A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinic al models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the p harmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy), Thirty patients (pts) were treated with BBR 2778 at dos es ranging from 5 to 150 mg/m(2)/week. The dose levels 5, 10, 16.5, 25, 37. 5, 75, 112.5, and 150 mg/m(2)/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 c y), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutrope nia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and v omiting and blue coloration of the skin and urine. No significant cardiac t oxicity was observed. The plasma dose concentration curve fitted a biexpone ntial profile, with a rapid distribution phase followed by a prolonged elim ination phase (mean t(1/2,z), 12 h) BBR 2778 displayed a large volume of di stribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1 .31 l/h/kg), Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m(2)/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studie s is 112.5 mg/m(2)/week days 1 and 8 with individual optional administratio n at day 15, every 4 weeks. Antitumor activity was observed in patients wit h breast, small cell lung carcinoma, and facial cylindroma. This trial show ed that BBR 2778 has a manageable toxicity profile on a weekly schedule. Th is lead compound of the aza-anthracenedione family shows promising antitumo r activity and deserves Phase II investigation in patients with high risk o f cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.