Phase II trial of RO4929097 Notch gamma-secretase inhibitor in metastatic melanoma: SWOG S0933.

8525 Background: The Notch pathway regulates expression of genes for cell cycle, tissue-specific differentiation, and vasculogenesis. Notch target genes affect melanomagenesis, and Notch levels can influence stemlike versus differentiated tumor cells. Gamma-secretase, which activates intracellular Notch, can be inhibited to kill melanoma cells. We designed this trial to test RO4929097 in pts with melanoma and its effects on T lymphocytes and tumor gene expression. Methods: To assess 6-month progression-free survival (PFS) and 1-year overall survival (OS) in advanced, untreated melanoma patients (pts), a 2-stage accrual design was used. Correlative studies: markers of Notch pathway activation in archived or fresh tumor and T cell functional assays pre-treatment (Rx) and at week 3. Rx dose was 20 mg orally on 3 consecutive days, weekly. Results: 33 pts were Rx’d in stage 1 (median age 61 [range 32-85]; 70% male; 42% elevated LDH; 30% unknown primary; 24% bone mets; 36% liver; 55% lung; 55% lymph node, skin ...