A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3)

BRIM 3: A Randomized, Open-Label, Controlled, Multicenter, Phase III Study in Previously Untreated Patients With Unresectable Stage IIIC or Stage IV Melanoma With V600E BRAF Mutation Receiving Vemurafenib (RO5185426) or Dacarbazine

This randomized, open-label study evaluated the efficacy, safety and tolerability of vemurafenib (RO5185426) as compared to dacarbazine in previously untreated patients with metastatic melanoma. Patients were randomized to receive either vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. Study treatment was continued until disease progression or unacceptable toxicity occurred. The data and safety monitoring board recommended that patients in the dacarbazine group be allowed to cross over to receive vemurafenib, and the protocol was amended accordingly on January 14, 2011, as both overall survival and progression-free survival endpoints had met the prespecified criteria for statistical significance in favor of vemurafenib.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Vemurafenib; Drug: Dacarbazine

• Study Type: Interventional
• Enrollment (Actual): 675
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Brisbane, Australia, 4006
  • Frankston, Australia, 3199
  • Malvern, Australia, 3144
  • Melbourne, Australia, 3002
  • Melbourne, Australia, 3128
  • Nedlands, Australia, 6009
  • Newcastle, Australia, 2310
  • St Leonards, Australia, 2065
  • Sydney, Australia, 2060
  • Westmead, Australia, 2145
  • Woolloongabba, Australia, 4102
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T5J 3N4
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
    • Toronto, Ontario, Canada, M5G 2M9
    • Toronto, Ontario, Canada, M4N 3M5
  • Quebec
    • Montreal, Quebec, Canada, H3A 1A1
    • Montreal, Quebec, Canada, H3T 1E2
    • Quebec City, Quebec, Canada, G1R 2J6
• France
  • Bordeaux, France, 33075
  • Lille, France, 59037
  • Marseille, France, 13005
  • Montpellier, France, 34298
  • Nantes, France, 44093
  • Nice, France, 06202
  • Paris, France, 75010
  • Pierre Benite, France, 69495
  • Rouen, France, 76031
  • Villejuif, France, 94805
• Germany
  • Buxtehude, Germany, 21614
  • Dresden, Germany, 01307
  • Erfurt, Germany, 99089
  • Essen, Germany, 45122
  • Frankfurt, Germany, 60596
  • Hannover, Germany, 30449
  • Heidelberg, Germany, 69120
  • Jena, Germany, 07743
  • Kiel, Germany, 24105
  • Koeln, Germany, 50924
  • Leipzig, Germany, 04103
  • Mainz, Germany, 55131
  • Minden, Germany, 32429
  • Muenchen, Germany, 81377
  • Regensburg, Germany, 93053
  • Tuebingen, Germany, 72076
  • Wuerzburg, Germany, 80337
• Israel
  • Jerusalem, Israel, 91200
  • Ramat Gan, Israel, 52621
  • Tel Aviv, Israel, 64239
• Italy
  • Bari, Italy, 70124
  • Genova, Italy, 16132
  • Milano, Italy, 20162
  • Milano, Italy, 20133
  • Milano, Italy, 20141
  • Napoli, Italy, 80131
  • Roma, Italy, 00158
  • Siena, Italy, 53100
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
  • Amsterdam, Netherlands, 1066 CX
  • Groningen, Netherlands, 9713 GZ
• New Zealand
  • Auckland, New Zealand
  • Dunedin, New Zealand, 9001
  • Hamilton, New Zealand, 2001
  • Palmerston North, New Zealand
  • Wellington, New Zealand, 6021
• Sweden
  • Linkoeping, Sweden, 58185
  • Lund, Sweden, 22185
  • Stockholm, Sweden, 17176
  • Umeå, Sweden
  • Uppsala, Sweden, 75185
• Switzerland
  • Lausanne, Switzerland, 1011
  • Zürich, Switzerland, 8091
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QH
  • Edinburgh, United Kingdom, EH4 2XU
  • Glasgow, United Kingdom, G12 0YN
  • London, United Kingdom, SE1 9RT
  • London, United Kingdom, NW3 2QG
  • London, United Kingdom, E1 1BB
  • London, United Kingdom, SW3 3JJ
  • Manchester, United Kingdom, M20 4BX
  • Newcastle Upon Tyne, United Kingdom, NE7 7DN
  • Northwood, United Kingdom, HA6 2RN
  • Nottingham, United Kingdom, NG5 1PB
  • Oxford, United Kingdom, OX3 7LJ
  • Southampton, United Kingdom, SO16 6YD
  • Sutton, United Kingdom, SM2 5PT
  • Swansea, United Kingdom, SA2 8QA
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35243
  • Arizona
    • Tucson, Arizona, United States, 85724
  • California
    • Los Angeles, California, United States, 90095-1752
    • San Francisco, California, United States, 94117
    • Santa Monica, California, United States, 90404
  • Colorado
    • Aurora, Colorado, United States, 80045
  • Georgia
    • Atlanta, Georgia, United States, 30322
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
    • Boston, Massachusetts, United States, 02114
    • Boston, Massachusetts, United States, 02115
  • Michigan
    • Detroit, Michigan, United States, 48201
  • Missouri
    • St Louis, Missouri, United States, 63110
  • New York
    • New York, New York, United States, 10016
    • New York, New York, United States, 10065
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
  • Oregon
    • Portland, Oregon, United States, 97213
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
    • Pittsburgh, Pennsylvania, United States, 15213-2584
  • Tennessee
    • Nashville, Tennessee, United States, 37232
    • Nashville, Tennessee, United States, 37203
  • Texas
    • Dallas, Texas, United States, 75246
  • Utah
    • Salt Lake City, Utah, United States, 84112
  • Washington
    • Seattle, Washington, United States, 98109

