Clinical trial NCT01689519: A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma
Official title: A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malignant Melanoma
Keywords: Zelboraf
vemurafenib
RG7204
PLX4032
Genentech MEK inhibitor
Genentech BRAF inhibitor
Roche MEK inhibitor
Roche BRAF inhibitor
RO5185426
metastatic melanoma
BRAF positive melanoma
BRAF mutant melanoma
advanced melanoma
Genentech RAF inhibitor
Roche RAF inhibitor
BRAF V600E kinase inhibitor
Oncogenic BRAF inhibitor
BRAF kinase inhibitor
GDC-0973
XL518
melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2012-09-21
Enrollment: 495
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.


Eligibility criteria: Inclusion Criteria:

* Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist
* Participants must be naïve to treatment for locally advanced unresectable or metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed
* Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test
* Measurable disease per RECIST v1.1
* Eastern Clinical Oncology Group performance status of 0 or 1
* Consent to provide archival for biomarker analyses
* Consent to undergo tumor biopsies for biomarker analyses
* Life expectancy greater than or equal to (≥) 12 weeks
* Adequate hematologic and end organ function

Exclusion Criteria:

* History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase pathway inhibitor treatment
* Palliative radiotherapy within 14 days prior to the first dose of study treatment
* Major surgery or traumatic injury within 14 days prior to first dose of study treatment
* Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Participants with a previous malignancy within the past 3 years are excluded except for participants with resected basal cell carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast
* History of or evidence of retinal pathology on ophthalmological examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion, or neovascular macular degeneration
* Uncontrolled glaucoma with intraocular pressure
* Serum cholesterol ≥ Grade 2
* Hypertriglyceridemia ≥ Grade 2
* Hyperglycemia (fasting) ≥ Grade 2
* History of clinically significant cardiac dysfunction
* Participants with active central nervous system (CNS) lesions (including carcinomatous meningitis) are excluded. However, participants are eligible if:

  1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND
  2. There has been no evidence of clinical and radiographic disease progression in the CNS for ≥ 3 weeks after radiotherapy or surgery
* Current severe, uncontrolled systemic disease
* History of malabsorption or other condition that would interfere with absorption of study drugs
* Pregnant, lactating, or breast feeding women

