Description:
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
Title
- Brief Title: BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER)
- 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
Clinical Trial IDs
- ORG STUDY ID:
C4221015
- SECONDARY ID:
2020-001288-99
- NCT ID:
NCT04607421
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| Encorafenib | Braftovi, PF-07263896, LGX818, ONO-7702 | Phase 3 Arm A |
| Cetuximab | Erbitux | Phase 3 Arm A |
| Oxaliplatin | Eloxatin | Phase 3 Arm B |
| Irinotecan | Campostar | Phase 3 Arm B |
| Leucovorin | Wellcovorin, Fusilev, Khapzory | Phase 3 Arm B |
| 5-FU | Fluorouracil | Phase 3 Arm B |
| Capecitabine | Xeloda | Phase 3 Arm C |
| Bevacizumab | Zirabev | Phase 3 Arm C |
Purpose
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
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Safety Lead-in Cohort 1 | Experimental | 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 | - Encorafenib
- Cetuximab
- Irinotecan
- Leucovorin
- 5-FU
|
| Safety Lead-in Cohort 2 | Experimental | 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 | - Encorafenib
- Cetuximab
- Oxaliplatin
- Leucovorin
- 5-FU
|
| Phase 3 Arm A | Experimental | Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks | |
| Phase 3 Arm B | Experimental | 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 -OR- 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 | - Encorafenib
- Cetuximab
- Oxaliplatin
- Irinotecan
- Leucovorin
- 5-FU
|
| Phase 3 Arm C | Active Comparator | 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- Every two weeks: Irinotecan 180 mg/m2 (90-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- 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) | - Oxaliplatin
- Irinotecan
- Leucovorin
- 5-FU
- Capecitabine
- Bevacizumab
|
Eligibility Criteria
Inclusion Criteria:
- Safety Lead-In = Male/female ≥ 18 years old
- Phase 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
- 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 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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 16 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs) |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
Secondary Outcome Measures
| Measure: | Safety Lead-in: Incidence of adverse events |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
| Measure: | Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| Description: | Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion. |
| 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 |
| Safety Issue: | |
| Description: | |
| Measure: | Safety Lead-in: Overall response rate by investigator |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
| Measure: | Safety Lead-in: Duration of response by Investigator |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
| Measure: | Safety Lead-in:Progression free survival by Investigator |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
| Measure: | Safety Lead-in: Time to response by Investigator |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| 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 |
| Measure: | Safety Lead-in: Overall survival |
| Time Frame: | After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months |
| Safety Issue: | |
| Description: | Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI |
| Measure: | Phase 3: Overall survival |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 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: Incidence of adverse events |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 or encorafenib + cetuximab + FOLFIRI (Arm B) |
| Measure: | Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 or encorafenib + cetuximab + FOLFIRI (Arm B) |
| 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 Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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. |
| Measure: | Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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 |
| Measure: | Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS) |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| Description: | 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 Change (PGIC) questionnaires |
| Time Frame: | Duration of Phase 3, approximately 34 months |
| Safety Issue: | |
| 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. |
| Measure: | Phase 3: Confirm the MSI-status in tumor tissue |
| Time Frame: | Once, pre-treatment |
| Safety Issue: | |
| Description: | Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue |
| Measure: | Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome |
| Time Frame: | 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 days |
| Safety Issue: | |
| Description: | BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment |
| 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 |
| Safety Issue: | |
| Description: | |
| 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. Each cycle is 28 days |
| Safety Issue: | |
| Description: | |
| 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 |
| Safety Issue: | |
| Description: | |
| 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 |
| Safety Issue: | |
| Description: | |
| 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 |
| Safety Issue: | |
| Description: | |
| Measure: | Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin |
| 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 |
| Safety Issue: | |
| 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) |
| 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 |
| Safety Issue: | |
| Description: | |
| Measure: | Phase 3: Trough concentrations of encorafenib and its metabolite LHY746 |
| Time Frame: | Predose on Cycle 1 through Cycle 6. Each cycle is 28 days |
| Safety Issue: | |
| Description: | Trough plasma concentrations in all patients in Arm A and Arm B |
Details
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Pfizer |
Trial Keywords
- Colorectal 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
Last Updated
August 3, 2021
