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Phase I Clinical Trial of Intrathecal Topotecan in Patients With Neoplastic Meningitis

From the Texas Children’s Cancer Center/Baylor College of Medicine; and M.D. Anderson Cancer Center, Houston, TX; St. Jude Children’s Research Hospital, Memphis, TN; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Children’s Hospital and Medical Center, Seattle, WA; Children’s Hospital National Medical Center, Washington, DC; and the University of California, San Francisco, San Francisco, CA.

Address reprint requests to Susan M. Blaney, MD, Texas Children’s Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; email: sblaney{at}txccc.org.

Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis.

Patients and Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs.

Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response.

Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress.

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