A phase I study of the antimetabolite (E)-2 '-fluoromethylene-2 '-deoxycytidine (MDL 101,731) administered as a twice-weekly infusion

PURPOSE (E)-2'-fluoromethylene-2'-deoxycytidine is a novel antimetabolite. Preclini cal tests have shown antiproliferative activity in various human tumor xeno graft models and have also indicated that efficacy is greatest with frequen t dosing schedules. We conducted a phase 1 trial of MDL 101,731 infusion in humans with advanced cancer to determine the maximum tolerated dose and th e dose-limiting toxicities of this drug when administered on a twice-weekly schedule. PATIENTS AND METHODS The drug was administered on a twice-weekly schedule for 3 weeks, followed by a 2-week rest. The initial dose was 16 mg/ m(2). This was reduced to 12 mg/m(2) if persistent neutropenia occurred. All toxicity in the first six p atients resolved by the end of the first rest week. The schedule was change d to 3 weeks of therapy followed by 1 rest week for the subsequent four pat ients. RESULTS Dose escalation beyond 16 mg/m(2) was not feasible because of dose-limiting toxicities, principally hematologic. No irreversible or life-threatening t oxicity was seen. Grade 2 noninfectious fever, mucositis, and anorexia were also seen. In patients with stable disease, there was a heavily pretreated patient with rectal cancer in whom a 38% reduction in indicator lesions of 7 months' duration occurred. DISCUSSION (E)-2'-fluoromethylene-2 '-deoxycytidine is a novel antimetabolite with evi dence of anticancer activity in heavily pretreated patients. The maximum to lerated dose when the agent is given twice weekly is 16 mg/m(2).