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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: Encorafenib
* Drug: Cetuximab
* Drug: Oxaliplatin
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: 5-FU
* Drug: Capecitabine
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Safety Lead-in Cohort 1<br>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<br>* 75 mg capsules<br>* Other names: Braftovi, PF-07263896, LGX818, ONO-7702;Drug: Cetuximab<br>* Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial<br>* Other names: Erbitux;Drug: Irinotecan<br>* Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial<br>* Other names: Campostar;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;|
| Experimental: Safety Lead-in Cohort 2<br>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<br>* 75 mg capsules<br>* Other names: Braftovi, PF-07263896, LGX818, ONO-7702;Drug: Cetuximab<br>* Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial<br>* Other names: Erbitux;Drug: Oxaliplatin<br>* Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial<br>* Other names: Eloxatin;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;|
| Experimental: Phase 3 Arm A<br>Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks | Drug: Encorafenib<br>* 75 mg capsules<br>* Other names: Braftovi, PF-07263896, LGX818, ONO-7702;Drug: Cetuximab<br>* Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial<br>* Other names: Erbitux;|
| Experimental: Phase 3 Arm B<br>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<br>* 75 mg capsules<br>* Other names: Braftovi, PF-07263896, LGX818, ONO-7702;Drug: Cetuximab<br>* Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial<br>* Other names: Erbitux;Drug: Oxaliplatin<br>* Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial<br>* Other names: Eloxatin;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;|
| Active Comparator: Phase 3 Arm C<br>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<br>* Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial<br>* Other names: Eloxatin;Drug: Irinotecan<br>* Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial<br>* Other names: Campostar;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;Drug: Capecitabine<br>* 150 mg or 500 mg Tablet<br>* Other names: Xeloda;Drug: Bevacizumab<br>* Optional Injection for intravenous use 100 mg/vial or 400 mg/vial<br>* Other names: Zirabev;|
| Experimental: Cohort 3 Arm D<br>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<br>* 75 mg capsules<br>* Other names: Braftovi, PF-07263896, LGX818, ONO-7702;Drug: Cetuximab<br>* Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial<br>* Other names: Erbitux;Drug: Irinotecan<br>* Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial<br>* Other names: Campostar;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;|
| Active Comparator: Cohort 3 Arm E<br>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<br>* Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial<br>* Other names: Campostar;Drug: Leucovorin<br>* Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial<br>* Other names: Wellcovorin, Fusilev, Khapzory;Drug: 5-FU<br>* Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial<br>* Other names: Fluorouracil;Drug: Bevacizumab<br>* Optional Injection for intravenous use 100 mg/vial or 400 mg/vial<br>* Other names: Zirabev;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, Colon cancer, Rectal cancer, Colorectal Neoplasms, Intestinal cancer, Intestinal Neoplasms, Gastrointestinal cancer, Gastrointestinal Neoplasms, Digestive system cancer, Digestive System Neoplasms, Digestive System Diseases, Gastrointestinal Diseases, Colonic Diseases, Intestinal Diseases, Rectal Diseases, BREAKWATER Study