A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly

The anthracenedione analogue, BBR 2778 is an active antitumour agent precli nically and has reduced potential for cardiotoxicity compared with other si milar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapid ly from 20 to 240 mg/m(2). The dose-limiting toxicity (DLT) was neutropenia , common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Othe r toxicities greater than or equal to CTC grade 3 were: vomiting, lymphopen ia, thrombocytopenia and lethargy. Blue discoloration of veins and urine wa s also noted. In 1 patient (120 mg/m(2), four cycles) left ventricular ejec tion reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2)beta at 180 mg/m(2)- 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a p atient with previously treated small cell lung carcinoma (SCLC), a 49% redu ction in measurable disease was noted with resolution of pericardial and pl eural effusions (120 mg/m(2) x eight cycles). From the results of this phas e I study a dose of 180 mg/m(2) as a 1 h infusion every 3 weeks would be re commended for phase II trials. (C) 2000 Elsevier Science Ltd. All rights re served.