Journal of Clinical Oncology, Vol 10, 143-148, Copyright © 1992 by American Society of Clinical Oncology
Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies
SL Berg, FM Balis, S Zimm, RF Murphy, J Holcenberg, J Sato, G Reaman, P Steinherz, A Gillespie and K Doherty
Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
PURPOSE: Because there is a compelling need to develop new agents for
intrathecal use, we investigated the safety, efficacy, and CSF
pharmacokinetics of diaziquone (AZQ) following intrathecal administration
in patients with refractory meningeal malignancies. PATIENTS AND METHODS:
Thirty-nine patients received 45 courses of intrathecal AZQ. Two schedules
were studied; twice-weekly administration of a 1- or 2-mg dose and
"concentration times time" (C x T) administration of 0.5 mg every 6 hours
for three doses, administered once weekly. RESULTS: Dose-limiting toxicity
consisting of headache, nausea, or vomiting occurred in only three patients
and only at the 2- mg, twice weekly dose. The schedules of 1 mg
twice-weekly and 0.5 mg every 6 hours for three doses were well tolerated.
Thirty-seven courses were assessable for response. The overall response
rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses (38%)
and partial responses (PRs) occurred in nine of 37 courses (24%). Among
patients with meningeal leukemia, CRs were observed in 11 of 26 courses
(42%) and PRs in nine of 26 courses (35%). There was no difference in
response rate related to dose or schedule. The pharmacokinetic behavior of
intrathecally administered AZQ was characterized by biexponential
disappearance from ventricular CSF, with mean half-lives of 18.2 and 78.6
minutes. The mean clearance rate was 0.37 mL/min. CONCLUSION: Intrathecal
AZQ is safe, well tolerated, and highly active against refractory meningeal
malignancies.
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