PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF TITANOCENE DICHLORIDE IN ADULTS WITH ADVANCED SOLID TUMORS

This Phase I dose-escalation clinical trial of a lyophilized formulati on of titanocene dichloride (MKT4) was conducted to determine the maxi mum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokine tics of titanium (Ti) after a single i.v. infusion of MKT4, Forty pati ents with refractory solid malignancies were treated with a total of 7 8 courses. Using a modified Fibonacci scheme, 15 mg/m(2) initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m(2)) if DLT was not observed. The maximum tole rated dose was 315 mg/m(2), and nephrotoxicity was DLT, Two minor resp onses (bladder carcinoma and non-small cell lung cancer) were observed . The pharmacokinetics of plasma Ti were assessed in 14 treatment cour ses by atomic absorption spectroscopy. The ratio for the area under th e curve(0-infinity) in plasma and whole blood was 1.2, The following p harmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t(1/2 beta) in plasma w as 22.8 +/- 11.2 h (x(h) +/- pseudo-SD), peak plasma concentration c(m ax) similar to 30 mu g/ml at a dose of 420 mg/m(2), distribution volum e V-ss = 5.34 +/- 2.1 L (x(a) +/- SD), and a total clearance Cl-total = 2.58 +/- 1.23 mymin (x(a) +/- SD). There was a linear correlation be tween the area under the curve(0-infinity)of Ti in plasma and the tita nocene dichloride dose administered with a correlation coefficient r(2 ) of 0.8856, Plasma protein binding of Ti was in the 70-80% range. Bet ween 3% and 16% of the total amount of Ti administered were renally ex creted during the first 36 h, The recommended dose for Phase II evalua tion is 240 mg/m(2) given every 3 weeks with i.v. hydration to reduce renal toxicity.