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
Name: Encorafenib
Name: Cetuximab
Name: Oxaliplatin
Name: Irinotecan
Name: Leucovorin
Name: 5-FU
Name: Capecitabine
Name: Bevacizumab
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
Measure: Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs) Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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 + (Arm A) vs Control Arm (Arm C) and encorafenib and cetuximab + mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B) vs the Control Arm (Arm C)
Measure: Phase 3: Progression free survival, by blinded independent review Time: Duration of Phase 3, approximately 34 monthsDescription: 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
Measure: Safety Lead-in: Incidence of adverse events Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.
Measure: Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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
Measure: Safety Lead-in: Overall response rate by investigator Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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
Measure: Safety Lead-in: Duration of response by Investigator Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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
Measure: Safety Lead-in:Progression free survival by Investigator Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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
Measure: Safety Lead-in: Time to response by Investigator Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI
Measure: Safety Lead-in: Overall survival Time: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Overall survival Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Overall response rate by blinded independent review and by Investigator Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Duration of response by blinded independent review and by Investigator Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Time to response by blinded independent review and by Investigator Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Progression free survival by Investigator Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Progression free survival 2 by Investigator Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Incidence of adverse events Time: Duration of Phase 3, approximately 34 monthsDescription: 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 or encorafenib + cetuximab + FOLFIRI (Arm B)
Measure: Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms Time: Duration of Phase 3, approximately 34 monthsDescription: 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.
Measure: Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) Time: Duration of Phase 3, approximately 34 monthsDescription: 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
Measure: Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire Time: Duration of Phase 3, approximately 34 monthsDescription: The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
Measure: Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS) Time: Duration of Phase 3, approximately 34 monthsDescription: 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.
Measure: Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires Time: Duration of Phase 3, approximately 34 monthsDescription: Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
Measure: Phase 3: Confirm the MSI-status in tumor tissue Time: Once, pre-treatmentDescription: BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment
Measure: Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome Time: Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15 and Cycle 7 Day 1. Each cycle is 28 days for all treatments except for oxaliplatin/capecitabine treatment which is 21 daysDescription: 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)
Measure: Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin Time: 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 daysDescription: Trough plasma concentrations in all patients in Arm A and Arm B
Measure: Phase 3: Trough concentrations of encorafenib and its metabolite LHY746 Time: Predose on Cycle 1 through Cycle 6. Each cycle is 28 daysAllocation: Randomized
Parallel Assignment
There is one SNP
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. --- V600E ---
BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER) 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 Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs). --- V600E ---
BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER) 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 Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs). --- V600E --- --- V600E ---
BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment. --- V600E ---
Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Neoplasms Colorectal Neoplasms 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. --- V600E ---
Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Neoplasms Colorectal Neoplasms 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. --- V600E --- --- V600E ---
Trough plasma concentrations in all patients in Arm A and Arm B. Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Inclusion Criteria: - Safety Lead-In = Male/female ≥ 18 years old - Phase 3: Male/female ≥ 16 years old - Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation - Prior systemic treatment in metastatic setting - SLI: 0-1 regimens - Phase 3: None - Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment - Measurable disease (Phase 3)/ Measurable or evaluable disease (Safety Lead-in) - ECOG PS 0-1 - Adequate organ function Exclusion Criteria: - Tumors that are locally confirmed 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 Neoplasms Colorectal Neoplasms 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. --- V600E --- --- V600E --- --- V600E ---