A Study of Encorafenib Plus Cetuximab With or Without Chemotherapy in People With Previously Untreated Metastatic Colorectal Cancer

Neoplasms Clinical Trial

Official title:

AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE 3 STUDY OF FIRST-LINE ENCORAFENIB PLUS CETUXIMAB WITH OR WITHOUT CHEMOTHERAPY VERSUS STANDARD OF CARE THERAPY WITH A SAFETY LEAD-IN OF ENCORAFENIB AND CETUXIMAB PLUS CHEMOTHERAPY IN PARTICIPANTS WITH METASTATIC BRAF V600E-MUTANT COLORECTAL CANCER

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04607421
• Other study ID #: C4221015
• Secondary ID: 2020-001288-99BR
• Status: Recruiting
• Phase: Phase 3
• Start date: December 21, 2020
• Est. completion date: November 15, 2026

Study information

• Verified date: May 2024
• Source: Pfizer
• Contact: Pfizer CT.gov Call Center
• Phone: 1-800-718-1021
• Email: ClinicalTrials.gov_Inquiries[@]pfizer.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate two study medicines (encorafenib plus cetuximab) taken alone or together with standard chemotherapy for the potential treatment of colorectal cancer that:

• has spread to other parts of the body (metastatic);

• has a certain type of abnormal gene called "BRAF"; and

• has not received prior treatment.

Participants in this study will receive one of the following study treatments:

• Encorafenib plus cetuximab: These participants will receive encorafenib by mouth at home every day and cetuximab once every two weeks by intravenous (IV) infusion (an injection into the vein) at the study clinic.

• Encorafenib plus cetuximab with chemotherapy: These participants will receive encorafenib and cetuximab in the way described in the bullet above. Additionally, they will receive standard chemotherapy by IV infusion and oral treatment at home.

• Chemotherapy alone: These participants will receive chemotherapy, the standard treatment for this condition, by IV infusion at the study clinics and oral treatment at home.

This study is currently enrolling participants who will receive either encorafenib plus cetuximab with chemotherapy or chemotherapy alone.

The study team will monitor how each participant responds to the study treatment for up to about 3 years.

Description:

The purpose of the study is to evaluate whether encorafenib plus cetuximab (EC), alone or in combination with chemotherapy, can improve clinical outcomes relative to current standard of-care chemotherapy in participants with previously untreated BRAF V600E-mutant mCRC. Since encorafenib has not previously been combined with chemotherapy, the tolerability and PK of EC in combination with mFOLFOX6 and in combination with FOLFIRI will be evaluated in separate cohorts in the safety lead-in portion of the trial in order to identify which chemotherapy combination is to be used in the Phase 3 portion of the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 815
• Est. completion date: November 15, 2026
• Est. primary completion date: January 6, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 16 Years and older

Eligibility

Inclusion Criteria:

• Safety Lead-In = Male/female = 18 years old

• Phase 3 and Cohort 3: Male/female = 16 years old (where permitted locally)

• Histologically or cytologically confirmed Stage IV CRC that contains BRAF V600E mutation

• Prior systemic treatment in metastatic setting: 0-1 regimens for Safety Lead In; none for Phase 3 and Cohort 3. (Note: Prior adjuvant or neoadjuvant therapy considered metastatic treatment if relapse/metastasis < 6 month from end of adj/neoadjuvant treatment )

• Measurable disease (Phase 3 and Cohort 3)/ Measurable or evaluable disease (Safety Lead-in)

• ECOG PS 0-1

• Adequate organ function

Exclusion Criteria:

• Tumors that are locally confirmed or unknown MSI-H or dMMR unless participant is ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition

• Active bacterial or viral infections in 2 weeks prior to starting dosing

• Symptomatic brain metastases

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Neoplasms

Intervention

Drug:
• Encorafenib
75 mg capsules
• Cetuximab
Injection for intravenous use 100 mg/vial, 200 mg/vial, or 500 mg/vial
• Oxaliplatin
Powder for solution for intravenous use 50 mg/vial, 100 mg/vial, or 200 mg/vial
• Irinotecan
Solution for intravenous infusion 40 mg/vial, 100 mg/vial, or 300 mg/vial
• Leucovorin
Injection 50 mg/vial, 100 mg/vial, 200 mg/vial, or 350 mg/vial
• 5-FU
Injection for intravenous use 250 mg/vial, 500 mg/vial, or 1000 mg/vial
• Capecitabine
150 mg or 500 mg Tablet
• Bevacizumab
Optional Injection for intravenous use 100 mg/vial or 400 mg/vial

