresolved": [], "usableSymbols": [ "KRAS", "NRAS", "BRAF", "PIK3CA" ] }, "generatedAtIso": "2026-04-03T18:27:38.970Z", "genes": [ { "centrality": 1, "depMapEssentiality": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "narrative": "KRAS is a well-established cancer dependency gene based on published CRISPR screen data.", "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "function": "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity (PubMed:20949621, PubMed:39809765). Plays an important role in the regulation of cell proliferation (PubMed:22711838, PubMed:23698361). Activates MAPK1/MAPK3 resulting in phosphorylation and ultimately degradation of GJA1 (By similar...", "gtexExpression": { "maxTpm": 24.5366, "narrative": "KRAS is most highly expressed in: Lung (15.96 TPM), B-lymphocytes (EBV) (13.44 TPM), Small intestine (13.42 TPM), Colon (13.33 TPM), Uterus (13.15 TPM).", "topTissues": [ { "medianTpm": 15.96, "tissue": "Lung", "tissueId": "Lung" }, { "medianTpm": 13.44, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 13.42, "tissue": "Small intestine", "tissueId": "Small_Intestine_Terminal_Ileum" }, { "medianTpm": 13.33, "tissue": "Colon", "tissueId": "Colon_Sigmoid" }, { "medianTpm": 13.15, "tissue": "Uterus", "tissueId": "Uterus" } ], "ubiquitous": false }, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.95, "monarchAssociations": { "contextRelevantCount": 3, "narrative": "KRAS is associated with 21 disease(s) in Monarch (OMIM/HPO/Orphanet). 3 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Shield chest, Nystagmus, Transitional cell carcinoma of the bladder.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0000914", "name": "Shield chest", "onset": null }, { "frequency": null, "hpoId": "HP:0000639", "name": "Nystagmus", "onset": null }, { "frequency": null, "hpoId": "HP:0006740", "name": "Transitional cell carcinoma of the bladder", "onset": null }, { "frequency": null, "hpoId": "HP:0000006", "name": "Autosomal dominant inheritance", "onset": null }, { "frequency": null, "hpoId": "HP:0001876", "name": "Pancytopenia", "onset": null } ], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0001056", "name": "gastric cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0001187", "name": "urinary bladder cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0016692", "name": "pilomyxoid astrocytoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0010854", "name": "Toriello-Lacassie-Droste syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 21 }, "name": "GTPase KRas", "symbol": "KRAS", "syntheticLethality": { "druggablePartners": [ { "context": "pan-cancer", "drugs": [ "Sotorasib (combination)" ], "evidence": "clinical", "partner": "SOS1", "pmids": [], "score": 0.88 } ], "hasDruggablePartner": true, "narrative": "KRAS has 3 known synthetic lethal partner(s). Top: STK33 (score 0.72, preclinical evidence). 1 partner(s) are druggable: SOS1.", "partners": [ { "context": "pan-cancer", "drugs": [], "evidence": "preclinical", "partner": "STK33", "pmids": [], "score": 0.72 }, { "context": "pan-cancer", "drugs": [], "evidence": "preclinical", "partner": "TBK1", "pmids": [], "score": 0.75 }, { "context": "pan-cancer", "drugs": [ "Sotorasib (combination)" ], "evidence": "clinical", "partner": "SOS1", "pmids": [], "score": 0.88 } ] }, "tissueExpression": "KRAS is most highly expressed in: Lung (15.96 TPM), B-lymphocytes (EBV) (13.44 TPM), Small intestine (13.42 TPM), Colon (13.33 TPM), Uterus (13.15 TPM).", "uniprotId": "P01116" }, { "centrality": 1, "depMapEssentiality": { "essentialFraction": null, "isStrongTarget": false, "meanChronos": null, "narrative": "No DepMap essentiality data available for NRAS.", "tier": "unknown", "tierLabel": "No DepMap data available", "tissueEssentiality": [] }, "function": "Ras proteins bind GDP/GTP and possess intrinsic GTPase activity", "gtexExpression": null, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.95, "monarchAssociations": { "contextRelevantCount": 2, "narrative": "NRAS is associated with 17 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Lymphoproliferative disorder, Bilateral ptosis, Coarctation of aorta.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0005523", "name": "Lymphoproliferative disorder", "onset": null }, { "frequency": null, "hpoId": "HP:0001488", "name": "Bilateral ptosis", "onset": null }, { "frequency": null, "hpoId": "HP:0001680", "name": "Coarctation of aorta", "onset": null }, { "frequency": null, "hpoId": "HP:0002665", "name": "Lymphoma", "onset": null }, { "frequency": null, "hpoId": "HP:0001561", "name": "Polyhydramnios", "onset": null } ], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0008566", "name": "thyroid cancer, nonmedullary, 2", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0044792", "name": "large congenital melanocytic nevus", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0011908", "name": "juvenile myelomonocytic leukemia", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018997", "name": "Noonan syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 17 }, "name": "GTPase NRas", "symbol": "NRAS", "syntheticLethality": null, "tissueExpression": "Unavailable", "uniprotId": "P01111" }, { "centrality": 0.375, "depMapEssentiality": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "narrative": "BRAF is a well-established cancer dependency gene based on published CRISPR screen data.", "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "function": "Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable). Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway (PubMed:21441910, PubMed:29433126). Phosphorylates PFKFB2 (PubMed:36402789). May play a role i...", "gtexExpression": { "maxTpm": 15.7943, "narrative": "BRAF is most highly expressed in: Thyroid (11.47 TPM), Uterus (11.14 TPM), Ovary (10.92 TPM), B-lymphocytes (EBV) (10.13 TPM), Lung (9.96 TPM).", "topTissues": [ { "medianTpm": 11.47, "tissue": "Thyroid", "tissueId": "Thyroid" }, { "medianTpm": 11.14, "tissue": "Uterus", "tissueId": "Uterus" }, { "medianTpm": 10.92, "tissue": "Ovary", "tissueId": "Ovary" }, { "medianTpm": 10.13, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 9.96, "tissue": "Lung", "tissueId": "Lung" } ], "ubiquitous": false }, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.54375, "monarchAssociations": { "contextRelevantCount": 3, "narrative": "BRAF is associated with 21 disease(s) in Monarch (OMIM/HPO/Orphanet). 3 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Hypoplastic nipples, Uveal melanoma, Relative macrocephaly.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0002557", "name": "Hypoplastic nipples", "onset": null }, { "frequency": null, "hpoId": "HP:0007716", "name": "Uveal melanoma", "onset": null }, { "frequency": null, "hpoId": "HP:0004482", "name": "Relative macrocephaly", "onset": null }, { "frequency": null, "hpoId": "HP:0000369", "name": "Low-set ears", "onset": null }, { "frequency": null, "hpoId": "HP:0000341", "name": "Narrow forehead", "onset": null } ], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0016692", "name": "pilomyxoid astrocytoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018997", "name": "Noonan syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 21 }, "name": "Serine/threonine-protein kinase B-raf", "symbol": "BRAF", "syntheticLethality": null, "tissueExpression": "BRAF is most highly expressed in: Thyroid (11.47 TPM), Uterus (11.14 TPM), Ovary (10.92 TPM), B-lymphocytes (EBV) (10.13 TPM), Lung (9.96 TPM).", "uniprotId": "P15056" }, { "centrality": 0.625, "depMapEssentiality": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "narrative": "PIK3CA is a well-established cancer dependency gene based on published CRISPR screen data.", "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "function": "Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to...", "gtexExpression": null, "gwasPValue": null, "gwasSupport": false, "gwasTrait": null, "importanceScore": 0.70625, "monarchAssociations": { "contextRelevantCount": 2, "narrative": "PIK3CA is associated with 24 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Hereditary nonpolyposis colorectal carcinoma, Congenital onset, Lipoma.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0006716", "name": "Hereditary nonpolyposis colorectal carcinoma", "onset": null }, { "frequency": null, "hpoId": "HP:0003577", "name": "Congenital onset", "onset": null }, { "frequency": null, "hpoId": "HP:0012032", "name": "Lipoma", "onset": null }, { "frequency": null, "hpoId": "HP:0000006", "name": "Autosomal dominant inheritance", "onset": null }, { "frequency": null, "hpoId": "HP:0012126", "name": "Stomach cancer", "onset": null } ], "topDiseases": [ { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008170", "name": "ovarian cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0031037", "name": "famililal cerebral cavernous malformations", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0020492", "name": "hemimegalencephaly", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0017812", "name": "segmental progressive overgrowth syndrome with fibroadipose hyperplasia", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "totalAssociations": 24 }, "name": "Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform", "symbol": "PIK3CA", "syntheticLethality": null, "tissueExpression": "Unavailable", "uniprotId": "P42336" } ], "gnomadConstraints": { "BRAF": { "available": true, "citation": "Karczewski et al. 