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

• ClinicalTrials.gov Identifier: NCT04607421
• Recruitment Status: Recruiting
• First Posted: October 29, 2020
• Last Update Posted: April 30, 2024
• Sponsor: Pfizer
• Collaborators: Ono Pharmaceutical Co. Ltd; Merck KGaA, Darmstadt, Germany; Eli Lilly and Company
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: October 5, 2020
• First Posted Date: October 29, 2020
• Last Update Posted Date: April 30, 2024
• Actual Study Start Date: December 21, 2020
• Estimated Primary Completion Date: January 6, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 2, 2023)

• 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 ]
  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
• Phase 3: Progression free survival, by blinded independent review [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Objective response rate by blinded independent review [ Time Frame: Duration of Phase 3, approximately 23 months ]
  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)
• Cohort 3: Objective response rate by blinded independent review [ Time Frame: Duration of Cohort 3, approximately 15 months. ]
  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

Original Primary Outcome Measures (submitted: October 22, 2020)

• 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 ]
  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
• Phase 3: Progression free survival, by blinded independent review [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)

Current Secondary Outcome Measures (submitted: March 2, 2023)

• 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 ]
  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
• 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 ]
  Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.
• 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 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 ]
  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
• 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 ]
  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
• 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 ]
  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
• 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 ]
  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
• Safety Lead-in: Overall survival [ Time Frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months ]
  Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI
• Phase 3: Overall survival [ Time Frame: Duration of Phase 3, approximately 50 months ]
  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)
• Phase 3: Overall response rate by Investigator and by blinded independent review [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Duration of response by Investigator and blinded independent review [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Time to response by blinded independent review and by Investigator [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Progression free survival by Investigator and by blinded independent review [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Progression free survival 2 by Investigator [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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
• Phase 3: Incidence of adverse events [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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)
• 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 36 months ]
  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.
• Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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
• Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS) [ Time Frame: Duration of Phase 3, approximately 36 months ]
  The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
• Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires [ Time Frame: Duration of Phase 3, approximately 36 months ]
  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.
• Phase 3: Confirm the MSI-status in tumor tissue [ Time Frame: Once, pre-treatment ]
  Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
• Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome [ 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. ]
  BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment
• 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 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. ]
• 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 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 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 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 ]
  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)
• 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 ]
• Phase 3: Trough concentrations of encorafenib and its metabolite LHY746 [ Time Frame: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days ]
  Trough plasma concentrations in all patients in Arm A and Arm B
• Cohort 3: Progression free survival by Investigator and by blinded independent review [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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.
• Cohort 3: Overall response rate by investigator [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1
• Cohort 3: Duration of response by Investigator and by blinded independent review [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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
• Cohort 3: Time to response by Investigator and by blinded independent review [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1
• Cohort 3: Overall survival [ Time Frame: Duration of Cohort 3, approximately 36 months ]
  Overall survival, defined as the time from the date of randomization to death due to any cause
• Cohort 3: Incidence of adverse events [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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)
• Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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)
• Cohort 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 Cohort 3, approximately 21 months ]
  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.
• Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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
• Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS) [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
• Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires [ Time Frame: Duration of Cohort 3, approximately 21 months ]
  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.
• Cohort 3: Confirm the MSI-status in tumor tissue [ Time Frame: Once, pre-treatment ]
  Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
• Cohort 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, Cycle 7 Day 1 and End of Treatment (Duration of Cohort 3, approximately 21 months). Each cycle is 28 days. ]
  BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment
• Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746 [ Time Frame: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days ]
  Trough plasma concentrations in all patients in Arm D

Original Secondary Outcome Measures (submitted: October 22, 2020)

• 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 ]
  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
• 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 ]
  Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.
• 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 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 ]
  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
• 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 ]
  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
• 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 ]
  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
• 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 ]
  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
• Safety Lead-in: Overall survival [ Time Frame: After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months ]
  Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI
• Phase 3: Overall survival [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Overall response rate by blinded independent review and by Investigator [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Duration of response by blinded independent review and by Investigator [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Time to response by blinded independent review and by Investigator [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Progression free survival by Investigator [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Progression free survival 2 by Investigator [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Incidence of adverse events [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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)
• 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 ]
  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.
• Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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
• Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS) [ Time Frame: Duration of Phase 3, approximately 34 months ]
  The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
• Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires [ Time Frame: Duration of Phase 3, approximately 34 months ]
  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.
• Phase 3: Confirm the MSI-status in tumor tissue [ Time Frame: Once, pre-treatment ]
  Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
• 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 ]
  BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment
• 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 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 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 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 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 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 ]
  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)
• 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 ]
• Phase 3: Trough concentrations of encorafenib and its metabolite LHY746 [ Time Frame: Predose on Cycle 1 through Cycle 6. Each cycle is 28 days ]
  Trough plasma concentrations in all patients in Arm A and Arm B

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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.

This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.

The study team will monitor how each participant responds to the study treatment for up to about 3 years.

• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Neoplasms

Intervention

• Drug: Encorafenib
  75 mg capsules
  Other Name: Braftovi, PF-07263896, LGX818, ONO-7702
• Drug: Cetuximab
  Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial
  Other Name: Erbitux
• Drug: Oxaliplatin
  Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial
  Other Name: Eloxatin
• Drug: Irinotecan
  Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial
  Other Name: Campostar
• Drug: Leucovorin
  Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial
  Other Name: Wellcovorin, Fusilev, Khapzory
• Drug: 5-FU
  Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial
  Other Name: Fluorouracil
• Drug: Capecitabine
  150 mg or 500 mg Tablet
  Other Name: Xeloda
• Drug: Bevacizumab
  Optional Injection for intravenous use 100 mg/vial or 400 mg/vial
  Other Name: Zirabev

Study Arms

• 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
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
  • Drug: Irinotecan
  • Drug: Leucovorin
  • Drug: 5-FU
• 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
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: 5-FU
• Experimental: Phase 3 Arm A
  Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
• 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
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
  • Drug: Oxaliplatin
  • Drug: Leucovorin
  • Drug: 5-FU
• 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)
  Interventions:

  • Drug: Oxaliplatin
  • Drug: Irinotecan
  • Drug: Leucovorin
  • Drug: 5-FU
  • Drug: Capecitabine
  • Drug: Bevacizumab
• 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
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
  • Drug: Irinotecan
  • Drug: Leucovorin
  • Drug: 5-FU
• 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)
  Interventions:

  • Drug: Irinotecan
  • Drug: Leucovorin
  • Drug: 5-FU
  • Drug: Bevacizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 29, 2023): 815
• Original Estimated Enrollment (submitted: October 22, 2020): 930
• Estimated Study Completion Date: November 15, 2026
• Estimated Primary Completion Date: January 6, 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 16 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Pfizer CT.gov Call Center; 1-800-718-1021; ClinicalTrials.gov_Inquiries@pfizer.com

• Listed Location Countries: 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, United States
• Removed Location Countries: Puerto Rico

Administrative Information

• NCT Number: NCT04607421
• Other Study ID Numbers: C4221015; 2020-001288-99 ( EudraCT Number ); BREAKWATER ( Other Identifier: Pfizer )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current

Collaborators

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

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2024