Toggle Main Menu Toggle Search

Open Access padlockePrints

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

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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 ≥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


Actions

Find at Newcastle University icon    Link to this publication


Share