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

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04657991
• Other study ID #: C4221016
• Secondary ID: STARBOARD2020-00
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 15, 2021
• Est. completion date: June 30, 2026

Study information

• Verified date: May 2024
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 216 eligible participants will be randomized in a 1:1 ratio to the Triplet Arm (at RP3D determined in the SLI) or Control Arm (approximately 108 participants per arm). Randomization will be stratified by prior systemic adjuvant therapy and stage of disease by AJCC (ED8).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 189
• Est. completion date: June 30, 2026
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Encorafenib
Encorafenib
• Binimetinib
Binimetinib
• Pembrolizumab
Pembrolizumab

Locations

Country	Name	City	State
Argentina	Instituto Alexander Fleming	Caba	Buenos Aires
Argentina	Instituto de Oncologia de Rosario	Rosario	Santa FE
Argentina	Clinica Viedma S. A	Viedma	RÍO Negro
Austria	Medizinische Universität Graz	Graz
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz	Oberösterreich
Austria	Universitätsklinikum St. Pölten	St. Pölten	Niederösterreich
Austria	Medizinische Universität Wien	Vienna	Wien
Belgium	AZ Sint-Jan Brugge-Oostende AV	Brugge	West-vlaanderen
Belgium	Cliniques universitaires Saint-Luc	Brussels
Belgium	UZ Brussel	Brussels	Bruxelles-capitale, Région DE
Belgium	UZ Gent	Gent	Oost-vlaanderen
Belgium	Centre Hospitalier de Jolimont	Haine Saint Paul
Belgium	VITAZ	Sint-Niklaas
Brazil	Fundação Pio XII - Hospital de Câncer de Barretos	Barretos	SÃO Paulo
Brazil	Instituto de Oncologia do Paraná - IOP Matriz Mateus Leme	Curitiba	Paraná
Brazil	Instituto de Oncologia do Paraná - IOP Oncoville	Curitiba	Paraná
Brazil	Hospital de Clínicas de Passo Fundo	Passo Fundo	RS
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RIO Grande DO SUL
Brazil	Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA	Rio de Janeiro	RJ
Brazil	Hospital Sírio-Libanês - Unidade Bela Vista	São Paulo
Bulgaria	Complex Oncology Center - Plovdiv EOOD	Plovdiv
Bulgaria	Complex Oncology Center-Ruse EOOD	Ruse
Bulgaria	Acibadem City Clinic Multiprofile Hospital for Active Treatment Tokuda EAD	Sofia
Bulgaria	Medical Center Nadezhda Clinical EOOD	Sofia
Bulgaria	Umhato Ead	Sofia
Canada	CIUSSS du Saguenay-Lac-Saint-Jean	Chicoutimi	Quebec
Canada	Kingston Health Sciences Centre-Kingston General Hospital Site	Kingston	Ontario
Canada	McGill University Health Centre - Glen Site	Montreal	Quebec
Canada	Saskatoon Cancer Center	Saskatoon	Saskatchewan
Czechia	Masarykuv Onkologicky Ustav	Brno
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Olomouc	Olomouc	Olomoucký KRAJ
Czechia	Olomouc University Hospital	Olomouc	Olomoucký KRAJ
Czechia	Fakultni nemocnice Ostrava	Ostrava-Poruba
Czechia	Všeobecná fakultní nemocnice	Praha 2
Czechia	Fakultni nemocnice Bulovka	Praha 8-Liben
Finland	Helsinki University Hospital - Comprehensive Cancer Center (HYKS - Syöpäkeskus)	Helsinki
Finland	Tampereen yliopistollinen sairaala	Tampere	Pirkanmaa
France	CHU d'Amiens - Hôpital Nord	Amiens
France	CHU d'Angers	Angers
France	Hôpital Saint André	Bordeaux
France	Hôpital Ambroise Paré	Boulogne-Billancourt
France	Hôpital Ambroise Paré	Boulogne-Billancourt
France	CHU de Dijon Bourgogne	Dijon Cedex
France	CHU Grenoble Alpes	La Tronche
France	CHG Le Mans	Le Mans
France	CHG Le Mans	Le Mans	Cedex 9
France	CHU de Lille - Hôpital Claude Huriez Service	Lille	Nord
France	CHU de Lille - Hôpital Claude Huriez Service	Lille
France	Hôpital de la Timone	Marseille
