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A Phase I Trial of ZD9331, a Water-Soluble, Nonpolyglutamatable, Thymidylate Synthase Inhibitor

University of Newcastle upon Tyne, Newcastle NE4 6BE, United Kingdom [R. P., A. H., M. H., S. G., H. C.]; Royal Marsden Hospital, Sutton, Surrey, United Kingdom [C. R., P. B., J. T., I. J.]; Institute of Cancer Research, Sutton, Surrey, United Kingdom [A. J., F. M.]; AstraZeneca, Macclesfield, Cheshire, United Kingdom [R. S.]; and AstraZeneca, Wilmington, Delaware [E. D.]

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.

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