Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.
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.
Bernardi
Ronald J
RJ
Texas Children's Hospital, Baylor College of Medicine, Houston, TX, 77030, USA.
Bomgaars
Lisa
L
Fox
Elizabeth
E
Balis
Frank M
FM
Egorin
Merrill J
MJ
Lagattuta
Theodore F
TF
Aikin
Alberta
A
Whitcomb
Patricia
P
Renbarger
Jamie
J
Lieberman
Frank S
FS
Berg
Stacey L
SL
Blaney
Susan M
SM
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
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000093542:Gemcitabine