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A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor

Lookup NU author(s): Professor Ruth Plummer, Dr Andrew Hughes, Dr Martin Highley, Dr Sathyarathna Gokul, Professor Alan Calvert


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Purpose: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific thymidylate synthase inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. Experimental Design: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received ≥3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m2/day. Results: Dose-limiting toxicity occurred at 162.5 mg/m2 ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting ≥7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant (P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a ≥50% reduction in CA125 levels. Conclusions: The maximum tolerated dose of this schedule was 130 mg/m2. The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.

Publication metadata

Author(s): Plummer ER, Rees C, Hughes AN, Beale P, Highley MS, Trigo J, Gokul S, Judson I, Calvert AH, Jackman A, Mitchell F, Smith R, Douglass E

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2003

Volume: 9

Issue: 4

Pages: 1313-1322

Print publication date: 01/04/2003

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

PubMed id: 12684399