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adults, >/=18 years of age
• metastatic melanoma, stage IIIC or IV (AJCC)
• treatment-naïve (no prior systemic anticancer therapy)
• positive for BRAF V600E mutation
• measurable disease by RECIST criteria
• negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion

Exclusion Criteria:

• active central nervous system metastases
• history of carcinomatous meningitis
• severe cardiovascular disease within 6 months prior to study drug administration
• previous malignancy within 5 years prior to study, except for basal or squamous cell carcinoma of the skin, melanoma in-situ, or carcinoma in-situ of the cervix

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dacarbazine	Drug: Dacarbazine; 1000 mg/m2 intravenously every 3 weeks
Experimental: Vemurafenib	Drug: Vemurafenib; 960 mg (as 240 mg tables) orally twice daily; Other Names: RO5185426; Zelboraf®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	An Overall survival event was defined as death due to any cause. The number of participants with overall survival events is reported.	From randomization (initiated January 2010) to December 30 2010. Median follow-up time in the vemurafenib group was 3.75 months (range 0.3 to 10.8) and in the dacarbazine group was 2.33 months (range <0.1 to 10.3).
Progression-free Survival	A progression-free survival (PFS) event was defined as disease progression or death due to any cause. Tumor response (progression) was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria using computed tomography (CT) scans or magnetic resonance imaging (MRI).	From randomization (initiated January 2010) to December 30 2010.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With a Best Overall Response (BOR) of Complete Response or Partial Response	BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Participants who never received study treatment and treated participants without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion and no new lesion.	From randomization (initiated January 2010) until December 30, 2010
Duration of Response	Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause. Duration of response was calculated only for participants who had a best overall response of Complete Response or Partial Response and was estimated using the Kaplan-Meier method.	From randomization (initiated in January 2010) until December 30, 2010.
Time to Confirmed Response	Time to response was defined as the time from randomization to confirmed response (complete response or partial response).	From randomization (initiated January 2010) until December 30, 2010.
Time to Treatment Failure	Treatment failure was defined as a secondary endpoint in the protocol, defined as death, disease progression or premature withdrawal of study treatment. This endpoint was not included in the Statistical analysis plan; therefore no analyses of time to treatment failure were performed.	approximately 3 years
Number of Participants With Adverse Events (AEs)	The intensity of AEs was graded according to the NCI Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a five-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening and Death). A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution, for example is life-threatening, requires hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or requires intervention to prevent one or other of the outcomes listed above.	From randomization (initiated January 2010) until December 30, 2010.
Pre and Post-dose Plasma Vemurafenib Concentration by Study Day	The pharmacokinetics of vemurafenib were assessed at the beginning of each 21-day cycle using pre-dose and 2-4 hours post-dose sampling.	Plasma samples were collected before the morning dose (troughs) and 2-4 hours after the morning dose at the beginning of each cycle (Days 1, 22, 43, 64, 106, 148 and 190).

