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Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis

  • Clinical Trial Report
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Abstract

Purpose

A phase I study of intrathecal (IT) gemcitabine was performed to define a safe dose and characterize the toxicity profile and CSF pharmacokinetics of gemcitabine and its major metabolite 2′,2′-difluoro-deoxyuridine (dFdU) in patients 3 years of age and older with neoplastic meningitis.

Experimental design

Gemcitabine was administered via Ommaya reservoir or lumbar puncture at three dose levels: 5 mg weekly, 5 mg twice-weekly, and 10 mg twice-weekly using a standard phase I dose escalation design. Serial CSF samples were obtained for pharmacokinetic studies in seven patients with Ommaya reservoirs. Serial blood samples for pharmacokinetic studies were also obtained from three patients.

Results

Ten patients were enrolled in this study. Significant neurological toxicities occurred in two patients including myelitis in a patient at the 5 mg twice-weekly dose level and somnolence in a patient at the 10 mg twice-weekly dose level. No complete responses were seen; however, three patients had stable disease. Gemcitabine was rapidly eliminated from the CSF with a terminal half-life of 61 ± 50 min. No gemcitabine or dFdU was detected in plasma.

Conclusions

IT gemcitabine was associated with significant neurotoxicity; therefore, its further development for IT use is not recommended.

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Acknowledgments

Eli Lilly and Company financially supported this research by providing a research grant.

Author information

Author notes

  1. Jamie Renbarger

    Present address: Riley Children’s Hospital, Indianapolis, IN, USA

Authors and Affiliations

  1. Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, 77030, USA

    Ronald J. Bernardi, Lisa Bomgaars, Jamie Renbarger, Stacey L. Berg & Susan M. Blaney

  2. The Pediatric Oncology Branch, National Cancer Institute, NIH Bethesda, Bethesda, MD, 20892, USA

    Elizabeth Fox, Frank M. Balis, Alberta Aikin & Patricia Whitcomb

  3. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin & Theodore F. Lagattuta

  4. Departments of Medicine and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Merrill J. Egorin & Frank S. Lieberman

  5. Texas Children’s Cancer Center, 6621 Fannin, MC 1410.00, Houston, TX, 77030, USA

    Susan M. Blaney

Authors
  1. Ronald J. Bernardi
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Corresponding author

Correspondence to Susan M. Blaney.

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Bernardi, R.J., Bomgaars, L., Fox, E. et al. Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis. Cancer Chemother Pharmacol 62, 355–361 (2008). https://doi.org/10.1007/s00280-007-0601-x

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  • DOI: https://doi.org/10.1007/s00280-007-0601-x

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