PHARMACOKINETIC AND PHASE-I STUDIES OF BREQUINAR (DUP-785, NSC-368390) IN COMBINATION WITH CISPLATIN IN PATIENTS WITH ADVANCED MALIGNANCIES

Brequinar (DUP 785; NSC 368390) is a quinoline carboxylic acid derivat ive that inhibits pyrimidine synthesis at the level of dihydro-orotate dehydrogenase and revealed synergy with cisplatin in preclinical mode ls. In this study investigating the pharmacokinetic and toxicity of br equinar in combination with cisplatin, patients were initially treated with weekly brequinar, in combination with an every-three week admini stration of cisplatin. Due to toxicity, the schedule was modified to a 28-day cycle with brequinar given on days 1, 8, 15, and cisplatin on day 1. A total of 24 patients (16 male, 8 female; median age 57; media n performance status 1) received 69 courses of therapy. Six dose level s were explored, with cisplatin/brequinar doses, respectively, of 50/5 00, 50/650, 50/860, 60/860, 75/650, and 75/860 mg/m(2). The serum conc entration versus time curves for brequinar were biphasic. A comparison of the pharmacokinetic results after the first and third doses of bre quinar indicate that the presence of 50, 60, and 75 mg/m(2)cisplatin d id not change the protein binding and the pharmacokinetics of brequina r in any of the three brequinar-dose groups. Total cisplatin plasma ph armacokinetic followed a triphasic-shape curve and unbound cisplatin d ecayed at a very rapid rate. Since pharmacokinetic parameters for tota l cisplatin in this study were similar to those reported in the litera ture, the presence of brequinar is unlikely to alter the pharmacokinet ics of cisplatin. Main dose-limiting toxicities included myelosuppress ion (including neutropenia and thrombocytopenia) and mucositis. Cispla tin/brequinar doses of 50/500, 50/650, 50/860, 60/860, 75/650, and 75/ 860 mg/m2, were associated with dose limiting toxicity in 0/3, 1/3, 1/ 3, 1/3, 2/4, 2/5, and 4/6 patients, respectively. This study shows tha t co-administration of brequinar and cisplatin does not affect the pha rmacokinetic properties of either drug and that the MTDs of cisplatin/ brequinar combinations are 60/860 mg/m2 or 75/650 mg/m(2). From this s tudy, we conclude that full dose of 75 mg/m(2) cisplatin (day 1) can b e administered with 650 mg/m(2) brequinar (days 1, 8 and 15) without s ignificant modifications of individual drug pharmacokinetic parameters .