Phase I and Pharmacologic Study of Oral ZD9331, A Novel Nonpolyglutamated Thymidylate Synthase Inhibitor, in Adult Patients With Solid Tumors

摘要: PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine maximum-tolerated dose, study pharmacokinetics of ZD9331 when administered orally patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated oral given once daily (od) or twice (bid) for 5, 7, 10 days; cycles repeated every 21 days at doses ranging from 2.5 40 mg. For pharmacokinetic analysis, plasma sampling was performed during first course assayed using a validated liquid chromatographic–tandem mass spectrometry assay. Plasma levels 2′-deoxyuridine measured as surrogate marker TS inhibition. RESULTS: Forty-two received total 166 courses. The DLTs myelosuppression skin rash. Dose escalation mg, single resulted in less than proportional increase area under concentration-time curve ZD9331. drug exposure per cycle sche...