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Annals of Oncology Advance Access published online on August 26, 2005
Annals of Oncology, doi:10.1093/annonc/mdi396
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© 2005 European Society for Medical Oncology
Received March 20, 2005
Revised July 15, 2005
Accepted July 18, 2005

Original article

A phase I trial of liposomal doxorubicin, paclitaxel and valspodar (PSC-833), an inhibitor of multidrug resistance

R. Advani 1, B. L. Lum 1, G. A. Fisher 1, J. Halsey 1, D. L. Chin 1, C. D. Jacobs 1, and B. I. Sikic 1*

1 Oncology Division, Stanford University Medical Center, Stanford, CA, USA

* To whom correspondence should be addressed.
B. I. Sikic, E-mail: brandy{at}stanford.edu


  Abstract

Purpose: The aim of this study was to determine (i) the maximum tolerated dose (MTD) of liposomal doxorubicin (L-DOX) and paclitaxel (DP), (ii) the MTD of DP plus valspodar (DPV) and (iii) pharmacokinetic (PK) interactions of valspodar with L-DOX and paclitaxel.

Methods: Twenty-three patients with metastatic cancers received DP, followed 4 weeks later by DPV. Dose levels of DP were (mg/m2 for L-DOX/paclitaxel): 30/135 (n = 7), 30/150 (n = 4), 35/150 (n = 8) and 40/150 (n = 4). Dose levels of DPV were 15/70 (n = 10) and 15/60 (n = 10). Serial, paired PK studies were performed.

Results: The MTD of DP was 40/150. For DPV at 15/70, five of 10 patients experienced grade 4 neutropenia. In the next cohort, a reduced dose of 15/60 was well tolerated. Valspodar produced reversible grade 3 ataxia in seven patients, requiring dose reduction from 5 to 4 mg/kg. Paired PK studies indicated no interaction between L-DOX and valspodar, and a 49% increase in the median half-life of paclitaxel. Two partial and one minor remissions were noted.

Conclusions: The use of valspodar necessitated dose reductions of DP, with neutropenia being dose limiting. Valspodar PK interactions were observed with paclitaxel but not L-DOX.

Keywords: doxorubicin; liposome; multidrug resistance; paclitaxel; valspodar.
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