France	Hôpital Lyon Sud	Pierre-Bénite
France	CHU de Poitiers	Poitiers
France	Chu Charles Nicolle	Rouen	Haute-normandie
France	Hôpital Charles Nicolle - CHU de Rouen	Rouen
France	CHU de Saint-Etienne - Hôpital Nord	Saint-Etienne Cedex 2
France	Gustave Roussy	Villejuif
Germany	Charité Universitaetsmedizin Berlin - Campus Mitte	Berlin
Germany	Vivantes Klinikum Neukölln	Berlin
Germany	Universitätsklinikum Bonn	Bonn	Nordrhein-westfalen
Germany	Elbe Kliniken Stade-Buxtehude, Klinikum Buxtehude	Buxtehude	Niedersachsen
Germany	Universitaetsklinikum Carl Gustav Carus Dresden	Dresden	Sachsen
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Universitaetsklinikum Erlangen	Erlangen	Bayern
Germany	Universitätsklinikum Essen (AöR)	Essen
Germany	SRH Wald-Klinikum Gera	Gera	Thüringen
Germany	Universitaetsklinikum Halle - Universitaetsklinik und Poliklinik fuer Dermatologie und Venerologie	Halle
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitaetsklinikum Schleswig-Holstein Campus Kiel	Kiel	Schleswig-holstein
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck	Schleswig-holstein
Germany	Universitätsmedizin Johannes Gutenberg Universität Mainz	Mainz	Rheinland-pfalz
Germany	Johannes Wesling Klinikum Minden	Minden	Nordrhein-westfalen
Germany	University Hospital Muenster	Muenster
Germany	Klinik und Poliklinik für Dermatologie und Allergologie	München	Bayern
Germany	Fachklinik Hornheide	Münster
Germany	Klinikum Nürnberg Nord	Nürnberg
Germany	Universitätsklinikum Regensburg	Regensburg
Germany	Universitaetsklinikum Tuebingen	Tuebingen	Baden-württemberg
Greece	General Hospital of Athens "Laiko"	Athens	Attikí
Greece	Laiko Hospital	Athens	Attikí
Greece	University General Hospital of Heraklion	Heraklion	Irakleío
Greece	Metropolitan Hospital	Piraeus	Attikí
Greece	Bioclinic Thessalonikis Private Clinic Single Member S.A.	Thessaloniki	Kentrikí Makedonía
Hungary	Orszagos Onkologiai Intezet	Budapest
Hungary	Semmelweis Egyetem	Budapest
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Pécsi Tudományegyetem Klinikai Központ	Pécs	Baranya
Hungary	Szent-Gyorgyi Albert Klinikai Kozpont	Szeged
Hungary	Jász-Nagykun-Szolnok Vármegyei Hetényi Géza Kórház	Szolnok
Israel	Ha'emek Medical Center.	Afula	Hatsafon
Israel	Soroka University Medical Center	Be'er-Sheva
Israel	Hadassah Medical Organization, Hadassah Medical Center, Ein-Karem	Jerusalem
Israel	Rabin Medical Center, Beilinson Hospital	Petah Tikva
Israel	The Chaim Sheba Medical Center	Tel Hashomer
Israel	Tel Aviv Sourasky Medical Center	Tel-Aviv
Italy	Istituto Tumori Giovanni Paolo II	Bari
Italy	Istituto di Candiolo IRCCS - Fondazione del Piemonte per l'Oncologia	Candiolo	Torino
Italy	IRCCS Ospedale Policlinico San Martino	Genova
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	MI
Italy	Istituto Europeo di Oncologia IRCCS	Milano
Italy	Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"	Napoli
Italy	Istituto Oncologico Veneto IOV - IRCCS	Padova
Italy	AO di Perugia - Ospedale S. Maria della Misericordia, S.C Oncologia Medica	Perugia
Italy	Istituto Dermopatico dell'Immacolata (IDI-IRCCS)	Roma	RM
Italy	Istituto Nazionale Tumori Regina Elena	Roma
Italy	A.O.U.S. Policlinico "Le Scotte"	Siena	SI
Italy	Azienda Sanitaria Universitaria Friuli Centrale	Udine	Friuli Venezia Giulia
Mexico	ONCARE Viaducto Nápoles	Benito Juárez	Ciudad DE México
Mexico	BRCR Global Mexico - CDMX	Ciudad de México
Mexico	Preparaciones Oncológicas S.C.	León	Guanajuato
Mexico	I Can Oncology Center S.A. de C.V.	Monterrey	Nuevo LEÓN
Mexico	El Cielo Medical Center	Puebla
Mexico	El Cielo Medical Center RSB, S.C	Puebla
New Zealand	Auckland City Hospital	Auckland