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Nature 2020; gnomAD v4.0", "constraintColor": "#dc2626", "constraintLabel": "Highly constrained", "constraintLevel": "essential", "expectedLof": 21.30589086396294, "geneSymbol": "NRAS", "loeuf": 0.556, "observedLof": 6, "oeLof": 0.282, "pLI": 0.932, "source": "gnomAD", "therapeuticWindow": "Narrow — full inhibition likely intolerable; allosteric or partial modulation required", "tooltip": "pLI=0.93, LOEUF=0.56 (gnomAD v4). Narrow — full inhibition likely intolerable; allosteric or partial modulation required." }, "PIK3CA": { "available": true, "citation": "Karczewski et al. Nature 2020; gnomAD v4.0", "constraintColor": "#dc2626", "constraintLabel": "Highly constrained", "constraintLevel": "essential", "expectedLof": 138.18183752284494, "geneSymbol": "PIK3CA", "loeuf": 0.269, "observedLof": 27, "oeLof": 0.195, "pLI": 1, "source": "gnomAD", "therapeuticWindow": "Narrow — full inhibition likely intolerable; allosteric or partial modulation required", "tooltip": "pLI=1.00, LOEUF=0.27 (gnomAD v4). Narrow — full inhibition likely intolerable; allosteric or partial modulation required." } }, "gtexEnrichment": { "BRAF": { "allKeyTissues": [ { "medianTpm": 11.47, "tissue": "Thyroid", "tissueId": "Thyroid" }, { "medianTpm": 11.14, "tissue": "Uterus", "tissueId": "Uterus" }, { "medianTpm": 10.92, "tissue": "Ovary", "tissueId": "Ovary" }, { "medianTpm": 10.13, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 9.96, "tissue": "Lung", "tissueId": "Lung" }, { "medianTpm": 8.78, "tissue": "Skin", "tissueId": "Skin_Sun_Exposed_Lower_leg" }, { "medianTpm": 8.53, "tissue": "Prostate", "tissueId": "Prostate" }, { "medianTpm": 8.1, "tissue": "Breast", "tissueId": "Breast_Mammary_Tissue" }, { "medianTpm": 7.83, "tissue": "Colon", "tissueId": "Colon_Sigmoid" }, { "medianTpm": 7.11, "tissue": "Brain (frontal cortex)", "tissueId": "Brain_Frontal_Cortex_BA9" }, { "medianTpm": 6.4, "tissue": "Spleen", "tissueId": "Spleen" }, { "medianTpm": 5.67, "tissue": "Small intestine", "tissueId": "Small_Intestine_Terminal_Ileum" }, { "medianTpm": 3.97, "tissue": "Whole blood", "tissueId": "Whole_Blood" }, { "medianTpm": 3.45, "tissue": "Kidney", "tissueId": "Kidney_Cortex" }, { "medianTpm": 3.16, "tissue": "Brain (hippocampus)", "tissueId": "Brain_Hippocampus" }, { "medianTpm": 2.83, "tissue": "Skeletal muscle", "tissueId": "Muscle_Skeletal" }, { "medianTpm": 2.76, "tissue": "Brain (substantia nigra)", "tissueId": "Brain_Substantia_nigra" }, { "medianTpm": 2.58, "tissue": "Pancreas", "tissueId": "Pancreas" }, { "medianTpm": 2.26, "tissue": "Liver", "tissueId": "Liver" }, { "medianTpm": 2.06, "tissue": "Heart", "tissueId": "Heart_Left_Ventricle" } ], "gencodeId": "ENSG00000157764.14", "gene": "BRAF", "maxTpm": 15.7943, "narrative": "BRAF is most highly expressed in: Thyroid (11.47 TPM), Uterus (11.14 TPM), Ovary (10.92 TPM), B-lymphocytes (EBV) (10.13 TPM), Lung (9.96 TPM).", "source": "GTEx v10", "tissueCount": 54, "topTissues": [ { "medianTpm": 11.47, "tissue": "Thyroid", "tissueId": "Thyroid" }, { "medianTpm": 11.14, "tissue": "Uterus", "tissueId": "Uterus" }, { "medianTpm": 10.92, "tissue": "Ovary", "tissueId": "Ovary" }, { "medianTpm": 10.13, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 9.96, "tissue": "Lung", "tissueId": "Lung" } ], "ubiquitous": false }, "KRAS": { "allKeyTissues": [ { "medianTpm": 15.96, "tissue": "Lung", "tissueId": "Lung" }, { "medianTpm": 13.44, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 13.42, "tissue": "Small intestine", "tissueId": "Small_Intestine_Terminal_Ileum" }, { "medianTpm": 13.33, "tissue": "Colon", "tissueId": "Colon_Sigmoid" }, { "medianTpm": 13.15, "tissue": "Uterus", "tissueId": "Uterus" }, { "medianTpm": 13.05, "tissue": "Skin", "tissueId": "Skin_Sun_Exposed_Lower_leg" }, { "medianTpm": 12.79, "tissue": "Brain (frontal cortex)", "tissueId": "Brain_Frontal_Cortex_BA9" }, { "medianTpm": 12.18, "tissue": "Thyroid", "tissueId": "Thyroid" }, { "medianTpm": 10.83, "tissue": "Spleen", "tissueId": "Spleen" }, { "medianTpm": 10.32, "tissue": "Breast", "tissueId": "Breast_Mammary_Tissue" }, { "medianTpm": 10.31, "tissue": "Ovary", "tissueId": "Ovary" }, { "medianTpm": 9.9, "tissue": "Prostate", "tissueId": "Prostate" }, { "medianTpm": 8.42, "tissue": "Whole blood", "tissueId": "Whole_Blood" }, { "medianTpm": 5.74, "tissue": "Brain (hippocampus)", "tissueId": "Brain_Hippocampus" }, { "medianTpm": 5.49, "tissue": "Brain (substantia nigra)", "tissueId": "Brain_Substantia_nigra" }, { "medianTpm": 5.45, "tissue": "Kidney", "tissueId": "Kidney_Cortex" }, { "medianTpm": 5.02, "tissue": "Liver", "tissueId": "Liver" }, { "medianTpm": 4.05, "tissue": "Skeletal muscle", "tissueId": "Muscle_Skeletal" }, { "medianTpm": 3.98, "tissue": "Pancreas", "tissueId": "Pancreas" }, { "medianTpm": 2.89, "tissue": "Heart", "tissueId": "Heart_Left_Ventricle" } ], "gencodeId": "ENSG00000133703.14", "gene": "KRAS", "maxTpm": 24.5366, "narrative": "KRAS is most highly expressed in: Lung (15.96 TPM), B-lymphocytes (EBV) (13.44 TPM), Small intestine (13.42 TPM), Colon (13.33 TPM), Uterus (13.15 TPM).", "source": "GTEx v10", "tissueCount": 54, "topTissues": [ { "medianTpm": 15.96, "tissue": "Lung", "tissueId": "Lung" }, { "medianTpm": 13.44, "tissue": "B-lymphocytes (EBV)", "tissueId": "Cells_EBV-transformed_lymphocytes" }, { "medianTpm": 13.42, "tissue": "Small intestine", "tissueId": "Small_Intestine_Terminal_Ileum" }, { "medianTpm": 13.33, "tissue": "Colon", "tissueId": "Colon_Sigmoid" }, { "medianTpm": 13.15, "tissue": "Uterus", "tissueId": "Uterus" } ], "ubiquitous": false } }, "hmdbEnrichment": { "KRAS": { "associatedMetabolites": [ { "direction": "up", "name": "L-lactate", "pathway": "glycolysis" }, { "direction": "up", "name": "malate", "pathway": "TCA anaplerosis" } ], "diseaseMatched": true, "evidenceTier": "pathway_linked", "fluxAxis": "glycolysis and redox buffering", "gene": "KRAS", "metaboliteBurdenScore": 0.84, "narrative": "KRAS maps to glycolysis and redox buffering with L-lactate up, malate up.", "source": "HMDB (metabolite context)" } }, "impliedTargets": [ { "avgConfidence": 0.67, "connectionCount": 3, "evidenceTypes": [ "experiments", "databases", "textmining" ], "gene": "RAF1", "panelConnections": [ "KRAS", "BRAF", "NRAS" ], "rationale": "Connects to 3 of 4 panel genes (KRAS, BRAF, NRAS) with avg confidence 0.67" }, { "avgConfidence": 0.85, "connectionCount": 2, "evidenceTypes": [], "gene": "RAP1GDS1", "panelConnections": [ "KRAS", "NRAS" ], "rationale": "Connects to 2 of 4 panel genes (KRAS, NRAS) with avg confidence 0.85" } ], "inputGenes": [ "KRAS", "NRAS", "BRAF", "PIK3CA" ], "interactions": { "avgConfidence": "0.408", "networkHubs": [ { "centrality": 1, "gene": "KRAS" }, { "centrality": 1, "gene": "NRAS" }, { "centrality": 0.625, "gene": "PIK3CA" }, { "centrality": 0.5, "gene": "PIK3R6" }, { "centrality": 0.5, "gene": "PIK3R5" } ], "networkImageUrl": "https://string-db.org/api/image/network?identifiers=BRAF%0AKRAS%0ANRAS%0APIK3CA&species=9606&required_score=700&network_flavor=confidence&hide_disconnected_nodes=1", "topInteractors": [ { "confidence": 1, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "RASSF5", "pubmedIds": [ "11857081" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 1, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "EPB42", "pubmedIds": [ "3276554" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 1, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "BRAF", "partner": "RAP1GAP", "pubmedIds": [ "11278445" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 1, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "PIK3CA", "partner": "HRAS", "pubmedIds": [ "14724584" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 1, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "PIK3CA", "partner": "RASD2", "pubmedIds": [ "14724584" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 0.925, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "RASSF2", "pubmedIds": [ "12732644" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 0.925, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "PIK3CG", "pubmedIds": [ "10542052" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 0.925, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "PIK3CA", "partner": "ADAP1", "pubmedIds": [ "12893243" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 0.85, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "RAP1GDS1", "pubmedIds": [ "11948427" ], "sources": [ "BioGRID" ], "validated": false }, { "confidence": 0.85, "confidenceLevel": "high", "evidenceCount": 0, "evidenceTypes": [], "gene": "KRAS", "partner": "PIK3CA", "pubmedIds": [ "10783161" ], "sources": [ "BioGRID" ], "validated": false } ], "totalInteractions": 91 }, "interpretability": { "metadata": { "analysisTime": 6446, "options": { "layer": 6, "model": "mgbam/innovative-biosae-weights", "saeConfig": { "fallbackReason": null, "layer": 6, "model": "mgbam/innovative-biosae-weights", "saeAvailable": true, "saePath": "mgbam/innovative-biosae-weights", "tier": "esm2_35m" }, "saePath": "mgbam/innovative-biosae-weights", "timeout": 300000, "topK": 15 }, "successfulAnalyses": 4, "totalProteins": 4 }, "proteins": [ { "causalMechanisms": [ { "causalConfidence": 0.95, "confidence": 0.95, "description": "BRAF exhibits post translational modification via Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus (Probable)....", "diseaseRelevance": 0.7, "evidenceStrength": 0.91, "featureCount": 4, "geneSymbol": "BRAF", "id": "post_translational_modification_BRAF_0", "interventionalSupport": 0.7, "keyFeatures": [ "F46", "F299", "F448" ], "mechanism": "Post-translational modification network", "primaryFeature": "F46", "type": "post_translational_modification", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.91, "interventionalSupport": 0.7, "isValid": true } }, { "causalConfidence": 0.95, "confidence": 0.95, "description": "BRAF exhibits allosteric regulation via Allosteric enzyme", "diseaseRelevance": 0.5, "evidenceStrength": 0.91, "featureCount": 4, "geneSymbol": "BRAF", "id": "allosteric_regulation_BRAF_2", "interventionalSupport": 0.5, "keyFeatures": [ "F66", "F350", "F219" ], "mechanism": "Allosteric regulation", "primaryFeature": "F66", "type": "allosteric_regulation", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.91, "interventionalSupport": 0.5, "isValid": true } } ], "confidence": "medium", "conflicts": [], "counterfactualAnalysis": [ { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.661, "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.748, "druggability": 0.72, "mechanisms": "allosteric_regulation", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "BRAF", "mechanismId": "allosteric_regulation_BRAF_2", "pathwayAnchors": [ { "genes": [ "KRAS", "NRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(BRAF=tuned)", "scenarios": [ { "confidence": 0.6759999999999999, "description": "What if only F66 was modulated?", "doOperator": "do(BRAF=tuned)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.676, "counterfactualScore": 0.661, "description": "do(BRAF=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.72, "feasibility": 0.672, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(BRAF=off)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.658, "description": "do(BRAF=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.535, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(BRAF=restore)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.444, "description": "do(BRAF=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). BRAF shows protein gain in CPTAC SKCM. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.496, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.66, "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.79, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC SKCM protein gain (z 1.5)", "GTEx: Thyroid highest expression", "AlphaFold: pLDDT 66.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "BRAF", "mechanismId": "post_translational_modification_BRAF_0", "pathwayAnchors": [ { "genes": [ "KRAS", "NRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "KRAS", "PIK3CA" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(BRAF=tuned)", "scenarios": [ { "confidence": 0.62, "description": "What if only F46 was modulated?", "doOperator": "do(BRAF=tuned)", "downstreamNodes": [ { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.62, "counterfactualScore": 0.66, "description": "do(BRAF=tuned) is predicted to shift the target into a more druggable intermediate state. 