ZD9331 in combination with topotecan: phase I and II experience

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/m(2) topotecan 0.5 mg/m(2)) and two at dose level 2 (ZD9331 65 mg/m(2), topotecan 0.75 mg/m(2)). The RD for the phase II study was ZD9331 65 mg/m(2) topotecan 0.5 mg/m(2). In both trials, the most common grade 3 and 4 adverse events were thrombocytopenia (15 of 57 patients, 26.3%), neutropenia (111 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 (112.2%) in phase II]. Seventeen patients achieved stable disease [three (18.8%) in phase 1, 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. (C) 2003 Lippincott Williams Wilkins.