Phase I and Pharmacokinetic Study of the Differentiating Agent Vesnarinone in Combination With Gemcitabine in Patients With Advanced Cancer

PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine. PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (Cmin) of vesnarinone were obtained weekly. Plasma gemcitabine and 2′,2′-difluorodeoxyuridine concentrations were obtained during courses 1 and 2. RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m2 dose level and one of 10 minimally pretreated new pat...