A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma

Melanoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01584648
• Other study ID #: 115306
• Secondary ID: 2011-006087-49CD
• Status: Completed
• Phase: Phase 3
• Start date: May 4, 2012
• Est. completion date: February 28, 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, 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 423
• Est. completion date: February 28, 2019
• Est. primary completion date: August 26, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Melanoma

Intervention

Drug:
• Dabrafenib
Dabrafenib 150 mg twice daily
• Trametinib
Trametinib 2 mg once daily
• Trametinib placebo
Dabrafenib 150 mg twice daily and trametinib placebo

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	Nedlands	Western Australia
Australia	Novartis Investigative Site	North Sydney	New South Wales
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Boulogne-Billancourt
France	Novartis Investigative Site	Lyon Cedex 08
France	Novartis Investigative Site	Marseille cedex 5
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris Cedex 10
France	Novartis Investigative Site	Toulouse Cedex
France	Novartis Investigative Site	Vandoeuvre les Nancy
Germany	Novartis Investigative Site	Augsburg	Bayern
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Bonn	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Buxtehude	Niedersachsen
Germany	Novartis Investigative Site	Darmstadt	Hessen
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	Homburg	Saarland
Germany	Novartis Investigative Site	Jena	Thueringen
Germany	Novartis Investigative Site	Kiel	Schleswig-Holstein
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Leipzig	Sachsen
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	Marburg	Hessen
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	Ulm	Baden-Wuerttemberg
Germany	Novartis Investigative Site	Wuerzburg	Bayern
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	N. Faliro
Greece	Novartis Investigative Site	Thessaloniki
Italy	Novartis Investigative Site	Bergamo	Lombardia
Italy	Novartis Investigative Site	Candiolo (TO)	Piemonte
Italy	Novartis Investigative Site	Genova	Liguria
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Milano	Lombardia
Italy	Novartis Investigative Site	Padova	Veneto
Italy	Novartis Investigative Site	Roma	Lazio
Italy	Novartis Investigative Site	Roma	Lazio
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Zwolle
Russian Federation	Novartis Investigative Site	Kazan
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St. Petersburg
Russian Federation	Novartis Investigative Site	Stavropol
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Pamplona
Spain	Novartis Investigative Site	Valencia
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Ukraine	Novartis Investigative Site	Dnipropetrovsk
Ukraine	Novartis Investigative Site	Dnipropetrovsk
Ukraine	Novartis Investigative Site	Donetsk
Ukraine	Novartis Investigative Site	Khmelnytskyi
Ukraine	Novartis Investigative Site	Kyiv
Ukraine	Novartis Investigative Site	Lviv
Ukraine	Novartis Investigative Site	Sumy
United Kingdom	Novartis Investigative Site	Aberdeen
United Kingdom	Novartis Investigative Site	Bebington
United Kingdom	Novartis Investigative Site	Edgbaston, Birmingham
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle upon Tyne
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Oxford
United Kingdom	Novartis Investigative Site	Preston
United Kingdom	Novartis Investigative Site	Sutton	Surrey
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Chattanooga	Tennessee
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Columbia	South Carolina
United States	Novartis Investigative Site	Fort Myers	Florida
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Saint Petersburg	Florida
United States	Novartis Investigative Site	Scottsdale	Arizona
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Canada,  France,  Germany,  Greece,  Italy,  Netherlands,  Russian Federation,  Spain,  Sweden,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS) as Assessed by the Investigator	PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.	From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)
Secondary	Overall Survival (OS)	OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival 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	Objective Response Rate (ORR) as Assessed by the Investigator	ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of =10mm). Only descriptive analysis performed.	From randomization until the first documented complete response or partial response (up to approximately 6 years)
Secondary	Duration of Response (DoR)	Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of =10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.	From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)
Secondary	Trametinib Pharmacokinetic Concentrations	Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.	Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Secondary	Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations	Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.	Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)
Secondary	Number of Participants With Adverse Events and Serious Adverse Events	Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.	From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).