ZD9331 in combination with topotecan: phase I and II experience.

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.

• Authors: Al Benson 3rd, Elizabeth Poplin, Ignace Vergote
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 14 Suppl 1 Pg. S21-7 (May 2003) ISSN: 0959-4973 [Print] England
• PMID: 14567437 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Review)

Chemical References

• Quinazolines
• ZD 9331
• Topotecan

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Quinazolines (administration & dosage, pharmacokinetics)
• Topotecan (administration & dosage, pharmacokinetics)