Phase I and pharmacologic study of oral (E)-2 '-deoxy-2 '-(fluoromethylene) cytidine: on a daily x 5-day schedule

(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC), one of the most potent in hibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumo r activity against experimental tumor models. This study was designed to de termine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic p rofile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 w eeks in patients with advanced solid tumors. The starting dose was 8 mg/m(2 )/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 cours es of FMdC at doses which were de-escalated from 8 mg/m(2)/day to 2 mg/m(2) /day because of unexpected severe toxicities at the starting dose level. Ne utropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicitie s. The MTD was 4 mg/m(2)/day, since four of six patients developed grade 3- 4 neutropenia. At the 4 mg/m(2)/day dose level, the mean terminal half-life , maximum plasma concentration (C-max), plasma clearance, and mean residenc e time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectiv ely. The recommended dose for phase II studies with this schedule is also 4 mg/m(2)/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.