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 unresectable or metastatic nRS mutation-positive cutaneous or unknown pirmary melanoma who are previously untreated or who have progressed on or after prior treatment with any number of lines of immunotheraphy for unsectable or metastatic disease. 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. Since the central lab's diagnostic test could be more sensitive and specific than local testing, patients that have a negative nRaS Q61 mutation result are eligible for prescreening. nRaS mutation-positive results must be documented before entering screening.
Patients cannot be randomized until central laboratory documentation of the
presence of nRaS Q61 mutation.
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.
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained prior to any study procedures.
1. Signed written informed consent;
2. Male or female patient, age >= 18 years;
3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic
cutaneous or unknown primary melanoma AJCC Stage IIIC or IV (Uveal and mucosal melanoma are excluded)
4. Presence of NRAS Q61 mutation in tumor tissue prior to randomization, as determined by
a Novartis designated central laboratory;
5. Naive untreated patient or patients who have progressed on or after prior treatment with any number of lines immunotherapy for unresectable or metastatic melanoma;
Note: Prior adjuvant therapy is permitted, except the administration of MEK
6. Evidence of at least one measurable lesion as detected by radiological or photographic
methods according to Novartis guideline version 3.1 based on RECIST version 1.1;
Note: A previously irradiated lesion is eligible to be considered as a measurable lesion
provided that there is objective evidence of progression of the lesion since discontinuation of
therapy and prior to starting study drug.
7. ECOG performance status of 0-1;
8. Adequate bone marrow, organ function and laboratory parameters:
* Absolute neutrophil count (ANC) >= 1.5 x 109/L,
* Hemoglobin (Hgb) >= 9 g/dL without transfusions,
* Platelets (PLT) >= 100 x 109/L without transfusions,
* AST and/or ALT <= 2.5 x upper limit of normal (ULN); patient with liver metastases <= 5 xULN,
* Total bilirubin <= 2 x ULN,
* Creatinine <= 1.5 mg/dL;
9. Adequate cardiac function:
* left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated
acquisition (MUGA) scan or echocardiogram,
* Triplicate average baseline QTc interval <= 480 ms;
10. Able to take oral medications;
11. Patient is deemed by the Investigator to have the initiative and means to be compliant with
the protocol (treatment and follow-up);
12. Negative serum β-HCG test (female patient of childbearing potential only) performed
locally within 72 hrs prior to first dose.