Phase I trial of ZDI694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors

Purpose: To perform a phase I clinical and pharmacologic study of ZD1694 (Tomudex, Alderley park, United Kingdom), a new folate-based thymidylate synthase (TS) inhibitor, in patients with advanced malignancy. Patients and Methods: From February 1991 to January 1993, 61 patients with a range of solid tumors received 161 courses of ZDI 694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m(2). Pharmacokinetic (PK) analysis was performed with the first two courses of treatment. There were 33 men and 28 women with a median age of 53 years (range, 21 to 73), Fifty-five patients (90%) had previously received chemotherapy. Results: Reversible liver toxicity and dose-related gastrointestinal (GI) and bone marrow toxicity occurred at greater than or equal to 1.6 mg/m(2). Liver function usually returned to normal with repeated treatment, but GI and bone marrow toxicities generally became more severe, No renal toxicity was observed. The maximum tolerated dose (MTD) was 3.5 mg/m(2), at which, in addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asthenia, with rapidly decreasing performance status that limited re-treatment, Abnormal liver function was also seen in four patients (67%). At 3.0 mg/m(2), grades III and IV diarrhea were seen in six of 23 patients (26%) and grade IV myelosuppression in two others, Liver toxicity was self-limiting and not associated with severe malaise. Two patients held a partial response to treatment. PK analysis showed that plasma elimination was triexponential, with pronounced variability in the mean terminal half-life (t(1/2 gamma)) for a given dose ranging from 8.2 to 105 hours, There was ct linear relationship between dose and both the area under the concentration-time curve (AUC) and maximum concentration (C-max), but no clear association between these parameters and response or toxicity. Conclusion: The dose of ZDI694 recommended for phase II trials is 3.0 mg/m(2). (C) 1996 by American Society of Clinical Oncology.