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"sequence": "I", "start": 24 }, { "end": 28, "score": 2.818315029144287, "sequence": "F", "start": 28 } ], "top_residues": [ { "aa": "I", "index": 24, "score": 2.8419690132141113 }, { "aa": "F", "index": 28, "score": 2.818315029144287 }, { "aa": "T", "index": 35, "score": 2.564915657043457 }, { "aa": "I", "index": 36, "score": 2.7239372730255127 }, { "aa": "L", "index": 52, "score": 2.701233148574829 }, { "aa": "L", "index": 79, "score": 7.386185169219971 } ], "uncertaintyMetrics": { "mcDropoutUncertainty": 0.05 } } ], "uncertaintyQuantification": { "aleatoricUncertainty": 0.00031521189566487373, "epistemicUncertainty": 0.04214130206940907, "overallUncertainty": 0.04245651396507394 }, "uniprotId": "P01111" }, { "causalMechanisms": [ { "causalConfidence": 0.95, "confidence": 0.95, "description": "PIK3CA exhibits post translational modification via Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at...", "diseaseRelevance": 0.7, "evidenceStrength": 0.76, "featureCount": 2, "geneSymbol": "PIK3CA", "id": "post_translational_modification_PIK3CA_1", "interventionalSupport": 0.7, "keyFeatures": [ "F46", "F219" ], "mechanism": "Post-translational modification network", "primaryFeature": "F46", "type": "post_translational_modification", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.76, "interventionalSupport": 0.7, "isValid": true } }, { "causalConfidence": 0.95, "confidence": 0.95, "description": "PIK3CA exhibits uncharacterized via Angiogenesis", "diseaseRelevance": 0.5, "evidenceStrength": 0.91, "featureCount": 4, "geneSymbol": "PIK3CA", "id": "uncharacterized_PIK3CA_5", "interventionalSupport": 0.5, "keyFeatures": [ "F66", "F79", "F38" ], "mechanism": "Uncharacterized mechanism", "primaryFeature": "F66", "type": "uncharacterized", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.91, "interventionalSupport": 0.5, "isValid": true } }, { "causalConfidence": 0.95, "confidence": 0.95, "description": "PIK3CA exhibits cellular localization via Phagocytosis", "diseaseRelevance": 0.5, "evidenceStrength": 0.76, "featureCount": 2, "geneSymbol": "PIK3CA", "id": "cellular_localization_PIK3CA_8", "interventionalSupport": 0.5, "keyFeatures": [ "F308", "F200" ], "mechanism": "Cellular localization/transport", "primaryFeature": "F308", "type": "cellular_localization", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.76, "interventionalSupport": 0.5, "isValid": true } } ], "confidence": "medium", "conflicts": [], "counterfactualAnalysis": [ { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.584, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.802, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "post_translational_modification_PIK3CA_1", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=tuned)", "scenarios": [ { "confidence": 0.62, "description": "What if only F46 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.62, "counterfactualScore": 0.584, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.65, "feasibility": 0.802, "offTargetEffects": 0.1, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.6599999999999999, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.66, "counterfactualScore": 0.373, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.658, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.7, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.582, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.748, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "uncharacterized_PIK3CA_5", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=off)", "scenarios": [ { "confidence": 0.7649999999999999, "description": "What if F66 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.38, "description": "What if only F66 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.38, "counterfactualScore": 0.576, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.35, "feasibility": 0.766, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.368, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.634, "functionalGain": 1.475, "pathwayReversal": 0.672, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.582, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.712, "druggability": 0.38, "mechanisms": "cellular_localization", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "cellular_localization_PIK3CA_8", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 }, { "genes": [ "BRAF", "KRAS" ], "name": "Central carbon metabolism in cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 }, { "genes": [ "BRAF", "KRAS" ], "name": "Colorectal cancer - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000004 }, { "genes": [ "BRAF", "KRAS" ], "name": "GnRH secretion - Homo sapiens (human)", "pvalue": 0, "qvalue": 0.000003 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(PIK3CA=off)", "scenarios": [ { "confidence": 0.7649999999999999, "description": "What if F308 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.673, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.404, "description": "What if only F308 was modulated?", "doOperator": "do(PIK3CA=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.404, "counterfactualScore": 0.576, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.38, "feasibility": 0.769, "offTargetEffects": 0.1, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F308 activity was enhanced 2x?", "doOperator": "do(PIK3CA=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.368, "description": "do(PIK3CA=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). 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"trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.226, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 777, "validated": 0 }, "hypothesis": { "note": "0/777 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "BRAF", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.584, "calibratedConfidence": 0.171, "calibrationDelta": -0.413, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "PIK3CA", "insufficientEvidence": true, "localEvidenceModalities": 1, "localEvidenceScore": 0.26, "mechanismId": "post_translational_modification_PIK3CA_1", "notes": [ "Base counterfactual score 0.584", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.582, "calibratedConfidence": 0.17, "calibrationDelta": -0.412, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "PIK3CA", "insufficientEvidence": true, "localEvidenceModalities": 1, "localEvidenceScore": 0.26, "mechanismId": "uncharacterized_PIK3CA_5", "notes": [ "Base counterfactual score 0.582", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=off)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.582, "calibratedConfidence": 0.17, "calibrationDelta": -0.412, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.164, "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "nodeId": "pathway:egfr_tyrosine_kinase_inhibitor_resistance_homo_sapiens_human", "path": [ "PIK3CA", "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Central carbon metabolism in cancer - Homo sapiens (human)", "nodeId": "pathway:central_carbon_metabolism_in_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Central carbon metabolism in cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" }, { "effectDirection": "increase", "effectSize": 0.164, "label": "Colorectal cancer - Homo sapiens (human)", "nodeId": "pathway:colorectal_cancer_homo_sapiens_human", "path": [ "PIK3CA", "Colorectal cancer - Homo sapiens (human)" ], "steps": 1, "type": "pathway" } ], "geneSymbol": "PIK3CA", "insufficientEvidence": true, "localEvidenceModalities": 1, "localEvidenceScore": 0.26, "mechanismId": "cellular_localization_PIK3CA_8", "notes": [ "Base counterfactual score 0.582", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "DepMap essentiality present (Essential (literature-curated))", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (single supporting modality)" ], "recommendedDoOperator": "do(PIK3CA=off)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 4, "validated": 0 }, "hypothesis": { "note": "0/4 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "PIK3CA", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.263, "calibratedConfidence": 0, "calibrationDelta": -0.263, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0.06, "mechanismId": "enzymatic_catalysis_NRAS_7", "notes": [ "Base counterfactual score 0.263", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Multi-node downstream propagation available in the causal DAG" ], "recommendedDoOperator": "do(NRAS=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.228, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 771, "validated": 0 }, "hypothesis": { "note": "0/771 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } }, { "baseCounterfactualScore": 0.249, "calibratedConfidence": 0, "calibrationDelta": -0.249, "calibrationTier": "speculative", "deescalated": true, "downstreamReach": [ { "effectDirection": "increase", "effectSize": 0.154, "label": "RAP1GDS1", "nodeId": "gene:RAP1GDS1", "path": [ "NRAS", "RAP1GDS1" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "MLLT4", "nodeId": "gene:MLLT4", "path": [ "NRAS", "MLLT4" ], "steps": 1, "type": "gene" }, { "effectDirection": "increase", "effectSize": 0.154, "label": "DNAJB1", "nodeId": "gene:DNAJB1", "path": [ "NRAS", "DNAJB1" ], "steps": 1, "type": "gene" } ], "geneSymbol": "NRAS", "insufficientEvidence": true, "localEvidenceModalities": 0, "localEvidenceScore": 0.06, "mechanismId": "uncharacterized_NRAS_4", "notes": [ "Base counterfactual score 0.249", "Hypothesis prior 0 from gene_disease_sparse", "Prediction prior 0.78 from disease_specific", "Circular reasoning penalty applied from the causal DAG", "Sparse orthogonal evidence penalty applied (no supporting modalities)", "Multi-node downstream propagation available in the causal DAG" ], "recommendedDoOperator": "do(NRAS=tuned)", "trackerPriors": { "geneValidation": { "averagePredictedConfidence": 0.228, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "gene_disease_sparse", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 771, "validated": 0 }, "hypothesis": { "note": "0/771 matching hypotheses have outcome data", "score": 0, "source": "gene_disease_sparse" }, "prediction": { "note": "Disease-level prospective prediction prior (70 checked predictions)", "score": 0.78, "source": "disease_specific" }, "workspaceGeneValidation": { "averagePredictedConfidence": null, "confirmed": 0, "disease": "colorectal cancer", "evidenceTier": "none", "gene": "NRAS", "observedAccuracy": null, "partial": 