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.

Clinical Trial Details

Geo Regions

Category Image

Melanoma

Encorafenib

Binimetinib

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
Phase 3
NCT04657991

Active Not-enrolling

Globe
Locations

United States, Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Mexico, New Zealand, Norway, Poland, Russian Federation, Slovakia, South Africa, Spain, Switzerland, Turkey, Ukraine, United Kingdom

Study design

Participant Group/Arm

EXPERIMENTAL: Triplet Arm

Encorafenib and Binimetinib in combination with Pembrolizumab

Intervention/Treatment

DRUG: Encorafenib

Encorafenib

DRUG: Binimetinib

Binimetinib

DRUG: Pembrolizumab

Pembrolizumab

Participant Group/Arm

ACTIVE_COMPARATOR: Control Arm

Pembrolizumab

Intervention/Treatment

DRUG: Pembrolizumab

Pembrolizumab

Key eligibility criteria

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 (including, but not limited to, a participant who is rapidly progressing or has clinically significant tumor related symptoms, in the judgment of the investigator).
  • 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)
  • 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, or history of radiation pnuemonitis
  • 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.
Exclusion criteria

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 (including, but not limited to, a participant who is rapidly progressing or has clinically significant tumor related symptoms, in the judgment of the investigator).
  • 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)
  • 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, or history of radiation pnuemonitis
  • 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.

Key dates

Study start date
  • January 2021
Estimated primary completion date
  • June 2026

Key endpoints

Primary Outcome Measures
Outcome Measure

Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs)

Measure 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.

Time Frame

First 2 Cycles of Treatment (cycles are 21 days)

Outcome Measure

Phase 3: Objective Response (OR) by Blinded Independent Central Review (BICR)

Measure Description

OR is defined as confirmed Best Overall response (BOR) of either CR or PR as determined by BICR assessment per RECIST 1.1

Time Frame

Time from the date of randomization until documented PD, start of subsequent anticancer therapy, or death due to any cause (approximately every 9 weeks).

Secondary Outcome Measures:
Outcome 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.

Measure 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).

Time Frame

Time from first dose of study intervention through 28 days after the last dose of study intervention.

Outcome Measure

Safety Lead in (SLI) and Phase 3: Objective Response (OR)

Measure Description

OR is defined as confirmed Best Overall Response (BOR) of either CR or PR as determined by investigator assessment per RECIST v1.1

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).

Outcome Measure

Safety Lead in (SLI) and Phase 3: Disease Control (DC)

Measure Description

DC is defined as confirmed BOR of CR, PR or SD, as determined by BICR and investigator assessment per RECIST v1.1.

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)

Outcome Measure

Safety Lead in (SLI) and Phase 3: Time to Response (TTR)

Measure 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.

Time Frame

Time from the date of randomization to the date of first documented response (CR or PR), as determined by investigator assessment per RECIST v1 (approximately every 9 weeks)

Outcome Measure

Phase 3: Overall Survival (OS)

Measure Description

OS is defined as the time from the date of randomization to the date of death due to any cause

Time Frame

Time from the date of randomization to the date of death due to any cause.

Outcome Measure

Safety Lead In (SLI) and Phase 3: Progression Free Survival (PFS) by Investigator and BICR assessment

Measure 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 and BICR assessment per RECIST 1.1 or death due to any cause, whichever occurs first.

Time Frame

The time from the date of randomization to the date of first documented disease progression, as determined by investigator and BICR assessment per RECIST v1.1, or death due to any cause, whichever occurs first (approximately every 9 weeks)

Outcome Measure

Phase 3: Duration of Response (DOR)

Measure 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.

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)

Outcome Measure

Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib.

Measure Description

To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

Time Frame

Cycle 2, Day 1

Outcome Measure

Phase 3: Plasma concentrations of encorafenib and binimetinib.

Measure Description

To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

Time Frame

Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 (Each Cycle is 21 days)

Outcome 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.

Measure 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

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

Outcome Measure

Phase 3: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) subscale score.

Measure 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

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

Outcome Measure

Phase 3: Change from baseline in 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS)

Measure 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).

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

Outcome Measure

Phase 3: Change from baseline in Patient Global Impression of Severity (PGIS) score

Measure 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".

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

Outcome Measure

Phase 3: Patient Global Impression of Change (PGIC) score

Measure 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"

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

Number of participants

189

Collaborators and investigators

Sponsor: Pfizer

Collaborator: Merck Sharp & Dohme LLC

This information is current as of May 17th 2024.