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A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors

Cancer Chemotherapy and Pharmacology volume 57, pages 671–677 (2006)Cite this article

Abstract

Purpose: The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans. Methods: The starting dose was pralatrexate 40 mg/m2 intravenously and probenecid 70 mg/m2 intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1. Results: Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m2 and probenecid 233 mg/m2. Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen. Conclusion: For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m2 and probenecid 140 mg/m2. Vitamin B12 and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.

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Affiliations

  1. Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Matthew G. Fury, Lee M. Krug, Christopher G. Azzoli, Mark G. Kris & Naiyer A. Rizvi

  2. Gastrointestinal Oncology Division, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Sunil Sharma & Nancy Kemeny

  3. Program of Molecular Pharmacology and Experimental Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA

    Nian Wu

Authors
  1. Matthew G. Fury
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  2. Lee M. Krug
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  3. Christopher G. Azzoli
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  4. Sunil Sharma
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  5. Nancy Kemeny
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  6. Nian Wu
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  7. Mark G. Kris
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  8. Naiyer A. Rizvi
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Correspondence to Naiyer A. Rizvi.

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Fury, M.G., Krug, L.M., Azzoli, C.G. et al. A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors. Cancer Chemother Pharmacol 57, 671–677 (2006). https://doi.org/10.1007/s00280-005-0080-x

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  • DOI: https://doi.org/10.1007/s00280-005-0080-x

Keywords

  • Phase I
  • Pralatrexate
  • Probenecid
  • Solid tumors