Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors.

Abstract

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.

• Authors: A Korfel, M E Scheulen, H J Schmoll, O Gründel, A Harstrick, M Knoche, L M Fels, M Skorzec, F Bach, J Baumgart, G Sass, S Seeber, E Thiel, W E Berdel
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 4 Issue 11 Pg. 2701-8 (Nov 1998) ISSN: 1078-0432 [Print] United States
• PMID: 9829732 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• Titanium
• titanocene dichloride

Topics

• Adult
• Aged
• Antineoplastic Agents (adverse effects, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Kidney (drug effects)
• Male
• Middle Aged
• Neoplasms (drug therapy)
• Organometallic Compounds (adverse effects, pharmacology, therapeutic use)
• Titanium
• Treatment Outcome