BBR 2778 is a novel aza-
anthracenedione with no
cardiotoxicity in preclinical models. This Phase I dose escalation trial of
BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic 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 doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/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 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was
neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally
thrombocytopenia,
lymphopenia,
alopecia,
nausea, and
vomiting and blue coloration of the skin and urine. No significant
cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h).
BBR 2778 displayed a large volume of distribution (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/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast,
small cell lung carcinoma, and facial
cylindroma. This trial showed that
BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-
anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative
cardiotoxicity, such as
anthracycline-pretreated
breast cancer patients.