This multicenter, randomized, double-blind, placebo-controlled phase 3 study will evaluate the safety and efficacy of vemurafenib alone and vemurafenib in combination with GDC-0973, a MEK inhibitor, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma. Patients will be randomized to one of two treatment arms, Arm A: vemurafenib 960 mg twice a day (days 1-28 of each cycle) and placebo (days 1-21 of each cycle); Arm B: vemurafenib 960 mg twice a day (days 1-28 of each cycle) and GDC-0973 60 mg once daily (days 1-21 of each cycle). Patients will receive treatment until disease progression, unacceptable toxicity or withdrawal of consent.
- Patients with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition.
- Unresectability of stage IIIc disease must have confirmation from a surgical oncologist.
- Patients must be 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 adjuvant immunotherapy (including ipilimumab) is allowed.
- Documentation of BRAFV600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test.
- Measurable disease per RECIST v1.1.
- Eastern Clinical Oncology Group performance status of 0 or 1.
- Consent to provide archival for biomarker analyses.
- Consent to undergo tumor biopsies for biomarker analyses.
- Life expectancy >/= 12 weeks.
- Adequate hematologic and end organ function
- History of prior RAF or MEK pathway inhibitor treatment.
- Palliative radiotherapy within 14 days prior to the first dose of study treatment.
- Major surgery or traumatic injury within 14 days prior to first dose of study treatment.
- Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Patients with a previous malignancy within the past 3 years are excluded except for patients with resected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast.
- History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration.
- Uncontrolled glaucoma with intra-ocular pressures
- Serum cholesterol >/= Grade 2
- Hypertriglyceridemia >/= Grade 2
- Hyperglycemia (fasting) >/= Grade 2
- History of clinically significant cardiac dysfunction
- Patients with active CNS lesions (including carcinomatous meningitis) are excluded. However, patients are eligible if:
1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND
2. There has been no evidence of clinical and radiographic disease progression in the CNS for >/= 3 weeks after radiotherapy or surgery
- Current severe, uncontrolled systemic disease.
- History of malabsorption or other condition that would interfere with absorption of study drugs.
- Pregnant, lactating, or breast feeding.
Last updated: 05/13/2013