A PHASE-I AND PHARMACOKINETIC STUDY OF ORAL URACIL, FTORAFUR, AND LEUCOVORIN IN PATIENTS WITH ADVANCED CANCER

A phase I and pharmacokinetic study of oral uracil, ftorafur, and leuc ovorin was performed in patients with advanced cancer. Uracil plus fto rafur (UFT) was given in a 4:1 molar ratio in three divided doses for 28 consecutive days. Patient cohorts were treated at 200, 250, 300, an d 350 mg/m(2) of UFT daily. For all patients, 150 mg of leucovorin was given daily in three oral doses. A 1-week rest period followed each 2 8-day treatment course. Gastrointestinal toxicity, characterized by di arrhea, nausea, and vomiting, was dose-limiting at 350 mg/m(2) UFT in patients who had received prior chemotherapy. Mild fatigue and transie nt hyperbilirubinemia were also common. In previously untreated patien ts, UFT at 350 mg/m(2) was well-tolerated, suggesting this as an accep table phase II dose in this schedule with leucovorin. Two of eight pre viously untreated patients with advanced colorectal cancer had partial responses with UFT (350 mg/m(2)) plus leucovorin. Pharmacokinetic par ameters [ftorafur, uracil, 5-fluorouracil (5-FU), 5-methyltetrahydrofo late] showed wide interpatient variations. Plasma levels of 5-FU (C-ma x 1.4 +/- 1.9 mu M) were comparable to those achieved with protracted venous infusions, and folate levels (C-max 6.1 +/- 3.6 mu M) were suff icient for biochemical modulation. Ongoing study will determine if thi s convenient oral regimen will compare favorably in terms of efficacy, toxicity, and cost with intravenous fluoropyrimidine programs.