Primary outcomes:
measure: Progression-free Survival
timeFrame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Secondary outcomes:
measure: Overall Survival
timeFrame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
measure: Percentage of Participants With an Objective Response
timeFrame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
measure: Duration of Response
timeFrame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute - W LA Office
state: California
city: Sacramento
country: United States
facility: University of California Davis Health System
state: California
city: Santa Rosa
country: United States
facility: Sutter Pacific Medical Foundation
state: California
city: Aurora
country: United States
facility: University Of Colorado
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists - Broadway
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Orlando
country: United States
facility: Orlando Health Inc.
state: Florida
city: Chicago
country: United States
facility: Northwestern Center For Clinical Research
state: Illinois
city: Kansas City
country: United States
facility: Uni of Kansas Medical Center; Dept of Neurology
state: Kansas
city: Louisville
country: United States
facility: U of L - Physicians Pulmonology; Dept of Neuroradiology and Dept of Diagnostic Radiology
state: Kentucky
city: Saint Louis
country: United States
facility: Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center; Department of Medicine
state: New Hampshire
city: Winston-Salem
country: United States
facility: Novant Health Oncology Specialists
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Bethlehem
country: United States
facility: St. Luke's University Health network
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital; Investigational Services
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Camperdown
country: Australia
facility: Chris O'Brien Lifehouse
state: New South Wales
city: Gateshead
country: Australia
facility: Lake Macquarie Private Hospital
state: New South Wales
city: Lismore
country: Australia
facility: Lismore Base Hospital; Cancer Care & Haematology Unit
state: New South Wales
city: North Sydney
country: Australia
facility: Melanoma Institute Australia
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: New South Wales
city: Casuarina
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Greenslopes
country: Australia
facility: Greenslopes Private Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital; Hepatology
state: South Australia
city: Ashford SA
country: Australia
facility: Ashford Cancer Centre
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Launceston
country: Australia
facility: Launceston General Hospital; Gastroenterology Research
state: Tasmania
city: Frankston
country: Australia
facility: Peninsula and South Eastern Haematology and Oncology Group
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre-East Melbourne
state: Victoria
city: Prahan
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen
city: St. Pölten
country: Austria
facility: Landesklinikum St. Pölten
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet; Department of Medical Oncology
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Hasselt
country: Belgium
facility: Jessa Zkh (Campus Virga Jesse)
city: Liège
country: Belgium
facility: CHU Sart-Tilman
city: Roeselare
country: Belgium
facility: AZ Delta (Campus Rumbeke)
city: Victoria
country: Canada
facility: BC Cancer Agency Vancouver Island Cancer Centre
state: British Columbia
city: Hamilton
country: Canada
facility: Juravinski Cancer Clinic; Department of Oncology
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Center; General Campus
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sunnybrook Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital; Department of Med Oncology
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre · Victoria Hospital;Department of Pediatrics
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre/Glen Site / Royal Victoria Hospital
state: Quebec
city: Brno
country: Czechia
facility: Masarykuv onkologicky ustav
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Olomouc
country: Czechia
facility: Fakultní nemocnice Olomouc
city: Ostrava - Poruba
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Pardubice
country: Czechia
facility: Multiscan s.r.o.
city: Prague
country: Czechia
facility: Nemocnice Na Bulovce
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha
country: Czechia
facility: Fakultni nemocnice Kralovske Vinohrady
city: Praha
country: Czechia
facility: Fakultni nemocnice Motol; Neurologicka klinika
city: Bordeaux
country: France
facility: Groupe Hospitalier Saint André - Hôpital Saint André
city: Boulogne Billancourt
country: France
facility: Hôpital Ambroise Paré - Boulogne-Billancourt; Respiratory
city: Clermont Ferrand cedex 1
country: France
facility: CHU Clermont Ferrand - Hôpital d'Estaing
city: Dijon
country: France
facility: CHU de Dijon - Hopital le Bocage
city: La Tronche
country: France
facility: Centre Hospitalier Universitaire de Grenoble - Albert Michallon
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille
city: Marseille
country: France
facility: Hopital de la Timone
city: Montpellier
country: France
facility: Hopital Saint Eloi
city: Nantes
country: France
facility: CHU NANTES - Hôtel Dieu; Pharmacy
city: Nice
country: France
facility: CHU Nice - Hopital de l'Archet 2
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Reims
country: France
facility: Hopital Robert Debre; DERMATOLOGIE
city: Rennes
country: France
facility: Centre Eugene Marquis; Service d'oncologie
city: Bochum
country: Germany
facility: St. Josef-Hospital; Studienambulanz
city: Buxtehude
country: Germany
facility: Elbekliniken Buxtehude GmbH
city: Dresden
country: Germany
facility: Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Kiel
country: Germany
facility: Universitaetsklinikum Schleswig-Holstein - Campus Kiel; Klinik fuer Allgemeine Innere Medizin
city: Koeln
country: Germany
facility: Universitaetsklinikum Koeln; Hematology/Oncology
city: Mainz
country: Germany
facility: Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz
city: Mannheim
country: Germany
