title: Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.
abstract: OBJECTIVE
  Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials.
  
  
  METHODS
  In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs.
  
  
  RESULTS
  The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease.
  
  
  CONCLUSIONS
  The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.
authors.affiliation: Texas Children's Cancer Center, 6621 Fannin St, CC 1410 00, Houston, TX 77030-2399, USA. sblaney@txccc.org
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Stacey
authors.initials: S
authors.lastname: Berg
authors.forename: Carola A S
authors.initials: CA
authors.lastname: Arndt
authors.forename: Richard
authors.initials: R
authors.lastname: Heideman
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.forename: Peter C
authors.initials: PC
authors.lastname: Adamson
authors.forename: Kurt
authors.initials: K
authors.lastname: Jaeckle
authors.forename: Renee
authors.initials: R
authors.lastname: Klenke
authors.forename: Alberta
authors.initials: A
authors.lastname: Aikin
authors.forename: Robert
authors.initials: R
authors.lastname: Murphy
authors.forename: Cynthia
authors.initials: C
authors.lastname: McCully
authors.forename: David G
authors.initials: DG
authors.lastname: Poplack
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000633:toxicity; D005240:Feasibility Studies; D006801:Humans; D007278:Injections, Spinal; D008253:Macaca mulatta; D008577:Meningeal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008581:Meningitis / Q000188:drug therapy / Q000378:metabolism; D009369:Neoplasms; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C048341:mafosfamide; D003520:Cyclophosphamide