Clinical trial NCT01597908: Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
Official title: A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Melanoma
Keywords: BRAF inhibitor
Metastatic Melanoma
Cancer
MEK inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-05-14
Enrollment: 704
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 was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.

Detailed description: Screening/Subject eligibility: Subjects with histologically confirmed cutaneous melanoma that was either unresectable or metastatic (Stages IIIC or IV), were screened for eligibility. Eligible subjects were BRAF V600E or V600K mutation positive. Subjects who had prior systemic anti-cancer treatment in the advanced or metastatic setting were not eligible although prior systemic treatment in the adjuvant setting was allowed.

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.

Eligibility criteria: Key Inclusion Criteria:

* \>= 18 years of age
* 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

Key Exclusion Criteria:

* Any prior use of a BRAF or MEK inhibitor
* 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)

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization until date of death due to any cause (up to approximately 6 years)
Secondary outcomes:
measure: Progression-Free Survival (PFS), as Assessed by the Investigator
timeFrame: From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
measure: Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator
timeFrame: From randomization until the first documented complete response or partial response (up to approximately 6 years)
measure: Duration of Response (DOR), as Assessed by the Investigator
timeFrame: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Gilbert
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Vallejo
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facility: Novartis Investigative Site
state: California
city: Aurora
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facility: Novartis Investigative Site
state: Colorado
city: Jacksonville
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state: Florida
city: Miami Beach
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facility: Novartis Investigative Site
state: Florida
city: Orlando
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facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Iowa City
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facility: Novartis Investigative Site
state: Iowa
city: Ann Arbor
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facility: Novartis Investigative Site
state: Michigan
city: Fridley
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Saint Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Las Vegas
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Hackensack
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: New Brunswick
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Chapel Hill
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Charlotte
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Bend
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Charleston
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facility: Novartis Investigative Site
state: South Carolina
city: Greenville
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Salt Lake City
country: United States
facility: Novartis Investigative Site
state: Utah
city: Salt Lake City
country: United States
facility: Novartis Investigative Site
state: Utah
city: Burlington
country: United States
facility: Novartis Investigative Site
state: Vermont
city: Charlottesville
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Milwaukee
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Capital Federal
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Viedma
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facility: Novartis Investigative Site
state: Río Negro
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: North Sydney
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Greenslopes
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: South Brisbane
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Woodville
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Box Hill
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Melbourne
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facility: Novartis Investigative Site
state: Victoria
city: Nedlands
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facility: Novartis Investigative Site
state: Western Australia
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Innsbruck
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facility: Novartis Investigative Site
city: Salzburg
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city: Wien
country: Austria
facility: Novartis Investigative Site
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Brasschaat
country: Belgium
facility: Novartis Investigative Site
city: Brussels
country: Belgium
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city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Kortrijk
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Ijui
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Itajai
country: Brazil
facility: Novartis Investigative Site
state: Santa Catarina
city: Sao Paulo - SP
country: Brazil
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Kelowna
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Winnipeg
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facility: Novartis Investigative Site
state: Manitoba
city: Halifax
country: Canada
facility: Novartis Investigative Site
state: Nova Scotia
city: Kingston
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Oshawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Olomouc
country: Czechia
facility: Novartis Investigative Site
city: Ostrava
country: Czechia
facility: Novartis Investigative Site
city: Praha 10
country: Czechia
facility: Novartis Investigative Site
city: Praha 2
country: Czechia
facility: Novartis Investigative Site
city: Zlin
country: Czechia
facility: Novartis Investigative Site
city: Arhus C
country: Denmark
facility: Novartis Investigative Site
city: Herlev
country: Denmark
facility: Novartis Investigative Site
city: Odense
country: Denmark
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Jyvaskyla
country: Finland
facility: Novartis Investigative Site
city: Tampere
country: Finland
facility: Novartis Investigative Site
city: Turku
country: Finland
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Marseille cedex 5
country: France
facility: Novartis Investigative Site
city: Montpellier cedex 5
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Reims Cedex
country: France
facility: Novartis Investigative Site
city: Rennes Cedex
country: France
facility: Novartis Investigative Site
city: Villejuif cedex
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Heilbronn
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Mannheim
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Nuernberg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Buxtehude
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facility: Novartis Investigative Site
state: Niedersachsen
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country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Bonn
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: Novartis Investigative Site
state: Nordrhein-Westfalen
city: Ludwigshafen
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Mainz
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Kiel
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Luebeck
country: Germany
facility: Novartis Investigative Site
state: Schleswig-Holstein
city: Erfurt
country: Germany
facility: Novartis Investigative Site
state: Thueringen
city: Gera
country: Germany
facility: Novartis Investigative Site
state: Thueringen
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Gyor
country: Hungary
facility: Novartis Investigative Site
city: Kaposvar
country: Hungary
facility: Novartis Investigative Site
city: Miskolc
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Co.Cork
country: Ireland
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Dublin
country: Ireland
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
state: Campania
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Genova
country: Italy
facility: Novartis Investigative Site
state: Liguria
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Milano
country: Italy
facility: Novartis Investigative Site
state: Lombardia
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: Toscana
city: Padova
country: Italy
facility: Novartis Investigative Site
state: Veneto
city: Goyang-si, Gyeonggi-Do
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Leeuwarden
country: Netherlands
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Christchurch
country: New Zealand
facility: Novartis Investigative Site
city: Newtown, Wellington
country: New Zealand
facility: Novartis Investigative Site
city: Kristiansand
country: Norway
facility: Novartis Investigative Site
city: Lorenskog
country: Norway
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Gdansk
country: Poland
facility: Novartis Investigative Site
city: Konin
country: Poland
facility: Novartis Investigative Site
city: Poznan
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Chelyabinsk
country: Russian Federation
facility: Novartis Investigative Site
city: Magnitogorsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Ryazan
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Hospitalet de Llobregat, Barcelona
country: Spain
facility: Novartis Investigative Site
city: Las Palmas De Gran Canaria
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Palma de Mallorca
country: Spain
facility: Novartis Investigative Site
city: Pamplona
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Linkoping
country: Sweden
facility: Novartis Investigative Site
city: Umea
country: Sweden
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Zurich
country: Switzerland
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Donetsk
country: Ukraine
facility: Novartis Investigative Site
city: Kharkiv
country: Ukraine
facility: Novartis Investigative Site
city: Kyiv
country: Ukraine
facility: Novartis Investigative Site
city: Lviv
country: Ukraine
facility: Novartis Investigative Site
city: Sumy
country: Ukraine
facility: Novartis Investigative Site
city: Uzhgorod
country: Ukraine
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Southampton
country: United Kingdom
facility: Novartis Investigative Site
city: Swansea
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.