Phase I study of liposomal vincristine

Purpose: A phase I study of vincristine encapsulated inside 120-nm-diameter disrearoylphosphatidylcholine-cholesterol liposomes was performed. The pri mary objectives were to determine the maximum-tolerated dose (MTD), recomme nded phase II dose, toxicity, and pharmacokinetics of liposomal vincristine (ONCO-TCS). Patients and Methods: Twenty-five patients with histologically confirmed ma lignancies were enrolled and assessable. Vincristine doses were increased f rom 0.5 mg/m(2) to 1.0, 1.5, 2.0, 2.4, and 2.8 mg/m(2) with cohorts of thre e or more patients per dose level. A total of 64 courses of ONCO-TCS were a dministered intravenously once every 3 weeks. The pharmacokinetics of total vincristine content in plasma were determined using a high-performance liq uid chromatography method. Results: Patients were treated with vincristine doses up to 2.8 mg/m(2); ho wever, 2.4 mg/m(2) was defined as the MTD and 2.0 mg/m(2) as the phase II r ecommended dose. Pain and obstipation were the dose-limiting toxicites. Oth er toxicities were fever, rigors, fatigue, myalgias, and peripheral neuropa thy. Hematologic toxicity was mild. All patients who were treated with dose s above 1.5 mg/m(2) received in excess of 2.0 mg of vincristine, with doses as high as 6.2 mg. One partial response was seen in a patient with pancrea tic cancer. Tumor response not meeting partial response criteria war seen i n two other patients. pharmacokinetic studies revealed significantly elevat ed concentrations of total vincristine, but parameters varied and were not directly correlated with toxicity or response. Conclusion: The ability to administer elevated doses of vincristine, as wel l as indications of efficacy, suggests that ONCO ICS warrants further clini cal investigation in a phase II setting. (C) 1999 by American Society of Cl inical Oncology.