Phase I dose-escalation trial of ZD9331 in Japanese patients with refractory, solid malignancies

ZD9331 is a novel thymidylate synthase inhibitor that, unlike some other antifolates, does not require polyglutamation for activity. This phase I dose-escalation trial investigated the tolerability, efficacy and pharmacokinetics of ZD9331 in Japanese patients with refractory, solid malignancies.

The mean age of patients was 57.6 years, and the most common primary tumours were gastric and colorectal cancer. Most patients had received prior chemotherapy and/or surgery. ZD9331 (69, 108 and 130 mg/m2/day) was administered as a 30-min i.v. infusion on days 1 and 8 of a 3-week cycle.

A total of 18 patients received ZD9331 treatment; six at each dose level. Patients received a median of 2 cycles of treatment ZD9331 demonstrated some antitumour activity, with one-third of patients showing no significant change in tumour size. ZD9331 was associated with non-dose-dependent myelosuppression, and dose-limiting toxicity was observed in one patient given 69 mg/m2/day and one patient given 130 mg/m2/day. The maximum plasma concentration and total area under the concentration-time curve increased with ZD9331 dose, whereas other pharmacokinetic parameters remained constant and independent of dose. Pharmacokinetic parameters were comparable following day 1 and 8 doses, with no accumulation of ZD9331 following the second dose.

ZD9331 has a manageable toxicity profile and shows some evidence of activity in Japanese patients with refractory, solid malignancies. The pharmacokinetic profile of ZD9331 in Japanese patients is similar to that observed in Western patients.