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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02908672




Registration number
NCT02908672
Ethics application status
Date submitted
19/09/2016
Date registered
21/09/2016
Date last updated
19/11/2020

Titles & IDs
Public title
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
Scientific 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
Secondary ID [1] 0 0
2016-002482-54
Secondary ID [2] 0 0
CO39262
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Atezolizumab
Treatment: Drugs - Atezolizumab Placebo
Treatment: Drugs - Cobimetinib
Treatment: Drugs - Vemurafenib
Treatment: Drugs - Vemurafenib Placebo

Experimental: Atezolizumab + Cobimetinib + Vemurafenib + Vemurafenib Placebo - Run-In Period (Cycle 1=28 days): Participants will receive vemurafenib 960 mg (four, 240 mg tablets) PO BID along with cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21 followed by vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 22 to 28 and vemurafenib placebo (1 tablet) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive atezolizumab 840 mg IV infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, vemurafenib 720 mg (three, 240 mg tablets) PO BID on Days 1 to 28, and vemurafenib placebo (1 tablet) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.

Experimental: Atezolizumab Placebo + Cobimetinib + Vemurafenib - Run-In Period (Cycle1=28 days): Participants will receive vemurafenib 960 milligrams (mg) (four, 240 mg tablets) orally (PO) twice a day (BID) along with cobimetinib 60 mg (three, 20 mg tablets) PO once a day (QD) on Days 1 to 21 followed by vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 22 to 28. Triple Combination Period (Cycle 1 onwards): Participants will receive ATZ placebo by intravenous (IV) infusion on Day 1 and 15, cobimetinib 60 mg (three, 20 mg tablets) PO QD on Days 1 to 21, and vemurafenib 960 mg (four, 240 mg tablets) PO BID on Days 1 to 28 of each 28-day cycle. Study treatment will continue until investigator-determined disease progression, death, unacceptable toxicity, withdrawal of consent, or pregnancy, whichever occurs first.


Treatment: Drugs: Atezolizumab
Will be administered as per the schedule described in individual arm.

Treatment: Drugs: Atezolizumab Placebo
Will be administered as per the schedule described in individual arm.

Treatment: Drugs: Cobimetinib
Will be administered as per the schedule described in individual arm.

Treatment: Drugs: Vemurafenib
Will be administered as per the schedule described in individual arm.

Treatment: Drugs: Vemurafenib Placebo
Will be administered as per the schedule described in individual arm.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [1] 0 0
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
Timepoint [1] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [2] 0 0
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
Timepoint [2] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [3] 0 0
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
Timepoint [3] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [4] 0 0
Overall Survival - OS is defined as the time from randomization to death from any cause
Timepoint [4] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [5] 0 0
Percentage of Participants Who Have Survived at 2 Years - 2-year landmark survival, defined as survival at 2 years
Timepoint [5] 0 0
2 years
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 33 months)
Secondary outcome [8] 0 0
Percentage of Participants With Adverse Events and Serious Adverse Events
Timepoint [8] 0 0
Baseline up to 6 months after the last dose of study treatment (approximately 33 months)
Secondary outcome [9] 0 0
Serum Concentration of Atezolizumab
Timepoint [9] 0 0
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 outcome [10] 0 0
Plasma Concentration of Cobimetinib Dose: 20/40 mg
Timepoint [10] 0 0
Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary outcome [11] 0 0
Plasma Concentration of Cobimetinib Dose: 60 mg
Timepoint [11] 0 0
Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary outcome [12] 0 0
Plasma Concentration of Vemurafenib
Timepoint [12] 0 0
Pre-dose (0 hour) and 3 to 6 hours post dose on Day 15 of Cy 1 and 4 (1 Cy = 28 days)
Secondary outcome [13] 0 0
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
Timepoint [13] 0 0
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)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Cancer-Related

- 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

- 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

- 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)

- 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

- 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [2] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 0 0
Peter Maccallum Cancer Centre - Melbourne
Recruitment hospital [4] 0 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 0 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 0 0
5000 - Adelaide
Recruitment postcode(s) [3] 0 0
3000 - Melbourne
Recruitment postcode(s) [4] 0 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Arizona
Country [3] 0 0
United States of America
State/province [3] 0 0
Arkansas
Country [4] 0 0
United States of America
State/province [4] 0 0
California
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Illinois
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
Austria
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Graz
Country [9] 0 0
Austria
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Innsbruck
Country [10] 0 0
Austria
State/province [10] 0 0
Wien
Country [11] 0 0
Belgium
State/province [11] 0 0
Bruxelles
Country [12] 0 0
Belgium
State/province [12] 0 0
Leuven
Country [13] 0 0
Belgium
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Liège
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Belgium
State/province [14] 0 0
Wilrijk
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Brazil
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RJ
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Brazil
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RS
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Brazil
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SC
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Brazil
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SP
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Canada
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Alberta
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Canada
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Ontario
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Quebec
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France
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Bordeaux
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Dijon
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La Tronche
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Lille
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Montpellier
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Nantes
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France
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Reims
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Rennes
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Rouen
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Villejuif
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Berlin
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Buxtehude
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Erfurt
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Erlangen
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Hannover
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Leipzig
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Lübeck
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Mainz
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München
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Münster
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Regensburg
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Tübingen
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Athens
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Pireaus
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Israel
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Friuli-Venezia Giulia
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Italy
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Lazio
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Italy
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Liguria
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Italy
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Lombardia
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Italy
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Piemonte
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Italy
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Puglia
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Toscana
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Korea, Republic of
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Gdansk
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Lisboa
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Porto
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Russian Federation
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Moskovskaja Oblast
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Russian Federation
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Moscow
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Russian Federation
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Russian Federation
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Navarra
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Sevilla
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Valencia
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Spain
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Zaragoza
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Bristol
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United Kingdom
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Glasgow
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United Kingdom
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Ipswich
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United Kingdom
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Leeds
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London
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United Kingdom
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New Castle Upon Tyne
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United Kingdom
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Swansea
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United Kingdom
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Truro

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02908672
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical Trials
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications