PHASE-I AND PHARMACOKINETIC STUDY OF BREQUINAR (DUP-785 NSC-368390) IN CANCER-PATIENTS

Brequinar (DUP 785, NSC 368390) is a 4-quinoline carboxylic acid deriv ative with broad spectrum antitumour activity in experimental models t hat acts as an antimetabolite by specific inhibition of de novo pyrimi dine synthesis. We performed a phase I study of brequinar administered as a 10 min intravenous (i.v.) infusion for 5 consecutive days, every 4 weeks. 67 evaluable patients were entered in this study and a total of 130 courses were administered at doses ranging from 2 to 350 mg/ml . The dose-limiting toxicity was myelosuppression with predominant thr omobocytopenia. Myelosuppression was dose-related and non-cumulative, with considerable interpatient variability depending on haematological risk factors. The maximum tolerated dose of brequinar was 210 mg/m2/d ay in poor risk patients whereas patients with good risk haematologica l profile tolerated higher doses (up to 350 mg/m2/day). Other non-limi ting toxicities included nausea and vomiting, mucositis and skin react ions. Brequinar plasma pharmacokinetic profiles were biphasic with alp ha half-life ranging from 0.1 to 0.7 h, and beta half-life ranging fro m 1.5 to 8.2 h. Increase in brequinar area under the plasma concentrat ion versus time curves (AUC) was nonlinear. Day 5 brequinar pharmacoki netics obtained in 21 patients indicated a significant increase in AUC (47%) and half-life beta (133%) compared to day 1 pharmacokinetics in the same patient. Brequinar plasma AUC and the per cent change in pla telet count at nadir were correlated (P < 0.001). Although no objectiv e response was observed in this study, one minor response was noted in cervical lymph nodes of a Hodgkin's disease patient.