Faivre S, Raymond E, Boige V, Gatineau M, Buthaut X, Rixe O, Bernareggi A, Camboni G, Armand J P
Department of Medicine, Institut Gustave-Roussy, Villejuif, France.
Clin Cancer Res. 2001 Jan;7(1):43-50.
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.
BBR 2778是一种新型氮杂蒽二酮，在临床前模型中无心脏毒性。开展这项BBR 2778的I期剂量递增试验，以确定晚期实体瘤患者中BBR 2778的最大耐受剂量、剂量限制性毒性和药代动力学特征。BBR 2778在4周周期内连续3周每周进行一次30分钟的静脉输注。30例患者接受了剂量范围为5至150mg/m²/周的BBR 2778治疗。剂量水平5、10、16.5、25、37.5、75、112.5和150mg/m²/周分别在4例患者（9个周期）、3例患者（3个周期）、3例患者（5个周期）、6例患者（9个周期）、1例患者（1个周期）、4例患者（9个周期）、6例患者（18个周期）和3例患者（4个周期）中进行了研究。剂量限制性毒性为中性粒细胞减少，通常发生在第14天。其他毒性为轻度至中度，主要为血小板减少、淋巴细胞减少、脱发、恶心、呕吐以及皮肤和尿液发蓝。未观察到明显的心脏毒性。血浆剂量浓度曲线符合双指数模型，快速分布期后为延长的消除期（平均t1/2,z为12小时）。BBR 2778的分布容积较大（范围为9.7 - 29.7L/kg），血浆清除率较高（0.75 - 1.31L/h/kg）。尿液中回收的原形药物不到剂量的10%。最大耐受剂量为每4周150mg/m²/周，共3周。基于这项研究，II期研究的推荐剂量为每4周第1天和第8天112.5mg/m²/周，第15天可个体化选择给药。在乳腺癌、小细胞肺癌和面部圆柱瘤患者中观察到了抗肿瘤活性。该试验表明，BBR 2778按每周给药方案具有可管理的毒性特征。这种氮杂蒽二酮家族的先导化合物显示出有前景的抗肿瘤活性，值得在有累积心脏毒性高风险的患者（如接受过蒽环类药物预处理的乳腺癌患者）中进行II期研究。
