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

Cancer Chemother Pharmacol. 2008 Jul;62(2):355-61. doi: 10.1007/s00280-007-0601-x. Epub 2007 Oct 2.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antimetabolites, Antineoplastic* / administration & dosage
  • Antimetabolites, Antineoplastic* / adverse effects
  • Antimetabolites, Antineoplastic* / pharmacokinetics
  • Antimetabolites, Antineoplastic* / therapeutic use
  • Child
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / adverse effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacokinetics
  • Deoxycytidine / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Female
  • Gemcitabine
  • Humans
  • Injections, Spinal
  • Male
  • Meningeal Neoplasms / blood
  • Meningeal Neoplasms / cerebrospinal fluid
  • Meningeal Neoplasms / drug therapy*
  • Meningeal Neoplasms / secondary
  • Middle Aged

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • Gemcitabine