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A phase I, pharmacokinetic and pharmacodynamic dose escalation trial of weekly paclitaxel with interferon-α2b in patients with solid tumors

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Abstract

Purpose: Paclitaxel and interferon have demonstrated anti-angiogenic activity in vitro and in vivo. The toxicity, pharmacokinetics, and pharmacodynamics of paclitaxel with interferon-α2b (IFN-α2b) were assessed in patients with solid tumors to assess the feasibility of this novel anti-angiogenic regimen. Methods: IFN-α2b (1 million units) was administered twice daily by subcutaneous injection. Paclitaxel was given weekly over 1 h starting at 30 mg/m2 and increased to 50 mg/m2. Cycles were repeated every 4 weeks. Results: Nineteen patients with a variety of solid tumors were enrolled. Dose-limiting toxicity in cycle 1 was observed at 50 mg/m2. Eleven patients were treated at 40 mg/m2 with no undue toxicity. Pharmacokinetic parameter comparison studies were completed in 11 patients who received days 1 and 29 paclitaxel. Mean paclitaxel clearance and area under the curve (0–∞) were not statistically different from days 1 to 29. There was a 50% increase in the average Cmax from days 1 to 29. There was also a 73% decrease of matrix metalloproteinase-9 (MMP-9) levels in these 11 patients from days 1 to 29 (p < 0.0005). All three patients with cutaneous angiosarcomas experienced clinically meaningful remissions. In addition, minor responses were observed in one patient with heavily pretreated ovarian cancer and another with adrenocortical carcinoma. Conclusion: This trial details the inability to dose escalate to the maximum tolerated dose of weekly paclitaxel when combined with low-dose interferon. However, this low-dose regimen caused a significant decrease in MMP-9 and demonstrated anti-cancer activity in cutaneous angiosarcomas.

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Acknowledgements

This study was supported by the Walther Cancer Institute, Bristol Myers Squibb, Schering Plough, Indiana University General Clinical Research Center at Indiana University, School of Medicine, M01RR00750.

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Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Indiana University, 535 Barnhill Drive, Rm 473, Indianapolis, IN, 46202, USA

    Bryan Schneider, Christy Yoder, Karen Fife, Anne Foster, Leslie Rosenberg & Christopher Sweeney

  2. Department of Pharmacy Practice, Purdue University, West Lafayette, IN, USA

    Anna Fukunaga

  3. College of Pharmacy, University of Iowa, Iowa City, IA, USA

    Daryl Murry

  4. Walther Cancer Institute, Indianapolis, IN, USA

    Stephanie Kelich

  5. Division of Biostatistics, Department of Medicine, Indiana University, Indianapolis, IN, USA

    Lang Li

Authors
  1. Bryan Schneider
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  2. Anna Fukunaga
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  9. Lang Li
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  10. Christopher Sweeney
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Correspondence to Christopher Sweeney.

Additional information

Presented in part at the 2003 Annual Meeting of American Association for Cancer Research.

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Schneider, B., Fukunaga, A., Murry, D. et al. A phase I, pharmacokinetic and pharmacodynamic dose escalation trial of weekly paclitaxel with interferon-α2b in patients with solid tumors. Cancer Chemother Pharmacol 59, 261–268 (2007). https://doi.org/10.1007/s00280-006-0264-z

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  • DOI: https://doi.org/10.1007/s00280-006-0264-z

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