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To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma harboring missenseA total of 245 adult patients with previously treated, advanced urothelial carcinoma entered the molecular screening program includingWe identified 16 (7%) missenseOral tipifarnib resulted in a manageable safety profile and encouraging antitumor efficacy against treatment-refractory urothelial carcinoma containing

Purpose: To evaluate the toxicity profile, pharmacologic, and biological properties of 3-pyridylmethyl N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate (MS-275), a histone deacetylase inhibitor, when administered orally on three different dosing schedules. Experimental Design: Patients with advanced solid malignancies and lymphomas were treated on three dose schedules: once every other week, twice weekly for 3 weeks every 28 days, and once weekly for 3 weeks every 28 days. First-cycle plasma pharmacokinetics and peripheral blood mononuclear cell histone acetylation were determined. Results: Twenty-seven patients received ≥149 courses of treatment. Hypophosphatemia and asthenia were dose limiting on the weekly and twice-weekly dosing schedules; there was no dose-limiting toxicity on the every other week schedule. Pharmacokinetic variables revealed dose-dependent and dose-proportional increases. Two of 27 patients showed partial remissions, including one patient with metastatic melanoma who had a partial response and has remained on study for >5 years. Six patients showed prolonged disease stabilization. Levels of histone H3 and H4 acetylation in peripheral blood mononuclear cells increased qualitatively but with a high degree of interpatient variation. Conclusions: MS-275 is well tolerated at doses up to 6 mg/m2 every other week or 4 mg/m2 weekly for 3 weeks followed by 1 week of rest and results in biologically relevant plasma concentrations and antitumor activity. Twice-weekly dosing was not tolerable due to asthenia, and further evaluation of this schedule was halted. The recommended dose for further disease-focused studies is 4 mg/m2 given weekly for 3 weeks every 28 days or 2 to 6 mg/m2 given once every other week.