A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

Cancer, Colorectal Cancer

Phase 3

Interventional Study

A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

Sponsor

Pfizer

Start Date

21/12/2020

Completion Date

16/11/2024

Sex

ALL

Enrollment

815

Ages From

Healthy Volunteers?

Contact

Pfizer CT.gov Call Center

Location

Kingston Health Sciences Centre-Kingston General Hospital Site

Trial Details

Brief Summary

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: - has spread to other parts of the body (metastatic); - has a certain type of abnormal gene called "BRAF"; and - has not received prior treatment. Participants in this study will receive one of the following study treatments: - 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. - 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. - 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. The study team will monitor how each participant responds to the study treatment for up to about 3 years.

Official Title

AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE 3 STUDY OF FIRST-LINE ENCORAFENIB PLUS CETUXIMAB WITH OR WITHOUT CHEMOTHERAPY VERSUS STANDARD OF CARE THERAPY WITH A SAFETY LEAD-IN OF ENCORAFENIB AND CETUXIMAB PLUS CHEMOTHERAPY IN PARTICIPANTS WITH METASTATIC BRAF V600E-MUTANT COLORECTAL CANCER

Detailed Description

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.

Selection Criteria

Eligibility Inclusion Criteria

- Safety Lead-In = Male/female ≥ 18 years old
- Phase 3 and Cohort 3: Male/female ≥ 16 years old (where permitted locally)
- Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation
- Prior systemic treatment in metastatic setting: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment )
- Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in)
- ECOG PS 0-1
- Adequate organ function

Eligibility Exclusion Criteria

- Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition
- Active bacterial or viral infections in 2 weeks prior to starting dosing
- Symptomatic brain metastases

ARMS & Interventions

PARTICIPANT GROUP ARM	INTERVENTION TREATMENT
Experimental: Safety Lead-in Cohort 1 Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks	Drug: Encorafenib - 75 mg capsules Other Names: - Braftovi, PF-07263896, LGX818, ONO-7702 Drug: Cetuximab - Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial Other Names: - Erbitux Drug: Irinotecan - Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial Other Names: - Campostar Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil
Experimental: Safety Lead-in Cohort 2 Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks	Drug: Encorafenib - 75 mg capsules Other Names: - Braftovi, PF-07263896, LGX818, ONO-7702 Drug: Cetuximab - Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial Other Names: - Erbitux Drug: Oxaliplatin - Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial Other Names: - Eloxatin Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil
Experimental: Phase 3 Arm A Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks	Drug: Encorafenib - 75 mg capsules Other Names: - Braftovi, PF-07263896, LGX818, ONO-7702 Drug: Cetuximab - Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial Other Names: - Erbitux
Experimental: Phase 3 Arm B Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120 minute IV infusion) every two weeks Oxaliplatin 85 mg/m2 (120-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks	Drug: Encorafenib - 75 mg capsules Other Names: - Braftovi, PF-07263896, LGX818, ONO-7702 Drug: Cetuximab - Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial Other Names: - Erbitux Drug: Oxaliplatin - Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial Other Names: - Eloxatin Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil
Active Comparator: Phase 3 Arm C Every two weeks: Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Every two weeks: Irinotecan 165 mg/m2 (90-minute IV infusion) Oxaliplatin 85 mg/m2 (120-minute IV infusion) Leucovorin 400 mg/m2 (120-minute IV infusion) 5-FU 2400 or 3200 mg/m2 continuous IV infusion over 46 48 hours Bevacizumab (optional; given per prescribing instructions) -OR- Oxaliplatin 130 mg/m2 (120-minute IV infusion) every 3 weeks Capecitabine 1000 mg/m2 oral tablet twice daily on Days 1-14 Bevacizumab (optional; given per prescribing instructions)	Drug: Oxaliplatin - Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial Other Names: - Eloxatin Drug: Irinotecan - Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial Other Names: - Campostar Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil Drug: Capecitabine - 150 mg or 500 mg Tablet Other Names: - Xeloda Drug: Bevacizumab - Optional Injection for intravenous use 100 mg/vial or 400 mg/vial Other Names: - Zirabev
Experimental: Cohort 3 Arm D Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks Irinotecan 180 mg/m2 (90-minute IV infusion) every two weeks Leucovorin 400 mg/m2 (120-minute IV infusion) every two weeks 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks	Drug: Encorafenib - 75 mg capsules Other Names: - Braftovi, PF-07263896, LGX818, ONO-7702 Drug: Cetuximab - Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial Other Names: - Erbitux Drug: Irinotecan - Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial Other Names: - Campostar Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil
Active Comparator: Cohort 3 Arm E Irinotecan 180 mg/m2 (90-minute IV infusion) every 2 weeks, Leucovorin 400 mg/m2 (120-minute IV infusion) every 2 weeks, 5-FU 400 mg/m2 IV bolus, then 5-FU 2400 mg/m2 continuous IV infusion over 46-48 hours every two weeks, Bevacizumab (optional; given per prescribing instructions)	Drug: Irinotecan - Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial Other Names: - Campostar Drug: Leucovorin - Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial Other Names: - Wellcovorin, Fusilev, Khapzory Drug: 5-FU - Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial Other Names: - Fluorouracil Drug: Bevacizumab - Optional Injection for intravenous use 100 mg/vial or 400 mg/vial Other Names: - Zirabev

