PHASE-I TRIAL OF URACIL-TEGAFUR (UFT) PLUS ORAL LEUCOVORIN - 14-DAY SCHEDULE

We previously reported results of a Phase II trial of UFT [Taiho Pharm aceutical Ltd., Tokyo, Japan; (BMS-200604) Bristol-Myers Squibb, Princ eton, NJ], an oral 4:1 molar concentration of uracil and tegafur, plus oral leucovorin for metastatic colorectal carcinoma (Pazdur et al., J . Clin. Oncol. 12:2296-2300, 1994]. Our results demonstrated that a 28 -day schedule of this combination produced a response rate similar to that obtained with conventional intravenous fluorouracil (5-FU)-plus-l eucovorin regimens but without the severe or life-threatening neutrope nia or oral mucositis that complicates intravenous 5-FU regimens. The current Phase I trial examines the dose-limiting toxic effects and max imum tolerated dose of a 14-consecutive-day schedule of UFT plus oral leucovorin in 14 patients who had histologically proven cancer and had received prior chemotherapy. The daily UFT plus leucovorin dose was d ivided into three doses administered orally every 8 hours. In this stu dy, the UFT dose was escalated while the leucovorin dose remained at 1 50 mg/day. Of the 14 patients, 4 were initially treated at the 350-mg/ m(2)/day UFT level for 14 days without any dose-limiting toxic reactio ns. Subsequently, another 7 patients were treated at the 400-mg/m(2)/d ay level; grade 3 diarrhea developed in 3 of these 7 (with severe abdo minal cramping in 2 cases and severe nausea and vomiting unresponsive to antiemetics in the third). To better define the starting dose for p hase II studies, an additional 3 patients were treated at the 350-mg/m (2)/day dose level. Of the total 7 patients treated at 350 mg/m(2)/day , grade 3 toxic events (diarrhea) developed in 2 patients. Grade 1-2 t oxic effects noted at this level included fatigue, stomatitis, skin ra sh, abdominal pain, nausea, and vomiting. Neither partial nor complete responses were observed in this trial. The maximum tolerated dose of this schedule is 350 mg/m(2)/day UFT plus 150 mg/day oral leucovorin. However, because of this schedule's inferior dose intensity compared w ith that of the 28-day schedule of UFT plus leucovorin, subsequent dev elopment of UFT in the United States has focused on the 28-day regimen .