Clinical trial NCT02908672: A Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFv600 Mutation-Positive Patients With Metastatic or Unresectable Locally Advanced Melanoma
Official title: A Phase III, Double-Blinded, Randomized, Placebo-Controlled Study of Atezolizumab Plus Cobimetinib and Vemurafenib Versus Placebo Plus Cobimetinib and Vemurafenib in Previously Untreated BRAFV600 Mutation-Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2016-09-21
Enrollment: 514
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: This is a Phase III, double-blinded, placebo-controlled, randomized, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of atezolizumab + cobimetinib + vemurafenib compared with placebo + cobimetinib + vemurafenib in patients with previously untreated BRAFv600 mutation-positive metastatic or unresectable locally advanced melanoma.


Eligibility criteria: Inclusion Criteria:

* Females of child bearing potential and males with female partners must and use of contraceptive methods with a failure rate of less than or equal to (\</=)1% per year is required during treatment and for 6 months post treatment. Males should not expose pregnant partners to sperm and refrain from donating sperm for 6 months post treatment. Women must refrain from donating eggs during this same period
* Histologically confirmed Stage IV (metastatic) or unresectable Stage IIIc (locally advanced) melanoma
* Naive to prior systemic anti-cancer therapy for melanoma (example: chemotherapy, hormonal therapy, targeted therapy, immunotherapy, or other biologic therapies) except adjuvant treatment with interferon (IFN), interleukin (IL)-2, or vaccine therapies or herbal therapies
* Documentation of BRAFv600 mutation-positive status in melanoma tumor tissue (archival or newly obtained) through use of a clinical mutation test approved by the local health authority
* Eastern Cooperative Oncology Group Performance (ECOG) Status of 0 or 1
* Measurable disease according to RECIST v1.1 (must be outside central nervous system (CNS))
* Life expectancy \>/=18 weeks
* For participants not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) less than or equal to (\</=) 1.5\*upper limit of normal (ULN) within 28 days prior to initiation of study treatment
* For participants receiving therapeutic anticoagulation: stable anticoagulant regimen and stable INR during the 28 days immediately preceding initiation of study treatment

Exclusion Criteria:

Cancer-Related Exclusion Criteria:

* Major surgical procedure within 4 weeks prior study treatment initiation
* Traumatic injury or palliative radiotherapy within 2 weeks prior study treatment initiation
* Active malignancy (other than BRAFv600 mutation-positive melanoma) or malignancy within 3 years prior to screening are excluded, with the exception of resected melanoma, resected basal cell carcinoma (BCC), resected cutaneous squamous cell carcinoma (SCC), resected carcinoma in situ of the cervix, resected carcinoma in situ of the breast, in situ prostate cancer, limited-stage bladder cancer, or any other curatively treated malignancies from which the participant has been disease-free for at least 3 years

Ocular Exclusion Criteria:

* History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, central serous chorioretinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration

Cardiac Exclusion Criteria:

* History of clinically significant cardiac dysfunction
* Left ventricular ejection fraction (LVEF) below the institutional lower limit of normal or below 50%

Central Nervous System (CNS) Exclusion Criteria:

* Untreated or actively progressing CNS lesions (carcinomatous meningitis)
* History of metastases to brain stem, midbrain, pons, or medulla, or within 10 millimeter (mm) of the optic apparatus (optic nerves and chiasm); or leptomeningeal metastatic disease; or intracranial hemorrhage

Additional Exclusion Criteria:

* Uncontrolled diabetes or symptomatic hyperglycemia
* Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease) other than cancer
* History of malabsorption or other clinically significant metabolic dysfunction
* Pregnant or breastfeeding, or intending to become pregnant during the study
* Prior allogeneic stem cell or solid organ transplantation
* History of idiopathic pulmonary fibrosis, organizing pneumonia (example: bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
* Active or history of autoimmune disease or immune deficiency
* Known clinically significant liver disease, inherited liver disease and active viral disease
* Active tuberculosis
* Treatment with therapeutic oral or intravenous (IV) antibiotics; or with a live, attenuated vaccine; or systemic immunosuppressive medication
* Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary cells or any component of the atezolizumab, cobimetinib, or vemurafenib formulations
* Any grade \>/=3 hemorrhage or bleeding event within 4 weeks prior to initiation of study treatment
* History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to initiation of study treatment

