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 ZD16 94 (Tomudex, Alderley park, United Kingdom), a new folate-based thymid ylate synthase (TS) inhibitor, in patients with advanced malignancy. P atients and Methods: From February 1991 to January 1993, 61 patients w ith a range of solid tumors received 161 courses of ZDI 694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating do ses from 0.1 to 3.5 mg/m(2). Pharmacokinetic (PK) analysis was perform ed with the first two courses of treatment. There were 33 men and 28 w omen with a median age of 53 years (range, 21 to 73), Fifty-five patie nts (90%) had previously received chemotherapy.Results: Reversible liv er toxicity and dose-related gastrointestinal (GI) and bone marrow tox icity 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 m arrow toxicities generally became more severe, No renal toxicity was o bserved. The maximum tolerated dose (MTD) was 3.5 mg/m(2), at which, i n addition to antiproliferative toxicities, four of six patients (67%) developed severe malaise that consisted of anorexia, nausea, and asth enia, with rapidly decreasing performance status that limited re-treat ment, 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 patien ts (26%) and grade IV myelosuppression in two others, Liver toxicity w as self-limiting and not associated with severe malaise. Two patients held a partial response to treatment. PK analysis showed that plasma e limination was triexponential, with pronounced variability in the mean terminal half-life (t(1/2 gamma)) for a given dose ranging from 8.2 t o 105 hours, There was ct linear relationship between dose and both th e area under the concentration-time curve (AUC) and maximum concentrat ion (C-max), but no clear association between these parameters and res ponse or toxicity. Conclusion: The dose of ZDI694 recommended for phas e II trials is 3.0 mg/m(2). (C) 1996 by American Society of Clinical O ncology.