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.
Recruiting
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Encorafenib | BRAFTOVI | Triplet Arm |
| Binimetinib | MEKTOVI | Triplet Arm |
| Pembrolizumab | KEYTRUDA | Control Arm |
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. The study will have an
open-label safety lead-in (SLI) phase to determine the safety recommended phase 3 dose (RP3D)
and pharmacokinetics (PK) of encorafenib and binimetinib plus pembrolizumab combination
therapy prior to initiation of the randomized Phase 3 part of the study. Two dose levels of
encorafenib in combination with binimetinib plus pembrolizumab will be explored in parallel.
A minimum of 12 evaluable participants will be enrolled per dose level. During the
double-blind randomized Phase 3 part of the study, approximately 600 eligible participants
will be randomized in a 1:1 ratio to the Triplet Arm (at RP3D determined in the SLI) or
Control Arm (approximately 300 participants per arm). Randomization will be stratified by
prior systemic adjuvant therapy and stage of disease by AJCC (ED8)
| Name | Type | Description | Interventions |
|---|---|---|---|
| Triplet Arm | Experimental | Encorafenib and Binimetinib in combination with Pembrolizumab |
|
| Control Arm | Active Comparator | Pembrolizumab |
|
Inclusion Criteria:
- Male or female participants ≥ 18 years at the time of informed consent.
- Participants who are willing and able to comply with all scheduled visits, treatment
plan, laboratory tests, lifestyle considerations, and other study procedures.
- Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage
IV) cutaneous melanoma, according to the AJCC 8th edition.
- Presence of at least 1 measurable lesion as detected by radiological and/or
photographic methods according to RECIST v1.1.
- 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.
- Submission of adequate tumor tissue (archival or newly obtained; block or slides to
the sponsor central laboratory(ies) during the screening period and prior to
enrollment (SLI)/randomization (Phase 3).
- Have not received prior first-line systemic therapy for metastatic or unresectable
locally advanced melanoma.
- Adequate bone marrow function, hepatic and renal function.
- Capable of giving signed informed consent.
Exclusion Criteria
- Other medical or psychiatric condition including recent (within the past year) or
active suicidal ideation/behavior or laboratory abnormality that may increase the risk
of study participation or, in the investigator's judgment, make the participant
inappropriate for the study.
- Mucosal or ocular melanoma.
- Diagnosis of immunodeficiency or an active autoimmune disease that required systemic
treatment in the past 2 years (ie, with use of disease modifying agents,
corticosteroids, or immunosuppressive drugs).
- Clinically significant multiple or severe drug allergies, intolerance to topical
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but
not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal
necrolysis, and exfoliative dermatitis).
- Unable to swallow, retain, and absorb oral medications.
- Impairment of GI function or disease which may significantly alter the absorption of
oral study intervention (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption
syndrome, including malabsorption syndrome secondary to prior GI surgery).
- Clinically significant cardiovascular diseases,
- History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to enrollment
(SLI)/randomization (Phase 3). Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive)
deep vein thrombosis or pulmonary emboli.
- History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled
glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability
syndromes); history of retinal degenerative disease.
- Concurrent neuromuscular disorder that is associated with the potential of elevated CK
(eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis,
spinal muscular atrophy).
- Current noninfectious pneumonitis or history of noninfectious pneumonitis requiring
steroids.
- Evidence of HBV or HCV infection.
- Known history of a positive test for HIV or known AIDS.
- Any active infection requiring systemic therapeutic treatment within 2 weeks prior to
enrollment (SLI)/ randomization (Phase 3).
- Participants with prior or current symptomatic brain metastasis, leptomeningeal
disease or other active CNS metastases.
- Concurrent or previous other malignancy within 2 years of study entry, except
curatively treated basal or squamous cell skin cancer, prostate intraepithelial
neoplasm, carcinoma in-situ of the cervix, Bowen's disease and Gleason ≤ 6 prostate
cancer. Participants with a history of other curatively treated cancers must be
reviewed with the sponsor or designee prior to entering the study.
- Participants who previously received and subsequently discontinued encorafenib and/or
binimetinib and/or anti-PD-1/-L1 due to severe toxicity.
- For participants in the SLI only: Current use or anticipated need for food or drugs
that are known moderate or strong CYP3A4 inhibitors during screening and through the
DLT-evaluation period
- Participant has not recovered to Grade ≤ 1 from toxic effects of prior therapy and/or
complications from prior surgical intervention before enrollment (SLI)/ randomization
(Phase 3).
- Receipt of protocol defined medications or treatments outside of required intervals
before enrollment (SLI)/randomization (Phase 3):
- Previous administration with an investigational drug ≤ 6 months prior to enrollment
(SLI)/randomization (Phase 3).
- Known sensitivity or contraindication to any component of study intervention
(encorafenib, binimetinib and pembrolizumab), or their excipients.
- Pregnant, confirmed by a positive β-hCG laboratory test result, or is breastfeeding
(lactating).
- Investigator site staff or Pfizer employees directly involved in the conduct of the
study, site staff otherwise supervised by the investigator, and their respective
family members.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs) |
| Time Frame: | First 2 Cycles of Treatment (cycles are 21 days) |
| Safety Issue: | |
| 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) and Phase 3: Incidence and severity of Adverse Events (AEs) and changes in clinical laboratory parameters, vital signs, and cardiac assessments. |
| Time Frame: | Time from first dose of study intervention through 28 days after the last dose of study intervention. |
| Safety Issue: | |
| 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: Objective Response Rate (ORR) |
| Time Frame: | 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). |
| Safety Issue: | |
| 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: Disease Control Rate (DCR) |
| Time Frame: | 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) |
| Safety Issue: | |
| 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: Time to Response (TTR) |
| Time Frame: | 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) |
| Safety Issue: | |
| 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: | Phase 3: Overall Survival (OS) |
| Time Frame: | Time from the date of randomization to the date of death due to any cause. |
| Safety Issue: | |
| Description: | OS is defined as the time from the date of randomization to the date of death due to any cause |
| Measure: | Phase 3: Progression Free Survival (PFS) by Investigator |
| Time Frame: | 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) |
| Safety Issue: | |
| 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: Duration of Response (DOR) |
| Time Frame: | 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) |
| Safety Issue: | |
| 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: Progression Free Survival 2 (PFS2) |
| Time Frame: | 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) |
| Safety Issue: | |
| 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: | Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib. |
| Time Frame: | Cycle 2, Day 1 |
| Safety Issue: | |
| Description: | To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032) |
| Measure: | Phase 3: Plasma concentrations of encorafenib and binimetinib. |
| Time Frame: | Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 (Each Cycle is 21 days) |
| Safety Issue: | |
| Description: | To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032) |
| 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 Frame: | 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 months |
| Safety Issue: | |
| 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: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) subscale score. |
| Time Frame: | 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 months |
| Safety Issue: | |
| Description: | 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 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS) |
| Time Frame: | 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 months |
| Safety Issue: | |
| Description: | 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 Patient Global Impression of Severity (PGIS) score |
| Time Frame: | 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 months |
| Safety Issue: | |
| Description: | 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: Patient Global Impression of Change (PGIC) score |
| Time Frame: | 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 months |
| Safety Issue: | |
| Description: | The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change since starting treatment as rated on a 5-point Likert scale anchored by (1) "much better" to (5) "much worse", with (4) = "no change" |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Pfizer |
August 26, 2021