Locations

Country	Name	City	State
Argentina	Instituto Médico Especializado Alexander Fleming	Ciudad Autónoma de Buenos Aires
Argentina	Clinica Universitaria Reina Fabiola	Cordoba
Argentina	Hospital Privado Centro Médico de Córdoba	Cordoba
Argentina	Hospital Privado Centro Médico de Córdoba	Córdoba
Argentina	Centro Medico San Roque	San Miguel De Tucumán	Tucumán
Argentina	Centro Medico San Roque	Tucuman	Tucumán
Australia	The Queen Elizabeth Hospital	Adelaide	South Australia
Australia	Chris O'Brien Lifehouse	Camperdown	New South Wales
Australia	Monash Health	Clayton	Victoria
Australia	Austin Health	Heidelberg	Victoria
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Alfred Health	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria
Australia	Slade Pharmacy	Mount Kuring-Gai	New South Wales
Australia	GenesisCare - North Shore	St Leonards	New South Wales
Australia	GenesisCare North Shore	St Leonards	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	ZNA Middelheim	Antwerpen
Belgium	Cliniques universitaires Saint-Luc	Brussels	Bruxelles-capitale, Région DE
Belgium	Université Libre de Bruxelles - Hôpital Erasme	Brussels	Bruxelles-capitale, Région DE
Belgium	Grand Hôpital de Charleroi	Charleroi	Hainaut
Belgium	AZ Groeninge Campus Kennedylaan	Kortrijk	West-vlaanderen
Belgium	UZ Leuven	Leuven
Belgium	Centre Hospitalier Universitaire de Liège - Domaine Universitaire du Sart Tilman	Liège
Belgium	CHR Verviers East Belgium	Verviers	Liège
Brazil	Fundação Pio XII - Hospital de Câncer de Barretos	Barretos	SÃO Paulo
Brazil	Hospital do Cancer de Barretos - Fundacao Pio XII	Barretos	SP
Brazil	Reichow - Centro de Ensino e Pesquisa	Blumenau	Santa Catarina
Brazil	Clínica de Neoplasias Litoral	Itajaí	Santa Catarina
Brazil	Hospital Bruno Born	Lajeado	RIO Grande DO SUL
Brazil	Hospital Bruno Born	Lajeado	RIO Grande DO SUL
Brazil	Hospital Bruno Born	Lajeado	RIO Grande DO SUL
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RIO Grande DO SUL
Brazil	INCA	Rio de Janeiro	RJ
Brazil	Instituto Nacional de Câncer José Alencar Gomes da Silva - INCA	Rio de Janeiro	RJ
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia - Faculdade de Medicina do ABC	Santo Andre	SP
Brazil	FUNDAÇÃO DO ABC - Faculdade de Medicina do ABC - Centro de Estudos e Pesquisas de Hematologia e Onc	Santo Andre	SP
Brazil	Fundacao do ABC-Faculdade de Medicina do ABC	Santo Andre	SP
Brazil	CEPHO - Centro de Estudos e Pesquisas de Hematologia e Oncologia - Faculdade de Medicina do ABC	Santo André	SP
Brazil	Medical School Famerp-HB-FUNFARME_Do not use - Duplicate facility	Sao jose do Rio Preto	SÃO Paulo
Brazil	Fundação Faculdade Regional de Medicina de São José do Rio Preto	São José do Rio Preto	SÃO Paulo
Brazil	Instituto do Cancer do Estado de Sao Paulo, ICESP	Sao Paulo	SP
Bulgaria	MHAT "Dr. Tota Venkova" AD	Gabrovo
Bulgaria	MHAT Uni Hospital OOD	Panagyurishte	Pazardzhik
Bulgaria	Complex Oncology Center - Plovdiv EOOD	Plovdiv
Bulgaria	Complex Oncology Center - Plovdiv EOOD	Plovdiv
Bulgaria	MHAT Central Onco Hospital OOD	Plovdiv
Bulgaria	Acibadem City Clinic MHAT Tokuda	Sofia
Bulgaria	Medical Center Nadezhda Clinical EOOD	Sofia
Bulgaria	University Multiprofile Hospital for Active Treatment Sofiamed	Sofia
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Kingston Health Sciences Centre-Kingston General Hospital Site	Kingston	Ontario
Canada	Centre Intégré de Santé et de Services Sociaux (CISSS) de Laval / Hôpital de la Cité-de-la-Sant	Laval	Quebec
Canada	London Regional Cancer Program, London Health Sciences Centre	London	Ontario
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
China	Beijing Cancer hospital	Beijing	Beijing
China	Beijing Hospital	Beijing	Beijing
China	Cancer Hospital Chinese Academy of Medical Science	Beijing	Beijing
China	Peking University First Hospital	Beijing
China	The Second Xiangya Hospital of Central South University	Changsha	Hunan
China	The Third Xiangya Hospital of Central South University	Changsha	Hunan
China	Sichuan Province Cancer Hospital	Chengdu	Sichuan
China	Chongqing University Cancer Hospital	Chongqing	Chongqing
China	Fujian Medical University Union Hospital-1 Bingfanglou	Fuzhou	Fujian
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	Guangdong Provincial People's Hospital	Guangzhou	Guangdong
China	The Sixth Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong
China	The second Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang
China	Anhui Provincial Cancer Hospital	Hefei	Anhui
China	The First Affiliated Hospital of Anhui Medical University	Hefei	Anhui
China	Jinan Central Hospital	Jinan	Shandong
China	Shandong province cancer hospital	Jinan	Shandong
China	Yunnan Cancer Hospital(The Third Affiliated Hospital of Kunming Medical University)	Kunming	Yunnan
China	Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School	Nanjing	Jiangsu
China	Affiliated Tumor Hospital of Guangxi Medical University	Nanning	Guangxi
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Fudan University Shanghai Cancer Center	Shanghai
China	Shanghai General Hospital	Shanghai	Shanghai
China	Shanghai Jiaotong University School of Medicine Ruijin Hospital	Shanghai	Shanghai
