This is a 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 who are previously untreated or who have progressed on or after prior first-line immunotherapy for metastatic disease. 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 immunotherapy (yes versus no). This study will use an Interactive Response Technology (IRT), a centralized Patient screening/randomization system for randomization. A specific informed consent for NRAS mutation analysis at a central
laboratory will be signed by every patient considered for this study. NRAS mutation-positive results from central laboratory determination must be received before entering the study.All patients will have a blood sample collected for genetic analysis to allow investigation of MEK162 at the molecular and cellular level. Two additional blood samples will be collected (one for serum and the other for plasma) from all patients to allow investigation of any plasma/serum based predictive markers.
In order to assess the pharmacokinetics of MEK162, pre-dose blood samples will be collected on Days 1, 22, 43, 64 and 85 from patients randomized to MEK162. Additionally, post-dose collections [one sample at 0.2 hour (12 minutes) -2 hours and one sample at 4 hours-10 hours] will be performed on Day 1. Furthermore, 1.5 hour post dose collections will be performed on Days 22 and 43. An additional PK collection will be performed at the End of Treatment visit if the reason for Treatment discontinuation is disease progression as per BIRC.
Patients randomized to MEK162 will be offered the option to provide fresh tumor biopsies, one before onset of treatment, one at treatment Day 22 and one at time of progression, for exploratory biomarker assessments. In addition, all patients randomized to MEK162 will have two blood
samples collected (one for plasma and one for serum) at Day 22 and at the time of disease progression in order to allow investigation of soluble biomarkers.
Patients who have documented progression per BIRC will cease tumor assessment follow-up and will be followed for 30 days for safety and then on a 12-weekly basis for survival and subsequent anti-cancer therapy.
Patients who discontinue treatment for reasons other than progression will continue to have tumor assessments according to Table 7-1 until documented progression per BIRC, start of new anticancer therapy, withdrawal of consent, lost to follow-up, study closure or death whichever occurs first. An interim analysis for futility is planned when approximately 50% of PFS events as per BIRC become available (i.e. 130 events of 260 targeted in total). This is anticipated to occur approximately 10 months after the first
patient first visit (FPFV) (based on a projected enrollment of 34 patients/month). The final PFS analysis will be performed when
approximately 260 PFS events per BIRC become available. This is expected approximately 16 months after FPFV. In case the required PFS
events are available prior to end of recruitment, the cut-off for final PFS analysis will still be chosen so that all patients can have at least one postbaseline
tumor assessment. Subsequent to the final PFS analysis, the study will remain open to collect survival and safety data until
approximately 80% of the patients (n=314 patients) have died.
