|Inclusion criteria||Exclusion criteria|
Disease-Specific Inclusion Criteria:
• Histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by AJCC 7th edition.
• Naïve to treatment for locally advanced unresectable or metastatic disease (i.e., no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior immunotherapy (including ipilimumab) is allowed.
• Documentation of BRAFV600E or BRAFV600K mutation-positive status in melanoma tumor tissue.
• Measurable disease per RECIST v1.1, which are accessible to biopsies.
• Biopsy lesion is within scan reach of contrast enhanced CT and PET/CT.
• ECOG performance status of 0 or 1.
• Consent to undergo tumor biopsies of accessible lesions.
Cancer-Related Exclusion Criteria:
• History of prior RAF or MEK pathway inhibitor treatment.
• Palliative radiotherapy, major surgery or traumatic injury within 14 days prior to the first dose of study treatment.
• Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures.
Exclusion Criteria Based on Organ Function:
• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vascular occlusion, or neovascular macular degeneration.
• History of clinically significant cardiac dysfunction, including current unstable angina, symptomatic congestive heart failure (NYHA classII), history of congenital long QT syndrome or mean QTcF >450 msec at baseline or uncorrectable abnormalities in serum electrolytes, uncontrolled hypertension ≥ Grade 2, left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%.
• Patients with active CNS lesions, except when all known CNS lesions have been treated with stereotactic therapy or surgery, AND there has been no evidence of clinical and radiographic disease progression in the CNS for ≥3 weeks after radiotherapy or surgery.
General Inclusion Criteria:
• Male or female patient aged ≥18 years.
• Able to participate and willing to give written informed consent.
• Life expectancy ≥12 weeks.
• Adequate hematologic, hepatic and renal function.
• Use of adequate contraception during the course of this study and for at least 6 months after completion of study therapy.
• Negative serum pregnancy test in women of childbearing potential.
• Absence of any psychological, familial, sociological, or geographical condition that potentially hampers compliance with the study protocol and follow-up after treatment discontinuation schedule.
General Exclusion Criteria:
• Current severe, uncontrolled systemic disease.
• History of malabsorption or other condition that would interfere with absorption of study drugs.
• Pregnant, lactating, or breast-feeding.
• Unwillingness or inability to comply with study and follow-up procedures.
• St. John’s wort or hyperforin (potent cytochrome P450 CYP3A4 enzyme inducer) and grapefruit juice (potent cytochrome P450 CYP3A4 enzyme inhibitor) are prohibited at least 7 days prior to initiation of and during treatment.