China	Shengjing Hospital Of China Medical University	Shenyang	Liaoning
China	Tianjin Union Medical Center	Tianjin
China	Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology	Wuhan	Hubei
China	Henan provincial people's hospital	Zhengzhou	Henan
Czechia	Fakultní nemocnice Brno Bohunice	Brno	Brno-mesto
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove	Hradec Králové
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Fakultni Thomayerova nemocnice	Prague	Praha 4
Czechia	Fakultni nemocnice v Motole	Praha 5
Czechia	Fakultni nemocnice Bulovka	Praha 8
Denmark	Aalborg Universitetshospital	Aalborg
Denmark	Aalborg Universitetshospital, Syd	Aalborg	Nordjylland
Denmark	Rigshospitalet	Copenhagen
Denmark	Herlev and Gentofte Hospital	Herlev
Denmark	Odense University Hospital	Odense C
Denmark	Vejle Hospital-Sygehus Lillebaelt	Vejle	Syddanmark
Denmark	Vejle Sygehus	Vejle	Syddanmark
Finland	Docrates Syöpäsairaala	Helsinki	Nyland
Finland	Helsinki University Central Hospital	Helsinki
Finland	Oulu University Hospital	Oulu
Finland	Satakunnan Keskussairaala	Pori
Finland	Tampereen yliopistollinen sairaala	Tampere
Finland	Tampereen yliopistollinen sairaala	Tampere	Pirkanmaa
Finland	Turku University Hospital	Turku
Germany	HELIOS Klinikum Berlin Buch GmbH	Berlin
Germany	Helios Klinikum Berlin-Buch	Berlin
Germany	Onkologische Schwerpunktpraxis Kurfuerstendamm	Berlin
Germany	Waage Apotheke	Berlin
Germany	Radiologie Berlin	Berlin - Charlottenburg
Germany	Technische Universität Dresden, Medizinische Fakultät Carl Gustav Carus	Dresden
Germany	Universitätsklinikum Carl Gustav Carus Dresden	Dresden
Germany	Institut für Klinisch Onkologische Forschung	Frankfurt	Hessen
Germany	Facharztzentrum Eppendorf	Hamburg
Germany	Radiologie im Israelitischen Krankenhaus	Hamburg
Germany	ZytoService Deutschland GmbH, Standort-Hamburg-Jenfeld	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover	Lower Saxony
Germany	Medizinische Hochschule Hannover	Hannover	Niedersachsen
Germany	Universitätsklinikum Leipzig	Leipzig	Sachsen
Germany	Muenchen Klinik Neuperlach, Klinik fuer Haematologie und Onkologie	Muenchen	Bayern
Germany	Klinikum Oldenburg AöR	Oldenburg
Germany	Klinikum Oldenburg AöR	Oldenburg
India	R K Birla Cancer Center, SMS Hospital	Jaipur	Rajasthan
India	Sawai Man Singh Medical College Hospital (SMS Hospital)	Jaipur	Rajasthan
India	Tata Memorial Hospital	Mumbai	Maharashtra
India	Rajiv Gandhi Cancer Institute And Research Centre	New Delhi	Delhi
India	Rajiv Gandhi Cancer Institute And Research Centre	New Delhi	Delhi
India	Deenanath Mangeshkar Hospital & Research Centre	Pune	Maharashtra
India	Sahyadri Speciality Hospital	Pune	Maharashtra
India	Bhakti Vedanta Hospital and Research Institute	Thane	Maharashtra
Italy	Fondazione Poliambulanza Istituto Ospedaliero	Brescia
Italy	Fondazione del Piemonte per l'Oncologia - Istituto di Candiolo IRCCS	Candiolo	Torino
Italy	ASST Grande Ospedale Metropolitano Niguarda	Milan	Milano
Italy	Istituto Europeo di Oncologia IRCCS	Milano
Italy	Azienda Ospedaliera Universitaria di Cagliari - Presidio Policlinico Universitario "D.Casula"	Monserrato (CA)	Cagliari
Italy	Azienda Ospedaliera Universitaria dell'Università "Luigi Vanvitelli" di Napoli	Napoli
Italy	Azienda Ospedaliero Universitaria San Luigi Gonzaga	Orbassano	Torino
Italy	IRCCS Istituto Oncologico Veneto (IOV)	Padova
Italy	Azienda USL - IRCCS di Reggio Emilia - Arcispedale Santa Maria Nuova	Reggio Emilia
Italy	IRCCS Casa Sollievo della Sofferenza	San Giovanni Rotondo	Foggia
Japan	Chiba cancer center	Chiba-shi	Chiba
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Hospital Organization Kyushu Cancer Center	Fukuoka
Japan	Saitama Medical University International Medical Center	Hidaka-city	Saitama
Japan	Saitama Prefectural Cancer Center	Ina-machi	Saitama
Japan	Kanazawa University Hospital	Kanazawa	Ishikawa
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	St. Marianna University Hospital	Kawasaki	Kanagawa
Japan	Japanese Foundation for Cancer Research	Koto-ku	Tokyo
Japan	National Hospital Organization Shikoku Cancer Center	Matsuyama	Ehime
Japan	Shizuoka Cancer Center	Nagaizumi	Shizuoka
Japan	Aichi Cancer Center Hospital	Nagoya	Nagoya, Aichi
Japan	National Hospital Organization - Osaka National Hospital - Institute For Clinical Research	Osaka
Japan	Osaka Prefectural Hospital Organization Osaka International Cancer Institute	Osaka-shi	Osaka
Japan	Kindai University Hospital	Osakasayama	Osaka
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Osaka University Hospital	Suita	Osaka
Japan	Osaka Medical and Pharmaceutical University Hospital	Takatsuki	Osaka
Japan	Keio university hospital	Tokyo
Japan	Kanagawa cancer center	Yokohama	Kanagawa
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	Kyungpook National University Hospital	Daegu	Taegu-kwangyokshi
Korea, Republic of	National Cancer Center	Goyang-si	Gyeonggi-do
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Chonnam National University Hwasun Hospital	Jeonnam
Korea, Republic of	Chonnam National University Hwasun Hospital Pharmacy	Jeonnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Mexico	Accelerium, S. de R.L. de C.V.	Monterrey	Nuevo LEON