Primary outcomes:
measure: Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcomes:
measure: Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Duration of Response, as Determined by Investigator Using RECIST v1.1
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Overall Survival
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Percentage of Participants Who Have Survived at 2 Years
timeFrame: 2 years
measure: Time to Deterioration in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Health Status Scale Score
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score
timeFrame: Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
measure: Percentage of Participants With Adverse Events and Serious Adverse Events
timeFrame: Baseline up to 6 months after the last dose of study treatment (approximately 33 months)
measure: Serum Concentration of Atezolizumab
timeFrame: Pre-infusion Day 1 of Cycles 1-4; 30 minutes post-infusion Day 1 of Cycles 1 and 4; at Atezolizumab discontinuation (up to approximately 33 months)(1 Cycle = 28 days)
measure: Plasma Concentration of Cobimetinib Dose: 20/40 mg
timeFrame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
measure: Plasma Concentration of Cobimetinib Dose: 60 mg
timeFrame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
measure: Plasma Concentration of Vemurafenib
timeFrame: Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
measure: Percentage of Participants Positive for Anti-Drug Antibodies (ADA) to Atezolizumab
timeFrame: Pre-infusion Day 1 of Cycles 1-4; at Atezolizumab discontinuation (up to approximately 90 months)(1 Cycle=28 days) (approximately up to 33 months)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tempe
country: United States
facility: Arizona Oncology Associates, PC - HAL
state: Arizona
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Orlando
country: United States
facility: UF Health Cancer Center at Orlando Health
state: Florida
city: Park Ridge
country: United States
facility: Oncology Specialists, S.C.
state: Illinois
city: Bethlehem
country: United States
facility: St. Luke's University Health network
state: Pennsylvania
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Graz
country: Austria
facility: Medical University of Graz, Department of Dermatology
city: Innsbruck
country: Austria
facility: LKH Innsbruck; Universitätsklinik für Dermatologie
city: Wien
country: Austria
facility: Medizinische Universität Wien; Univ.Klinik für Dermatologie
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Leuven
country: Belgium
facility: UZ Leuven Gasthuisberg
city: Liège
country: Belgium
facility: CHU Sart-Tilman
city: Wilrijk
country: Belgium
facility: Sint Augustinus Wilrijk
city: Rio De Janeiro
country: Brazil
facility: Clinicas Oncologicas Integradas - COI
state: RJ
city: Porto Alegre
country: Brazil
facility: Hospital das Clinicas - UFRGS
state: RS
city: Florianopolis
country: Brazil
facility: Centro de Pesquisa e Ensino em Oncologia de Santa Catarina - CEPEN
state: SC
city: Sao Paulo
country: Brazil
facility: Instituto do Cancer do Estado de Sao Paulo - ICESP
state: SP
city: São Paulo
country: Brazil
facility: Beneficencia Portuguesa de Sao Paulo
state: SP
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre-Calgary
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Cancer Clinic; Department of Oncology
state: Ontario
city: London
country: Canada
facility: LHSC - Victoria Hospital; London Regional Cancer Program
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa; Oncology
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital Cancer Centre; Oncology
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
city: Quebec
country: Canada
facility: CHU de Quebec - Hopital de l'Enfant-Jesus; Unite de Recherche en Hematologie et Oncologie
city: Bordeaux
country: France
facility: Groupe Hospitalier Saint André - Hôpital Saint André
city: Dijon
country: France
facility: Hopital du Bocage; Dermatologie
city: La Tronche
country: France
facility: Centre Hospitalier Universitaire de Grenoble - Albert Michallon
city: Lille
country: France
