A Phase I Trial of Weekly Paclitaxel Plus Prolonged Oral Eniluracil/5-Fluorouracil in Patients with Refractory Malignancies

Abstract

Purpose. This phase I study was conducted to determine the dose-limiting toxicity (DLT), maximum-tolerated doses, and recommended phase II doses of the combination of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU).Patients and Methods. Patients received paclitaxel i.v. over 1 hour weekly for four consecutive weeks of each cycle. Oral eniluracil/5-FU was administered orally twice daily for 28 consecutive days starting on day 1 of each cycle. Cycles were repeated every 35 days. Patients were accrued at six different dosing combinations. Weekly paclitaxel doses ranged from 60 mg/m2 to 80 mg/m2, and oral eniluracil/5-FU doses ranged from 8.0/0.8 mg/m2 to 11.5/1.15 mg/m2 twice daily.Results. Thirty-seven patients received 126 cycles of therapy. Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or thrombocytopenia reported. DLT was reported in three out of six patients enrolled at the highest dose level and consisted of grade 3 diarrhea (two patients) and grade 3 mucositis (one patient). No DLTs were reported in patients enrolled at lower dose levels. One complete response and three partial responses were reported in patients with taxane-resistant metastatic breast cancer.Conclusion. The combination of paclitaxel and eniluracil/5-FU was generally well tolerated. The recommended doses for further phase II testing are paclitaxel 80 mg/m2 i.v. weekly for 4 weeks plus eniluracil/ 5-FU 10.0/1.0 mg/m2 orally twice daily on days 1-28 with cycles repeated every 35 days.