Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma

Melanoma Clinical Trial

— COMBI-v  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01597908
• Other study ID #: 116513
• Secondary ID: CDRB436B23022011
• Status: Completed
• Phase: Phase 3
• Start date: June 4, 2012
• Est. completion date: April 25, 2019

Study information

• Verified date: February 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 704
• Est. completion date: April 25, 2019
• Est. primary completion date: April 17, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Dabrafenib
Dabrafenib 150 mg twice daily orally
• Vemurafenib
Vemurafenib 960 mg twice daily orally
• Trametinib
Trametinib 2 mg once daily orally

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  Finland,  France,  Germany,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Norway,  Poland,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.	From the date of randomization until date of death due to any cause (up to approximately 6 years)
Secondary	Progression-Free Survival (PFS), as Assessed by the Investigator	Progression-free survival (PFS) was defined as the interval of time between the date of randomization and the first documented occurrence of disease progression or death due to any cause. PFS for investigator-assessed response was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.	From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
Secondary	Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator	Overall response was defined as the percentage of confirmed responders (complete response [CR] + partial response [PR] per RECIST, Version 1.1) as summarized by Investigator assessment. CR was defined as the disappearance of all evidence of target lesions. PR was defined as at least a 30% reduction from Baseline in the sum of the longest diameter (LD) of all target lesions. Data were reported as those participants with measureable disease at Baseline.	From randomization until the first documented complete response or partial response (up to approximately 6 years)
Secondary	Duration of Response (DOR), as Assessed by the Investigator	Duration of Response (DOR) was defined as the time from the first documented evidence of a CR (disappearance of all evidence of target lesions) or a PR (at least a 30% reduction from Baseline in the sum of the longest diameter of all target lesions) until disease progression or death due to any cause. PD was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of at least1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Data were summarized per RECIST, Version 1.1.	From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)