title: Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Bernardi
authors.forename: Lisa
authors.initials: L
authors.lastname: Bomgaars
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Lagattuta
authors.forename: Alberta
authors.initials: A
authors.lastname: Aikin
authors.forename: Patricia
authors.initials: P
authors.lastname: Whitcomb
authors.forename: Jamie
authors.initials: J
authors.lastname: Renbarger
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008577:Meningeal Neoplasms / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine