Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01689519




Registration number
NCT01689519
Ethics application status
Date submitted
18/09/2012
Date registered
21/09/2012
Date last updated
2/05/2022

Titles & IDs
Public title
A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma
Scientific 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
Secondary ID [1] 0 0
2012-003008-11
Secondary ID [2] 0 0
GO28141
Universal Trial Number (UTN)
Trial acronym
coBRIM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant 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 - Placebo
Treatment: Drugs - Vemurafenib
Treatment: Drugs - Cobimetinib

Active comparator: Placebo + Vemurafenib - Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.

Experimental: Cobimetinib + Vemurafenib - Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.


Treatment: Drugs: Placebo
Placebo supplied as tablets

Treatment: Drugs: Vemurafenib
Vemurafenib supplied as tablets

Treatment: Drugs: Cobimetinib
Cobimetinib supplied as tablets
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Progression-free Survival
Timepoint [1] 0 0
Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Secondary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Secondary outcome [2] 0 0
Percentage of Participants With an Objective Response
Timepoint [2] 0 0
Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)
Secondary outcome [3] 0 0
Duration of Response
Timepoint [3] 0 0
Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

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 assessing the outcomes
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
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/01/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
21/07/2019
Sample size
Target
Accrual to date
Final
495
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,VIC,WA
Recruitment hospital [1] 0 0
Chris O'Brien Lifehouse - Camperdown
Recruitment hospital [2] 0 0
Lake Macquarie Private Hospital - Gateshead
Recruitment hospital [3] 0 0
Lismore Base Hospital; Cancer Care & Haematology Unit - Lismore
Recruitment hospital [4] 0 0
Melanoma Institute Australia - North Sydney
Recruitment hospital [5] 0 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [6] 0 0
Royal Darwin Hospital - Casuarina
Recruitment hospital [7] 0 0
Greenslopes Private Hospital - Greenslopes
Recruitment hospital [8] 0 0
Royal Brisbane and Women's Hospital - Herston
Recruitment hospital [9] 0 0
Royal Adelaide Hospital; Hepatology - Adelaide
Recruitment hospital [10] 0 0
Ashford Cancer Centre - Ashford SA
Recruitment hospital [11] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [12] 0 0
Launceston General Hospital; Gastroenterology Research - Launceston
Recruitment hospital [13] 0 0
Peninsula and South Eastern Haematology and Oncology Group - Frankston
Recruitment hospital [14] 0 0
Austin Hospital - Heidelberg
Recruitment hospital [15] 0 0
Peter MacCallum Cancer Centre-East Melbourne - Melbourne
Recruitment hospital [16] 0 0
The Alfred Hospital - Prahan
Recruitment hospital [17] 0 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 0 0
2050 - Camperdown
Recruitment postcode(s) [2] 0 0
2290 - Gateshead
Recruitment postcode(s) [3] 0 0
2480 - Lismore
Recruitment postcode(s) [4] 0 0
2060 - North Sydney
Recruitment postcode(s) [5] 0 0
2050 - Woolloongabba
Recruitment postcode(s) [6] 0 0
0811 - Casuarina
Recruitment postcode(s) [7] 0 0
4120 - Greenslopes
Recruitment postcode(s) [8] 0 0
4029 - Herston
Recruitment postcode(s) [9] 0 0
5000 - Adelaide
Recruitment postcode(s) [10] 0 0
5035 - Ashford SA
Recruitment postcode(s) [11] 0 0
7000 - Hobart
Recruitment postcode(s) [12] 0 0
7250 - Launceston
Recruitment postcode(s) [13] 0 0
3199 - Frankston
Recruitment postcode(s) [14] 0 0
3084 - Heidelberg
Recruitment postcode(s) [15] 0 0
3000 - Melbourne
