Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

• Overall Survival (OS) [ Time Frame: Final analysis is expected to occur 21 months after FPFV ] [ Designated as safety issue: No ]
  To compare OS between treatment arms. OS is calculated as the time from date of randomization to date of death due to any cause.
• Overall Response Rate (ORR) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  ORR calculated as the proportion of patient with a best overall response of complete response (CR) or partial response (PR). ORR will be calculated for confirmed and unconfirmed responses separately.
• Time to Objective Response (TTR) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response(PR).
• Duration of objective response (DOR) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer
• Disease control rate (DCR) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  DCR calculated as the proportion of patient with a best overall response of CR, PR or stable disease (SD)
• Number of patients with adverse events [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: Yes ]
  To assess the safety and tolerability of MEK162 in this patient, changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), MUGA(Multi Gated Acquisition Scan)/echocardiogram and assessment of physical and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03
• Number of patients with serious adverse events [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: Yes ]
  To assess the safety and tolerability of MEK162 in this patient, changes in hematology and chemistry values, vital signs, ECGs, MUGA/echocardiogram and assessment of physical and ocular examinations graded according to the NCI CTCAE v4.03
• Time to definitive 10% deterioration in the global health status score of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  To compare the global health status between the treatments.
• Change from baseline in the global health status score of the EORTC QLQ-C30 [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  To compare the global health status between the treatment.
• Change from baseline in the EQ-5D (EuroQol Group standardised instrument for use as a measure of health outcome) [ Time Frame: Approximately 16 months after the FPFV ] [ Designated as safety issue: No ]
  To compare the global health status between the treatment.

Two-arm, randomized, prospective, open-label, multi-center, phase III study to compare the efficacy and safety of MEK162 (45 mg BID) versus dacarbazine (1000 mg/m2 IV every 3 weeks) in patients with advanced (Stage IIIC) unresectable or metastatic (Stage IV) NRAS Q61 mutation-positive melanoma. The mutation analysis will be performed at a central laboratory. Only those patients with Q61 mutation per central laboratory and meet all eligibility criteria will be randomized. A total of 393 patients will be randomized 2:1 to receive either MEK162 or dacarbazine. Patients will be stratified according to AJCC stage (IIIC, IVM1a, and IVM1b versus IVM1c), ECOG Performance status (0 versus 1) and prior first-line therapy (Ipilimumab-immunotherapies versus none). This study will use an Interactive Response Technology (IRT). The primary end point of the study is progression-free survival. Key secondary end point is overall survival

• Drug: MEK162
  MEK162 will be administered as a fixed dose of 45 mg (3 x 15 mg tablets) BID, with a glass of water. Patients should be fasted 1 hour before and after the dose.
• Drug: Dacarbazine
  Patients randomized to dacarbazine will receive an IV infusion of dacarbazine 1000 mg/m2 over the course of 1 hour on day 1 and then every three weeks.

• Experimental: MEK162
  Intervention: Drug: MEK162
• Active Comparator: Dacarbazine
  Intervention: Drug: Dacarbazine

Inclusion Criteria:

• Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma (AJCC Stage IIIC or IV)
• Presence of NRAS Q61 mutation in tumor tissue prior to randomization
• Naïve untreated patients or patients who have progressed on or after prior first-line immunotherapy for unresectable locally advanced or metastatic melanoma
• Evidence of at least one measurable lesion as detected by radiological or photographic methods
• Adequate bone marrow, organ function, cardiac and laboratory parameters
• Normal functioning of daily living activities

Exclusion Criteria:

• Any active/non-stable brain lesion
• Non-cutaneous melanoma
• History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease.

Patients with washout period < 12 weeks from the last dose of ipilimumab or other immunotherapy.

Previous chemotherapy for unresectable locally advanced or metastatic melanoma.

• History of Gilbert's syndrome
• Prior therapy with a MEK- inhibitor
• Impaired cardiovascular function or clinically significant cardiovascular diseases
• Uncontrolled arterial hypertension despite medical treatment
• HIV positive or active Hepatitis A or B
• Impairment of gastrointestinal function or gastrointestinal disease
• Patients with neuromuscular disorders that are associated with elevated CK.
• Pregnant or nursing (lactating) women
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

Other protocol-defined inclusion/exclusion criteria may apply