A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma (coBRIM)

• ClinicalTrials.gov Identifier: NCT01689519
• Recruitment Status: Completed
• First Posted: September 21, 2012
• Results First Posted: October 30, 2015
• Last Update Posted: May 2, 2022
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: September 18, 2012
• First Posted Date: September 21, 2012
• Results First Submitted Date: July 1, 2015
• Results First Posted Date: October 30, 2015
• Last Update Posted Date: May 2, 2022
• Actual Study Start Date: January 8, 2013
• Actual Primary Completion Date: May 9, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 14, 2020)

Progression-free Survival [ Time Frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) ]

Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

• Original Primary Outcome Measures (submitted: September 18, 2012): Progression-free survival according to Response Evaluation Criteria in Solid Tumors v1.1 [ Time Frame: Approximately 5 years ]

Current Secondary Outcome Measures (submitted: September 14, 2020)

• Overall Survival [ Time Frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) ]
  Overall survival was defined as the time from randomization until the date of death from any cause.
• Percentage of Participants With an Objective Response [ Time Frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) ]
  An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.
• Duration of Response [ Time Frame: Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months) ]
  Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Original Secondary Outcome Measures (submitted: September 18, 2012)

• Overall survival [ Time Frame: Approximately 5 years ]
• Objective response rate according to Response Evaluation Criteria in Solid Tumors v1.1 [ Time Frame: Approximately 5 years ]
• Duration of response according to Response Evaluation Criteria in Solid Tumors v1.1 [ Time Frame: Approximately 5 years ]
• Safety: incidence of adverse events [ Time Frame: Approximately 5 years ]
• Pharmacokinetics: Area under the plasma concentration time curve trough 24 hours [ Time Frame: Cycle 1, days 1 and 15; cycle 2, day 15 ]
• Pharmacokinetics: Minimum observed plasma concentration [ Time Frame: Cycle 1, days 1 and 15; cycle 2, day 15 ]
• Pharmacokinetics: Apparent clearance following oral dosing [ Time Frame: Cycle 1, days 1 and 15; cycle 2, day 15 ]
• Quality of life as measured by the European Organization for Research and Cancer Quality of Life Questionnaire (QLQ-30) [ Time Frame: Approximately 5 years ]
• Quality of life as measured by the EuroQol 5 dimension (EQ-5D) [ Time Frame: Approximately 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Malignant Melanoma

Intervention

• Drug: Placebo
  Placebo supplied as tablets
• Drug: Vemurafenib
  Vemurafenib supplied as tablets
  Other Name: RO518426
• Drug: Cobimetinib
  Cobimetinib supplied as tablets
  Other Names:

  • GDC-0973
  • RO5514041
  • XL518

Study Arms

• 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.
  Interventions:

  • Drug: Placebo
  • Drug: Vemurafenib
• 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.
  Interventions:

  • Drug: Vemurafenib
  • Drug: Cobimetinib

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 1, 2015): 495
• Original Estimated Enrollment (submitted: September 18, 2012): 500
• Actual Study Completion Date: July 21, 2019
• Actual Primary Completion Date: May 9, 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Israel, Italy, Netherlands, New Zealand, Norway, Russian Federation, Spain, Sweden, Switzerland, United Kingdom, United States
• Removed Location Countries: Czech Republic, Turkey

Administrative Information

• NCT Number: NCT01689519
• Other Study ID Numbers: GO28141; 2012-003008-11 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: April 2022