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Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial

From the Texas Children's Cancer Center/Department of Pediatrics, Baylor College of Medicine, Houston, TX; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Mayo Clinic, Rochester, MN; St. Jude Children's Research Hospital, Memphis, TN; Children's Hospital and Medical Center, Seattle, WA; Children's Hospital National Medical Center, Washington, DC; M.D. Anderson Cancer Center, Houston, TX; current address (R.H.): Department of Pediatrics, University of New Mexico, Albuquerque, NM; current address (P.C.A.): Children's Hospital Philadelphia, Philadelphia, PA; current address (K.J.): Mayo Clinic, Jacksonville, FL.

Address reprint requests to Susan M. Blaney, MD, Texas Children's Cancer Center, 6621 Fannin St, CC 1410 00, Houston, TX 77030-2399; e-mail: sblaney{at}txccc.org

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.

Supported by grant MO1RR00188, General Clinical Research Center, National Center for Research Resources, National Institutes of Health, Bethesda, MD, and Asta Medica, Frankfurt, Germany.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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