Clinical trial NCT01584648: A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma
Official title: A Phase III, Randomized, Double-blinded Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to Dabrafenib and Placebo as First-line Therapy 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: Randomized study
combination therapy
BRAF inhibitor
GSK1120212
BRAF V600E/K mutation-positive cutaneous melanoma
trametinib
GSK2118436
MEK inhibitor
Phase III
dabrafenib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-04-25
Enrollment: 423
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, double-blinded, randomized, Phase III study comparing dabrafenib and trametinib combination therapy to dabrafenib administered with a placebo (dabrafenib monotherapy). Subjects with histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV, and BRAF V600E/K mutation positive were screened for eligibility. 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. Subjects were stratified according to the baseline lactate dehydrogenase level and BRAF genotype.

Detailed description: Dabrafenib and trametinib was administered orally at their recommended monotherapy doses of 150 mg b.i.d and 2 mg q.d., respectively. Subjects in the combination therapy arm received both agents; subjects in the dabrafenib monotherapy arm received dabrafenib and placebo. Treatment was continued in both arms until disease progression, death, unacceptable toxicity, or withdrawal of consent.

After treatment discontinuation, subjects were followed for survival and disease progression as applicable to collect data for the secondary objective of overall survival (OS).

Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive using the bioMerieux (bMx) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). The assay will be conducted by a central reference laboratory. Subjects with ocular or mucosal melanoma are not eligible.
* The subject must have a radiologically measurable tumor
* The subject is able to carry out daily life activities without significant difficulty (ECOG performance status score of 0 or 1).
* Able to swallow and retain oral medication
* Sexually active subjects must use acceptable methods of contraception during the course of the study
* Adequate organ system function and blood counts

Exclusion Criteria:

* Prior treatment with a BRAF or a MEK inhibitor
* Prior systemic anti-cancer treatment for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.)
* The subject has received major surgery or certain tyes of cancer therapy with 21 days of starting treatment
* Current use of prohibited medication listed in the protocol
* Left ventricular ejection fraction less than the lower limit of normal
* Uncontrolled blood pressurl
* History or current evidence of retinal vein occlusion or central serous retinopathy
* Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks
* The subject is pregnant or nursing

Primary 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)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization until date of death due to any cause (up to approximately 6 years)
measure: Objective Response Rate (ORR) 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)
timeFrame: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
measure: Trametinib Pharmacokinetic Concentrations
timeFrame: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
measure: Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations
timeFrame: Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
measure: Number of Participants With Adverse Events and Serious Adverse Events
timeFrame: From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Tucson
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: Fort Myers
country: United States
facility: Novartis Investigative Site
state: Florida
city: Saint Petersburg
country: United States
facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: West Palm Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Peoria
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Columbia
country: United States
facility: Novartis Investigative Site
state: South Carolina
city: Chattanooga
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Fort Worth
country: United States
facility: Novartis Investigative Site
state: Texas
city: Richmond
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Capital Federal
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
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: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Heidelberg
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: London
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: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Boulogne-Billancourt
country: France
facility: Novartis Investigative Site
city: Lyon Cedex 08
country: France
facility: Novartis Investigative Site
city: Marseille cedex 5
country: France
facility: Novartis Investigative Site
city: Paris Cedex 10
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex
country: France
facility: Novartis Investigative Site
city: Vandoeuvre les Nancy
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: Ulm
country: Germany
facility: Novartis Investigative Site
state: Baden-Wuerttemberg
city: Augsburg
country: Germany
facility: Novartis Investigative Site
state: Bayern
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: Darmstadt
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Marburg
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Buxtehude
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Hannover
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: Mainz
country: Germany
facility: Novartis Investigative Site
state: Rheinland-Pfalz
city: Homburg
country: Germany
facility: Novartis Investigative Site
state: Saarland
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: Jena
country: Germany
facility: Novartis Investigative Site
state: Thueringen
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: N. Faliro
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
state: Lazio
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: Candiolo (TO)
country: Italy
facility: Novartis Investigative Site
state: Piemonte
city: Padova
country: Italy
facility: Novartis Investigative Site
state: Veneto
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Zwolle
country: Netherlands
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Stavropol
country: Russian Federation
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Pamplona
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
city: Goteborg
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Donetsk
country: Ukraine
facility: Novartis Investigative Site
city: Khmelnytskyi
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: Northwood
country: United Kingdom
facility: Novartis Investigative Site
state: Middlesex
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Aberdeen
country: United Kingdom
facility: Novartis Investigative Site
city: Bebington
country: United Kingdom
facility: Novartis Investigative Site
city: Edgbaston, Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
city: Preston
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: Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.
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: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.
citation: Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandala M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. doi: 10.1016/j.ejca.2015.03.004. Epub 2015 Mar 17.
citation: Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, Infante JR, Kim KB, Gonzalez R, Hamid O, Schuchter L, Cebon J, Sosman JA, Little S, Sun P, Aktan G, Ouellet D, Jin F, Long GV, Daud A. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015 Feb;26(2):415-21. doi: 10.1093/annonc/mdu529. Epub 2014 Nov 18.
citation: Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi: 10.1056/NEJMoa1406037. Epub 2014 Sep 29.