Mexico	Centro de Investigacion Clinica de Oaxaca	Oaxaca
Netherlands	Amsterdam UMC, location VUMc	Amsterdam
Netherlands	Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)	Amsterdam	Noord-holland
Netherlands	Catharina Ziekenhuis	Eindhoven	Noord-brabant
Netherlands	Haaglanden Medisch Centrum	Leidschendam	Zuid-holland
Netherlands	Maastricht UMC+	Maastricht	Limburg
Netherlands	Maastricht University Medical Center	Maastricht
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
New Zealand	Auckland City Hospital	Auckland
New Zealand	Auckland District Health Board Charitable Trust	Auckland
New Zealand	Tauranga Hospital	Tauranga	BAY OF Plenty
Norway	Haukeland University Hospital	Bergen	Hordaland
Norway	Sørlandet Sykehus Kristiansand	Kristiansand	Vest-agder
Norway	Oslo Universitetssykehus Ullevål	Oslo
Norway	Oslo universitetssykehus, Radiumhospitalet	Oslo
Norway	Stavanger Universitetssykehus	Stavanger	Rogaland
Norway	St. Olavs hospital	Trondheim	Sør-trøndelag
Poland	Szpital Specjalistyczny W Brzozowie, Podkarpacki Osrodek Onkologiczny Im.Ks.B.Markiewicza	Brzozow
Poland	Wojewodzki Szpital Specjalistyczny Nr 4 w Bytomiu Oddzial Onkologii	Bytom
Poland	COPERNICUS PL sp. z. o. o. Wojewodzkie Centrum Onkologii w Gdansku Ambulatoryjna	Gdansk
Poland	COPERNICUS Podmiot Leczniczy Sp. z o.o. Wojewodzkie Centrum Onkologii	Gdansk
Poland	Przychodnia Lekarska KOMED	Konin
Poland	Przychodnia Lekarska KOMED	Konin	Wielkopolskie
Russian Federation	GBUZ	Chelyabinsk
Russian Federation	Kaluga Regional Clinical Oncology Center	Kaluga
Russian Federation	FSAEI HE I.M Sechenov First MSMU MoH Russia (Sechenovskiy University),	Moscow
Russian Federation	BHI of Omsk Region "Clinical Oncology Dispensary"	Omsk
Russian Federation	BHI of Omsk Region "Clinical Oncology Dispensary"	Omsk
Russian Federation	Private Medical Institution "Euromedservice"	Pushkin	Saint-petersburg
Russian Federation	Private Medical Institution "Euromedservice"	Pushkin	Sankt-peterburg
Russian Federation	LLC "EuroCityClinic"	Saint Petersburg
Russian Federation	LLC "Medicina Severnoy Stolitsy"	Saint-Petersburg
Russian Federation	LLC "Severo-Zapadny Medical Center"	Saint-Petersburg
Russian Federation	Private Healthcare Institution "Clinical Hospital "RZD-Medicine" of St. Petersburg	Saint-Petersburg
Russian Federation	FSBI "Russian Scientific Center For Radiology and Surgical Technologies n.a. Academician A.M. Granov	St. Petersburg
Russian Federation	SHI YR Regional Clinical Oncology Hospital	Yaroslav
Russian Federation	SHI YR Regional Clinical Oncology Hospital	Yaroslavl
Russian Federation	SHI YR Regional Clinical Oncology Hospital	Yaroslavl
Slovakia	Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska Bystrica	Banska Bystrica
Slovakia	Fakultna nemocnica s poliklinikou F. D. Roosevelta Banska 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	POKO Poprad s.r.o.	Poprad
South Africa	Cape Town Oncology Trials	Cape Town	Western CAPE
South Africa	Charlotte Maxeke Johannesburg Academic Hospital	Johannesburg	Gauteng
South Africa	Wits Health Consortium (Pty) Ltd	Johannesburg
South Africa	Wits Clinical Research	Parktown, Johannesburg	Gauteng
South Africa	Cancercare Langenhoven Drive Oncology Centre	Port Elizabeth	Eastern CAPE
South Africa	Mary Potter Oncology Centre	Pretoria
South Africa	Cancercare Rondebosch Oncology	Rondebosch	Cape Town
Spain	Hospital Clinic Barcelona	Barcelona
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital General Universitario de Elche	Elche	Alicante
Spain	ICO L'Hospitalet (Hospital Duran i Reynals)	Hospitalet de Llobregat	Barcelona
Spain	Hospital General Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario 12 de octubre	Madrid
Spain	Hospital Universitario Ramon Y Cajal	Madrid
Spain	Complejo Hospitalario Universitario Santiago de Compostela	Santiago de Compostela	A Coruña
Spain	Hospital Universitario Virgen Del Rocio	Sevilla
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg	Västra Götalands LÄN [se14]
Sweden	Karolinska Universitetssjukhuset Solna	Solna	Stockholms LÄN [se-01]
Sweden	Norrlands universitetssjukhus	Umeå	Västerbottens LÄN [se-24]
Sweden	Akademiska sjukhuset	Uppsala	Uppsala LÄN [se-03]
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chi Mei Hospital, Liouying	Tainan
Taiwan	National Cheng-Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Medical University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Medical Foundation-Linkou Branch	Taoyuan
Ukraine	Municipal Non-profit Enterprise "City Clinical Hospital #4" of Dnipro City Council	Dnipro
Ukraine	Ivano-Frankivsk National Medical University	Ivano-Frankivsk
Ukraine	MNPE "Prykarpatski Clinical Oncological Center" of Ivano-Frankivsk Regional Council"	Ivano-Frankivsk
Ukraine	PRECARPATHIAN NUCLEAR MEDICINE CENTER, Limited Liability Company	Ivano-Frankivsk
Ukraine	Communal Non-Profit Enterprise "Regional Center of Oncology"	Kharkiv
Ukraine	Municipal non-profit enterprise "City clinical hospital #2 named after O.O.Shalimov"	Kharkiv
Ukraine	Communal enterprise "Kryvyi Rih Oncology Dispensary" of Dnipropetrovsk Regional Council	Kryvyi Rih
