A Study of Vemurafenib Adjuvant Therapy in Participants With Surgically Resected Cutaneous BRAF-Mutant Melanoma (BRIM8)

• ClinicalTrials.gov Identifier: NCT01667419
• Recruitment Status: Completed
• First Posted: August 17, 2012
• Results First Posted: October 17, 2018
• Last Update Posted: July 23, 2019
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: August 15, 2012
• First Posted Date: August 17, 2012
• Results First Submitted Date: June 5, 2018
• Results First Posted Date: October 17, 2018
• Last Update Posted Date: July 23, 2019
• Actual Study Start Date: September 24, 2012
• Actual Primary Completion Date: June 23, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2018)

Disease-Free Survival (DFS) as Assessed Using Contrast-Enhanced Magnetic Resonance Imaging (MRI) or Contrast Enhanced Computed Tomography (CT) [ Time Frame: From randomization until the date of the first local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause (up to the April 17, 2017 data cut-off, approximately 4.5 years) ]

DFS was defined as the time from randomization until the date of the first local, regional, or distant melanoma recurrence, occurrence of new primary melanoma, or death from any cause.

• Original Primary Outcome Measures (submitted: August 15, 2012): Disease-free survival [ Time Frame: Approximately 37 months ]

Current Secondary Outcome Measures (submitted: July 11, 2019)

• Distant Metastasis-Free Survival (DMFS) as Assessed Using Contrast-Enhanced MRI or Contrast Enhanced CT [ Time Frame: From randomization until the date of diagnosis of distant (i.e., non-locoregional) metastases or death from any cause (up to the April 17, 2017 data cut-off, approximately 4.5 years) ]
  DMFS was defined as the time from randomization until the date of diagnosis of distant (i.e. non-locoregional) metastases or death from any cause.
• Overall Survival (OS) [ Time Frame: From randomization until the date of death from any cause (up until 13-July-2018, approximately 6 years) ]
  OS is defined as the time from randomization until the date of death from any cause.
• Percentage of Participants With Adverse Events [ Time Frame: From randomization up to study completion or discontinuation (up until 13-July-2018, approximately 6 years) ]
  An adverse event is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution.
• Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) 30-Item Quality of Life Questionnaire (QLQ-C30) Score [ Time Frame: Day 1, Day 8, Day 15, Day 22 of Cycle 1;Day 1, Day 15 of Cycle 2;Day 1 Cycles 3-13;end of treatment(up to 13 months);every 13 weeks thereafter until recurrence or occurrence of a new primary melanoma (up to 17-Apr-17 data cut-off,approximately 4.5 years) ]
  European Organisation for Research and Treatment of Cancer 30-Item Quality of Life Questionnaire assesses 8 symptoms, function, financial difficulties, and a global health status/health-related quality of life (HRQoL). Most questions use a 4-point scale (1 'Not at all' to 4 'Very much';2 questions use a 7-point scale (1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to a 0-100 scale. Higher scores for the function and HRQoL represent higher levels of functioning and HRQoL, higher scores for the symptom represent higher levels of symptoms/problems, higher score for financial difficulty represent higher level of perceived financial burden of treatment. Changes of 5-10 points are considered to represent a minimally important difference to participants. A positive value means an increase, and negative value means a decrease in score at the indicated time-point relative to the score at baseline (Cycle 1 Day 1).
• Plasma Concentration of Vemurafenib [ Time Frame: Pre-morning dose (0 hour [hr]) and 1 to 4 hrs post-dose on Days 1, 8, 15, and 22 of Cycle 1; pre-morning dose (0 hr) on Days 1 and 15 of Cycle 2; pre-morning dose (0 hr) on Day 1 of Cycles 3-13; at end of treatment (up to 13 months) ]

Original Secondary Outcome Measures (submitted: August 15, 2012)

• Overall survival [ Time Frame: Approximately 7 years ]
• Distant metastases-free survival [ Time Frame: Approximately 37 months ]
• Safety: incidence of adverse events [ Time Frame: 5 years ]
• Quality of life according to European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 [ Time Frame: 5 years ]
• Pharmacokinetics: plasma concentration of vemurafenib [ Time Frame: Cycle 1: Day 1, 8, 15, 22; Cycle 2: Day 1, 15; cycles thereafter: Day 1, and end of treatment ]

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

Descriptive Information

• Brief Title: A Study of Vemurafenib Adjuvant Therapy in Participants With Surgically Resected Cutaneous BRAF-Mutant Melanoma
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Vemurafenib (RO5185426) Adjuvant Therapy in Patients With Surgically Resected, Cutaneous BRAF-Mutant Melanoma at High Risk for Recurrence
• Brief Summary: This multicenter, randomized, double-blind, placebo-controlled study will evaluate the efficacy and safety of vemurafenib in participants with completely resected, cutaneous BRAF mutation-positive melanoma at high risk for recurrence. Participants will be enrolled in two separate cohorts: Cohort 1 will include participants with completely resected Stage IIC, IIIA (participants with one or more nodal metastasis greater than [>] 1 millimeter [mm] in diameter), or IIIB cutaneous melanoma, as defined by the American Joint Committee on Cancer (AJCC) Classification, Version 7; Cohort 2 will include participants with Stage IIIC cutaneous melanoma, as defined by this classification scheme. Within each cohort, participants will be randomized (1:1 ratio) to receive vemurafenib or matching placebo over a 52-week period.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: Vemurafenib
  4 tablets of vemurafenib 240 mg each (total 960 mg) were administered orally as per the schedule specified in the respective arm.
  Other Name: RO5185426/F17, Zelboraf
• Drug: Placebo
  Placebo matching to vemurafenib were administered orally as per the schedule specified in the respective arm.

