[Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules]
>>Clinical Cancer Research Vol. 11, 7834-7840, November 1, 2005
A Phase I and Pharmacokinetic Study of Paclitaxel Poliglumex (XYOTAX), Investigating Both 3-Weekly and 2-Weekly Schedules
Alan V. Boddy1, E. Ruth Plummer1,2, Radha Todd2, Julieann Sludden1, Melanie Griffin1, Lesley Robson3, James Cassidy4, Donald Bissett4, Alberto Bernareggi5, Mark W. Verrill1,2 and A. Hilary Calvert1,2
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@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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