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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
Group Labels: 2

Doublet Arm Safety Lead-in, Triplet Arm

Name: Binimetinib

Description: Orally, twice daily.
Type: Drug
Group Labels: 1

Safety Lead-in, Triplet Arm

Name: Cetuximab

Description: Standard of care.
Type: Drug
Group Labels: 3

Control Arm Doublet Arm Safety Lead-in, Triplet Arm

Name: Irinotecan

Description: Standard of care.
Type: Drug
Group Labels: 1

Control Arm

Name: Folinic Acid

Description: Standard of care.
Type: Drug
Group Labels: 1

Control Arm

Name: 5-Fluorouracil

Description: Standard of care.
Type: Drug
Group Labels: 1

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 ---



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