A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules

Purpose: To determine the safety, maximum tolerated dose, pharmacokinetics, and toxicities associated with administration of paclitaxel poliglumex (PPX, XYOTAX, Cell Therapeutics, Inc., Bresso, Italy) given on either 3-weekly or 2-weekly schedule. Experimental Design: Nineteen patients were investigated on the 3-weekly phase la study and 11 patients on the 2-weekly phase lb study. Dose escalation starting with 100% increments and one patient per dose level was modulated in accordance with the observed toxicities. Conjugated and unconjugated paclitaxel were measured in plasma. Results: Dose-limiting toxicity of neutropenia was encountered at 266 mg/m(2) (paclitaxel equivalents) in phase la and the maximum tolerated dose was 233 mg/m(2). Neuropathy was dose-limiting in phase lb with a maximum tolerated dose of 177 mg/m(2). Pharmacokinetic investigations indicated a prolonged half-life of > 100 hours for conjugated taxanes. Plasma concentrations of unconjugated paclitaxel were similar to those following administration of an equivalent dose of Taxol. Two partial responses were observed, one in a patient with mesothelioma at 177 mg/m(2) in phase la and one in a patient with gastric carcinoma at 175 mg/m(2) in phase lb. Conclusion: PPX is a water-soluble paclitaxel-polymer conjugate with a prolonged half-life and limited volume of distribution. Dose-limiting toxicities were neutropenia and neuropathy. PPX showed activity in this patient population.