facility: Hopital Claude Huriez - CHU Lille
city: Montpellier
country: France
facility: Hopital Saint Eloi; CHU de Montpellier; Svc de Dermatologie
city: Nantes
country: France
facility: CHU de Nantes; Cancéro-dermatologie
city: Reims
country: France
facility: Hopital Robert Debre; DERMATOLOGIE
city: Rennes
country: France
facility: Centre Eugene Marquis; Service d'oncologie
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
city: Villejuif
country: France
facility: Institut Gustave Roussy; Dermatologie
city: Berlin
country: Germany
facility: Charite - Universitätsmedizin Berlin
city: Buxtehude
country: Germany
facility: Elbekliniken Buxtehude; Klinik für Dermatologie
city: Erfurt
country: Germany
facility: HELIOS Klinikum Erfurt; Klinik für Dermatologie & Allergologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen; Hautklinik
city: Essen
country: Germany
facility: Universitatsklinikum Essen; Klinik für Dermatologie
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen; Klinik für Gastroenterologie, gastrointestinale
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover; Klinik für Dermatologie, Allergologie und Venerologie
city: Heidelberg
country: Germany
facility: Universitatsklinik Heidelberg; Universitätshautklinik und Nationales Centrum für Tumorerkrankungen
city: Kiel
country: Germany
facility: UKSH Kiel; Klinik für Dermatologie, Venerologie und Allergologie
city: Köln
country: Germany
facility: Klinikum d.Universität zu Köln Klinik u.Poliklinik f.Dermatologie
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig; Klinik für Dermatologie, Venerologie und Allergologie
city: Lübeck
country: Germany
facility: UKSH Universitatsklinikum Schleswig-Holstein; Studienzentrum Dermatologie 10d
city: Mainz
country: Germany
facility: Universitatsklinikum Mainz; Klinik und Poliklinik fur Dermatologie
city: München
country: Germany
facility: Klinikum der Ludwigs-Maximilians-Universität München; Dermatologie
city: Münster
country: Germany
facility: Fachklinik Hornheide; Dermatologie
city: Quedlinburg
country: Germany
facility: Harzklinikum Dorothea Christiane Erxleben GmbH, Standort Quedlinburg; Hautkrebszentrum Harz
city: Regensburg
country: Germany
facility: Universitätsklinikum Regensburg; Klinik und Poliklinik für Dermatologie
city: Tübingen
country: Germany
facility: Zentrum für Dermatoonkologie, Universitäts-Hautklinik Tübingen
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg; Med. Klinik 1, Pneumologie
city: Athens
country: Greece
facility: Laiko General Hospital Athen
city: Pireaus
country: Greece
facility: Metropolitan Hospital; Dept. of Oncology
city: Budapest
country: Hungary
facility: Orszagos Onkologiai Intezet; Borgyogyaszati Osztaly
city: Szeged
country: Hungary
facility: University of Szeged Szent-Györgyi Albert Clinical Center; Department of Dermatology and Allergology
city: Haifa
country: Israel
facility: Rambam Health Care Campus; Oncology
city: Jerusalem
country: Israel
facility: Sharett Institute - Hadassah Hebrew University Medical Center
city: Petach Tikva
country: Israel
facility: Rabin MC; Davidof Center - Oncology Institute
city: Ramat-Gan
country: Israel
facility: Ella Institute - Sheba Medical Center
city: Napoli
country: Italy
facility: IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica B
state: Campania
city: Meldola
country: Italy
facility: IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica
state: Emilia-Romagna
city: Udine
country: Italy
facility: A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: IFO - Istituto Regina Elena; Oncologia Medica
state: Lazio
city: Genova
country: Italy
facility: IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A
state: Liguria
city: Milano
country: Italy
facility: Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2
state: Lombardia
city: Milano
country: Italy
facility: Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica
state: Lombardia
city: Candiolo
country: Italy
facility: Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico
state: Piemonte
city: Bari
country: Italy
facility: Istituto Tumori ?Giovanni Paolo II?, Oncologia
state: Puglia
