A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

• Overall survival (OS) defined as the time from randomization to death due to any cause [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• PFS, defined for subjects randomized to the DTIC treatment groups as the time to progression or death after cross-over to GSK2118436 after initial progression on DTIC. [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Overall response rate (ORR), defined as the percentage of subjects achieving either a commplete or partial tumor response. [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Duration of response, defined for those subjects who show a complete or partial tumor response, the time from first documented complete response or partial response until the first documented sign of disease progression or death due to any cause. [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Duration of response in subjects who cross-over to GSK2118436, after initial progression on DTIC [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Rate of treatment-emergent non-melanoma skin lesions in each treatment group, defined as the percentage of subjects with non-melanoma skin lesions reported [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]
• Validation of the BRAF mutation assay. [ Time Frame: approximately 2 years ] [ Designated as safety issue: No ]

BRF113683 is a Phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of GSK2118436 to dacarbazine (DTIC), in subjects with BRAF mutant advanced (Stage III) or metastatic (Stage IV) melanoma. Subjects will be randomized to receive 150 mg of GSK2118436 twice daily or 1000 mg/m2 DTIC every 3 weeks and continue on treatment until disease progression, death, or unacceptable adverse event. Subjects who progress on DTIC will be allowed to crossover to an optional extension arm of the study to receive GSK2118436.

• Drug: GSK2118436
  150 mg twice daily
• Drug: Dacarbazine (DTIC)
  Intravenous (IV), 1000 mg/m2 every 3 weeks until initial progression

• Experimental: GSK2118436
  Subjects in this arm will receive GSK2118436 150 mg twice daily.
  Intervention: Drug: GSK2118436
• Active Comparator: Dacarbazine (DTIC)
  Subjects will receive intravenous dacarbazine (DTIC) 1000 mg/m2 every 3 weeks
  Intervention: Drug: Dacarbazine (DTIC)
• Experimental: Crossover
  Subjects who initially receive DTIC will be allowed to receive GSK2118436 after initial progression.
  Intervention: Drug: GSK2118436

Inclusion Criteria:

• Adults at least 18 years of age
• Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E)
• Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed.
• Has measurable disease according to RECIST 1.1 criteria.
• Women of child-bearing potential must have a negative pregnancy test within 14 days prior to the first dose of study treatment.
• Women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 4 weeks after the last dose of study medication.
• Men with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 16 weeks after the last dose of study medication.
• Must have adequate organ function.
• Must have Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

Exclusion Criteria:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy or surgery).
• Evidence of active central nervous system (CNS) disease.
• Previous treatment for metastatic melanoma, including treatment with BRAF or MEK inhibitor.
• A history of other malignancy. Subjects who have been disease-free for 5 years or subjects with a history of complete resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
• History of Human Immunodeficiency Virus (HIV) infection.
• Certain cardiac abnormalities