title: Phase I/II trial and pharmacokinetics of intrathecal diaziquone in refractory meningeal malignancies.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Intrathecal AZQ is safe, well tolerated, and highly active against refractory meningeal malignancies.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: S
authors.initials: S
authors.lastname: Zimm
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Holcenberg
authors.forename: J
authors.initials: J
authors.lastname: Sato
authors.forename: G
authors.initials: G
authors.lastname: Reaman
authors.forename: P
authors.initials: P
authors.lastname: Steinherz
authors.forename: A
authors.initials: A
authors.lastname: Gillespie
authors.forename: K
authors.initials: K
authors.lastname: Doherty
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001388:Aziridines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016227:Benzoquinones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000556:secondary; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D016227:Benzoquinones; C029108:diaziquone