Abstract
Purpose
To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of weekly docosahexaenoic acid-paclitaxel (DHA-paclitaxel), a taxane fatty acid conjugate.
Experimental design
Docosahexaenoic acid-paclitaxel was administered by 2-hour i.v. infusion weekly for three out of four weeks. DHA-paclitaxel 200 mg/m2 was dose escalated by 100 mg/m2 per cohort to 600 mg/m2. Blood samples for pharmacokinetics of DHA-paclitaxel and paclitaxel derived from DHA-paclitaxel were collected.
Results
Twenty-one patients received 42 cycles of treatment over five dose levels. Grade 3/4 neutropenia occurred in five patients but was not dose limiting. Grade 3 hyperbilirubinemia, a DLT, and grade 1 sensory neuropathy occurred at the highest dose level. PK analyses demonstrated dose proportional C max and AUC0−24. Limited accumulation of DHA-paclitaxel or paclitaxel occurred with weekly treatment. Increased DHA-paclitaxel and paclitaxel AUC0−24 were associated with increased neutropenia. Of the 19 patients evaluable for response, three patients with esophageal, melanoma and colon carcinoma had stable disease for 11, 16, and 17 weeks, respectively.
Conclusion
Docosahexaenoic acid-paclitaxel administered weekly to a maximum dose of 600 mg/m2 was well-tolerated. The slow release of paclitaxel from DHA-paclitaxel and the weekly schedule approximates continuous infusion paclitaxel which may be more active than every 3 week or weekly taxanes.
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Acknowledgments
We wish to thank the patients and their families for their participation in this study. We also thank the nurses, clinical research and regulatory coordinators at Siteman Cancer Center for their care of the patients on this study.
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Supported by The St Louis Men’s Group Against Cancer and Luitpold Pharmaceuticals, Inc.
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Fracasso, P.M., Picus, J., Wildi, J.D. et al. Phase 1 and pharmacokinetic study of weekly docosahexaenoic acid-paclitaxel, Taxoprexin®, in resistant solid tumor malignancies. Cancer Chemother Pharmacol 63, 451–458 (2009). https://doi.org/10.1007/s00280-008-0756-0
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DOI: https://doi.org/10.1007/s00280-008-0756-0