PHASE-I CLINICAL AND PHARMACOLOGICAL STUDY OF ENILURACIL PLUS FLUOROURACIL IN PATIENTS WITH ADVANCED CANCER

Purpose: To determine the highest dose of fluorouracil(S-FU) that coul d be safely administered with Eniluracil (776C85; Glare Wellcome Inc, Research Triangle Park, NC), an inactivator af dihydropyrimidine dehyd rogenase (DPD), on a daily schedule for 5 days, and to define the toxi cities of the combination and the pharmacokinetics of 5-FU when admini stered with 776C85. Patients and Methods: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutio ns. The study consisted of three periods designed to evaluate the safe ty, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of a, least three patients each received oral 776C85 alone at doses of 3. 7 mg/m(2)/d, 18.5 mg/m(2)/d and 0.74 mg/m(2)/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a si ngle intravenous (IV) bolus dose of 5-FU 10 mg/m(2) on day 2. After a second washout period, patients were treated with 776C85 daily for 7 d ays and 5-FU IV bolus on days 2 through 6. The starting dose of 5-FU 1 0 mg/m(2)/d was escalated until the MTD was determined. After determin ation of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovor in in the presence of 776C85. Near the completion of the study, additi onal cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. Results: Sixty-five patients were enr olled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activit y in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug disp layed linear pharmacokinetics. Recommended doses for further testing o n a daily for 5-day schedule are 776C85 10 mg/d with IV 5-FU 25 mg/m(2 )/d; 776C85 10 mg/d with IV 5-FU 20 mg/m(2)/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m(2)/d with leucovorin at 50 mg/d. Conclusion: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally use d, caused, at least in part, by marked alterations in 5-FU plasma phar macokinetics. (C) 1998 by American Society of Clinical Oncology.