0, "recentSubmissions": [], "rejected": 0, "totalHypotheses": 0, "validated": 0, "workspaceId": null }, "workspaceLearning": null } } ], "summary": { "averageCalibratedConfidence": 0.208, "deescalatedCount": 9, "directlyCalibratedCount": 0, "narrative": "GaiaLab recalibrated intervention confidence for 9 routes using outcome history, disease-level prediction follow-through, and orthogonal evidence support. Top calibrated targets: KRAS, BRAF.", "topCalibratedTargets": [ "KRAS", "BRAF" ] }, "trackerPriors": { "diseasePredictionResearchDirectionRate": 0.9, "diseasePredictionTrialMatchRate": 0.6, "hypothesisAccuracy": 0, "totalDiseaseCheckedPredictions": 70, "totalValidatedHypotheses": 0, "workspaceObservedAccuracy": null, "workspaceValidatedHypotheses": 0 } }, "interventionSummary": { "available": true, "averageCounterfactualScore": 0.569, "narrative": "Top intervention-ready genes for colorectal cancer are KRAS, BRAF based on pathway anchoring, dependency, structure, and variant directionality.", "preferredModes": [ { "count": 9, "mode": "selective_modulation" } ], "topGenes": [ "KRAS", "BRAF" ], "totalCounterfactuals": 9 }, "ioResistanceProfile": null, "ioResponseScore": null, "lead": { "drug": { "drug": "REGORAFENIB", "score": 68 }, "pathway": { "id": "pathway-1", "name": "Colorectal cancer" }, "strategy": null }, "leadingResearchers": [ { "avgCitations": 430, "name": "A. Aguirre", "paperCount": 1, "role": "Senior Researcher", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "M. Awad", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "Shengwu Liu", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "I. Rybkin", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "K. Arbour", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "Julien Dilly", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "V. Zhu", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "M. Johnson", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "T. Patil", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 }, { "avgCitations": 430, "name": "Gregory Riely", "paperCount": 1, "role": "Active Contributor", "topPaper": { "citationCount": 430, "pmid": "34161704", "title": "Acquired Resistance to KRAS Inhibition in Cancer.", "year": "2021" }, "totalCitations": 430 } ], "learningMemory": null, "matchingTrials": [ { "briefSummary": "This phase II trial tests whether adding nivolumab to the usual treatment (encorafenib and cetuximab) works better than the usual treatment alone to shrink tumors in patients with colorectal cancer that has spread to other places in the body (metastatic) or that cannot be removed by surgery (unresectable) and whose tumor has a mutation in a gene called BRAF. Encorafenib is in a class of medications called kinase inhibitors. It is used in patients whose cancer has a certain mutation (change) in the BRAF gene. It works by blocking the action of mutated BRAF that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab in combination with encorafenib and cetuximab may be more effective than encorafenib and cetuximab alone at stopping tumor growth and spreading in patients with metastatic or unresectable BRAF-mutant colorectal cancer.", "completionDate": "2026-09-30", "conditionSummary": "Metastatic Colon Adenocarcinoma · Metastatic Rectal Adenocarcinoma · Stage III Colon Cancer AJCC v8", "conditions": [ "Metastatic Colon Adenocarcinoma", "Metastatic Rectal Adenocarcinoma", "Stage III Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": true, "isInterventional": true, "matchScore": 15, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology", "neuro" ] }, "enrollmentCount": 84, "firstPostedDate": "2022-04-04", "hasResults": false, "interventions": [ "Cetuximab", "Encorafenib", "Nivolumab" ], "nctId": "NCT05308446", "phase": "Phase 2", "primaryCompletionDate": "2026-09-30", "startDate": "2022-07-19", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "PRIMARY OBJECTIVE:\n\nI. To compare progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with microsatellite stable (MSS), BRAF\\^V600E metastatic and/or unresectable colorectal cancer (CRC) randomized to treatment with nivolumab + encorafenib + cetuximab compared to encorafenib + cetuximab.\n\nSECONDARY OBJECTIVES:\n\nI. To compare overall response rate (ORR), including confirmed and unconfirmed, complete and partial response, according to RECIST 1.1 criteria between the two arms.\n\nII. To compare overall survival (OS) between the two arms. III. To compare duration of response between the two arms. IV. To compare safety and tolerability between the two arms. V. To assess immune-related PFS using modified response criteria adapted for immunotherapy (irRC-PFS) in patients treated with nivolumab + encorafenib + cetuximab.\n\nBANKING OBJECTIVE:\n\nI. To bank tissue and blood specimens for future correlative studies.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) once daily (QD) on days 1-28, cetuximab intravenously (IV) on days 1 and 15, and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nARM II: Patients receive encorafenib PO QD on days 1-28 and cetuximab IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed until death or 3 years after registration, whichever occurs first.", "title": "Testing the Addition of Nivolumab to Standard Treatment for Patients With Metastatic or Unresectable Colorectal Cancer That Have a BRAF Mutation", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05308446", "whyStopped": "" }, { "briefSummary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "completionDate": "2029-05-31", "conditionSummary": "Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 30, "firstPostedDate": "2023-01-31", "hasResults": false, "interventions": [ "Encorafenib Oral Capsule + Cetuximab" ], "nctId": "NCT05706779", "phase": "Phase 2", "primaryCompletionDate": "2026-12-30", "startDate": "2023-02-13", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "This is a pilot trial which aims to assess the concept of anti-BRAF neoadjuvant treatment (encorafenib) in combination with cetuximab in patients with colon cancer or rT3/T4 supra-peritoneal upper rectal cancer based on a pre-operative CT-scan. About 10% of patients will have a mutated BRAF V600E tumour and the objective is to include 30 patients with this mutation.\n\nIf the tumour is not confirmed as a carrier of the BRAF V600E mutation or has an RAS mutation according to centralised assessment, treatment will be discontinued in this patient and cancer surgery will be organised as soon as possible. The patient will be excluded from the statistical analysis and will be replaced by a new patient in order to obtain 30 patients with confirmed BRAF V600E mutation and RAS wild type . It should be noted that less than a 3% discrepancy between the numbers of local laboratory results and central analysis results, has been reported in over 600 BRAF V600E mutated colon cancers in the BEACON CRC study. Based on these figures, there should be 0 or 1 patient with discrepant results in the study presented here.\n\nFurthermore, in the hypothetical case of a patient who is an early permanent discontinuation of the study prior to surgery, this patient will be replaced in order to obtain a total of 30 patients who underwent surgery after neoadjuvant treatment.", "title": "Encorafenib Plus Cetuximab in a Neoadjuvant Setting in Patients With BRAF Mutation Localised Colon or Upper Rectum Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": false, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05706779", "whyStopped": "" }, { "briefSummary": "This is a Phase II, open label, single-arm trial study of adding hydroxychloroquine to encorafenib and cetuximab in patients with metastatic BRAF V600E colon cancer with progression on at least 1 prior line of therapy. We hypothesize that autophagy is a major mechanism of resistance to BRAF inhibition in stage IV BRAF V600E colorectal cancer, and that the addition of hydroxychloroquine to standard encorafenib and cetuximab therapy will help overcome this resistance.", "completionDate": "2028-07-01", "conditionSummary": "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation · Colorectal Cancer · Colorectal Cancer Stage IV", "conditions": [ "Stage IV Colorectal Cancer Positive for BRAF V600E Mutation", "Colorectal Cancer", "Colorectal Cancer Stage IV" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 2, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 14, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 43, "firstPostedDate": "2022-10-13", "hasResults": false, "interventions": [ "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab" ], "nctId": "NCT05576896", "phase": "Phase 2", "primaryCompletionDate": "2026-07-01", "startDate": "2022-10-10", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Primary Objective -Determine the Objective Response Rate (ORR) of encorafenib, cetuximab or panitumumab, and hydroxychloroquine in patients with stage IV BRAF V600E mutated colorectal cancer.\n\nSecondary Objectives\n\n-Determine progression-free survival (PFS) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nNote: progression is defined as either radiological progression (with CT scan) OR clinical progression, which will be defined as 'clinical deterioration associated with rising CEA biomarker' (laboratory date of collection of sample to be noted).\n\n* Determine overall survival (OS) by RECIST v1.1 criteria of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Response' (DoR) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Determine 'Duration of Stable Disease'(DoSD) of patients treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n* Estimate rates of drug-related toxicities when patients are treated with encorafenib, cetuximab or panitumumab, and hydroxychloroquine.\n\nOUTLINE:\n\nPrior to starting therapy, patients will have a pretreatment cross-sectional scan. Patients will then begin with encorafenib 300 mg daily starting with Cycle 1 day 1; then patients will receive IV cetuximab weekly, with 400 mg/m2 on C1D1 as a loading dose and 250 mg/m2 on all other days.\n\nCycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.