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Su F, Viros A, Milagre C, Trunzer K, Bollag G, Spleiss O, Reis-Filho JS, Kong X, Koya RC, Flaherty KT, Chapman PB, Kim MJ, Hayward R, Martin M, Yang H, Wang Q, Hilton H, Hang JS, Noe J, Lambros M, Geyer F, Dhomen N, Niculescu-Duvaz I, Zambon A, Niculescu-Duvaz D, Preece N, Robert L, Otte NJ, Mok S, Kee D, Ma Y, Zhang C, Habets G, Burton EA, Wong B, Nguyen H, Kockx M, Andries L, Lestini B, Nolop KB, Lee RJ, Joe AK, Troy JL, Gonzalez R, Hutson TE, Puzanov I, Chmielowski B, Springer CJ, McArthur GA, Sosman JA, Lo RS, Ribas A, Marais R. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012 Jan 19;366(3):207-15. doi: 10.1056/NEJMoa1105358.
• Frederick DT, Salas Fragomeni RA, Schalck A, Ferreiro-Neira I, Hoff T, Cooper ZA, Haq R, Panka DJ, Kwong LN, Davies MA, Cusack JC, Flaherty KT, Fisher DE, Mier JW, Wargo JA, Sullivan RJ. Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics. PLoS One. 2014 Jul 1;9(7):e101286. doi: 10.1371/journal.pone.0101286. eCollection 2014.
• Lacouture ME, Duvic M, Hauschild A, Prieto VG, Robert C, Schadendorf D, Kim CC, McCormack CJ, Myskowski PL, Spleiss O, Trunzer K, Su F, Nelson B, Nolop KB, Grippo JF, Lee RJ, Klimek MJ, Troy JL, Joe AK. Analysis of dermatologic events in vemurafenib-treated patients with melanoma. Oncologist. 2013;18(3):314-22. doi: 10.1634/theoncologist.2012-0333. Epub 2013 Mar 1.
• 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.
• Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, Hamid O, Ascierto PA, Testori A, Lorigan PC, Dummer R, Sosman JA, Flaherty KT, Chang I, Coleman S, Caro I, Hauschild A, McArthur GA. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. 2017 Oct 1;28(10):2581-2587. doi: 10.1093/annonc/mdx339.
• Yamazaki N, Kiyohara Y, Sugaya N, Uhara H. Phase I/II study of vemurafenib in patients with unresectable or recurrent melanoma with BRAF(V) (600) mutations. J Dermatol. 2015 Jul;42(7):661-6. doi: 10.1111/1346-8138.12873. Epub 2015 Apr 17.
• McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, Ribas A, Hogg D, Hamid O, Ascierto PA, Garbe C, Testori A, Maio M, Lorigan P, Lebbe C, Jouary T, Schadendorf D, O'Day SJ, Kirkwood JM, Eggermont AM, Dreno B, Sosman JA, Flaherty KT, Yin M, Caro I, Cheng S, Trunzer K, Hauschild A. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014 Mar;15(3):323-32. doi: 10.1016/S1470-2045(14)70012-9. Epub 2014 Feb 7.
• Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.

Study record dates

Study Major Dates

• Study Start: January 1, 2010
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: October 30, 2009
• First Submitted That Met QC Criteria: November 2, 2009
• First Posted (Estimate): November 3, 2009

Study Record Updates

• Last Update Posted (Estimate): September 28, 2016
• Last Update Submitted That Met QC Criteria: August 19, 2016
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Dacarbazine; Vemurafenib
• Other Study ID Numbers: NO25026; 2009-012293-12