This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma.
Name: Encorafenib
Name: Binimetinib
Name: Pembrolizumab
Description: A DLT is defined as any adverse event or laboratory value that is assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring within the first 2 cycles of treatment.
Measure: Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs) Time: First 2 Cycles of Treatment (cycles are 21 days)Description: PFS is defined as the time from the date of randomization to the first date of documented disease progression as determined by BICR assessment per RECIST 1.1 or death due to any cause, whichever occurs first.
Measure: Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) Time: Time from the date of randomization to the date of first documented disease progression, as determined by BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks for 24 months)Description: AEs, laboratory parameters, vital signs and cardiac abnormalities will be graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.03).
Measure: Safety Lead in (SLI) and Phase 3: Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments. Time: Time from first dose of study intervention through 28 days after the last dose of study intervention.Description: ORR is defined as the proportion of participants with a confirmed BOR of either CR or PR, as determined by BICR and investigator assessment per RECIST v1.1
Measure: Safety Lead in (SLI) and Phase 3: Objective Response Rate (ORR) Time: Time from the date after the first dose of first dose (SLI) or the date of randomization (Phase 3) until documented PD, or start of subsequent anticancer therapy (approximately every 9 weeks).Description: DCR is defined as the proportion of participants with a confirmed BOR of CR, PR or SD, as determined by BICR and investigator assessment per RECIST v1.1.
Measure: Safety Lead in (SLI) and Phase 3: Disease Control Rate (DCR) Time: Time from the date after the first dose of first dose (SLI) or the date of randomization (Phase 3) until documented PD, or start of subsequent anticancer therapy (approximately every 9 weeks)Description: TTR is defined as the time from the date of randomization to the date of first documented response (CR or PR), as determined by BICR and investigator or assessment per RECIST v1.1.
Measure: Safety Lead in (SLI) and Phase 3: Time to Response (TTR) Time: Time from the date of first dose to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1 (approximately every 9 weeks)Description: OS is defined as the time from the date of randomization to the date of death due to any cause
Measure: Phase 3: Overall Survival (OS) Time: Time from the date of randomization to the date of death due to any cause.Description: PFS by investigator is defined as the time from the date of randomization to the first date of documented disease progression as determined by investigator assessment per RECIST 1.1 or death due to any cause, whichever occurs first.
Measure: Phase 3: Progression Free Survival (PFS) by Investigator Time: The time from the date of randomization to the date of first documented disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)Description: DOR is defined as the time from the date of first documented response to the date of first documented disease progression, as determined by BICR and investigator assessment or death due to any cause, whichever occurs first.
Measure: Phase 3: Duration of Response (DOR) Time: Time from date of first documented response (CR or PR) to the date of first documented disease progression, as determined by BICR and investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)Description: PFS2 is defined as the time from the date of randomization to the date of second objective disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first.
Measure: Phase 3: Progression Free Survival 2 (PFS2) Time: The time from the date of randomization to the date of second objective disease progression, as determined by investigator assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)Description: To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)
Measure: Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib. Time: Cycle 2, Day 1Description: To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)
Measure: Phase 3: Plasma concentrations of encorafenib and binimetinib. Time: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 (Each Cycle is 21 days)Description: EORTC QLQ-30 includes 5 functional scales (physical, role, emotional, cognitive and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/Quality of Life scale
Measure: Phase 3: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30): change from baseline in the global health status/QoL score. Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 monthsDescription: The FACT-M is a melanoma-specific quality of life questionnaire that is composed of items from the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, melanoma-specific items, and items related to melanoma surgery
Measure: Phase 3: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) subscale score. Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 monthsDescription: The EQ-5D-5L is a standardized measure of health utility that provides a single index value of health status and contains 1 item for each of 5 dimensions of HRQoL (ie, mobility, self-care, usual activities, pain or discomfort, and anxiety or depression).
Measure: Phase 3: Change from baseline in 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS) Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 monthsDescription: The PGIS is a single 1-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time by using a 4-point Likert scale that ranges from (1) = "none (no symptoms)" to (4) = "severe".
Measure: Phase 3: Change from baseline in Patient Global Impression of Severity (PGIS) score Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 monthsDescription: The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) "much better" to (5) "much worse", with (4) = "no change"
Measure: Phase 3: Patient Global Impression of Change (PGIC) score Time: Day 1 of every 3 cycles: C4D1, C7D1, C10D1, etc. for the first 24 months and then Day 1 of every 4 cycles after 24 monthsAllocation: Randomized
Parallel Assignment
There are 2 SNPs
A Phase 3, Randomized, Double-blind Study of Encorafenib and Binimetinib Plus Pembrolizumab Versus Placebo Plus Pembrolizumab in Participants With BRAF V600E/K Mutation-Positive Metastatic OR Unresectable Locally Advanced Melanoma. --- V600E ---
Encorafenib and Binimetinib Plus Pembrolizumab Versus Pembrolizumab for V600E/K Positive Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E ---
Encorafenib and Binimetinib Plus Pembrolizumab Versus Pembrolizumab for V600E/K Positive Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E --- --- V600E ---
- ECOG performance status 0 or 1. - Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory. --- V600E ---
Melanoma Melanoma This is a randomized, double-blind, placebo-controlled, Phase 3 study to compare the efficacy, safety, and tolerability of encorafenib and binimetinib plus pembrolizumab (Triplet Arm) versus placebo plus pembrolizumab (Control Arm) in participants with metastatic or unresectable locally advanced BRAF V600E/K mutation-positive melanoma. --- V600E ---
- ECOG performance status 0 or 1. - Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory. --- V600E --- --- V600K ---