Molecular Medicine in Practice Phase I Clinical Trial of MPC-6827 ( Azixa ) , a Microtubule Destabilizing Agent , in Patients with Advanced Cancer
MPC-6827 (Azixa) is a small-moleculemicrotubule-destabilizing agent that binds to the same (or nearby) sites on b-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerateddose (MTD), andpharmacokinetics (PK) ofMPC-6827 inpatientswith solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1to 2-hour intravenous administration of MPC-6827 for 3 consecutiveweeks every 28 days (1 cycle). Dose escalation beganwith 0.3, 0.6, 1, and 1.5mg/m, with subsequent increments of 0.6 mg/m until the MTD was determined. A 3 þ 3 design was used. Pharmacokinetics ofMPC-6827 and itsmetaboliteMPI-0440627were evaluated. Forty-eightpatients received therapy; 79 cycleswere completed (median, 1; range, 1–10). Themost commonadverse eventswerenausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m (1/6 patients) and at 4.5mg/m (1/7patients). TheMTDwasdetermined tobe3.3mg/m (0/13patientshadaDLT). 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-6827administered intravenouslyover2hoursat adoseof3.3mg/monceweekly for 3weeks every 28days was safe inpatientswithheavilypretreated cancer.Clinical trialswithMPC-6827and chemotherapyareongoing. Mol Cancer Ther; 9(12); 3410–9. 2010 AACR.