\n\nAfter completion of study treatment, patients are followed up every 3 months (+/- 1 month) for the next 18 months.", "title": "Hydroxychloroquine in Combination With Encorafenib and Cetuximab or Panitumumab in the Treatment of Metastatic BRAF-mutated Colorectal Cancer Refractory", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05576896", "whyStopped": "" }, { "briefSummary": "This phase II/III trial compares treatment with encorafenib and cetuximab to usual care (patient observation) for reducing the chance of cancer recurrence after standard surgery and chemotherapy in patients with BRAF-mutated stage IIB-III colon cancer. Encorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Giving encorafenib and cetuximab after standard surgery and chemotherapy may be more effective at reducing the chance of cancer recurrence compared to the usual patient observation.", "completionDate": "2034-06-01", "conditionSummary": "Colon Adenocarcinoma · Microsatellite Stable Colon Carcinoma · Stage IIB Colon Cancer AJCC v8", "conditions": [ "Colon Adenocarcinoma", "Microsatellite Stable Colon Carcinoma", "Stage IIB Colon Cancer AJCC v8" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": true, "ioHit": false, "isInterventional": true, "matchScore": 11, "passesIoRequirement": true, "specificity": "disease_specific", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 1, "firstPostedDate": "2023-02-02", "hasResults": false, "interventions": [ "Encorafenib", "Cetuximab", "Biospecimen Collection", "Computed Tomography", "Magnetic Resonance Imaging" ], "nctId": "NCT05710406", "phase": "Phase 2/PHASE3", "primaryCompletionDate": "2034-06-01", "startDate": "2023-08-16", "status": "ACTIVE_NOT_RECRUITING", "studyType": "INTERVENTIONAL", "summary": "The primary and secondary objectives of the study:\n\nPRIMARY OBJECTIVES:\n\nI. To evaluate and compare 6 month circulating tumor deoxyribonucleic acid (ctDNA) clearance rate in study patients with detectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) II. To evaluate and compare 6 month ctDNA recurrence-free survival (ctDNA-RFS) rate in study patients with undetectable ctDNA prior to randomization to targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase II) III. To evaluate and compare disease-free survival (DFS) (measured from randomization) in patients with resected stage III or high-risk (pT4) stage II mismatch repair protein (MMR) proficient BRAF V600E colon cancer treated with targeted BRAF therapy versus usual care after standard adjuvant chemotherapy. (Phase III)\n\nSECONDARY OBJECTIVES:\n\nI. To evaluate and compare overall survival (OS) between the two treatment arms.\n\nII. To evaluate and compare the toxicity profile between the two treatment arms.\n\nIII. To evaluate and compare the alternative DFS endpoint (measured from date of primary tumor resection) between the two treatment arms.\n\nIV. To evaluate and compare DFS in the subset of patients with detectable ctDNA prior to randomization between the two treatment arms.\n\nEXPLORATORY OBJECTIVE:\n\nI. To evaluate and compare patient-reported outcomes for symptoms of rash, diarrhea, and fatigue according to Patient Reported Outcomes Version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) between the two treatment arms.\n\nOUTLINE: Patients are randomized to 1 of 2 arms.\n\nARM I: Patients receive encorafenib orally (PO) and cetuximab intravenously (IV) on study. Patients also undergo collection of blood samples throughout the study and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and follow-up.\n\nARM II: Patients undergo observation per usual care on study. Patients also undergo collection of blood samples throughout the study and CT or MRI during screening and follow-up.", "title": "Testing the Use of BRAF-Targeted Therapy After Surgery and Usual Chemotherapy for BRAF-Mutated Colon Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05710406", "whyStopped": "" }, { "briefSummary": "The study will be conducted in patients with metastatic colorectal cancer (mCRC) harboring a BRAFV600E mutation, to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with this pathology.", "completionDate": "2028-07", "conditionSummary": "Metastatic Colorectal Cancer · BRAF V600E Mutation Positive", "conditions": [ "Metastatic Colorectal Cancer", "BRAF V600E Mutation Positive" ], "contextFit": { "diseaseDomains": [ "oncology" ], "diseaseHits": 1, "diseaseMatched": true, "domainOverlapCount": 1, "exactDiseasePhraseMatch": false, "ioHit": true, "isInterventional": true, "matchScore": 9, "passesIoRequirement": true, "specificity": "disease_aligned", "studyType": "interventional", "subtypeHits": 0, "subtypeTracks": [], "therapeuticIntent": true, "trialDomains": [ "oncology" ] }, "enrollmentCount": 400, "firstPostedDate": "2022-12-06", "hasResults": false, "interventions": [ "Collection of blood samples" ], "nctId": "NCT05639413", "phase": "NA", "primaryCompletionDate": "2027-07", "startDate": "2023-07-24", "status": "RECRUITING", "studyType": "INTERVENTIONAL", "summary": "Despite substantial progress made in the first- and second line mCRC settings, there are still unmet clinical needs for patients harboring BRAFV600E mutations, especially those with microsatellite stability (MSS) / proficient mismatch repair (pMMR) tumor. The overall survival and access to different treatment in the real-life setting are unknown. Moreover, patient prognosis remains poor and therapeutic resistance to combinations with BRAF inhibitors, is at present, nearly universal. Therefore, it seems essential to prospectively collect clinical and biological data about this rare mCRC subtype. These data will allow us to improve knowledge and to identify clinical and biological factors that could drive therapeutic decisions, predict resistance to treatments, and that are prognostic for survival. In this context, we designed this large, prospective, cohort study to collect clinical data and biological samples to be used for research but also to gather real-world clinical data concerning the treatments and the survival outcomes in patients with BRAFV600E mCRC.\n\nThis collection of clinical and biological data (tumor tissue and blood samples) will allow us to identify predictive and prognostic biomarkers with several research work packages planned:\n\ni. To evaluate the circulating tumor DNA (ctDNA) during the metastatic first-, second-, and third-line treatment to:\n\n* Evaluate its positive and negative predictive value.\n* Identify molecular alterations preceding and explaining clinical resistance during BRAF/EGFR inhibition therapy and immunotherapy.\n\nii. To evaluate BRAFV600E mCRC immune environment both at the tumor and blood level (immunomonitoring).\n\niii. To study specific the dMMR/MSI BRAFV600E subgroup. Furthermore, the data collected will describe the therapeutic management of BRAFV600E mCRC patients in the routine-practice setting which will bring very useful data. The results of the COBRAF study could lay the groundwork to better understand BRAFV600E mCRC and to identify prognostic and predictive biomarkers helping the development of new therapeutic approaches in this population.", "title": "A Clinical-biological Prospective Cohort of Patients With BRAFV600E-mutated Metastatic Colorectal Cancer", "trialEndpointStrength": "pending", "trialHasPrimaryEndpointMention": false, "trialHasQuantitativeOutcomeSignal": true, "trialHasResultsSignal": true, "trialOutcomeSignal": "neutral", "trialPrimaryEndpointFailure": false, "trialPrimaryEndpointMet": false, "url": "https://clinicaltrials.gov/study/NCT05639413", "whyStopped": "" } ], "mechanisticChains": [ { "citations": [], "confidence": "low", "id": "chain-0", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "BRAF, KRAS, NRAS", "type": "genes" }, { "description": "Pathway enrichment detected; mechanistic grounding is limited — treat as background context pending targeted validation.", "label": "Central carbon metabolism in cancer", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "colorectal cancer", "type": "disease" } ], "title": "BRAF, KRAS, NRAS → Central carbon metabolism in cancer → colorectal cancer" }, { "citations": [], "confidence": "low", "id": "chain-1", "steps": [ { "description": "Input genes implicated in the pathway.", "label": "BRAF, KRAS, PIK3CA", "type": "genes" }, { "description": "Pathway enrichment detected; mechanistic grounding is limited — treat as background context pending targeted validation.", "label": "Colorectal cancer", "type": "pathway" }, { "description": "Phenotypic impact in the disease context.", "label": "colorectal cancer", "type": "disease" } ], "title": "BRAF, KRAS, PIK3CA → Colorectal cancer → colorectal cancer" } ], "mlSignals": { "biomedicalDepth": { "biomedicalDepthScore": 1.5, "dimensionScores": { "biomarker": 0, "clinical": 0.62, "molecular": 0, "pathway": 0.07, "pharmacology": 0.06 }, "evidenceWeights": { "biomarker": 0, "clinical": 1, "molecular": 0, "pathway": 0.11, "pharmacology": 0.1 }, "geneCoverage": 1, "matchedTerms": [ "cancer" ], "weightedDepthScore": 1.41, "weightedScores": { "biomarker": 0, "clinical": 0.62, "molecular": 0, "pathway": 0.05, "pharmacology": 0.04 } }, "confidenceCalibration": { "calibrationFactor": 1.02, "score": 0.98, "tier": "high" }, "crossDomainConsistency": { "hypotheses": { "hits": 0, "ratio": 0, "total": 0 }, "pathways": { "hits": 0, "ratio": 0, "total": 1 }, "strategies": { "hits": 1, "ratio": 1, "total": 1 }, "warnings": [ "Pathway narratives rarely mention seed genes; verify mapping." ] }, "intent": { "confidence": 0.59, "label": "research", "multiplier": 1.1, "rationale": "Intent inferred from query keywords and researcher audience alignment.", "score": 2, "scores": { "clinical": 0, "diagnostic": 0, "drug_discovery": 0, "educational": 0, "research": 2 }, "signals": [] }, "learningState": { "calibrationFactor": 1.02, "contradictionThreshold": 0.72, "lastCalibratedAt": "2026-04-02T21:42:53.767Z", "performanceMAE": 19858.9, "performanceSamples": 53, "runs": 65 }, "performancePrediction": { "basis": "global", "confidenceLevel": 0.7, "lowerMs": 166282, "predictionMs": 187595, "sampleSize": 64, "upperMs": 211640 }, "semanticContradictions": { "index": 0, "pairs": [], "threshold": 0.72, "total": 0 } }, "modelConfig": { "aiModelUsed": "Fallback (no AI)", "forceModel": null, "includeDrugs": true, "modelIds": { "anthropic": "claude-sonnet-4-6", "deepseek": "deepseek-chat", "gemini": "gemini-1.5-pro", "openai": "gpt-4o" }, "modelTimeoutMs": 90000, "providers": { "anthropic": true, "deepseek": true, "gemini": true, "openai": true }, "rigorMode": false, "stabilityMode": true }, "molecularStructures": [ { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-predicted_aligned_error_v6.png", "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-model_v6.pdb", "uniprotId": "P15056" }, "analysisTimestamp": "2026-04-03T18:28:28.159Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "BRAF", "geneSymbol": "BRAF", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "Serine/threonine-protein kinase B-raf", "sequenceLength": 766, "stability": { "domainCoverage": 0, "prediction": "Partially disordered", "score": 0.5, "sequenceLength": 766 }, "uniprotId": "P15056" }, { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-P01116-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": "https://alphafold.ebi.ac.uk/files/AF-P01116-F1-predicted_aligned_error_v6.png", "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-P01116-F1-model_v6.pdb", "uniprotId": "P01116" }, "analysisTimestamp": "2026-04-03T18:28:28.921Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "KRAS", "geneSymbol": "KRAS", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "GTPase