CLINICAL-PHASE-I AND PHARMACOKINETIC TRIAL OF THE NEW TITANIUM COMPLEX BUDOTITANE

Budotitane is-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established s creening models indicate considerable antitumor activity. We have perf ormed a clinical Phase I and pharmacokinetic trial with budotitane adm inistered as i.v. infusion twice weekly. The starting dose of 100 mg/m (2) was derived from a prior single dose Phase I study. Eighteen patie nts with solid tumors refractory to all other known treatment modaliti es were entered. 17 patients had received prior chemotherapy. Dose lev els ranged from 100 mg/m(2) to 230 mg/m(2), with a total of 122 budoti tane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m(2) and 2/4 pts at 230 mg/m(2) developed a 3-fold increase of reticulocytes without signs of hemolysis or bleed ing. Nonhematologic toxicity was moderate at doses of < 180 mg/m(2). F ifteen patients reported loss of taste at the day of infusion. At 230 mg/m(2), 2/4 pts developed WHO grade 3 cardiac arrhythmias with polyto pe premature ventricular beats and nonsustained ventricular tachycardi a. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m(2) and 230 mg/m(2). At 180 mg/m(2), C-max was 2.9 +/- 1.2 mu g/m l, t(1/2) 78.7 +/- 24.4 h, Cl-tot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h .mu g/ml. At 230 mg/m(2), C-max was 2.2 +/- 0.8 mu g/ml, t(1/2) 59.3 +/- 12.1 h, Cl-tot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h .mu g/ml. No objective tumor response was observed. We conclude tha t the maximum tolerated dose of budotitane administered twice weekly i s 230 mg/m(2), the dose limiting toxicity is cardiac arrhythmia. Furth er evaluation of the nature of the cardiac toxicities observed is warr anted. Using this schedule, 180 mg/m(2) is a safe dose for subsequent clinical studies.