The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.

Clinical Trial Details

Geo Regions

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Gastrointestinal Cancer

Encorafenib

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
Phase 3
NCT04607421

Active enrolling

Globe
Locations

United States, Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Denmark, Finland, Germany, India, Italy, Japan, Korea, Republic of, Mexico, Netherlands, New Zealand, Norway, Poland, Russian Federation, Slovakia, South Africa, Spain, Sweden, Taiwan, Ukraine, United Kingdom

Study design

Participant Group/Arm

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

Intervention/Treatment

DRUG: Encorafenib

75 mg capsules

DRUG: Cetuximab

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

DRUG: Irinotecan

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

Participant Group/Arm

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

Intervention/Treatment

DRUG: Encorafenib

75 mg capsules

DRUG: Cetuximab

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

DRUG: Oxaliplatin

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

Participant Group/Arm

EXPERIMENTAL: Phase 3 Arm A

Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks

Intervention/Treatment

DRUG: Encorafenib

75 mg capsules

DRUG: Cetuximab

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

Participant Group/Arm

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

Intervention/Treatment

DRUG: Encorafenib

75 mg capsules

DRUG: Cetuximab

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

DRUG: Oxaliplatin

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

Participant Group/Arm

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)

Intervention/Treatment

DRUG: Oxaliplatin

Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial

DRUG: Irinotecan

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

DRUG: Capecitabine

150 mg or 500 mg Tablet

DRUG: Bevacizumab

Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Participant Group/Arm

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

Intervention/Treatment

DRUG: Encorafenib

75 mg capsules

DRUG: Cetuximab

Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial

DRUG: Irinotecan

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

Participant Group/Arm

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)

Intervention/Treatment

DRUG: Irinotecan

Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial

DRUG: Leucovorin

Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial

DRUG: 5-FU

Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial

DRUG: Bevacizumab

Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Key eligibility criteria

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

Key dates

Study start date
  • December 2020
Estimated primary completion date
  • November 2026

Key endpoints

Primary Outcome Measures
Outcome Measure

Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Phase 3: Progression free survival, by blinded independent review

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Objective response rate by blinded independent review

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 23 months

Outcome Measure

Cohort 3: Objective response rate by blinded independent review

Measure Description

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

Time Frame

Duration of Cohort 3, approximately 15 months.

Secondary Outcome Measures:
Outcome Measure

Safety Lead-in: Incidence of adverse events

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Measure Description

Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in: Overall response rate by investigator

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in: Duration of response by Investigator

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in:Progression free survival by Investigator

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in: Time to response by Investigator

Measure Description

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

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months

Outcome Measure

Safety Lead-in: Overall survival

Measure Description

Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI

Time Frame

After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months

Outcome Measure

Phase 3: Overall survival

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 50 months

Outcome Measure

Phase 3: Overall response rate by Investigator and by blinded independent review

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Duration of response by Investigator and blinded independent review

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Time to response by blinded independent review and by Investigator

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Progression free survival by Investigator and by blinded independent review

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Progression free survival 2 by Investigator

Measure Description

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

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Incidence of adverse events

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Measure Description

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)

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)

Measure Description

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.

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire

Measure Description

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

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)

Measure Description

The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires

Measure Description

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.

Time Frame

Duration of Phase 3, approximately 36 months

Outcome Measure

Phase 3: Confirm the MSI-status in tumor tissue

Measure Description

Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue

Time Frame

Once, pre-treatment

Outcome Measure

Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome

Measure Description

BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment

Time Frame

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.

Outcome Measure

Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38

Time Frame

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

Outcome Measure

Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Time Frame

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.

Outcome Measure

Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38

Time Frame

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

Outcome Measure

Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746 and oxaliplatin

Time Frame

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

Outcome Measure

Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time Frame

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

Outcome Measure

Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin

Measure Description

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)

Time Frame

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

Outcome Measure

Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746 and oxaliplatin

Time Frame

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

Outcome Measure

Phase 3: Trough concentrations of encorafenib and its metabolite LHY746

Measure Description

Trough plasma concentrations in all patients in Arm A and Arm B

Time Frame

Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

Outcome Measure

Cohort 3: Progression free survival by Investigator and by blinded independent review

Measure Description

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.

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Overall response rate by investigator

Measure Description

Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Duration of response by Investigator and by blinded independent review

Measure Description

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

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Time to response by Investigator and by blinded independent review

Measure Description

Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Overall survival

Measure Description

Overall survival, defined as the time from the date of randomization to death due to any cause

Time Frame

Duration of Cohort 3, approximately 36 months

Outcome Measure

Cohort 3: Incidence of adverse events

Measure Description

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)

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms

Measure Description

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)

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)

Measure Description

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.

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire

Measure Description

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

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)

Measure Description

The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires

Measure Description

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.

Time Frame

Duration of Cohort 3, approximately 21 months

Outcome Measure

Cohort 3: Confirm the MSI-status in tumor tissue

Measure Description

Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue

Time Frame

Once, pre-treatment

Outcome Measure

Cohort 3: Determine the correlation between cfDNA genetic alterations and clinical outcome

Measure Description

BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment

Time Frame

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.

Outcome Measure

Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746

Measure Description

Trough plasma concentrations in all patients in Arm D

Time Frame

Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

Number of participants

815

Collaborators and investigators

Sponsor: Pfizer

Collaborator: Ono Pharmaceutical Co. Ltd, Merck KGaA, Darmstadt, Germany, Eli Lilly and Company

This information is current as of May 17th 2024.