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

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.

• Authors: Ronald J Bernardi, Lisa Bomgaars, Elizabeth Fox, Frank M Balis, Merrill J Egorin, Theodore F Lagattuta, Alberta Aikin, Patricia Whitcomb, Jamie Renbarger, Frank S Lieberman, Stacey L Berg, Susan M Blaney
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 62 Issue 2 Pg. 355-61 (Jul 2008) ISSN: 0344-5704 [Print] Germany
• PMID: 17909804 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Deoxycytidine
• Gemcitabine

Topics

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