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria Alle Scotte
state: Toscana
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Mc - Daniel Den Hoed Kliniek; Interne Oncologie
city: Auckland
country: New Zealand
facility: Auckland city hospital; Auckland Regional Cancer Centre and Blood Service
city: Newtown
country: New Zealand
facility: Wellington Hospital; Wellington Blood and Cancer Centre
city: Palmerston North
country: New Zealand
facility: Mid Central DHB
city: Tauranga
country: New Zealand
facility: Tauranga Hospital, Clinical Trials Unit; BOP Clinical School
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne; Klinika Onkologii i Radioterapii
city: Kraków
country: Poland
facility: Narodowy Inst.Onkol.im.Sk?odowskiej-Curie Pa?stw.Inst.Badawczy Kraków; Klinika Onkologii Klinicznej
city: Lublin
country: Poland
facility: COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej
city: Pozna?
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Poznaniu
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sk?odowskiej-Curie - Pa?stwowy Instytut Badawczy
city: Wroc?aw
country: Poland
facility: Dolno?l?skie Centrum Onkologii, Pulmonologii i Hematologii
city: Lisboa
country: Portugal
facility: IPO de Lisboa; Servico de Oncologia Medica
city: Porto
country: Portugal
facility: IPO do Porto; Servico de Oncologia Medica
city: Moscovskaya Oblast
country: Russian Federation
facility: Moscow City Oncology Hospital #62
state: Moskovskaja Oblast
city: Moscow
country: Russian Federation
facility: FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"
state: Moskovskaja Oblast
city: Saint-Petersburg
country: Russian Federation
facility: FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"
state: Sankt Petersburg
city: Sankt-peterburg
country: Russian Federation
facility: St. Petersburg Oncology Hospital
state: Sankt Petersburg
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra; Servicio de Oncologia
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron; Oncology
city: Barcelona
country: Spain
facility: Hospital Clínic i Provincial; Servicio de Oncología
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal; Servicio de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz; Servicio de Oncologia
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen de la Macarena;
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia (IVO)
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia; Servicio de oncologia
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet; Servicio Oncologia
city: Bristol
country: United Kingdom
facility: Bristol Haematology and Oncology centre
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital; Oncology Pharmacy
city: Leeds
country: United Kingdom
facility: St James Uni Hospital; Icrf Cancer Medicine Research Unit
city: London
country: United Kingdom
facility: Guys and St Thomas NHS Foundation Trust, Guys Hospital
city: New Castle Upon Tyne
country: United Kingdom
facility: Freeman Hospital; Northern Centre For Cancer Care
city: Swansea
country: United Kingdom
facility: Singleton Hospital; Pharmacy Department
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Robert C, Lewis KD, Gutzmer R, Stroyakovskiy D, Gogas H, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Caro I, Forbes H, Shah K, Yan Y, Li H, McArthur GA, Ascierto PA. Biomarkers of treatment benefit with atezolizumab plus vemurafenib plus cobimetinib in BRAFV600 mutation-positive melanoma. Ann Oncol. 2022 May;33(5):544-555. doi: 10.1016/j.annonc.2022.01.076. Epub 2022 Feb 4.
citation: de Azevedo SJ, de Melo AC, Roberts L, Caro I, Xue C, Wainstein A. First-line atezolizumab monotherapy in patients with advanced BRAFV600 wild-type melanoma. Pigment Cell Melanoma Res. 2021 Sep;34(5):973-977. doi: 10.1111/pcmr.12960. Epub 2021 Feb 15.
citation: Gutzmer R, Stroyakovskiy D, Gogas H, Robert C, Lewis K, Protsenko S, Pereira RP, Eigentler T, Rutkowski P, Demidov L, Manikhas GM, Yan Y, Huang KC, Uyei A, McNally V, McArthur GA, Ascierto PA. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Jun 13;395(10240):1835-1844. doi: 10.1016/S0140-6736(20)30934-X.