PHASE-I TRIALS OF URACIL-TEGAFUR (UFT) USING 5 AND 28 DAY ADMINISTRATION SCHEDULES - DEMONSTRATION OF SCHEDULE-DEPENDENT TOXICITIES

We conducted two consecutive phase I clinical trials to identify the q ualitative and quantitative toxic effects of uracil-tegafur (UFT) [Tai ho Pharmaceutical Co. Ltd, Tokyo, Japan; (EMS-200604) Bristol-Myers Sq uibb, Princeton, NJ] administered either on a 5 or 28 day schedule and to determine the phase II trial starting doses for both schedules. Ni neteen patients were entered on the 5 day schedule and 23 patients wer e entered on the 28 day schedule; a minimum of three patients were ent ered at each dose level studied. In both phase I trials, the daily UFT dose was divided into three doses administered every 8 h. Dose levels examined with the 5 day schedule were 360, 720, 900 and subsequent de -escalation to 800 mg/m(2)/day. Dose levels studied with the 28 day sc hedule were 180, 360, 450 and subsequent de-escalation to 400 mg/m(2)/ day. With the 5 day schedule, the dose-limiting toxicity (DLT) was gra nulocytopenia, with four of five patients experiencing grade 4 granulo cytopenia at the 900 mg/m(2)/day dose level. With the 28 day schedule, the DLT was diarrhea, which was noted in three of eight patients trea ted at 400 mg/m(2)/day and in three of six patients treated at 450 mg/ m(2)/day. At these dose levels, four of these patients required prolon ged hospitalizations for their diarrhea. The toxic effects of UFT are schedule dependent, with marked differences in the toxic effect profil e (neutropenia versus diarrhea). With the 5 day schedule, the phase II UFT starting dose is 800 mg/m(2)/day. On the 28 day schedule, the sug gested phase II UFT starting dose is 360 mg/m(2)/day. Future clinical trials examining the combination of UFT plus oral folinic acid are bei ng conducted to develop oral regimens of therapy for advanced colorect al carcinoma and adjuvant therapy for colon carcinoma.