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

Plummer, R; Rees, C; Hughes, A; Beale, P; Highley, M; Trigo, J; Gokul, S; ... Douglass, E; + view all (2003) A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor. CLIN CANCER RES , 9 (4) 1313 - 1322.

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Abstract

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 greater than or equal to3 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/m(2)/day.Results: Dose-limiting toxicity occurred at 162.5 mg/m(2) ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting greater than or equal to7 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 greater than or equal to50% reduction in CA125 levels.Conclusions: The maximum tolerated dose of this schedule was 130 mg/m(2). 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.

Type: Article
Title: A phase I trial of ZD9331, a water-soluble, nonpolyglutamatable, thymidylate synthase inhibitor
Keywords: SOLID TUMORS, 2'-DEOXYURIDINE, DIHYDROCHLORIDE, SYNTHETASE, INFUSION, PLASMA, DRUGS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/191422
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