The safety and efficacy of this agent(s), or use in this setting, has not been established or is subject to confirmation. For an agent(s) whose safety and efficacy has not been established or confirmed, future regulatory approval or commercial availability is not guaranteed.
Active Not-enrolling
United States, Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Denmark, Finland, Germany, India, Italy, Japan, Korea, Republic of, Mexico, Netherlands, New Zealand, Norway, Poland, Russian Federation, Slovakia, South Africa, Spain, Sweden, Taiwan, Ukraine, United Kingdom
for more information at clinicaltrials.gov
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
DRUG: Encorafenib
75 mg capsulesDRUG: Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vialDRUG: Irinotecan
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialEXPERIMENTAL: 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
DRUG: Encorafenib
75 mg capsulesDRUG: Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vialDRUG: Oxaliplatin
Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialEXPERIMENTAL: Phase 3 Arm A
Encorafenib 300 mg orally once daily Cetuximab 500 mg/m2 (120-minute IV infusion) every two weeks
DRUG: Encorafenib
75 mg capsulesDRUG: Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vialEXPERIMENTAL: 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
DRUG: Encorafenib
75 mg capsulesDRUG: Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vialDRUG: Oxaliplatin
Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialACTIVE_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)
DRUG: Oxaliplatin
Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vialDRUG: Irinotecan
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialDRUG: Capecitabine
150 mg or 500 mg TabletDRUG: Bevacizumab
Optional Injection for intravenous use 100 mg/vial or 400 mg/vialEXPERIMENTAL: 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
DRUG: Encorafenib
75 mg capsulesDRUG: Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vialDRUG: Irinotecan
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialACTIVE_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)
DRUG: Irinotecan
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vialDRUG: Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vialDRUG: 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vialDRUG: Bevacizumab
Optional Injection for intravenous use 100 mg/vial or 400 mg/vialSafety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Phase 3: Progression free survival, by blinded independent review
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)
Duration of Phase 3, approximately 36 months
Phase 3: Objective response rate by blinded independent review
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)
Duration of Phase 3, approximately 23 months
Cohort 3: Objective response rate by blinded independent review
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
Duration of Cohort 3, approximately 15 months.
Safety Lead-in: Incidence of adverse events
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms
Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events
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
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Duration of response by Investigator
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in:Progression free survival by Investigator
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Time to response by Investigator
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
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Safety Lead-in: Overall survival
Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI
After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months
Phase 3: Overall survival
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)
Duration of Phase 3, approximately 50 months
Phase 3: Overall response rate by Investigator and by blinded independent review
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)
Duration of Phase 3, approximately 36 months
Phase 3: Duration of response by Investigator and blinded independent review
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)
Duration of Phase 3, approximately 36 months
Phase 3: Time to response by blinded independent review and by Investigator
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)
Duration of Phase 3, approximately 36 months
Phase 3: Progression free survival by Investigator and by blinded independent review
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)
Duration of Phase 3, approximately 36 months
Phase 3: Progression free survival 2 by Investigator
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
Duration of Phase 3, approximately 36 months
Phase 3: Incidence of adverse events
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)
Duration of Phase 3, approximately 36 months
Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms
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)
Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)
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.
Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire
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
Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)
The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
Duration of Phase 3, approximately 36 months
Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires
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.
Duration of Phase 3, approximately 36 months
Phase 3: Confirm the MSI-status in tumor tissue
Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
Once, pre-treatment
Phase 3: To determine the correlation between ctDNA levels, BRAF V600 alterations, and clinical outcome
ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment
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.
Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38
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
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
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
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
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
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)
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 and oxaliplatin
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
Trough plasma concentrations in all patients in Arm A and Arm B
Predose on Cycle 1 through Cycle 6. Each cycle is 28 days
Cohort 3: Progression free survival by Investigator and by blinded independent review
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.
Duration of Cohort 3, approximately 21 months
Cohort 3: Overall response rate by investigator
Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1
Duration of Cohort 3, approximately 21 months
Cohort 3: Duration of response by Investigator and by blinded independent review
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
Duration of Cohort 3, approximately 21 months
Cohort 3: Time to response by Investigator and by blinded independent review
Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1
Duration of Cohort 3, approximately 21 months
Cohort 3: Overall survival
Overall survival, defined as the time from the date of randomization to death due to any cause
Duration of Cohort 3, approximately 36 months
Cohort 3: Incidence of adverse events
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)
Duration of Cohort 3, approximately 21 months
Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms
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)
Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)
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.
Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire
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
Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)
The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.
Duration of Cohort 3, approximately 21 months
Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires
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.
Duration of Cohort 3, approximately 21 months
Cohort 3: Confirm the MSI-status in tumor tissue
Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue
Once, pre-treatment
Cohort 3: To determine the correlation between ctDNA levels, BRAF V600 alterations, and clinical outcome
ctDNA levels and BRAF V600 VAF from ctDNA analysis of plasma samples collected at baseline and on treatment
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.
Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746
Trough plasma concentrations in all patients in Arm D
Predose on Cycle 1 through Cycle 6. Each cycle is 28 days
808
Sponsor: Pfizer
Collaborator: Ono Pharmaceutical Co. Ltd, Merck KGaA, Darmstadt, Germany, Eli Lilly and Company
For more information, call or email the Pfizer Clinical Trial Contact Center:
When calling, please reference this study number:
NCT# stands for National Clinical Trial number. This is a unique identification code given to each clinical trial registered on ClinicalTrials.gov. The format is "NCT" followed by an 8-digit number (for example, NCT00000419). Also called the ClinicalTrials.gov identifier.
NCT04607421
Back
