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

Novartis

Status and phase: Completed; Phase 3

Conditions: Melanoma

Treatments: Drug: Trametinib placebo; Drug: Dabrafenib; Drug: Trametinib

Study type: Interventional

Funder types: Industry

Identifiers

NCT01584648

CDRB436B2301 (Other Identifier)

115306

2011-006087-49 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 423 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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423 participants in 2 patient groups

Dabrafenib + Trametinib

Experimental group

Description:

Dabrafenib and Trametinib combination

Treatment:

Drug: Trametinib

Drug: Dabrafenib

Dabrafenib + Placebo

Active Comparator group

Description:

Dabrafenib and Trametinib placebo

Treatment:

Drug: Dabrafenib

Drug: Trametinib placebo