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Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis

From the Texas Children's Cancer Center/Baylor College of Medicine, Houston; University of Texas Southwestern Medical School, Dallas TX; Children's Hospital and Medical Center, Seattle, WA; Children's Hospital Los Angeles, Los Angeles; Stanford University Medical Center, Stanford, CA

Address reprint requests to Lisa Bomgaars, MD, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; e-mail: lbomgaars{at}txccc.org

PURPOSE: We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children 3 years of age with advanced meningeal malignancies.

PATIENTS AND METHODS: Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients.

RESULTS: Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response.

CONCLUSION: The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Supported by DepoTech Corporation/Skye Pharma Inc, San Diego, CA.

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

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