Clinical Cancer Research CTRC-AACR San Antonio Breast Cancer Symposium Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
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Clinical Cancer Research Vol. 9, 3589-3597, September 1, 2003
© 2003 American Association for Cancer Research

Clinical Trials

Phase I Study of Docosahexaenoic Acid-Paclitaxel

a Taxane-Fatty Acid Conjugate with a Unique Pharmacology and Toxicity Profile1

Antonio C. Wolff2, Ross C. Donehower, M. Katherine Carducci, Michael A. Carducci, Julie R. Brahmer, Yelena Zabelina, Matthews O. Bradley, Forrest H. Anthony, Charles S. Swindell, Philip A. Witman, Nigel L. Webb and Sharyn D. Baker

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and The Johns Hopkins University School of Medicine, Baltimore, Maryland, 21230-1000 [A. C. W., R. C. D., M. K. C., M. A. C., J. R. B., Y. Z., S. D. B.], and Protarga, Inc., King of Prussia, Pennsylvania 19406 [M. O. B., F. H. A., C. S. S., P. A. W., N. L. W.]

Purpose: Docosahexaenoic acid (DHA)-paclitaxel, a novel conjugate formed by covalently linking the natural fatty acid DHA to paclitaxel, was designed as a prodrug targeting intratumoral activation. This Phase I trial examined its toxicity and pharmacokinetics (PKs).

Experimental Design: Patients with advanced refractory solid tumors received a 2-h i.v. infusion of DHA-paclitaxel every 3 weeks. Plasma and urine samples were obtained to characterize the pharmacological profile of DHA-paclitaxel and paclitaxel.

Results: Twenty-four patients received 78 cycles of DHA-paclitaxel over five dose levels (200–1100 mg/m2). Median number of cycles was 2 (range, 1–8). Myelosuppression was the principal toxicity observed (grade 3/4 neutropenia in 21%/53% of courses at 1100 mg/m2); during cycle 1, febrile neutropenia occurred in 1 of 9 patients treated at 1100 mg/m2. Other grade 3 toxicities were infrequent. No patients developed alopecia, peripheral neuropathy > grade 1, or musculoskeletal toxicity > grade 1. At 1100 mg/m2, DHA-paclitaxel had a mean (CV%) volume of distribution of 7.5 (64) liters, ß half-life of 112 (56) h, and clearance of 0.11 (30) liters/h. Paclitaxel PK parameters at 1100 mg/m2 were: Cmax, 282 (46) ng/ml; AUC, 10,705 (60) ng/ml x h; and terminal half-life, 85 (101) h. Paclitaxel plasma exposure represented <=0.06% of DHA-paclitaxel exposure. Paclitaxel AUC was correlated with neutropenia. One partial response was observed.

Conclusions: The starting dose recommended for subsequent studies is 1100 mg/m2. DHA-paclitaxel dramatically alters the PK profile of derived paclitaxel compared with values observed after a 3-h infusion of paclitaxel (175 mg/m2). In addition, its favorable toxicity profile offers potential advantages over existing taxanes.




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Copyright © 2003 by the American Association for Cancer Research.