Clinical trial NCT01006980: A Study of Vemurafenib (RO5185426) in Comparison With Dacarbazine in Previously Untreated Patients With Metastatic Melanoma (BRIM 3)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malignant Melanoma
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2009-11-03
Enrollment: 675
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 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).
measure: Progression-free Survival
timeFrame: From randomization (initiated January 2010) to December 30 2010.
Secondary outcomes:
measure: Participants With a Best Overall Response (BOR) of Complete Response or Partial Response
timeFrame: From randomization (initiated January 2010) until December 30, 2010
measure: Duration of Response
timeFrame: From randomization (initiated in January 2010) until December 30, 2010.
measure: Time to Confirmed Response
timeFrame: From randomization (initiated January 2010) until December 30, 2010.
measure: Time to Treatment Failure
timeFrame: approximately 3 years
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From randomization (initiated January 2010) until December 30, 2010.
measure: Pre and Post-dose Plasma Vemurafenib Concentration by Study Day
timeFrame: 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).
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Tucson
country: United States
state: Arizona
city: Los Angeles
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Santa Monica
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Atlanta
country: United States
state: Georgia
city: Indianapolis
country: United States
state: Indiana
city: Boston
country: United States
state: Massachusetts
city: Boston
country: United States
state: Massachusetts
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: St Louis
country: United States
state: Missouri
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Portland
country: United States
state: Oregon
city: Philadelphia
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: Nashville
country: United States
state: Tennessee
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Seattle
country: United States
state: Washington
city: Brisbane
country: Australia
city: Frankston
country: Australia
city: Malvern
country: Australia
city: Melbourne
country: Australia
city: Melbourne
country: Australia
city: Nedlands
country: Australia
city: Newcastle
country: Australia
city: St Leonards
country: Australia
city: Sydney
country: Australia
city: Westmead
country: Australia
city: Woolloongabba
country: Australia
city: Edmonton
country: Canada
state: Alberta
city: Winnipeg
country: Canada
state: Manitoba
city: Hamilton
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Quebec City
country: Canada
state: Quebec
city: Bordeaux
country: France
city: Lille
country: France
city: Marseille
country: France
city: Montpellier
country: France
city: Nantes
country: France
city: Nice
country: France
city: Paris
country: France
city: Pierre Benite
country: France
city: Rouen
country: France
city: Villejuif
country: France
city: Buxtehude
country: Germany
city: Dresden
country: Germany
city: Erfurt
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Hannover
country: Germany
city: Heidelberg
country: Germany
city: Jena
country: Germany
city: Kiel
country: Germany
city: Koeln
country: Germany
city: Leipzig
country: Germany
city: Mainz
country: Germany
city: Minden
country: Germany
city: Muenchen
country: Germany
city: Regensburg
country: Germany
city: Tuebingen
country: Germany
city: Wuerzburg
country: Germany
city: Jerusalem
country: Israel
city: Ramat Gan
country: Israel
city: Tel Aviv
country: Israel
city: Bari
country: Italy
city: Genova
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Napoli
country: Italy
city: Roma
country: Italy
city: Siena
country: Italy
city: Amsterdam
country: Netherlands
city: Amsterdam
country: Netherlands
city: Groningen
country: Netherlands
city: Auckland
country: New Zealand
city: Dunedin
country: New Zealand
city: Hamilton
country: New Zealand
city: Palmerston North
country: New Zealand
city: Wellington
country: New Zealand
city: Linkoeping
country: Sweden
city: Lund
country: Sweden
city: Stockholm
country: Sweden
city: Umeå
country: Sweden
city: Uppsala
country: Sweden
city: Lausanne
country: Switzerland
city: Zürich
country: Switzerland
city: Cambridge
country: United Kingdom
city: Edinburgh
country: United Kingdom
city: Glasgow
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Newcastle Upon Tyne
country: United Kingdom
city: Northwood
country: United Kingdom
city: Nottingham
country: United Kingdom
city: Oxford
country: United Kingdom
city: Southampton
country: United Kingdom
city: Sutton
country: United Kingdom
city: Swansea
country: United Kingdom
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.