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Report for Clinical Trial NCT02928224

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

NCT02928224 BRAF V600E-mutant Metastatic Colorectal Cancer
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

6 Interventions

Name: Encorafenib

Description: Orally, once daily.

Type: Drug

Doublet Arm Safety Lead-in, Triplet Arm

Name: Binimetinib

Description: Orally, twice daily.

Type: Drug

Safety Lead-in, Triplet Arm

Name: Cetuximab

Description: Standard of care.

Type: Drug

Control Arm Doublet Arm Safety Lead-in, Triplet Arm

Name: Irinotecan

Description: Standard of care.

Type: Drug

Control Arm

Name: Folinic Acid

Description: Standard of care.

Type: Drug

Control Arm

Name: 5-Fluorouracil

Description: Standard of care.

Type: Drug

Control Arm


Primary Outcomes

Measure: (Safety Lead-in) Incidence of dose-limiting toxicities (DLTs)

Time: Cycle 1 (up to 28 days)

Measure: (Safety Lead-in) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Incidence of dose interruptions, dose modifications and discontinuations due to adverse events (AEs)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Response Rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Secondary Outcomes

Measure: (Safety Lead-in) Response Rate (ORR)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Duration of Response (DOR)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Time to Response

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Progression-free Survival (PFS)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm and Triplet Arm vs. Doublet Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Objective Response Rate (ORR) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of the Quality of Life in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Evaluation of the area under the concentration-time curve (AUC) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the maximum concentration (Cmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the time of maximum observed concentration (Tmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the steady-state concentration measured just before the next dose of study drug (Ctrough) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Purpose: Treatment

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 V600E

A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer. --- V600E ---

Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. --- V600E ---

Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses BRAF V600E-mutant Metastatic Colorectal Cancer Colorectal Neoplasms null --- V600E ---



HPO Nodes


HPO:
Neoplasm of the large intestine
Genes 120
FLCN SDHC MLH1 PMS2 APC EPCAM SDHC PALLD SRC BUB1 APC GREM1 NTHL1 PMS1 PTEN SDHB MSH6 APC KIT SDHD KRAS BMPR1A FAN1 CTNNB1 MSH3 POLD1 KRAS RNF43 KEAP1 DICER1 DLC1 BMPR1A MSH2 MSH6 PIK3CA CDKN2A FGFR3 BMPR1A MUTYH PIK3CA BMPR1A EP300 FOXE1 ENG SMAD7 AXIN2 CHEK2 MLH1 RPS20 BRCA1 RPS19 PRKAR1A APC GPR35 MLH1 AKT1 POLE SMAD4 KIT TP53 TRIP13 COL14A1 MDM2 SMAD4 POLE BRCA2 AKT1 MSH6 HABP2 NRAS MUTYH BUB1B DOCK8 TGFBR2 STK11 AXIN2 EPCAM BUB3 DCC AXIN2 TCF4 KLLN MSH2 APC TP53 SEC23B PTEN TGFBR2 SEMA4A POLD1 PIK3CA PDGFRA MINPP1 APC SH3KBP1 BMPR1A TP53 BUB1 AAGAB SMAD4 BMPR1A MST1 MLH3 MSH2 PALB2 FLCN SDHA PMS2 SDHB BUB1B MSH2 MLH1 CEP57 MLH3 TP53 PTPRJ PMS1 APC CDKN2A APC