title: A phase I clinical and pharmacokinetic study of Brequinar sodium, DUP 785 (NSC 368390), using a weekly and a biweekly schedule.
abstract: Brequinar, DUP 785, is a substituted 4-quinoline carboxylic acid derivative which in preclinical studies has shown broad antitumor activity. It is a novel antimetabolite blocking pyrimidine nucleotide synthesis. In a clinical phase I study, 83 patients were treated on a weekly schedule and 18 patients on a biweekly schedule. The drug was given intravenously as a short infusion. Three patients were entered on each dose level from a starting dose of 6 mg/m2 up to 2600 mg/m2 weekly. The dose ranges on a biweekly schedule were 500-850 mg/m2. There was no dose escalation in individual patients. Pharmacokinetic studies were performed in 19 patients on a weekly schedule and in two patients on a biweekly schedule. A biphasic decay in plasma was observed with a median half life of 10 h (5.1-23.4). The main dose-limiting toxicity was thrombocytopenia. Of non-hematologic side-effects, stomatitis/mucositis occurred frequently. Skin eruptions occurred rarely, but were a major problem when found. All side-effects were fully reversible; there were no signs of cumulative toxicity. Antitumor activity was observed in one patient with a lung metastasis from a bladder cancer and in a patient with an unknown primary tumor. The recommended doses for phase II trials with DUP 785 are: 1500-2000 mg/m2 on a weekly schedule and 500-750 mg/m2 on a biweekly schedule dependent on status before treatment.
authors.affiliation: Department of Oncology ONB, Finsen Institute, Copenhagen, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Bork
authors.forename: S
authors.initials: S
authors.lastname: Vest
authors.forename: H H
authors.initials: HH
authors.lastname: Hansen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010976:Platelet Count; D014571:Urologic Neoplasms / Q000188:drug therapy; D011798:Quinaldines
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C046943:brequinar; D011798:Quinaldines