Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
NCT ID: NCT01597908
Last Updated: 2021-02-24
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
704 participants
INTERVENTIONAL
2012-06-04
2019-04-25
Brief Summary
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Detailed Description
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Randomization: A total of 704 subjects were randomized in a ratio of 1:1 to receive combination therapy (352 subjects) or vemurafenib treatment (352 subjects). Subjects were stratified by LDH level (\> the ULN versus =\< ULN) and BRAF mutation (V600E versus V600K).
Study treatment: Dabrafenib and trametinib were administered orally at their recommended doses of 150 mg b.i.d. and 2.0 mg once daily, respectively. Subjects randomized in the combination therapy arm received both the agents. Subjects randomized in the vemurafenib arm received vemurafenib at the recommended dose of 960 mg orally b.i.d. Subjects in both the arms continued treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent. The protocol was amended on 07-Aug-2014 which allowed subjects who were still receiving vemurafenib to cross over to the dabrafenib and trametinib combination arm, including those subjects who were still receiving vemurafenib monotherapy treatment after disease progression. A washout period of a minimum of 7 days was considered prior to initiating dabrafenib in combination with trametinib. Subjects who experienced disease progression on the vemurafenib monotherapy arm, discontinued vemurafenib monotherapy, and subsequently received another anticancer therapy were ineligible for cross over to the dabrafenib and trametinib combination arm.
Follow-up/Study closure: After study treatment discontinuation, subjects were followed for survival and disease progression as applicable. This study completed once all the subjects had at least the 5-years of follow-up.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Dabrafenib plus Trametinib
BRAF inhibitor plus MEK inhibitor
Dabrafenib
Dabrafenib 150 mg twice daily orally
Trametinib
Trametinib 2 mg once daily orally
Vemurafenib
BRAF inhibitor
Vemurafenib
Vemurafenib 960 mg twice daily orally
Interventions
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Dabrafenib
Dabrafenib 150 mg twice daily orally
Vemurafenib
Vemurafenib 960 mg twice daily orally
Trametinib
Trametinib 2 mg once daily orally
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
* Measurable disease according to RECIST 1.1
* Women of childbearing potential with negative serum pregnancy test prior to randomisation
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
* Adequate baseline organ function
Exclusion Criteria
* Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
* History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
* Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
* Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for \>= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for \>= 12 weeks, and are asymptomatic with no corticosteroid requirements for \>= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for \>= 4 weeks prior to randomisation
* History or evidence of cardiovascular risk (LVEF \< LLN; QTcB \>= 480 msec; blood pressure or systolic \>=140 mmHg or diastolic \>= 90 mmHg which cannot be controlled by anti-hypertensive therapy)
* History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR)
18 Years
ALL
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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Birmingham, Alabama, United States
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Gilbert, Arizona, United States
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Beverly Hills, California, United States
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San Francisco, California, United States
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Vallejo, California, United States
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Aurora, Colorado, United States
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Jacksonville, Florida, United States
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Miami Beach, Florida, United States
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Orlando, Florida, United States
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Atlanta, Georgia, United States
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Atlanta, Georgia, United States
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Iowa City, Iowa, United States
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Ann Arbor, Michigan, United States
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Fridley, Minnesota, United States
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St Louis, Missouri, United States
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Las Vegas, Nevada, United States
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Hackensack, New Jersey, United States
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New Brunswick, New Jersey, United States
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New York, New York, United States
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Chapel Hill, North Carolina, United States
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Charlotte, North Carolina, United States
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Durham, North Carolina, United States
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Cincinnati, Ohio, United States
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Columbus, Ohio, United States
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Bend, Oregon, United States
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Portland, Oregon, United States
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Portland, Oregon, United States
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Charleston, South Carolina, United States
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Greenville, South Carolina, United States
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Nashville, Tennessee, United States
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Dallas, Texas, United States
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Salt Lake City, Utah, United States
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Burlington, Vermont, United States
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Charlottesville, Virginia, United States
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Milwaukee, Wisconsin, United States
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Capital Federal, Buenos Aires, Argentina
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Viedma, Río Negro Province, Argentina
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Rosario, Santa Fe Province, Argentina
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Buenos Aires, , Argentina
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San Miguel de Tucumán, , Argentina
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Santa Fe, , Argentina
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North Sydney, New South Wales, Australia
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Westmead, New South Wales, Australia
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Greenslopes, Queensland, Australia
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Herston, Queensland, Australia
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South Brisbane, Queensland, Australia
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Woodville, South Australia, Australia
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Box Hill, Victoria, Australia
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Melbourne, Victoria, Australia
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Nedlands, Western Australia, Australia
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Graz, , Austria
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Innsbruck, , Austria
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Salzburg, , Austria
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Vienna, , Austria
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Vienna, , Austria
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Leuven, , Belgium
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Wilrijk, , Belgium
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Ijuí, Rio Grande do Sul, Brazil
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Itajaí, Santa Catarina, Brazil
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Amsterdam, , Netherlands
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Groningen, , Netherlands
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Leeuwarden, , Netherlands
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Leiden, , Netherlands
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Newtown, Wellington, , New Zealand
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Kristiansand, , Norway
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Lorenskog, , Norway
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Oslo, , Norway
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Gdansk, , Poland
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Konin, , Poland
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Poznan, , Poland
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Warsaw, , Poland
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Chelyabinsk, , Russia
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Magnitogorsk, , Russia
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Moscow, , Russia
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Moscow, , Russia
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Nizhny Novgorod, , Russia
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Ryazan, , Russia
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Saint Petersburg, , Russia
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Goyang-si, Gyeonggi-Do, , South Korea
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Seoul, , South Korea
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Seoul, , South Korea
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Barcelona, , Spain
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Hospitalet de Llobregat, Barcelona, , Spain
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Las Palmas de Gran Canaria, , Spain
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Madrid, , Spain
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Palma de Mallorca, , Spain
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Pamplona, , Spain
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Valencia, , Spain
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Valencia, , Spain
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Linköping, , Sweden
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Umeå, , Sweden
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Basel, , Switzerland
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Taoyuan District, , Taiwan
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Kharkiv, , Ukraine
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Kyiv, , Ukraine
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Lviv, , Ukraine
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Sumy, , Ukraine
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Uzhhorod, , Ukraine
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Cambridge, , United Kingdom
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Glasgow, , United Kingdom
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London, , United Kingdom
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London, , United Kingdom
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Manchester, , United Kingdom
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Southampton, , United Kingdom
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Swansea, , United Kingdom
Countries
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References
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Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.
Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X.
Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.
Other Identifiers
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CDRB436B2302
Identifier Type: OTHER
Identifier Source: secondary_id
2011-006088-23
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
116513
Identifier Type: -
Identifier Source: org_study_id
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