Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer
Christodoulou CV., Ferry DR., Fyfe DW., Young A., Doran J., Sheehan TMT., Eliopoulos A., Hale K., Baumgart J., Sass G., Kerr DJ.
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.