Clinical Trials /

BRAF V600E-mutant Colorectal Cancer Study of Encorafenib Taken With Cetuximab Plus or Minus Chemotherapy (BREAKWATER)

NCT04607421

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

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 3

Trial Eligibility

Document

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

  • Neoplasms

Interventions

DrugSynonymsArms
EncorafenibBraftovi, PF-07263896, LGX818, ONO-7702Phase 3 Arm A
CetuximabErbituxPhase 3 Arm A
OxaliplatinEloxatinPhase 3 Arm B
IrinotecanCampostarPhase 3 Arm B
LeucovorinWellcovorin, Fusilev, KhapzoryPhase 3 Arm B
5-FUFluorouracilPhase 3 Arm B
CapecitabineXelodaPhase 3 Arm C
BevacizumabZirabevPhase 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

NameTypeDescriptionInterventions
Safety Lead-in Cohort 1ExperimentalEncorafenib 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 2ExperimentalEncorafenib 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 AExperimentalEncorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks
  • Encorafenib
  • Cetuximab
Phase 3 Arm BExperimentalEncorafenib 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 CActive ComparatorEvery 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

          -  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
      
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:Not yet recruiting
Lead Sponsor:Pfizer

Last Updated

October 22, 2020