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A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules

Authors' Affiliations: ¹ Northern Institute for Cancer Research, University of Newcastle; ² Northern Centre for Cancer Treatment, Newcastle upon Tyne, United Kingdom; ³ Cancer Research UK, London, United Kingdom; ⁴ Aberdeen Royal Infirmary, Aberdeen, United Kingdom; and ⁵ Cell Therapeutics, Inc. (Europe), Bresso, Italy

Requests for reprints: Alan V. Boddy, Northern Institute for Cancer Research Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, United Kingdom. Phone: 44-19-1246-4412; Fax: 44-19-1246-4301; E-mail: alan.boddy{at}ncl.ac.uk.

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 Ia study and 11 patients on the 2-weekly phase Ib 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/m² (paclitaxel equivalents) in phase Ia and the maximum tolerated dose was 233 mg/m². Neuropathy was dose-limiting in phase Ib with a maximum tolerated dose of 177 mg/m². 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/m² in phase Ia and one in a patient with gastric carcinoma at 175 mg/m² in phase Ib.

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.

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