Recruitment postcode(s) [16] 0 0
3181 - Prahan
Recruitment postcode(s) [17] 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
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Kansas
Country [7] 0 0
United States of America
State/province [7] 0 0
Kentucky
Country [8] 0 0
United States of America
State/province [8] 0 0
Missouri
Country [9] 0 0
United States of America
State/province [9] 0 0
New Hampshire
Country [10] 0 0
United States of America
State/province [10] 0 0
North Carolina
Country [11] 0 0
United States of America
State/province [11] 0 0
Ohio
Country [12] 0 0
United States of America
State/province [12] 0 0
Pennsylvania
Country [13] 0 0
United States of America
State/province [13] 0 0
Rhode Island
Country [14] 0 0
United States of America
State/province [14] 0 0
Tennessee
Country [15] 0 0
Austria
State/province [15] 0 0
Linz
Country [16] 0 0
Austria
State/province [16] 0 0
St. Pölten
Country [17] 0 0
Austria
State/province [17] 0 0
Wien
Country [18] 0 0
Belgium
State/province [18] 0 0
Bruxelles
Country [19] 0 0
Belgium
State/province [19] 0 0
Edegem
Country [20] 0 0
Belgium
State/province [20] 0 0
Hasselt
Country [21] 0 0
Belgium
State/province [21] 0 0
Liège
Country [22] 0 0
Belgium
State/province [22] 0 0
Roeselare
Country [23] 0 0
Canada
State/province [23] 0 0
British Columbia
Country [24] 0 0
Canada
State/province [24] 0 0
Ontario
Country [25] 0 0
Canada
State/province [25] 0 0
Quebec
Country [26] 0 0
Czechia
State/province [26] 0 0
Brno
Country [27] 0 0
Czechia
State/province [27] 0 0
Hradec Kralove
Country [28] 0 0
Czechia
State/province [28] 0 0
Olomouc
Country [29] 0 0
Czechia
State/province [29] 0 0
Ostrava - Poruba
Country [30] 0 0
Czechia
State/province [30] 0 0
Pardubice
Country [31] 0 0
Czechia
State/province [31] 0 0
Prague
Country [32] 0 0
Czechia
State/province [32] 0 0
Praha 2
Country [33] 0 0
Czechia
State/province [33] 0 0
Praha
Country [34] 0 0
France
State/province [34] 0 0
Bordeaux
Country [35] 0 0
France
State/province [35] 0 0
Boulogne Billancourt
Country [36] 0 0
France
State/province [36] 0 0
Clermont Ferrand cedex 1
Country [37] 0 0
France
State/province [37] 0 0
Dijon
Country [38] 0 0
France
State/province [38] 0 0
La Tronche
Country [39] 0 0
France
State/province [39] 0 0
Lille
Country [40] 0 0
France
State/province [40] 0 0
Marseille
Country [41] 0 0
France
State/province [41] 0 0
Montpellier
Country [42] 0 0
France
State/province [42] 0 0
Nantes
Country [43] 0 0
France
State/province [43] 0 0
Nice
Country [44] 0 0
France
State/province [44] 0 0
Pierre Benite
Country [45] 0 0
France
State/province [45] 0 0
Reims
Country [46] 0 0
France
State/province [46] 0 0
Rennes
Country [47] 0 0
Germany
State/province [47] 0 0
Bochum
Country [48] 0 0
Germany
State/province [48] 0 0
Buxtehude
Country [49] 0 0
Germany
State/province [49] 0 0
Dresden
Country [50] 0 0
Germany
State/province [50] 0 0
Erfurt
Country [51] 0 0
Germany
State/province [51] 0 0
Essen
Country [52] 0 0
Germany
State/province [52] 0 0
Freiburg
Country [53] 0 0
Germany
State/province [53] 0 0
Gera
Country [54] 0 0
Germany
State/province [54] 0 0
Göttingen
Country [55] 0 0
Germany
State/province [55] 0 0
Hamburg
Country [56] 0 0
Germany
State/province [56] 0 0
Hannover
Country [57] 0 0
Germany
State/province [57] 0 0
Heidelberg
Country [58] 0 0
Germany
State/province [58] 0 0
Kiel
Country [59] 0 0
Germany
State/province [59] 0 0
Koeln
Country [60] 0 0
Germany
State/province [60] 0 0
Mainz
Country [61] 0 0
Germany
State/province [61] 0 0
Mannheim
Country [62] 0 0
Germany
State/province [62] 0 0
Muenster
Country [63] 0 0
Germany
State/province [63] 0 0
München
Country [64] 0 0
Germany
State/province [64] 0 0
Regensburg
Country [65] 0 0
Germany
State/province [65] 0 0
Tuebingen
Country [66] 0 0
Germany
State/province [66] 0 0
Würzburg
Country [67] 0 0
Hungary
State/province [67] 0 0
Budapest
Country [68] 0 0
Hungary
State/province [68] 0 0
Gyula
Country [69] 0 0
Hungary
State/province [69] 0 0
Pecs
Country [70] 0 0
Hungary
State/province [70] 0 0
Szeged
Country [71] 0 0
Israel
State/province [71] 0 0
Beer Sheva
Country [72] 0 0
Israel
State/province [72] 0 0
Haifa
Country [73] 0 0
Israel
State/province [73] 0 0
Jerusalem
Country [74] 0 0
Israel
State/province [74] 0 0
Petach Tikva
Country [75] 0 0
Israel
State/province [75] 0 0
Ramat Gan
Country [76] 0 0
Israel
State/province [76] 0 0
Tel Aviv
Country [77] 0 0
Italy
State/province [77] 0 0
Campania
Country [78] 0 0
Italy
State/province [78] 0 0
Emilia-Romagna
Country [79] 0 0
Italy
State/province [79] 0 0
Lazio
Country [80] 0 0
Italy
State/province [80] 0 0
Liguria
Country [81] 0 0
Italy
State/province [81] 0 0
Lombardia
Country [82] 0 0
Italy
State/province [82] 0 0
Puglia
Country [83] 0 0
Italy
State/province [83] 0 0
Toscana
Country [84] 0 0
Italy
State/province [84] 0 0
Veneto
Country [85] 0 0
Netherlands
State/province [85] 0 0
Amsterdam
Country [86] 0 0
Netherlands
State/province [86] 0 0
Leiden
Country [87] 0 0
Netherlands
State/province [87] 0 0
Maastricht
Country [88] 0 0
New Zealand
State/province [88] 0 0
Auckland
Country [89] 0 0
New Zealand
State/province [89] 0 0
Hamilton
Country [90] 0 0
Norway
State/province [90] 0 0
Oslo
Country [91] 0 0
Russian Federation
State/province [91] 0 0
Barnaul
Country [92] 0 0
Russian Federation
State/province [92] 0 0
Moscow
Country [93] 0 0
Russian Federation
State/province [93] 0 0
Omsk
Country [94] 0 0
Russian Federation
State/province [94] 0 0
Pyatigorsk
Country [95] 0 0
Spain
State/province [95] 0 0
LA Coruña
Country [96] 0 0
Spain
State/province [96] 0 0
Navarra
Country [97] 0 0
Spain
State/province [97] 0 0
Sevilla
Country [98] 0 0
Spain
State/province [98] 0 0
Barcelona
Country [99] 0 0
Spain
State/province [99] 0 0
Madrid
Country [100] 0 0
Spain
State/province [100] 0 0
Valencia
Country [101] 0 0
Spain
State/province [101] 0 0
Zaragoza
Country [102] 0 0
Sweden
State/province [102] 0 0
Jönköping
Country [103] 0 0
Sweden
State/province [103] 0 0
Lund
Country [104] 0 0
Sweden
State/province [104] 0 0
Mölnlycke
Country [105] 0 0
Sweden
State/province [105] 0 0
Uppsala
Country [106] 0 0
Switzerland
State/province [106] 0 0
Bern
Country [107] 0 0
Switzerland
State/province [107] 0 0
Chur
Country [108] 0 0
United Kingdom
State/province [108] 0 0
Bristol
Country [109] 0 0
United Kingdom
State/province [109] 0 0
Cambridge
Country [110] 0 0
United Kingdom
State/province [110] 0 0
Cardiff
Country [111] 0 0
United Kingdom
State/province [111] 0 0
Edinburgh
Country [112] 0 0
United Kingdom
State/province [112] 0 0
Glasgow
Country [113] 0 0
United Kingdom
State/province [113] 0 0
Liverpool
Country [114] 0 0
United Kingdom
State/province [114] 0 0
London
Country [115] 0 0
United Kingdom
State/province [115] 0 0
Newcastle upon Tyne
Country [116] 0 0
United Kingdom
State/province [116] 0 0
Nottingham
Country [117] 0 0
United Kingdom
State/province [117] 0 0
Southampton
Country [118] 0 0
United Kingdom
State/province [118] 0 0
Truro
Country [119] 0 0
United Kingdom
State/province [119] 0 0
Wolverhampton

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

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT01689519
Trial related presentations / publications
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.
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.
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.
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.
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.
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.
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.
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

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01689519