Study Arms

• Experimental: Cohort 1 Vemurafenib
  Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib, 960 milligrams (mg) twice daily, in 28-day cycles, for up to 52 weeks
  Intervention: Drug: Vemurafenib
• Placebo Comparator: Cohort 1 Placebo
  Participants with completely resected Stage IIC, IIIA, or IIIB cutaneous melanoma) received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks
  Intervention: Drug: Placebo
• Experimental: Cohort 2 Vemurafenib
  Participants with Stage IIIC cutaneous melanoma received vemurafenib, 960 mg twice daily, in 28-day cycles, for up to 52 weeks
  Intervention: Drug: Vemurafenib
• Placebo Comparator: Cohort 2 Placebo
  Participants with Stage IIIC cutaneous melanoma received vemurafenib-matching placebo twice daily, in 28-day cycles, for up to 52 weeks
  Intervention: Drug: Placebo

Publications *

• Ascierto PA, Lewis KD, Di Giacomo AM, Demidov L, Mandala M, Bondarenko I, Herbert C, Mackiewicz A, Rutkowski P, Guminski A, Simmons B, Ye C, Hooper G, Wongchenko MJ, Goodman GR, Yan Y, Schadendorf D. Prognostic impact of baseline tumour immune infiltrate on disease-free survival in patients with completely resected, BRAFv600 mutation-positive melanoma receiving adjuvant vemurafenib. Ann Oncol. 2020 Jan;31(1):153-159. doi: 10.1016/j.annonc.2019.10.002.
• Maio M, Lewis K, Demidov L, Mandala M, Bondarenko I, Ascierto PA, Herbert C, Mackiewicz A, Rutkowski P, Guminski A, Goodman GR, Simmons B, Ye C, Yan Y, Schadendorf D; BRIM8 Investigators. Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):510-520. doi: 10.1016/S1470-2045(18)30106-2. Epub 2018 Feb 21. Erratum In: Lancet Oncol. 2018 Apr;19(4):e184.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 21, 2018): 498
• Original Estimated Enrollment (submitted: August 15, 2012): 725
• Actual Study Completion Date: July 13, 2018
• Actual Primary Completion Date: June 23, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically confirmed melanoma of cutaneous origin
• Participants with BRAFV600 mutation-positive, cutaneous melanoma (either pathologic Stage IIC or Stage III according to AJCC Staging Criteria version 7 that has been completely resected
• BRAF V600 mutation status of the current primary tumor or involved lymph node determined to be positive using the cobas BRAF V600 mutation test
• Surgically rendered free of disease within 90 days of randomization
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 5 years
• Fully recovered from the effects of any major surgery or significant traumatic injury prior to the first dose of study treatment
• Adequate hematologic, hepatic, and renal function

Exclusion Criteria:

• History of any systemic or local therapy (e.g., chemotherapy, biologic or targeted therapy, hormonal therapy, or photodynamic therapy) for the treatment or prevention of melanoma, including interferon alpha-2b and pegylated interferon alpha-2b
• History of limb perfusion therapy
• History of radiotherapy for the treatment of melanoma
• Invasive malignancy other than melanoma at the time of enrollment or within 5 years prior to first dose of study treatment
• Family history of inherited colon cancer syndromes
• Known personal history of >3 adenomatous colorectal polyps or a personal history of adenomatous colorectal polyp(s) >2 centimeters (cm) in size
• History of or current clinical, radiographic, or pathologic evidence of in-transit metastases, satellite, or microsatellite lesions
• History of or current clinical, radiographic, or pathologic evidence of recurrent lymph node involvement after resection of a primary melanoma with lymph node involvement at any time in the past
• History of local and/or regional and/or distant melanoma recurrence
• History or current radiographic or pathologic evidence of distant metastases
• History of clinically significant cardiac or pulmonary dysfunction
• Major surgical procedure or significant traumatic injury within 4 weeks prior to first dose of study treatment
• Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus

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: Argentina, Australia, Austria, Belgium, Brazil, Canada, Croatia, Czechia, Estonia, France, Germany, Ireland, Israel, Italy, Mexico, Netherlands, New Zealand, Norway, Poland, Portugal, Russian Federation, Serbia, South Africa, Spain, Sweden, Switzerland, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic, Turkey

Administrative Information

• NCT Number: NCT01667419
• Other Study ID Numbers: GO27826; 2011-004011-24 ( 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: July 2019