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

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.