New Zealand	New Zealand Clinical Research (Christchurch)	Christchurch	Canterbury
New Zealand	Palmerston North Hospital	Palmerston North	Manawatu
Norway	Akershus Universitetssykehus	Lørenskog	Akershus
Norway	Oslo universitetssykehus, Radiumhospitalet	Oslo
Poland	Uniwersyteckie Centrum Kliniczne	Gdansk
Poland	Jagiellonskie Centrum Innowacji Sp. z o .o.	Krakow
Poland	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie Sp. z o .o.	Krakow
Poland	Szpital Kliniczny im. Heliodora Swiecickiego UM w Poznaniu	Poznan
Poland	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy	Warszawa
Russian Federation	Ars Medika Center, LLC	Kaliningrad
Russian Federation	BIH of Omsk Region "Clinical Oncological Dispensary"	Omsk
Russian Federation	Private Medical Institution "Euromedservice"	Pushkin	Saint-petersburg
Russian Federation	Eurocityclinic LLC	St.Petersburg
Slovakia	Fakultná nemocnica s poliklinikou F.D. Roosevelta Banská Bystrica	Banska Bystrica
Slovakia	Narodny onkologicky ustav	Bratislava
Slovakia	Onkologicky ustav sv. Alzbety, s.r.o.	Bratislava
Slovakia	Vychodoslovensky onkologicky ustav, a.s.	Kosice
Slovakia	Nemocnica na okraji mesta, n.o.	Partizanske
Slovakia	POKO Poprad, s.r.o.	Poprad
South Africa	Sandton Oncology Medical Group (Pty) Ltd	Johannesburg	Gauteng
South Africa	Wits Clinical Research	Johannesburg	Gauteng
South Africa	Drs Alberts, Bouwer and Jordaan Inc.	Pretoria	Gauteng
South Africa	Mary Potter Oncology Centre	Pretoria
Spain	CHUAC-Hospital Teresa Herrera	A Coruña
Spain	ICO-Badalona Hospital Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital Universitari Vall D'Hebron, Servicio de Oncología Médica	Barcelona
Spain	Hospital Universitario Reina Sofía	Cordoba
Spain	Hospital Clinico Universitario Virgen de la Arrixaca	El Palmar	Murcia
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Hospital Universitario Arnau de Vilanova	Lleida
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario Ramón y Cajal	Madrid
Spain	Hospital Universitario Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Hospital Regional Universitario de Malaga - Hospital Civil	Málaga
Spain	Complejo Hospitalario De Navarra	Pamplona	Navarra
Spain	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria
Spain	CHUS - Hospital Clinico Universitario	Santiago De Compostela	A Coruna
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario Virgen Macarena	Sevilla
Spain	Fundacion Instituto Valenciano de Oncologia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Switzerland	Kantonsspital Winterthur	Winterthur
Switzerland	UniversitätsSpital Zürich	Zürich Flughafen
Turkey	Ankara Sehir Hastanesi	Ankara
Turkey	Memorial Ankara Hastanesi	Ankara
Turkey	Istanbul University Cerrahpasa Medical Faculty Hospital	Istanbul	I?stanbul
Turkey	Medipol Mega Universite Hastanesi	Istanbul	I?stanbul
Turkey	TC Saglik Bakanligi Goztepe Prof. Dr. Suleyman Yalcin Sehir Hastanesi	Istanbul	I?stanbul
Ukraine	Municipal Non-profit Enterprise "City Clinical Hospital #4" of Dnipro City Council	Dnipro
Ukraine	Municipal non-profit enterprise Khmelnytsky regional antitumor center of Khmelnytsky regional	Khmelnytskyi
Ukraine	Municipal non-profit enterprise "Kyiv City Clinical Hospital No. 2" of the executive body of the	Kyiv
Ukraine	National Cancer Institute	Kyiv
Ukraine	Communal Noncommercial Enterprise of Lviv Regional Council "Lviv Oncological Regional Therapeutical	Lviv
Ukraine	Derzhavna ustanova Instytut zahalnoi ta nevidkladnoi khirurhii im.V.T.Zaitseva Natsionalnoi akademii	M. Kharkiv
Ukraine	Komunalne nekomertsiine pidpryiemstvo Kharkivskoi oblasnoi rady "Oblasnyi klinichnyi spetsializovany	M. Kharkiv
Ukraine	Medical and diagnostic center of MedX-Ray International Group Limited Liability Company Israeli	Pliuty Village	KYIV Region, Obukhiv District
Ukraine	Municipal non-profit enterprise "Zaporizhzhia Regional Antitumor Center" Zaporizhzhya Regional Counc	Zaporizhzhia
United Kingdom	St. Bartholomew's Hospital, Barts Health NHS Trust	London
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham	Nottinghamshire
United Kingdom	The South West Wales Cancer Institute, Swansea Bay University Health Board	Swansea
United States	Utah Cancer Specialists	American Fork	Utah
United States	UCHealth Sue Anschutz-Rodgers Eye Center	Aurora	Colorado
United States	University of Colorado Denver CTO/CTRC	Aurora	Colorado
United States	University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)	Aurora	Colorado
United States	University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)	Aurora	Colorado
United States	University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)	Aurora	Colorado
United States	St. Vincent Frontier Cancer Center	Billings	Montana
United States	St. Vincent Healthcare	Billings	Montana
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ophthalmic Consultants of Boston Inc (OCB)	Boston	Massachusetts
United States	Utah Cancer Specialists	Bountiful	Utah
United States	Florida Cancer Specialists	Cape Coral	Florida
United States	Texas Oncology - Carrollton	Carrollton	Texas
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Michigan Health Professionals	Farmington Hills	Michigan
United States	Revive Research Institute, Inc.	Farmington Hills	Michigan
United States	North Dallas Eye Associates	Flower Mound	Texas
United States	Texas Oncology - Flower Mound	Flower Mound	Texas
United States	Florida Cancer Specialists	Fort Myers	Florida
United States	Baylor Clinic	Houston	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	Baylor College of Medicine Medical Center	Houston	Texas
United States	CHI St. Luke's Health Baylor College of Medicine Medical Center	Houston	Texas
United States	Harris Health System - Ben Taub Hospital	Houston	Texas
United States	Harris Health System - Smith Clinic	Houston	Texas
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	Utah Cancer Specialists	Layton	Utah
United States	Ronald Reagan UCLA Medical Center Drug Information Center , Dept. of Pharmaceutical Services (Drug	Los Angeles	California
United States	Ronald Reagan UCLA Medical Center, Drug Information Center, Dept. of Pharmaceutical Services (Main O	Los Angeles	California
United States	UCLA - Hematology/Oncology - Administrative Office	Los Angeles	California
United States	UCLA Hematology/Oncology - Westwood (Building 100)	Los Angeles	California
United States	Utah Cancer Specialists	Murray	Utah
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Tennessee Oncology, PLLC	Nashville	Tennessee
United States	Utah Cancer Specialists	Ogden	Utah
United States	AdventHealth Orlando	Orlando	Florida
United States	AdventHealth Orlando Infusion Center	Orlando	Florida
United States	AdventHealth Orlando, Investigational Drug Services	Orlando	Florida
United States	Dan Brown O.D.	Paris	Texas
United States	Texas Oncology-Paris	Paris	Texas
United States	Advocate Medical Group-Park Ridge, Luther Lane-Oncology	Park Ridge	Illinois
United States	Utah Cancer Specialists	Provo	Utah
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Baylor Scott & White Medical Center - Temple	Temple	Texas
United States	University of Cincinnati Medical Center	West Chester	Ohio
United States	Utah Cancer Specialists	West Jordan	Utah
United States	Utah Cancer Specialists	West Valley City	Utah
United States	The University of Kansas Cancer Center	Westwood	Kansas

Sponsors (2)

Lead Sponsor	Collaborator
Pfizer	Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

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, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Lead In (SLI): Incidence of Dose Limiting Toxicities (DLTs)	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.	First 2 Cycles of Treatment (cycles are 21 days)
Primary	Phase 3: Objective Response (OR) by Blinded Independent Central Review (BICR)	OR is defined as confirmed Best Overall response (BOR) of either CR or PR as determined by BICR assessment per RECIST 1.1	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	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.	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 from first dose of study intervention through 28 days after the last dose of study intervention.
Secondary	Safety Lead in (SLI) and Phase 3: Objective Response (OR)	OR is defined as confirmed Best Overall Response (BOR) of either CR or PR as determined by investigator assessment per RECIST v1.1	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).
Secondary	Safety Lead in (SLI) and Phase 3: Disease Control (DC)	DC is defined as confirmed BOR of CR, PR or SD, as determined by BICR and investigator assessment per RECIST v1.1.	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)
Secondary	Safety Lead in (SLI) and Phase 3: Time to Response (TTR)	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 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)
Secondary	Phase 3: Overall Survival (OS)	OS is defined as the time from the date of randomization to the date of death due to any cause	Time from the date of randomization to the date of death due to any cause.
Secondary	Safety Lead In (SLI) and Phase 3: Progression Free Survival (PFS) by Investigator and BICR assessment	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.	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)
Secondary	Phase 3: Duration of Response (DOR)	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 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)
Secondary	Safety Lead in (SLI): Plasma concentration-time profiles and Pharmacokinetic (PK) parameter estimates for encorafenib and binimetinib.	To measure plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)	Cycle 2, Day 1
Secondary	Phase 3: Plasma concentrations of encorafenib and binimetinib.	To measure the plasma concentrations of encorafenib and its metabolite (LHY746), and binimetinib and its metabolite (AR00426032)	Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1 (Each Cycle is 21 days)
Secondary	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.	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	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
Secondary	Phase 3: Change from baseline in Functional Assessment of Cancer Therapy-Melanoma (FACT-M) subscale score.	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	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
Secondary	Phase 3: Change from baseline in 5-level EuroQol-5D (EQ-5D-5L) index score and visual analog scale (VAS)	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).	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
Secondary	Phase 3: Change from baseline in Patient Global Impression of Severity (PGIS) score	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".	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
Secondary	Phase 3: Patient Global Impression of Change (PGIC) score	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"	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

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