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Purpose: To determine the maximum-tolerated dose (MTD) and the dose- limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. Patients and Methods: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). Results: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (C(max)) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t 1/4 ; 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 described by a one-compartment model with a t 1/4 of 0.41 hours; peak levels of UFTi were 5.2% ± 2.5% those of TPTi. Conclusion: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.

Original publication

DOI

10.1200/JCO.1998.16.8.2761

Type

Journal article

Journal

Journal of Clinical Oncology

Publication Date

01/01/1998

Volume

16

Pages

2761 - 2769