facility: Klinikum Mannheim GmbH Universitätsklinikum
city: Muenster
country: Germany
facility: Fachklinik Hornheide
city: München
country: Germany
facility: Klinikum der Ludwigs-Maximilians-Universitaet Muenchen
city: Regensburg
country: Germany
facility: Universitaetsklinikum Regensburg
city: Tuebingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Würzburg
country: Germany
facility: Universitätsklinikum Wurzburg
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet
city: Gyula
country: Hungary
facility: Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza
city: Pecs
country: Hungary
facility: Somogy Megyei Kaposi Mor Oktato Korhaz
city: Szeged
country: Hungary
facility: Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.
city: Beer Sheva
country: Israel
facility: Soroka Medical Center; Oncology Dept
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: HADASSAH UNIVERSITY HOSPITAL, EIN KAREM; Oncology
city: Petach Tikva
country: Israel
facility: Rabin Medical Center-Beilinson Campus;Hematology-Oncology
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky MC, Dana children's hospital;Oncology Division
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione G. Pascale
state: Campania
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori
state: Emilia-Romagna
city: Modena
country: Italy
facility: A.O.U. Policlinico di Modena
state: Emilia-Romagna
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena IRCCS
state: Lazio
city: Genova
country: Italy
facility: Istituto Nazionale per la Ricerca sul Cancro di Genova
state: Liguria
city: Bergamo
country: Italy
facility: Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)
state: Lombardia
city: Brescia
country: Italy
facility: Asst Degli Spedali Civili Di Brescia
state: Lombardia
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
state: Lombardia
city: Bari
country: Italy
facility: Istituto Tumori Giovanni Paolo II IRCSS; Ospedale Oncologico Bari
state: Puglia
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria Alle Scotte
state: Toscana
city: Padova
country: Italy
facility: IOV - Istituto Oncologico Veneto IRCCS
state: Veneto
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC Location VUMC
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum; Cardiology
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Oslo
country: Norway
facility: Radiumhospitalet
city: Barnaul
country: Russian Federation
facility: TSBHI Altai Territorial oncological dispensary
city: Moscow
country: Russian Federation
facility: FSBSI "N. N. Blokhin Russian Cancer Research Center"
city: Moscow
country: Russian Federation
facility: Moscow city oncology hospital #62 of Moscow Healthcare Department
city: Omsk
country: Russian Federation
facility: BHI of Omsk region Clinical Oncology Dispensary
city: Pyatigorsk
country: Russian Federation
facility: Pyatigorsky Oncologic Dispensary
city: Santiago de Compostela
country: Spain
facility: Complexo Hospitalario Universitario de Santiago
state: LA Coruña
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Sevilla
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial de Barcelona
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet
city: Jönköping
country: Sweden
facility: Länssjukhuset Ryhov
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus
city: Mölnlycke
country: Sweden
facility: Sahlgrenska Sjukhuset
city: Uppsala
country: Sweden
facility: Akademiska Sjukhuset
city: Bern
country: Switzerland
facility: Inselspital-Universitaetsspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology Centre
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Liverpool
country: United Kingdom
facility: The Clatterbridge Cancer Centre NHS Foundation Trust
city: London
country: United Kingdom
facility: Barts and the London NHS Trust.
city: London
country: United Kingdom
facility: St George's Hospital; Courtyard Clinic
city: London
country: United Kingdom
facility: Royal Marsden Hospital - Fulham
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
city: Newcastle upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals; QMC Campus
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Barteselli G, Goodman GR, Patel Y, Caro I, Xue C, McCallum S. Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies. Drug Saf. 2022 Dec;45(12):1491-1499. doi: 10.1007/s40264-022-01248-2. Epub 2022 Oct 30.
citation: Ascierto PA, Dreno B, Larkin J, Ribas A, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Atkinson V, Dutriaux C, Garbe C, Hsu J, Jones S, Li H, McKenna E, Voulgari A, McArthur GA. 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study. Clin Cancer Res. 2021 Oct 1;27(19):5225-5235. doi: 10.1158/1078-0432.CCR-21-0809.
citation: Ascierto PA, Ribas A, Larkin J, McArthur GA, Lewis KD, Hauschild A, Flaherty KT, McKenna E, Zhu Q, Mun Y, Dreno B. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib +/- cobimetinib: a pooled analysis of four clinical trials. J Transl Med. 2020 Aug 3;18(1):294. doi: 10.1186/s12967-020-02458-x.
citation: de la Cruz-Merino L, Di Guardo L, Grob JJ, Venosa A, Larkin J, McArthur GA, Ribas A, Ascierto PA, Evans JTR, Gomez-Escobar A, Barteselli G, Eng S, Hsu JJ, Uyei A, Dreno B. Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study. J Transl Med. 2017 Jun 24;15(1):146. doi: 10.1186/s12967-017-1246-0.
citation: Dreno B, Ribas A, Larkin J, Ascierto PA, Hauschild A, Thomas L, Grob JJ, Koralek DO, Rooney I, Hsu JJ, McKenna EF, McArthur GA. Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Ann Oncol. 2017 May 1;28(5):1137-1144. doi: 10.1093/annonc/mdx040.
citation: Ascierto PA, McArthur GA, Dreno B, Atkinson V, Liszkay G, Di Giacomo AM, Mandala M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Yan Y, Wongchenko M, Chang I, Hsu JJ, Koralek DO, Rooney I, Ribas A, Larkin J. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1248-60. doi: 10.1016/S1470-2045(16)30122-X. Epub 2016 Jul 30.
citation: Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Mandala M, Demidov L, Stroyakovskiy D, Thomas L, de la Cruz-Merino L, Dutriaux C, Garbe C, Sovak MA, Chang I, Choong N, Hack SP, McArthur GA, Ribas A. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014 Nov 13;371(20):1867-76. doi: 10.1056/NEJMoa1408868. Epub 2014 Sep 29.