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

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02908672
• Other study ID #: CO39262
• Secondary ID: 2016-002482-54
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: January 13, 2017
• Est. completion date: May 15, 2024

Study information

• Verified date: March 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 514
• Est. completion date: May 15, 2024
• Est. primary completion date: October 11, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Atezolizumab
Will be administered as per the schedule described in individual arm.
• Atezolizumab Placebo
Will be administered as per the schedule described in individual arm.
• Cobimetinib
Will be administered as per the schedule described in individual arm.
• Vemurafenib
Will be administered as per the schedule described in individual arm.
• Vemurafenib Placebo
Will be administered as per the schedule described in individual arm.

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Peter Maccallum Cancer Centre	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Austria	Medical University of Graz, Department of Dermatology	Graz
Austria	LKH Innsbruck; Universitätsklinik für Dermatologie	Innsbruck
Austria	Medizinische Universität Wien; Univ.Klinik für Dermatologie	Wien
Belgium	Cliniques Universitaires St-Luc	Bruxelles
Belgium	UZ Leuven Gasthuisberg	Leuven
Belgium	CHU Sart-Tilman	Liège
Belgium	Sint Augustinus Wilrijk	Wilrijk
Brazil	Centro de Pesquisa e Ensino em Oncologia de Santa Catarina - CEPEN	Florianopolis	SC
Brazil	Hospital das Clinicas - UFRGS	Porto Alegre	RS
Brazil	Clinicas Oncologicas Integradas - COI	Rio De Janeiro	RJ
Brazil	Instituto do Cancer do Estado de Sao Paulo - ICESP	Sao Paulo	SP
Brazil	Beneficencia Portuguesa de Sao Paulo	São Paulo	SP
Canada	Tom Baker Cancer Centre-Calgary	Calgary	Alberta
Canada	Juravinski Cancer Clinic; Department of Oncology	Hamilton	Ontario
Canada	LHSC - Victoria Hospital; London Regional Cancer Program	London	Ontario
Canada	Lakeridge Health Oshawa; Oncology	Oshawa	Ontario
Canada	The Ottawa Hospital Cancer Centre; Oncology	Ottawa	Ontario
Canada	CHU de Quebec - Hopital de l'Enfant-Jesus; Unite de Recherche en Hematologie et Oncologie	Quebec
Canada	Princess Margaret Hospital	Toronto	Ontario
France	Groupe Hospitalier Saint André - Hôpital Saint André	Bordeaux
France	Hopital du Bocage; Dermatologie	Dijon
France	Centre Hospitalier Universitaire de Grenoble - Albert Michallon	La Tronche
France	Hopital Claude Huriez - CHU Lille	Lille
France	Hopital Saint Eloi; CHU de Montpellier; Svc de Dermatologie	Montpellier
France	CHU de Nantes; Cancéro-dermatologie	Nantes
France	Hopital Robert Debre; DERMATOLOGIE	Reims
France	Centre Eugene Marquis; Service d'oncologie	Rennes
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen
France	Institut Gustave Roussy; Dermatologie	Villejuif
Germany	Charite - Universitätsmedizin Berlin	Berlin
Germany	Elbekliniken Buxtehude; Klinik für Dermatologie	Buxtehude
Germany	HELIOS Klinikum Erfurt; Klinik für Dermatologie & Allergologie	Erfurt
Germany	Universitätsklinikum Erlangen; Hautklinik	Erlangen
Germany	Universitatsklinikum Essen; Klinik für Dermatologie	Essen
Germany	Universitätsmedizin Göttingen; Klinik für Gastroenterologie, gastrointestinale	Göttingen
Germany	Medizinische Hochschule Hannover; Klinik für Dermatologie, Allergologie und Venerologie	Hannover
Germany	Universitatsklinik Heidelberg; Universitätshautklinik und Nationales Centrum für Tumorerkrankungen	Heidelberg
Germany	UKSH Kiel; Klinik für Dermatologie, Venerologie und Allergologie	Kiel
Germany	Klinikum d.Universität zu Köln Klinik u.Poliklinik f.Dermatologie	Köln
Germany	Universitätsklinikum Leipzig; Klinik für Dermatologie, Venerologie und Allergologie	Leipzig
Germany	UKSH Universitatsklinikum Schleswig-Holstein; Studienzentrum Dermatologie 10d	Lübeck
Germany	Universitatsklinikum Mainz; Klinik und Poliklinik fur Dermatologie	Mainz
Germany	Klinikum der Ludwigs-Maximilians-Universität München; Dermatologie	München
Germany	Fachklinik Hornheide; Dermatologie	Münster
Germany	Harzklinikum Dorothea Christiane Erxleben GmbH, Standort Quedlinburg; Hautkrebszentrum Harz	Quedlinburg
Germany	Universitätsklinikum Regensburg; Klinik und Poliklinik für Dermatologie	Regensburg
Germany	Zentrum für Dermatoonkologie, Universitäts-Hautklinik Tübingen	Tübingen
Germany	Universitätsklinikum Würzburg; Med. Klinik 1, Pneumologie	Würzburg
Greece	Laiko General Hospital Athen	Athens
Greece	Metropolitan Hospital; Dept. of Oncology	Pireaus
Hungary	Orszagos Onkologiai Intezet; Borgyogyaszati Osztaly	Budapest
Hungary	University of Szeged Szent-Györgyi Albert Clinical Center; Department of Dermatology and Allergology	Szeged
Israel	Rambam Health Care Campus; Oncology	Haifa
Israel	Sharett Institute - Hadassah Hebrew University Medical Center	Jerusalem
Israel	Rabin MC; Davidof Center - Oncology Institute	Petach Tikva
Israel	Ella Institute - Sheba Medical Center	Ramat-Gan
Italy	Istituto Tumori ?Giovanni Paolo II?, Oncologia	Bari	Puglia
Italy	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte
Italy	IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A	Genova	Liguria
Italy	IRST Istituto Scientifico Romagnolo Per Lo Studio E Cura Dei Tumori, Sede Meldola; Oncologia Medica	Meldola	Emilia-Romagna
Italy	Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica	Milano	Lombardia
Italy	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2	Milano	Lombardia
Italy	IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica B	Napoli	Campania
Italy	IFO - Istituto Regina Elena; Oncologia Medica	Roma	Lazio
Italy	A.O.U. Senese Policlinico Santa Maria Alle Scotte	Siena	Toscana
Italy	A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia	Udine	Friuli-Venezia Giulia