Ukraine	Municipal non-profit enterprise of Kyiv regional council "Kyiv regional clinical hospital"	Kyiv
Ukraine	SI "Insitute of Neurosurgery n.a.acad. A.P.	Kyiv
Ukraine	SI "Insitute of Neurosurgery n.a.acad. A.P.	Kyiv
Ukraine	Medical and diagnostic center of MediX-Ray International Group LLC Israeli Oncology Hospital "LISOD"	Pliuty Village	KYIV Region, Obuhovskiy District
Ukraine	Municipal non-profit enterprise "Zaporizhzhia Regional Antitumor Center" Zaporizhzhia Regional	Zaporizhzhia
United Kingdom	Heartlands Hospital	Birmingham
United Kingdom	Hammersmith Hospital	London
United Kingdom	Hammersmith Hospital, Imperial College Healthcare NHS Trust	London
United Kingdom	Royal Marsden NHS Foundation Trust	London
United Kingdom	Freeman Hospital	Newcastle upon Tyne	HIGH Heaton
United Kingdom	Churchill Hospital - Oncology	Oxford
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton	Surrey
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Michigan Hospitals	Ann Arbor	Michigan
United States	Mount Sinai Comprehensive Cancer Center, Aventura	Aventura	Florida
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	Babylon	New York
United States	Memorial Sloan Kettering Cancer Center - Basking Ridge	Basking Ridge	New Jersey
United States	Summit Medical Group	Berkeley Heights	New Jersey
United States	Tower Hematology Oncology Medical Group (THO)	Beverly Hills	California
United States	St Vincent Healthcare	Billings	Montana
United States	St. Vincent Frontier Cancer Center	Billings	Montana
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	Bronx	New York
United States	Atrium Health Mercy	Charlotte	North Carolina
United States	Atrium Health Pineville	Charlotte	North Carolina
United States	Atrium Health University City	Charlotte	North Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Carolinas Medical Center Investigational Drug Services	Charlotte	North Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Levine Cancer Institute - Southpark	Charlotte	North Carolina
United States	Levine Cancer Institute University City	Charlotte	North Carolina
United States	The University of Chicago Medical Center, CCD - Investigational Drug Service Pharmacy	Chicago	Illinois
United States	UChicago Medicine - River East	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	Vanderbilt Health Clinic at Walgreens Clarksville	Clarksville	Tennessee
United States	Cleveland Clinic	Cleveland	Ohio
United States	Cleveland Clinic Taussig Cancer Center Investigational Pharmacy	Cleveland	Ohio
United States	Investigational Drug Service, The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Martha Morehouse Medical Plaza	Columbus	Ohio
United States	Stefanie Spielman Comprehensive Breast Cancer	Columbus	Ohio
United States	The James Outpatient Care West Campus	Columbus	Ohio
United States	The Ohio State University James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	Memorial Sloan Kettering Cancer Center Commack	Commack	New York
United States	Atrium Health Cabarrus	Concord	North Carolina
United States	Levine Cancer Institute - Concord	Concord	North Carolina
United States	Sylvester Comprehensive Cancer Center- The Lennar Foundation Medical Center	Coral Gables	Florida
United States	Siteman Cancer Center - West County	Creve Coeur	Missouri
United States	Summit Medical Group	Florham Park	New Jersey
United States	Siteman Cancer Center - North County	Florissant	Missouri
United States	UChicago Medicine at Ingalls - Flossmoor	Flossmoor	Illinois
United States	Holy Cross Hospital - Michael and Dianne Bienes Comprehensive Cancer Center	Fort Lauderdale	Florida
United States	Vanderbilt Health Clinic at Walgreens Cool Springs	Franklin	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Gallatin	Gallatin	Tennessee
United States	The West Clinic. PLLC. dba West Cancer Center	Germantown	Tennessee
United States	Memorial Sloan Kettering Cancer Center - Westchester	Harrison	New York
United States	UChicago Medicine Ingalls Memorial	Harvey	Illinois
United States	Vanderbilt Health Clinic at Walgreens Hendersonville	Hendersonville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Hermitage	Hermitage	Tennessee
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	AHN Cancer Institute at Jefferson Hospital	Jefferson Hills	Pennsylvania
United States	Vanderbilt Health Clinic at Walgreens La Vergne	La Vergne	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Lebanon	Lebanon	Tennessee
United States	Cedars- Sinai Medical Center	Los Angeles	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California
United States	Keck Hospital of USC	Los Angeles	California
United States	LAC & USC Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	USC/Norris Comprehensive Cancer Center / Investigational Drug Services	Los Angeles	California
United States	University of Wisconsin Clinical Science Center	Madison	Wisconsin
United States	The West Clinic PLLC dba West Cancer Center	Memphis	Tennessee
United States	Baptist Hospital of Miami	Miami	Florida
United States	Miami Cancer Institute	Miami	Florida
United States	Sylvester Comprehensive Cancer Center	Miami	Florida
