ZD0473 pharmacokinetics in Japanese patients: a Phase I dose-escalation study

ZD0473 is new platinum agent that was rationally designed to circumvent platinum resistance and reduce the potential for nephroand neurotoxicity. This Phase I dose-escalating study investigated the pharmacokinetics, tolerability and efficacy of ZD0473 in Japanese patients with solid, refractory tumours. ZD0473 was administered as a 1-h intravenous infusion every 3 weeks. Nine patients received a total of 16 cycles of ZD0473 (median I cycle/patient), with 3 patients treated at each of 3 doses (60, 90, 120 mg/m(2)). The maximum plasma concentration (C-max and the area under the concentration-time curve to infinity (AUC(0-infinity)) increased with dose in a linear fashion for both total platinum and ZD0473 in plasma ultrafiltrate, suggesting that the pharmacokinetics of ZD0473 are linear. Haematological and non-haematological toxicities such as nausea and vomiting were mild (grade 1 or 2) and transient. No clinically significant nephro-, oto- or neurotoxicity was observed. Dose-limiting toxicity (DLT) was not observed and the maximum tolerated dose (MTD) was not identified. ZD0473 treatment showed evidence of disease stabilisation in 3 patients (33%). In conclusion, ZD0473 appears to have linear pharmacokinetics, and an acceptable tolerability profile at doses up to 120 mg/m(2) in Japanese patients with refractory solid malignancies. Following evaluation of the data from all the Western trials, the ZD0473 development programme changed and this Japanese trial was stopped. (C) 2002 Elsevier Science-Ltd. All rights reserved.