Korea, Republic of	Asan Medical Center	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
Netherlands	Erasmus Mc - Daniel Den Hoed Kliniek; Interne Oncologie	Rotterdam
New Zealand	Auckland city hospital; Auckland Regional Cancer Centre and Blood Service	Auckland
New Zealand	Wellington Hospital; Wellington Blood and Cancer Centre	Newtown
New Zealand	Mid Central DHB	Palmerston North
New Zealand	Tauranga Hospital, Clinical Trials Unit; BOP Clinical School	Tauranga
Poland	Uniwersyteckie Centrum Kliniczne; Klinika Onkologii i Radioterapii	Gdansk
Poland	Narodowy Inst.Onkol.im.Sk?odowskiej-Curie Pa?stw.Inst.Badawczy Kraków; Klinika Onkologii Klinicznej	Kraków
Poland	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin
Poland	Uniwersytecki Szpital Kliniczny w Poznaniu	Pozna?
Poland	Narodowy Instytut Onkologii im. Marii Sk?odowskiej-Curie - Pa?stwowy Instytut Badawczy	Warszawa
Poland	Dolno?l?skie Centrum Onkologii, Pulmonologii i Hematologii	Wroc?aw
Portugal	IPO de Lisboa; Servico de Oncologia Medica	Lisboa
Portugal	IPO do Porto; Servico de Oncologia Medica	Porto
Russian Federation	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast
Russian Federation	FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"	Moscow	Moskovskaja Oblast
Russian Federation	FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"	Saint-Petersburg	Sankt Petersburg
Russian Federation	St. Petersburg Oncology Hospital	Sankt-peterburg	Sankt Petersburg
Spain	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona
Spain	Hospital Universitari Vall d'Hebron; Oncology	Barcelona
Spain	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid
Spain	Hospital Universitario La Paz; Servicio de Oncologia	Madrid
Spain	Clinica Universitaria de Navarra; Servicio de Oncologia	Pamplona	Navarra
Spain	Hospital Universitario Virgen de la Macarena;	Sevilla
Spain	Fundacion Instituto Valenciano de Oncologia (IVO)	Valencia
Spain	Hospital General Universitario de Valencia; Servicio de oncologia	Valencia
Spain	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza
United Kingdom	Bristol Haematology and Oncology centre	Bristol
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Ipswich Hospital; Oncology Pharmacy	Ipswich
United Kingdom	St James Uni Hospital; Icrf Cancer Medicine Research Unit	Leeds
United Kingdom	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London
United Kingdom	Freeman Hospital; Northern Centre For Cancer Care	New Castle Upon Tyne
United Kingdom	Singleton Hospital; Pharmacy Department	Swansea
United Kingdom	Royal Cornwall Hospital	Truro
United States	St. Luke's University Health network	Bethlehem	Pennsylvania
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	UC Irvine Medical Center	Orange	California
United States	UF Health Cancer Center at Orlando Health	Orlando	Florida
United States	Oncology Specialists, S.C.	Park Ridge	Illinois
United States	Highlands Oncology Group	Springdale	Arkansas
United States	Arizona Oncology Associates, PC - HAL	Tempe	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Poland,  Portugal,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS), as Determined by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Progression-Free Survival (PFS), as Determined by Independent Review Committee Using RECIST v1.1	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Percentage of Participants With Objective Response, as Determined by Investigator Using RECIST v1.1	Objective response is defined as a CR or PR on two consecutive occasions = 4 weeks apart, as determined by the investigator according to RECIST v1.1	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Duration of Response, as Determined by Investigator Using RECIST v1.1	DOR, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Overall Survival	OS is defined as the time from randomization to death from any cause	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Percentage of Participants Who Have Survived at 2 Years	2-year landmark survival, defined as survival at 2 years	2 years
Secondary	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	Time to deterioration in global health status/healthrelated quality of life (GHS/HRQoL), defined as the time from randomization to first observed = 10-point decrease in EORTC QLQ-C30 linearly transformed GHS/HRQoL scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment.; The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Time to Deterioration in Physical Functioning Using EORTC QLQ-C30 Physical Functioning Scale Score	Time to deterioration in physical functioning, defined as the time from randomization to first observed = 10-point decrease in EORTC QLQ-C30 linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the participant is on treatment.; The score range for each EORTC QLQ-C30 scale is from 0 to 100, with higher scores indicating better functioning and better GHS/HRQoL.	Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary	Percentage of Participants With Adverse Events and Serious Adverse Events		Baseline up to 6 months after the last dose of study treatment (approximately 33 months)
Secondary	Serum Concentration of Atezolizumab		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)
Secondary	Plasma Concentration of Cobimetinib Dose: 20/40 mg		Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary	Plasma Concentration of Cobimetinib Dose: 60 mg		Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary	Plasma Concentration of Vemurafenib		Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary	Percentage of Participants Positive for Anti-Drug Antibodies (ADA) to Atezolizumab	Presence of ADAs against atezolizumab during the study relative to the presence of ADAs at baseline	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)