United States	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Memorial Sloan Kettering Cancer Center- Monmouth	Middletown	New Jersey
United States	Froedtert Hospital and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Atrium Health Union	Monroe	North Carolina
United States	AHN Cancer Institute Forbes Hospital	Monroeville	Pennsylvania
United States	Memorial Sloan Kettering Cancer Center- Bergen	Montvale	New Jersey
United States	Vanderbilt Health Clinic at Walgreens Murfreesboro	Murfreesboro	Tennessee
United States	Henry-Joyce Cancer Center	Nashville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Belle Meade	Nashville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Bellevue	Nashville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Donelson	Nashville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Hart Lane	Nashville	Tennessee
United States	Vanderbilt Health Clinic at Walgreens Nippers Corner	Nashville	Tennessee
United States	Vanderbilt Oncology IDS Pharmacy	Nashville	Tennessee
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	University of Chicago Comprehensive Cancer Center at Silver Cross Hospital	New Lenox	Illinois
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Ochsner Clinic Foundation Research Pharmacy	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center - Main Campus	New York	New York
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	New York	New York
United States	University of Oklahoma Health Sciences Center, OU Health Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Oncology Hematology West PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	Oncology Hematology West PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	Oncology Hematology West PC dba Nebraska Cancer Specialists	Omaha	Nebraska
United States	Oncology Hematology West, PC dba Nebraska Cancer Specialists - IP Storage	Omaha	Nebraska
United States	The University of Chicago Medicine Center for Advanced Care Orland Park	Orland Park	Illinois
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Orlando Health, Inc	Orlando	Florida
United States	Orlando Health, Inc.	Orlando	Florida
United States	Oncology Hematology West PC dba Nebraska Cancer Specialists	Papillion	Nebraska
United States	Keck Hospital of USC Pasadena	Pasadena	California
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	Patchogue	New York
United States	Mayo Clinic - Phoenix Oncology Pharmacy	Phoenix	Arizona
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	AHN Cancer Institute - Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	AHN Cancer Institute Pharmacy	Pittsburgh	Pennsylvania
United States	AHN Cancer Institute West Penn Hospital	Pittsburgh	Pennsylvania
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC Hillman Cancer Center Investigational Drug Service	Pittsburgh	Pennsylvania
United States	BRCR Global	Plantation	Florida
United States	BRCR Medical Center Inc.	Plantation	Florida
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	Port Jefferson Station	New York
United States	Providence Cancer Institute Franz Clinic	Portland	Oregon
United States	Providence Onc and Heme Care Clinic - Westside	Portland	Oregon
United States	Providence Oncology and Hematology Care Clinic - Westside	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence St Vincent Medical Center	Portland	Oregon
United States	Providence St. Vincent Medical Center	Portland	Oregon
United States	VCU Health - Adult Outpatient Pavilion (AOP) Investigational Drug Services	Richmond	Virginia
United States	VCU Health System, Investigational Drug Service Pharmacy	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	North Shore Hematology Oncology Assoc. P.C. DBA NY Cancer and Blood Specialists	Riverhead	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	Mayo Clinic in Rochester, Minnesota	Rochester	Minnesota
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Barnes- Jewish Hospital	Saint Louis	Missouri
United States	Siteman Cancer Center - South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Siteman Cancer Center - St Peters	Saint Peters	Missouri
United States	Lewis Cancer & Research Pavilion at St Joseph's/Candler Health System	Savannah	Georgia
United States	Lewis Cancer & Research Pavilion Pharmacy	Savannah	Georgia
United States	St. Joseph's/Candler Health System, Inc.	Savannah	Georgia
United States	St. Joseph's/Candler Health System, Inc.	Savannah	Georgia
United States	Summit Cancer Care	Savannah	Georgia
United States	Summit Cancer Care, P.C.	Savannah	Georgia
United States	Mayo Clinic in Arizona - Scottsdale	Scottsdale	Arizona
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Vanderbilt Health Clinic at Walgreens Smyrna	Smyrna	Tennessee
United States	UChicago Medicine at Ingalls - Tinley Park	Tinley Park	Illinois
United States	Torrance Memorial Medical Center (TMMC)	Torrance	California
United States	Memorial Sloan Kettering Cancer Center- Nassau	Uniondale	New York
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Medstar Georgetown University Hospital	Washington	District of Columbia
United States	Wexford Health and Wellness Pavilion	Wexford	Pennsylvania

