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A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma

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: NCT04657991
Recruitment Status : Recruiting
First Posted : December 8, 2020
Last Update Posted : May 18, 2023
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Pfizer

Study Description
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Brief Summary:

The purpose of this study is to learn about the effects of three study medicines (encorafenib, binimetinib, and pembrolizumab) given together for the treatment of melanoma that:

  • is advanced or metastatic (spread to other parts of the body);
  • has a certain type of abnormal gene called "BRAF"; and
  • has not received prior treatment.

All participants in this study will receive pembrolizumab at the study clinic once every 3 weeks as an intravenous (IV) infusion (given directly into a vein). In addition, half of the participants will take encorafenib and binimetinib orally (by mouth) at home every day.

Participants may receive pembrolizumab for up to two years. Those participants taking encorafenib and binimetinib can continue until their melanoma is no longer responding. The study team will monitor how each participant is doing with the study treatment during regular visits at the study clinic.


Condition or disease Intervention/treatment Phase
Melanoma Drug: Encorafenib Drug: Binimetinib Drug: Pembrolizumab Phase 3

Detailed Description:
This study will 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 recommend 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).
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 624 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : January 15, 2021
Estimated Primary Completion Date : September 30, 2024
Estimated Study Completion Date : February 9, 2030

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Triplet Arm
Encorafenib and Binimetinib in combination with Pembrolizumab
 Drug: Encorafenib
Encorafenib
Other Name: BRAFTOVI

Drug: Binimetinib
Binimetinib
Other Name: MEKTOVI

Drug: Pembrolizumab
Pembrolizumab
Other Name: KEYTRUDA
Active Comparator: Control Arm
Pembrolizumab
 Drug: Pembrolizumab
Pembrolizumab
Other Name: KEYTRUDA


Outcome Measures
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Primary Outcome Measures :
  1. Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: First 2 Cycles of Treatment (cycles are 21 days) ]
    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.

  2. Phase 3: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) [ Time Frame: 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) ]
    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.


Secondary Outcome Measures :
  1. 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. ]
    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).

  2. 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). ]
    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

  3. 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) ]
    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.

  4. Safety Lead in (SLI) and Phase 3: Time to Response (TTR) [ 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) ]
    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.

  5. Phase 3: Overall Survival (OS) [ Time Frame: Time from the date of randomization to the date of death due to any cause. ]
    OS is defined as the time from the date of randomization to the date of death due to any cause

  6. 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) ]
    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.

  7. 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) ]
    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.

  8. Phase 3: Progression Free Survival 2 (PFS2) [ Time Frame: The time from the date of randomization to the date of discontinuation of next-line treatment after first objective disease progression by investigator assessment per RECIST v1.1 (approximately every 9 weeks) ]
    PFS2 is defined as the time from the date of randomization to the date of discontinuation of next-line treatment after first objective disease progression by investigator assessment per RECIST v1.1

  9. Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib. [ Time Frame: Cycle 2, Day 1 ]
    To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

  10. 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) ]
    To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)

  11. 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 ]
    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

  12. 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 ]
    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

  13. 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 ]
    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).

  14. 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 ]
    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".

  15. 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 ]
    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"


Eligibility Criteria
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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.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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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): NCT04657991


Contacts
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Contact: Pfizer CT.gov Call Center 1-800-718-1021 ClinicalTrials.gov_Inquiries@pfizer.com

Locations
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Sponsors and Collaborators
Pfizer
Merck Sharp & Dohme LLC
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT04657991    
Other Study ID Numbers: C4221016
STARBOARD ( Other Identifier: Alias Study Number )
2020-004850-31 ( EudraCT Number )
KEYNOTE-B80 ( Other Identifier: Alias Study Number )
First Posted: December 8, 2020    Key Record Dates
Last Update Posted: May 18, 2023
Last Verified: May 2023
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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pfizer:
BRAF V600E/K Melanoma
BRAF
Melanoma
Advanced Melanoma
Metastatic Melanoma
Skin Cancer
 Advanced Skin Cancer
Starboard
Stage 3 Melanoma
Stage 4 Melanoma
BRAF Melanoma
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
 Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action