Intrathecal mafosfamide: A preclinical pharmacology and phase I trial

Susan M. Blaney, Frank M. Balis, Stacey Berg, Carola A.S. Arndt, Richard Heideman, J. Russell Geyer, Roger Packer, Peter C. Adamson, Kurt Jaeckle, Renee Klenke, Alberta Aikin, Robert Murphy, Cynthia McCully, David G. Poplack

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Purpose: 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. Patients and 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 μmol/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 μmol/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. Conclusion: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Original languageEnglish (US)
Pages (from-to)1555-1563
Number of pages9
JournalJournal of Clinical Oncology
Volume23
Issue number7
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Blaney, S. M., Balis, F. M., Berg, S., Arndt, C. A. S., Heideman, R., Geyer, J. R., Packer, R., Adamson, P. C., Jaeckle, K., Klenke, R., Aikin, A., Murphy, R., McCully, C., & Poplack, D. G. (2005). Intrathecal mafosfamide: A preclinical pharmacology and phase I trial. Journal of Clinical Oncology, 23(7), 1555-1563. https://doi.org/10.1200/JCO.2005.06.053