Phase I Clinical Trials Program, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Mol Cancer Ther. 2010 Dec;9(12):3410-9. doi: 10.1158/1535-7163.MCT-10-0516.
MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on β-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m(2), with subsequent increments of 0.6 mg/m(2) until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1-10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m(2) (1/6 patients) and at 4.5 mg/m(2) (1/7 patients). The MTD was determined to be 3.3 mg/m(2) (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m(2) once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing.
MPC-6827（阿齐扎）是一种小分子微管蛋白稳定剂，与秋水仙碱结合在β-微管蛋白的相同（或附近）位置。这项 I 期研究旨在确定 MPC-6827 在实体瘤患者中的剂量限制毒性（DLT）、最大耐受剂量（MTD）和药代动力学（PK）。晚期/转移性癌症患者接受每周一次、1-2 小时静脉输注 MPC-6827，连续 3 周，每 28 天（1 个周期）一次。剂量递增从 0.3、0.6、1 和 1.5 mg/m2 开始，随后递增 0.6 mg/m2，直到确定 MTD。采用 3+3 设计。评估了 MPC-6827 及其代谢物 MPI-0440627 的药代动力学。48 例患者接受了治疗；完成了 79 个周期（中位数为 1；范围为 1-10）。最常见的不良反应是恶心、疲劳、潮红和高血糖。3.9mg/m2（1/6 例患者）和 4.5mg/m2（1/7 例患者）时出现非致命性 3 级心肌梗死为 DLT。确定 MTD 为 3.3mg/m2（13 例患者中无 DLT）。48 例患者中有 5 例（10.4%）达到了 4 个月或更长时间的稳定疾病（实体瘤反应评估标准）。MPC-6827 的分布容积和清除率较高。半衰期范围为 3.8 至 7.5 小时。总之，MPC-6827 以 3.3mg/m2 的剂量每周静脉输注 2 小时，每 28 天 3 周，在接受过多线治疗的癌症患者中是安全的。正在进行 MPC-6827 与化疗联合的临床试验。