Sponsors (4)

Lead Sponsor	Collaborator
Pfizer	Eli Lilly and Company, Merck KGaA, Darmstadt, Germany, Ono Pharmaceutical Co. Ltd

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Bulgaria,  Canada,  China,  Czechia,  Denmark,  Finland,  Germany,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  New Zealand,  Norway,  Poland,  Russian Federation,  Slovakia,  South Africa,  Spain,  Sweden,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety Lead-in Study: Incidence of Dose Limiting Toxicities (DLTs)	Incidence of dose limiting toxicity defined as any adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness or concomitant medications/therapies occurring during the first 28 days of treatment	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Primary	Phase 3: Progression free survival, by blinded independent review	Progression free survival, defined as the time from the date of randomization to the earliest documented disease progression or death due to any cause: encorafenib and cetuximab + mFOLFOX6 (Arm B) vs the Control Arm (Arm C)	Duration of Phase 3, approximately 36 months
Primary	Phase 3: Objective response rate by blinded independent review	Objective response defined as complete response (CR), or partial response (PR) according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of progression of disease (PD)	Duration of Phase 3, approximately 23 months
Primary	Cohort 3: Objective response rate by blinded independent review	Defined as CR, or PR according to RECIST v1.1 based on BICR assessment, from the date of randomization until the date of the first documentation of PD, death or start of new anticancer therapy	Duration of Cohort 3, approximately 15 months.
Secondary	Safety Lead-in: Incidence of adverse events	An adverse event is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship as assessed by CTCAE 4.03	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion.	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Incidence of dose interruptions, dose modifications and discontinuations due to adverse events		After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Overall response rate by investigator	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Duration of response by Investigator	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in:Progression free survival by Investigator	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Time to response by Investigator	Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 12 months
Secondary	Safety Lead-in: Overall survival	Overall survival defined as the time from the first dose to death due to any cause: encorafenib and cetuximab + mFOLFOX6 or FOLFIRI	After 30 evaluable patients in each cohort complete 1 cycle (up to 28 days), approximately 36 months
Secondary	Phase 3: Overall survival	Overall survival, defined as the time from the date of randomization to death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 50 months
Secondary	Phase 3: Overall response rate by Investigator and by blinded independent review	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Duration of response by Investigator and blinded independent review	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Time to response by blinded independent review and by Investigator	Time to response, defined as the time from first dose to first radiographic evidence of response per RECIST v1.1: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Progression free survival by Investigator and by blinded independent review	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause:: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Progression free survival 2 by Investigator	Progression free survival 2, defined as the time from the date of randomization to the second objective disease progression per RECIST v1.1, or death from any cause, whichever occurs first: encorafenib + cetuximab (Arm A) vs Control Arm (Arm C) and encorafenib + cetuximab +mFOLFOX6 (Arm B) vs Control Arm (Arm C) and encorafenib + cetuximab (Arm A) vs encorafenib + cetuximab +mFOLFOX6	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Incidence of adverse events	An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire	The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)	The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires	The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.	Duration of Phase 3, approximately 36 months
Secondary	Phase 3: Confirm the MSI-status in tumor tissue	Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue	Once, pre-treatment
Secondary	Phase 3: Determine the correlation between cfDNA genetic alterations and clinical outcome	BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment	Predose on Cycle 1 Day 1, 15, Cycle 2 Day 15, Cycle 7 Day 1 and EOT. Arm C sampling on Day 1 of Cycles 1-3, 9 and EOT. EOT is approx 36 months.
Secondary	Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days.
