Phase I clinical trial of pegylated liposomal mitoxantrone plm60-s: pharmacokinetics, toxicity and preliminary efficacy.

PURPOSE: Plm60-s is a pegylated liposomal mitoxantrone formulation, in which mitoxantrone was loaded into small unilamellar vesicles (~60 nm) made from solid lipid membrane. This two-arm, dose-escalating phase I study was designed to determine safety and pharmacokinetics of plm60-s, and to compare with those of conventional mitoxantrone injection (c-MI).

METHODS

Patients received an intravenous infusion of plm60-s at 6, 10, 12, 14, 16 and 18 mg/m(2) every 4 weeks. Three or 6 patients were in each group of dose level. If more than one third patients of a group experienced dose-limiting toxicity, dose climbing will stop. The control group of 3 patients received c-MI at 10 mg/m(2) every 28 days. Samples for pharmacokinetic studies were collected. The analysis of the safety and tolerability was done according to the record and laboratory examination, etc.

RESULTS

Twenty patients were enrolled. One grade 3 leukocytopenia occurred in plm60-s groups. Plm60-s was safer than c-MI at the same dose of 10 mg/m(2). Two complete responses and one partial response occurred in plm60-s group. In plasma, plm60-s exhibited sustained release of the content, resulting in the reduced peak concentrations and enhanced AUC of released MIT. Total mitoxantrone was linearly cleared, and mitoxantrone was predominantly in the liposomal encapsulation form. Repeated administration of plm60-s did not affect the clearance kinetics.

CONCLUSIONS

At a dose of up to 18 mg/m(2), plm60-s could be well tolerated and potential efficacy could be observed. The pharmacokinetic profile of plm60-s was remarkably altered. Further investigations are in progression.