KRas", "sequenceLength": 189, "stability": { "domainCoverage": 0, "prediction": "Partially disordered", "score": 0.5, "sequenceLength": 189 }, "uniprotId": "P01116" }, { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-P01111-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": "https://alphafold.ebi.ac.uk/files/AF-P01111-F1-predicted_aligned_error_v6.png", "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-P01111-F1-model_v6.pdb", "uniprotId": "P01111" }, "analysisTimestamp": "2026-04-03T18:28:28.716Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "NRAS", "geneSymbol": "NRAS", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "GTPase NRas", "sequenceLength": 189, "stability": { "domainCoverage": 0, "prediction": "Partially disordered", "score": 0.5, "sequenceLength": 189 }, "uniprotId": "P01111" }, { "alphafold": { "available": true, "avgPlddt": null, "cifUrl": "https://alphafold.ebi.ac.uk/files/AF-P42336-F1-model_v6.cif", "modelConfidence": "unknown", "paeImageUrl": "https://alphafold.ebi.ac.uk/files/AF-P42336-F1-predicted_aligned_error_v6.png", "pdbUrl": "https://alphafold.ebi.ac.uk/files/AF-P42336-F1-model_v6.pdb", "uniprotId": "P42336" }, "analysisTimestamp": "2026-04-03T18:28:28.158Z", "bindingEnergy": { "estimated": false, "reason": "No binding sites identified" }, "bindingSites": [], "domains": [], "druggability": { "factors": [ "No annotated domains (lower druggability)" ], "recommendation": "Low druggability: may require novel modalities (gene therapy, ASOs)", "score": 0.1, "tier": "low" }, "gene": "PIK3CA", "geneSymbol": "PIK3CA", "interactionSurface": { "domains": [], "interactionDomainCount": 0, "prediction": "Limited annotated interaction surfaces" }, "proteinName": "Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform", "sequenceLength": 1068, "stability": { "domainCoverage": 0, "prediction": "Largely disordered / intrinsically disordered protein", "score": 0.4, "sequenceLength": 1068 }, "uniprotId": "P42336" } ], "monarchEnrichment": { "BRAF": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0016692", "name": "pilomyxoid astrocytoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018997", "name": "Noonan syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0044792", "name": "large congenital melanocytic nevus", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0015447", "name": "differentiated thyroid carcinoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0015280", "name": "cardiofaciocutaneous syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0009050", "name": "Cushing disease due to pituitary adenoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018907", "name": "craniopharyngioma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 3, "gene": "BRAF", "hgncId": "1097", "narrative": "BRAF is associated with 21 disease(s) in Monarch (OMIM/HPO/Orphanet). 3 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Hypoplastic nipples, Uveal melanoma, Relative macrocephaly.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0002557", "name": "Hypoplastic nipples", "onset": null }, { "frequency": null, "hpoId": "HP:0007716", "name": "Uveal melanoma", "onset": null }, { "frequency": null, "hpoId": "HP:0004482", "name": "Relative macrocephaly", "onset": null }, { "frequency": null, "hpoId": "HP:0000369", "name": "Low-set ears", "onset": null }, { "frequency": null, "hpoId": "HP:0000341", "name": "Narrow forehead", "onset": null }, { "frequency": null, "hpoId": "HP:0001636", "name": "Tetralogy of Fallot", "onset": null }, { "frequency": null, "hpoId": "HP:0000358", "name": "Posteriorly rotated ears", "onset": null }, { "frequency": null, "hpoId": "HP:0001597", "name": "Abnormal nail morphology", "onset": null } ], "source": "Monarch Initiative", "totalAssociations": 21 }, "KRAS": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0001056", "name": "gastric cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0001187", "name": "urinary bladder cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008903", "name": "lung cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0016692", "name": "pilomyxoid astrocytoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0010854", "name": "Toriello-Lacassie-Droste syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0008097", "name": "linear nevus sebaceous syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0013074", "name": "encephalocraniocutaneous lipomatosis", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0015447", "name": "differentiated thyroid carcinoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0013767", "name": "autoimmune lymphoproliferative syndrome type 4", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0005835", "name": "Lynch syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 3, "gene": "KRAS", "hgncId": "6407", "narrative": "KRAS is associated with 21 disease(s) in Monarch (OMIM/HPO/Orphanet). 3 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Shield chest, Nystagmus, Transitional cell carcinoma of the bladder.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0000914", "name": "Shield chest", "onset": null }, { "frequency": null, "hpoId": "HP:0000639", "name": "Nystagmus", "onset": null }, { "frequency": null, "hpoId": "HP:0006740", "name": "Transitional cell carcinoma of the bladder", "onset": null }, { "frequency": null, "hpoId": "HP:0000006", "name": "Autosomal dominant inheritance", "onset": null }, { "frequency": null, "hpoId": "HP:0001876", "name": "Pancytopenia", "onset": null }, { "frequency": null, "hpoId": "HP:0001582", "name": "Redundant skin", "onset": null }, { "frequency": null, "hpoId": "HP:0001510", "name": "Growth delay", "onset": null }, { "frequency": null, "hpoId": "HP:0007957", "name": "Corneal opacity", "onset": null } ], "source": "Monarch Initiative", "totalAssociations": 21 }, "NRAS": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0008566", "name": "thyroid cancer, nonmedullary, 2", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0044792", "name": "large congenital melanocytic nevus", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0011908", "name": "juvenile myelomonocytic leukemia", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018997", "name": "Noonan syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0018310", "name": "Langerhans cell histiocytosis", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0015447", "name": "differentiated thyroid carcinoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0008097", "name": "linear nevus sebaceous syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0013767", "name": "autoimmune lymphoproliferative syndrome type 4", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0013767", "name": "autoimmune lymphoproliferative syndrome type 4", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 2, "gene": "NRAS", "hgncId": "7989", "narrative": "NRAS is associated with 17 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Lymphoproliferative disorder, Bilateral ptosis, Coarctation of aorta.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0005523", "name": "Lymphoproliferative disorder", "onset": null }, { "frequency": null, "hpoId": "HP:0001488", "name": "Bilateral ptosis", "onset": null }, { "frequency": null, "hpoId": "HP:0001680", "name": "Coarctation of aorta", "onset": null }, { "frequency": null, "hpoId": "HP:0002665", "name": "Lymphoma", "onset": null }, { "frequency": null, "hpoId": "HP:0001561", "name": "Polyhydramnios", "onset": null }, { "frequency": null, "hpoId": "HP:0001263", "name": "Global developmental delay", "onset": null }, { "frequency": null, "hpoId": "HP:0000826", "name": "Precocious puberty", "onset": null }, { "frequency": null, "hpoId": "HP:0000629", "name": "Periorbital fullness", "onset": null } ], "source": "Monarch Initiative", "totalAssociations": 17 }, "PIK3CA": { "associations": [ { "contextRelevant": true, "diseaseId": "MONDO:0005575", "name": "colorectal cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": true, "diseaseId": "MONDO:0008170", "name": "ovarian cancer", "pmids": [], "predicate": "biolink:causes", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0031037", "name": "famililal cerebral cavernous malformations", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0020492", "name": "hemimegalencephaly", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0017812", "name": "segmental progressive overgrowth syndrome with fibroadipose hyperplasia", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0013125", "name": "CLAPO syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0016216", "name": "adult hepatocellular carcinoma", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0011240", "name": "megalencephaly-capillary malformation-polymicrogyria syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0017566", "name": "macrodactyly of toes, unilateral", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" }, { "contextRelevant": false, "diseaseId": "MONDO:0007864", "name": "angioosteohypertrophic syndrome", "pmids": [], "predicate": "biolink:gene_associated_with_condition", "score": 0.5, "source": "MONDO" } ], "contextRelevantCount": 2, "gene": "PIK3CA", "hgncId": "8975", "narrative": "PIK3CA is associated with 24 disease(s) in Monarch (OMIM/HPO/Orphanet). 2 match(es) to disease context \"colorectal cancer\". 