PHASE-I TRIAL OF WEEKLY SCHEDULING AND PHARMACOKINETICS OF TITANOCENEDICHLORIDE IN PATIENTS WITH ADVANCED CANCER

Purpose: To determine the maximum-tolerated dose (MTD) and the dose-li miting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and uri ne. Patients and Methods: Twenty patients with a median age of 58 year s received 83 courses of TD. TD was given as 1-hour infusion at escala ting doses from 70 to 185 mg/m(2)/wk. pharmacokinetic analysis was per formed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). Results: At the fifth do se level (185 mg/m(2)/wk), a variety of DLTs were seen in five patient s: fatigue in three, bilirubinemia in one, and hypokalemia in two. A f urther six patients were treated at 140 mg/m(2); only one had dose-lim iting creatinine elevation and this dose wets therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokineti c analysis showed that TPTi maximum concentration (C-max) values were linear with dose and elimination of TPTi was triphasic with a long ter minal half-life (t(1/2); median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was descr ibed by a one-compartment model with a t(1/2) of 0.41 hours; peak leve ls of UFTi were 5.2% +/- 2.5% those of TPTi, Conclusion: The MTD of TD given on a weekly schedule is 140 mg/m(2), with cumulative, but rever sible creatinine and bilirubin elevation being the DLTs, J Clin Oncol 16:2761-2769. (C) 1998 by American Society of Clinical Oncology.