Secondary	Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746, irinotecan and SN-38		Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Safety Lead-in: Maximum plasma concentration of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Safety Lead-in: Area under the plasma concentration time curve of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Safety Lead-in: Clearance of irinotecan, SN-38 and oxaliplatin	Changes in exposures of irinotecan and its metabolite (SN-38) on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 1 (encorafenib and cetuximab + FOLFIRI) Changes in exposures of oxaliplatin on Cycle 1 Day 15 compared to Cycle 1 Day 1 in Cohort 2 (encorafenib and cetuximab + mFOLFOX6)	Cycle 1 Day 1 and Day 15: predose, and 0.75, 1.5, 2.5, 3.5, 5.5 and 7.5 hours after dosing, Cycle 1 Day 3 and Day 17:predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Safety Lead-in: Time to maximim plasma concentration time curve of encorafenib, LHY746 and oxaliplatin		Cycle 1 Day 1 and Day 15: predose, and 1, 2, 3, 4, 6 and 8 hours after dosing, Cycle 1 Day 3 and Day 17: predose and Cycle 2 through Cycle 6: Day 1 predose. Each cycle is 28 days
Secondary	Phase 3: Trough concentrations of encorafenib and its metabolite LHY746	Trough plasma concentrations in all patients in Arm A and Arm B	Predose on Cycle 1 through Cycle 6. Each cycle is 28 days
Secondary	Cohort 3: Progression free survival by Investigator and by blinded independent review	Progression free survival, defined as the time from the first dose to the earliest documented disease progression per RECIST v1.1, or death due to any cause.	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Overall response rate by investigator	Overall response rate, defined as the proportion of participants who have achieved a confirmed best overall response per RECIST v 1.1	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Duration of response by Investigator and by blinded independent review	Duration of response, defined as the time from the date of first radiographic evidence of response to the earliest documented disease progression per RECIST v1.1, or death due to any cause	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Time to response by Investigator and by blinded independent review	Time to response, defined as the time from the date of randomization to first radiographic evidence of response per RECIST v1.1	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Overall survival	Overall survival, defined as the time from the date of randomization to death due to any cause	Duration of Cohort 3, approximately 36 months
Secondary	Cohort 3: Incidence of adverse events	An adverse event was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Incidence of abnormal clinical laboratory parameters, abnormal vital signs and abnormal electrocardiograms	Changes in clinical laboratory parameters, vital signs and electrocardiograms determined clinically significant at the investigator's discretion: encorafenib + cetuximab (Arm A) and encorafenib + cetuximab +mFOLFOX6 (Arm B)	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Change from Baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30)	EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms.	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Change from Baseline in the EuroQol-5D-5L (EQ-5D-5L) Questionnaire	The EQ-5D-5L is a standardized measure of health utility that provides a single index value for the participant's health status. It is frequently used for economic evaluations of health care and has been shown to be a valid and reliable instrument, and comprises a short descriptive system questionnaire and a visual analogue scale (EQ VAS) that are cognitively undemanding, taking about 2 minutes to complete	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Change from Baseline in the Patient Global Impression of Severity (PGIS)	The PGIS is a single-item questionnaire designed to assess participant's overall impression of disease severity at a given point in time.	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Change from Baseline in the Patient Global Impression of Change (PGIC) questionnaires	The PGIC is a single-item questionnaire designed to assess the participant's overall sense of whether there has been a change in symptoms or quality of life since starting treatment.	Duration of Cohort 3, approximately 21 months
Secondary	Cohort 3: Confirm the MSI-status in tumor tissue	Summarize MSI-status as determined by retrospective central testing of baseline tumor tissue	Once, pre-treatment
Secondary	Cohort 3: Determine the correlation between cfDNA genetic alterations and clinical outcome	BRAF V600E variant allele fraction (VAF) and/or overall mean VAF from cfDNA analysis of plasma samples collected at baseline and on treatment	Predose on Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 15, Cycle 7 Day 1 and End of Treatment (Duration of Cohort 3, approximately 21 months). Each cycle is 28 days.
Secondary	Cohort 3: Trough concentrations of encorafenib and its metabolite LHY746	Trough plasma concentrations in all patients in Arm D	Predose on Cycle 1 through Cycle 6. Each cycle is 28 days

External Links

•   Breakwater Study on Pfizer Clinical Trials
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