15 HPO phenotype(s) including: Hereditary nonpolyposis colorectal carcinoma, Congenital onset, Lipoma.", "omimDiseaseCount": 0, "orphaDiseaseCount": 0, "phenotypes": [ { "frequency": null, "hpoId": "HP:0006716", "name": "Hereditary nonpolyposis colorectal carcinoma", "onset": null }, { "frequency": null, "hpoId": "HP:0003577", "name": "Congenital onset", "onset": null }, { "frequency": null, "hpoId": "HP:0012032", "name": "Lipoma", "onset": null }, { "frequency": null, "hpoId": "HP:0000006", "name": "Autosomal dominant inheritance", "onset": null }, { "frequency": null, "hpoId": "HP:0012126", "name": "Stomach cancer", "onset": null }, { "frequency": null, "hpoId": "HP:0001442", "name": "Typified by somatic mosaicism", "onset": null }, { "frequency": null, "hpoId": "HP:0001252", "name": "Hypotonia", "onset": null }, { "frequency": null, "hpoId": "HP:0001852", "name": "Sandal gap", "onset": null } ], "source": "Monarch Initiative", "totalAssociations": 24 } }, "mskImpactFrequency": null, "multiAgentInsights": { "consensus": { "clinicalRelevance": 0.45, "confidence": 0.45, "evidenceQuality": "sparse", "insights": [ { "clinicalRelevance": 0.45, "confidence": 0.45, "evidenceQuality": "sparse", "novelty": 0.4, "statement": "Conservative synthesis only: full multi-agent debate exceeded time budget for colorectal cancer. Prioritize validation around KRAS, NRAS, BRAF, PIK3CA." } ], "novelty": "emerging" }, "debateRounds": 0, "degraded": true, "degradedReason": "Multi-agent timeout", "disagreements": [], "duration": 0 }, "multiOmicsPortrait": { "available": true, "conflictSummary": { "averageConflictIndex": 0.08, "convergentGenes": 1, "flaggedGenes": 2, "highestConflictGene": "KRAS", "highestConflictIndex": 0.15 }, "diseaseContext": "colorectal cancer", "diseaseTissueFocus": [ "Colon", "Small intestine" ], "genes": [ { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 79.4, "cellxgene": { "atlas": "CELLxGENE PDAC atlas", "cellType": "malignant ductal cells", "compartment": "malignant", "detectionFraction": 0.79, "direction": "up", "diseaseMatched": false, "enrichment": 0.91, "stateLabel": "malignant-state enriched" }, "classification": "high-confidence target candidate", "cptac": { "cohort": "CPTAC COAD", "direction": "up", "diseaseMatched": true, "evidenceTier": "cohort_matched", "phosphoSignal": 1.6, "phosphoState": "ERK signaling elevated", "proteinAbundanceZ": 1.2, "significant": true }, "crossOmicsConflict": { "directionalSignals": 2, "index": 0.15, "notes": [ "CELLxGENE evidence is not disease-matched and is downweighted." ], "offContextModalities": [ "CELLxGENE" ], "penaltyPoints": 0.8, "state": "convergent", "supportingModalities": 4 }, "depMap": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "evidenceBadges": [ "Disease-tissue aligned", "CRISPR-essential", "Structured target", "CPTAC protein gain", "Single-cell malignant", "Metabolic axis linked", "Cross-omics convergent", "Survival-linked" ], "foldChange": null, "gene": "KRAS", "gtex": { "diseaseAligned": true, "maxTpm": 24.54, "topTissue": "Lung", "topTissues": [ { "medianTpm": 15.96, "tissue": "Lung" }, { "medianTpm": 13.44, "tissue": "B-lymphocytes (EBV)" }, { "medianTpm": 13.42, "tissue": "Small intestine" } ] }, "hmdb": { "associatedMetabolites": [ { "direction": "up", "name": "L-lactate", "pathway": "glycolysis" }, { "direction": "up", "name": "malate", "pathway": "TCA anaplerosis" } ], "diseaseMatched": true, "fluxAxis": "glycolysis and redox buffering", "metaboliteBurdenScore": 0.84 }, "modalityOutlook": "direct tractability: target with convergent structure and proteomics", "narrative": "CPTAC shows protein gain in CPTAC COAD (protein z 1.2, phospho 1.6). GTEx shows highest expression in Lung aligned with Colon, Small intestine context. CELLxGENE places the signal in malignant ductal cells (malignant compartment). DepMap classifies it as essential (literature-curated) (Chronos -0.65). HMDB-linked context points to glycolysis and redox buffering via L-lactate, malate. AlphaFold indicates well-structured (high classical druggability). Cross-omics evidence is concordant across the strongest available modalities. Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients. Implication: direct tractability: target with convergent structure and proteomics.", "omicsPriorityScore": 79.5, "scoreAdjustments": { "conflictPenaltyPoints": 0.8, "survivalBoostPoints": 0.87 }, "scores": { "dependency": 30.3, "foldChange": 0, "metabolic": 7.17, "proteomics": 9.04, "singleCell": 9.89, "structure": 11.52, "tissue": 11.52 }, "structure": { "druggabilityLabel": "well-structured (high classical druggability)", "druggabilityScore": 96, "meanPlddt": 91.5, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-P01116-F1-model_v6.pdb" }, "survivalCalibration": { "available": true, "boostPoints": 0.87, "ciExcludesNeutral": false, "effectDirection": "protective_association", "hazardRatio": 0.854, "hazardRatio95Ci": { "lower": 0.576, "upper": 1.267 }, "logRankPValue": 0.433622, "matchMode": "panel_level", "matched": true, "note": "Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients.", "patientCount": 530, "supportLevel": "exploratory" } }, { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 53.2, "cellxgene": null, "classification": "emerging omics signal", "cptac": { "cohort": "CPTAC SKCM", "direction": "up", "diseaseMatched": false, "evidenceTier": "curated_pan_cancer", "phosphoSignal": 2.3, "phosphoState": "MAPK phospho-output elevated", "proteinAbundanceZ": 1.5, "significant": true }, "crossOmicsConflict": { "directionalSignals": 1, "index": 0.15, "notes": [ "CPTAC evidence is not disease-matched and is downweighted." ], "offContextModalities": [ "CPTAC" ], "penaltyPoints": 0.8, "state": "sparse", "supportingModalities": 1 }, "depMap": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "evidenceBadges": [ "CRISPR-essential", "CPTAC protein gain", "Survival-linked" ], "foldChange": null, "gene": "BRAF", "gtex": { "diseaseAligned": false, "maxTpm": 15.79, "topTissue": "Thyroid", "topTissues": [ { "medianTpm": 11.47, "tissue": "Thyroid" }, { "medianTpm": 11.14, "tissue": "Uterus" }, { "medianTpm": 10.92, "tissue": "Ovary" } ] }, "hmdb": null, "modalityOutlook": "tractable with medicinal chemistry or binder discovery", "narrative": "CPTAC shows protein gain in CPTAC SKCM (protein z 1.5, phospho 2.3). GTEx shows highest expression in Thyroid. DepMap classifies it as essential (literature-curated) (Chronos -0.65). AlphaFold indicates partially disordered (cryptic pocket possible). Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients. Implication: tractable with medicinal chemistry or binder discovery.", "omicsPriorityScore": 53.3, "scoreAdjustments": { "conflictPenaltyPoints": 0.8, "survivalBoostPoints": 0.87 }, "scores": { "dependency": 30.3, "foldChange": 0, "metabolic": 0, "proteomics": 9.9, "singleCell": 0, "structure": 6.96, "tissue": 6.06 }, "structure": { "druggabilityLabel": "partially disordered (cryptic pocket possible)", "druggabilityScore": 58, "meanPlddt": 66.4, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-P15056-F1-model_v6.pdb" }, "survivalCalibration": { "available": true, "boostPoints": 0.87, "ciExcludesNeutral": false, "effectDirection": "protective_association", "hazardRatio": 0.854, "hazardRatio95Ci": { "lower": 0.576, "upper": 1.267 }, "logRankPValue": 0.433622, "matchMode": "panel_level", "matched": true, "note": "Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients.", "patientCount": 530, "supportLevel": "exploratory" } }, { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 41.8, "cellxgene": null, "classification": "emerging omics signal", "cptac": null, "crossOmicsConflict": { "directionalSignals": 0, "index": 0, "notes": [], "offContextModalities": [], "penaltyPoints": 0, "state": "sparse", "supportingModalities": 1 }, "depMap": { "essentialFraction": 0.55, "isStrongTarget": true, "meanChronos": -0.65, "tier": "essential", "tierLabel": "Essential (literature-curated)", "tissueEssentiality": [] }, "evidenceBadges": [ "CRISPR-essential", "Structured target", "Survival-linked" ], "foldChange": null, "gene": "PIK3CA", "gtex": null, "hmdb": null, "modalityOutlook": "direct tractability: small molecule or antibody", "narrative": "DepMap classifies it as essential (literature-curated) (Chronos -0.65). AlphaFold indicates well-structured (high classical druggability). Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients. Implication: direct tractability: small molecule or antibody.", "omicsPriorityScore": 42.7, "scoreAdjustments": { "conflictPenaltyPoints": 0, "survivalBoostPoints": 0.87 }, "scores": { "dependency": 30.3, "foldChange": 0, "metabolic": 0, "proteomics": 0, "singleCell": 0, "structure": 11.52, "tissue": 0 }, "structure": { "druggabilityLabel": "well-structured (high classical druggability)", "druggabilityScore": 96, "meanPlddt": 92.4, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-P42336-F1-model_v6.pdb" }, "survivalCalibration": { "available": true, "boostPoints": 0.87, "ciExcludesNeutral": false, "effectDirection": "protective_association", "hazardRatio": 0.854, "hazardRatio95Ci": { "lower": 0.576, "upper": 1.267 }, "logRankPValue": 0.433622, "matchMode": "panel_level", "matched": true, "note": "Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients.", "patientCount": 530, "supportLevel": "exploratory" } }, { "appliedWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "baseOmicsPriorityScore": 11.5, "cellxgene": null, "classification": "emerging omics signal", "cptac": null, "crossOmicsConflict": { "directionalSignals": 0, "index": 0, "notes": [], "offContextModalities": [], "penaltyPoints": 0, "state": "sparse", "supportingModalities": 0 }, "depMap": { "essentialFraction": 0, "isStrongTarget": false, "meanChronos": 0, "tier": "unknown", "tierLabel": "No DepMap data available", "tissueEssentiality": [] }, "evidenceBadges": [ "Structured target", "Survival-linked" ], "foldChange": null, "gene": "NRAS", "gtex": null, "hmdb": null, "modalityOutlook": "follow-up profiling required", "narrative": "DepMap classifies it as no depmap data available (Chronos 0). AlphaFold indicates well-structured (high classical druggability). Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients. Implication: follow-up profiling required.", "omicsPriorityScore": 12.4, "scoreAdjustments": { "conflictPenaltyPoints": 0, "survivalBoostPoints": 0.87 }, "scores": { "dependency": 0, "foldChange": 0, "metabolic": 0, "proteomics": 0, "singleCell": 0, "structure": 11.52, "tissue": 0 }, "structure": { "druggabilityLabel": "well-structured (high classical druggability)", "druggabilityScore": 96, "meanPlddt": 92.1, "structureUrl": "https://alphafold.ebi.ac.uk/files/AF-P01111-F1-model_v6.pdb" }, "survivalCalibration": { "available": true, "boostPoints": 0.87, "ciExcludesNeutral": false, "effectDirection": "protective_association", "hazardRatio": 0.854, "hazardRatio95Ci": { "lower": 0.576, "upper": 1.267 }, "logRankPValue": 0.433622, "matchMode": "panel_level", "matched": true, "note": "Survival calibration (panel-level) with log-rank p=0.433622; HR=0.854 across 530 patients.", "patientCount": 530, "supportLevel": "exploratory" } } ], "panelSummary": { "biomarkerCandidates": [], "cautions": [ "No uploaded differential-expression evidence was provided for this run.", "Survival calibration is present but remains exploratory; hazard-ratio confidence is limited for this panel." ], "dominantSignals": [ "3 genes show CRISPR-essentiality support in DepMap.", "2 genes are reinforced by CPTAC protein-level signal.", "1 gene localize to high-enrichment CELLxGENE single-cell states.", "1 gene connect to HMDB-linked metabolic pressure axes.", "1 gene align with disease-relevant GTEx tissues (Colon, Small intestine)." ], "narrative": "Top multi-omics priorities for colorectal cancer are KRAS, BRAF, PIK3CA. GaiaLab fused tissue expression, dependency, structure, and uploaded differential-expression evidence with CPTAC proteomics, CELLxGENE single-cell states, and HMDB-linked metabolite context to rank these genes. Conflict-aware scoring downweights cross-omics disagreement and off-context cohort evidence, while available survival cohorts calibrate ranking strength.", "prioritizedGenes": [ { "classification": "high-confidence