A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04607421 |
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Recruitment Status :
Recruiting
First Posted : October 29, 2020
Last Update Posted : March 19, 2024
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Sponsor:
Pfizer
Collaborators:
Ono Pharmaceutical Co. Ltd
Merck KGaA, Darmstadt, Germany
Eli Lilly and Company
Information provided by (Responsible Party):
Pfizer
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Neoplasms | Drug: Encorafenib Drug: Cetuximab Drug: Oxaliplatin Drug: Irinotecan Drug: Leucovorin Drug: 5-FU Drug: Capecitabine Drug: Bevacizumab | Phase 3 |
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 (Clinical Trial) |
| Estimated Enrollment : | 815 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | December 21, 2020 |
| Estimated Primary Completion Date : | November 16, 2024 |
| Estimated Study Completion Date : | November 15, 2026 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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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
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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: 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 |
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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
|
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: 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 |
|
Experimental: 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 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 |
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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
|
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: 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 |
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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)
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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 |
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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
|
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: 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 |
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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)
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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: Bevacizumab Optional Injection for intravenous use 100 mg/vial or 400 mg/vial
Other Name: Zirabev |
Primary Outcome Measures :
- 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
Secondary Outcome Measures :
- 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
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 16 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04607421
Contacts
| Contact: Pfizer CT.gov Call Center | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
Locations
Show 412 study locations
Sponsors and Collaborators
Pfizer
Ono Pharmaceutical Co. Ltd
Merck KGaA, Darmstadt, Germany
Eli Lilly and Company
Investigators
| Study Director: | Pfizer CT.gov Call Center | Pfizer |
Additional Information:
| Responsible Party: | Pfizer |
| ClinicalTrials.gov Identifier: | NCT04607421 |
| Other Study ID Numbers: |
C4221015 2020-001288-99 ( EudraCT Number ) BREAKWATER ( Other Identifier: Pfizer ) |
| First Posted: | October 29, 2020 Key Record Dates |
| Last Update Posted: | March 19, 2024 |
| Last Verified: | March 2024 |
| Individual Participant Data (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 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Pfizer:
|
Colorectal cancer Colon cancer Rectal 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 BREAKWATER Study |
Additional relevant MeSH terms:
|
Neoplasms Colorectal Neoplasms Intestinal Neoplasms Gastrointestinal Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Gastrointestinal Diseases Colonic Diseases Intestinal Diseases Rectal Diseases Leucovorin Bevacizumab Cetuximab Capecitabine |
Fluorouracil Oxaliplatin Irinotecan Antineoplastic Agents, Immunological Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Immunosuppressive Agents Immunologic Factors |