Primary Outcome

Measures	Measure Description	MEASURE TIME FRAME
Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)	Incidence of dose limiting toxicity defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring during the first 28 days of treatment	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Phase 3: Progression free survival, by blinded independent review	Progression free survival, defined as the time from the date of randomization to the earliest documented disease progression or death due to any cause: encorafenib and cetuximab + mFOLFOX6 (Arm B) vs the Control Arm (Arm C)	Duration of Phase 3, approximately 36 months
Phase 3: Objective response rate by blinded independent review	Objective response defined as complete response (CR), or partial response (PR) according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of progression of disease (PD)	Duration of Phase 3, approximately 23 months
Cohort 3: Objective response rate by blinded independent review	Defined as CR, or PR according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of PD, death or start of new anticancer therapy	Duration of Cohort 3, approximately 15 months.

Secondary Outcome

MEASURES	MEASURE DESCRIPTION	MEASURE TIME FRAME
Safety Lead-in: Incidence of adverse events	An adverse event is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship as assessed by CTCAE 4.03	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events		After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Overall response rate by investigator	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Duration of response by Investigator	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in:Progression free survival by Investigator	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Time to response by Investigator	Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Overall survival	Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months
Phase 3: Overall survival	Overall survival, defined as the time from the date of randomization to death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 50 months
Phase 3: Overall response rate by Investigator and by blinded independent review	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Duration of response by Investigator and blinded independent review	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Time to response by blinded independent review and by Investigator	Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Progression free survival by Investigator and by blinded independent review	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause:: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Progression free survival 2 by Investigator	Progression free survival 2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause, whichever occurs first: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6	Duration of Phase 3, approximately 36 months
Phase 3: Incidence of adverse events	An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.	Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire	The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete	Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)	The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.	Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires	The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.	Duration of Phase 3, approximately 36 months
Phase 3: Confirm the MSI-status in tumor tissue	Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue	Once, pre-treatment
Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome	BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment	Predose on Cycle 1 Day 1, 15, Cycle 2 Day 15, Cycle 7 Day 1 and EOT. Arm C sampling on Day 1 of Cycles 1-3, 9 and EOT. EOT is approx 36 months.
Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days.
Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin	Changes in exposures of irinotecan and its metabolite (SN-38) on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 1 (encorafenib and cetuximab + FOLFIRI) Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (encorafenib and cetuximab + mFOLFOX6)	Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Phase 3: Trough concentrations of encorafenib and its metabolite LHY746	Trough plasma concentrations in all patients in Arm A and Arm B	Predose on Cycle 1 through Cycle 6. Each cycle is 28 days
Cohort 3: Progression free survival by Investigator and by blinded independent review	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause.	Duration of Cohort 3, approximately 21 months
Cohort 3: Overall response rate by investigator	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1	Duration of Cohort 3, approximately 21 months
Cohort 3: Duration of response by Investigator and by blinded independent review	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause	Duration of Cohort 3, approximately 21 months
Cohort 3: Time to response by Investigator and by blinded independent review	Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1	Duration of Cohort 3, approximately 21 months
Cohort 3: Overall survival	Overall survival, defined as the time from the date of randomization to death due to any cause	Duration of Cohort 3, approximately 36 months
Cohort 3: Incidence of adverse events	An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Cohort 3, approximately 21 months
Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.	Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire	The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete	Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)	The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.	Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires	The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.	Duration of Cohort 3, approximately 21 months
Cohort 3: Confirm the MSI-status in tumor tissue	Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue	Once, pre-treatment
Cohort 3: Determine the correlation between cfDNA genetic alterations and clinical outcome	BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment	Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 7 Day 1 and End of Treatment (Duration of Cohort 3, approximately 21 months). Each cycle is 28 days.
Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746	Trough plasma concentrations in all patients in Arm D	Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

Other Outcome

Cancer, Colorectal Cancer

Phase 3

Interventional Study