target candidate", "evidenceBadges": [ "Disease-tissue aligned", "CRISPR-essential", "Structured target", "CPTAC protein gain", "Single-cell malignant", "Metabolic axis linked", "Cross-omics convergent", "Survival-linked" ], "gene": "KRAS", "modalityOutlook": "direct tractability: target with convergent structure and proteomics", "omicsPriorityScore": 79.5 }, { "classification": "emerging omics signal", "evidenceBadges": [ "CRISPR-essential", "CPTAC protein gain", "Survival-linked" ], "gene": "BRAF", "modalityOutlook": "tractable with medicinal chemistry or binder discovery", "omicsPriorityScore": 53.3 }, { "classification": "emerging omics signal", "evidenceBadges": [ "CRISPR-essential", "Structured target", "Survival-linked" ], "gene": "PIK3CA", "modalityOutlook": "direct tractability: small molecule or antibody", "omicsPriorityScore": 42.7 }, { "classification": "emerging omics signal", "evidenceBadges": [ "Structured target", "Survival-linked" ], "gene": "NRAS", "modalityOutlook": "follow-up profiling required", "omicsPriorityScore": 12.4 } ], "topTargetCandidates": [ "KRAS", "BRAF", "PIK3CA" ] }, "sourceCoverage": { "alphaFoldGenes": 4, "cellxgeneGenes": 1, "coveredGenes": 4, "cptacGenes": 2, "depMapGenes": 4, "foldChangeGenes": 0, "gtexGenes": 2, "hmdbGenes": 1, "totalGenes": 4 }, "subtypeContext": { "ambiguous": false, "explicit": false, "focusTissues": [], "label": null, "modalityWeights": { "dependency": 1, "foldChange": 1, "metabolic": 1, "proteomics": 1, "singleCell": 1, "structure": 1, "tissue": 1 }, "rationale": null, "weightingMode": "default" }, "survivalCalibration": { "available": true, "hazardRatio": 0.854, "hazardRatio95Ci": { "lower": 0.576, "upper": 1.267 }, "logRankPValue": 0.433622, "matchMode": "panel_level", "matchedGeneSymbols": 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.775, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F66 activity was enhanced 2x?", "doOperator": "do(KRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.552, "description": "do(KRAS=restore) is predicted to restore the missing suppressive signal. 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Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). KRAS shows protein gain in CPTAC COAD. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human). Single-cell data localizes the signal to malignant ductal cells. Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.76, "essentialGene": true, "feasibility": 0.775, "functionalImpact": 0.855, "lethalityRisk": 0.8, "pathwayReversal": 0.672 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.38, "description": "What if only F46 was modulated?", "doOperator": "do(KRAS=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.38, "counterfactualScore": 0.76, "description": "do(KRAS=tuned) is predicted to shift the target into a more druggable intermediate state. 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Metabolic context links this route to glycolysis and redox buffering.", "diseaseSignalReduction": 0.69, "druggability": 0.35, "feasibility": 0.867, "offTargetEffects": 0.2, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "CPTAC: CPTAC COAD protein gain (z 1.2)", "CELLxGENE: malignant ductal cells malignant signal", "HMDB: glycolysis and redox buffering", "GTEx: Lung highest expression", "AlphaFold: pLDDT 91.5", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(KRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.5, "counterfactualScore": 0.552, "description": "do(KRAS=restore) is predicted to restore the missing suppressive signal. 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Estimated disease-signal reduction 22% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.22, "feasibility": 0.538, "functionalGain": 1.475, "pathwayReversal": 0.178, "therapeuticPotential": 0.5, "toxicityRisk": 0.15 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] } ] }, { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.5, "intervention": "knockout", "safetyProfile": 0.9, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.5, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.249, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "drugTargetPotential": { "developabilityScore": 0.595, "druggability": 0.35, "mechanisms": "uncharacterized", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ], "geneSymbol": "NRAS", "mechanismId": "uncharacterized_NRAS_4", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "PIK3CA" ], "name": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "pvalue": 0, "qvalue": 0 } ], "preferredIntervention": "selective_modulation", "recommendedDoOperator": "do(NRAS=tuned)", "scenarios": [ { "confidence": 0.38, "description": "What if only F46 was modulated?", "doOperator": "do(NRAS=tuned)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.38, "counterfactualScore": 0.249, "description": "do(NRAS=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 48% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.48, "druggability": 0.35, "feasibility": 0.67, "offTargetEffects": 0.2, "pathwayReversal": 0.178, "specificityIndex": 0.7 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(NRAS=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": true, "compensatoryRisk": 0.678, "confidence": 0.765, "counterfactualScore": 0.139, "description": "do(NRAS=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 28% with 18% pathway reversal support. The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human).", "diseaseSignalReduction": 0.28, "essentialGene": false, "feasibility": 0.577, "functionalImpact": 0.855, "lethalityRisk": 0.1, "pathwayReversal": 0.178 }, "rationale": [ "DepMap: No DepMap data available", "AlphaFold: pLDDT 92.1", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)" ] }, { "confidence": 0.5, "description": "What if F46 activity was enhanced 2x?", "doOperator": "do(NRAS=restore)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "PIK3CA", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" } ], "intervention": "amplification", "isPreferred": false, "prediction": { "compensatoryRisk": 0.578, "confidence": 0.5, "counterfactualScore": 0.122, "description": "do(NRAS=restore) is predicted to restore the missing suppressive signal. Estimated disease-signal reduction 22% with 18% pathway reversal support. 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"sequence": "I", "start": 24 }, { "end": 28, "score": 2.818315029144287, "sequence": "F", "start": 28 } ], "top_residues": [ { "aa": "I", "index": 24, "score": 2.8419690132141113 }, { "aa": "F", "index": 28, "score": 2.818315029144287 }, { "aa": "T", "index": 35, "score": 2.564915657043457 }, { "aa": "I", "index": 36, "score": 2.7239372730255127 }, { "aa": "L", "index": 52, "score": 2.701233148574829 }, { "aa": "L", "index": 79, "score": 7.386185169219971 } ], "uncertaintyMetrics": { "mcDropoutUncertainty": 0.05 } } ], "uncertaintyQuantification": { "aleatoricUncertainty": 0.00031521189566487373, "epistemicUncertainty": 0.04214130206940907, "overallUncertainty": 0.04245651396507394 }, "uniprotId": "P01111" }, { "causalMechanisms": [ { "causalConfidence": 0.95, "confidence": 0.95, "description": "PIK3CA exhibits post translational modification via Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at...", "diseaseRelevance": 0.7, 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"description": "PIK3CA exhibits cellular localization via Phagocytosis", "diseaseRelevance": 0.5, "evidenceStrength": 0.76, "featureCount": 2, "geneSymbol": "PIK3CA", "id": "cellular_localization_PIK3CA_8", "interventionalSupport": 0.5, "keyFeatures": [ "F308", "F200" ], "mechanism": "Cellular localization/transport", "primaryFeature": "F308", "type": "cellular_localization", "validation": { "causalConfidence": 0.95, "evidenceStrength": 0.76, "interventionalSupport": 0.5, "isValid": true } } ], "confidence": "medium", "conflicts": [], "counterfactualAnalysis": [ { "_tractabilityAssessment": { "category": "druggable", "tractabilityScore": 0.7 }, "clinicalImplications": [ { "clinicalFeasibility": 0.7, "intervention": "knockout", "safetyProfile": 0.19999999999999996, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "amplification", "safetyProfile": 0.85, "therapeuticWindow": 0.865 }, { "clinicalFeasibility": 0.7, "intervention": "selective_modulation", "safetyProfile": 0.85, "therapeuticWindow": 0.865 } ], "counterfactualScore": 0.584, "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "drugTargetPotential": { "developabilityScore": 0.802, "druggability": 0.65, "mechanisms": "post_translational_modification", "potency": 0.865, "selectivity": 0.6 }, "evidenceAnchors": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ], "geneSymbol": "PIK3CA", "mechanismId": "post_translational_modification_PIK3CA_1", "pathwayAnchors": [ { "genes": [ "BRAF", "KRAS", "NRAS" ], "name": "EGFR tyrosine 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} ], "intervention": "selective_modulation", "isPreferred": true, "prediction": { "compensatoryRisk": 0.388, "confidence": 0.62, "counterfactualScore": 0.584, "description": "do(PIK3CA=tuned) is predicted to shift the target into a more druggable intermediate state. Estimated disease-signal reduction 69% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). The intervention is anchored to EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human) and Central carbon metabolism in cancer - Homo sapiens (human).", "diseaseSignalReduction": 0.69, "druggability": 0.65, "feasibility": 0.802, "offTargetEffects": 0.1, "pathwayReversal": 0.672, "specificityIndex": 0.7 }, "rationale": [ "DepMap: Essential (literature-curated) (Chronos -0.65)", "AlphaFold: pLDDT 92.4", "Pathways: EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human), Central carbon metabolism in cancer - Homo sapiens (human)" ] }, { "confidence": 0.7649999999999999, "description": "What if F46 was completely inhibited?", "doOperator": "do(PIK3CA=off)", "downstreamNodes": [ { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" }, { "label": "NRAS", "type": "panel_gene" }, { "label": "EGFR tyrosine kinase inhibitor resistance - Homo sapiens (human)", "type": "pathway" }, { "label": "BRAF", "type": "panel_gene" }, { "label": "KRAS", "type": "panel_gene" } ], "intervention": "knockout", "isPreferred": false, "prediction": { "compensatoryMechanisms": false, "compensatoryRisk": 0.388, "confidence": 0.765, "counterfactualScore": 0.582, "description": "do(PIK3CA=off) is predicted to reduce the disease-driving signal. Estimated disease-signal reduction 76% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). 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Estimated disease-signal reduction 22% with 67% pathway reversal support. DepMap essentiality supports a measurable viability effect (55% essential cell lines). 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