ZD9331 in combination with topotecan: Phase I and II experience

Al Benson*, Elizabeth Poplin, Ignace Vergote

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Background: ZD9331, a novel, direct-acting thymidylate synthase inhibitor, and the topoisomerase inhibitor topotecan have antitumour activity in a range of solid tumours. We report results from two open-label, multicentre, phase I and phase II trials, investigating the pharmacokinetics, tolerability and efficacy of ZD9331, when used in combination with topotecan in patients with relapsed or refractory tumours. Patients and methods: Patients in the phase II trial had progressed following first- or second-line treatment with platinum and paclitaxel. The recommended dose (RD) from the phase I study was subsequently used in the phase II trial. ZD9331 was given as a 30-min i.v. infusion on days 1 and 8 combined with a 30-min i.v. infusion of topotecan on days 1-5 of each 3-week cycle. Results: Sixteen patients with a selection of solid tumours were recruited to the phase I trial. Forty-one patients were included in the combination therapy arm of the phase II study; 95% of which had ovarian cancer and 5% had peritoneal cancer. Three patients experienced dose-limiting toxicity during the phase I trial, one at dose level 1 (ZD9331 65 mg/m2, topotecan 0.5 mg/m2) and two at dose level 2 (ZD9331 65 mg/m2, topotecan 0.75 mg/m2). The RD for the phase II study was ZD9331 65 mg/m2, topotecan 0.5 mg/m2. In both trials, the most common grade 3 and 4 adverse events were thrombocytopenia (15 of 57 patients, 26.3%), neutropenia (11 of 57 patients, 19.3%) and anaemia (9 of 57 patients, 15.8%). One patient (2.4%) in the phase II trial experienced a complete response and six patients overall experienced a partial response [one (6.3%) in phase I, five (12.2%) in phase II]. Seventeen patients achieved stable disease [three (18.8%) in phase I, 14 (34.1%) in phase II]. Conclusions: ZD9331, in combination with topotecan, showed manageable toxicity and some evidence of activity in patients with ovarian cancer.

Original languageEnglish (US)
Pages (from-to)S21-S27
JournalAnti-Cancer Drugs
Volume14
Issue numberSUPPL. 1
DOIs
StatePublished - May 2003

Keywords

  • Combination therapy
  • Ovarian cancer
  • Topotecan
  • Treatment refractory
  • ZD9331

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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