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Phase I Study of Targeted Radioimmunotherapy for Leptomeningeal Cancers Using Intra-Ommaya 131-I-3F8

Kim Kramer, John L. Humm, Mark M. Souweidane, Pat B. Zanzonico, Ira J. Dunkel, William L. Gerald, Yasmin Khakoo, Samuel D. Yeh, Henry W. Yeung, Ronald D. Finn, Suzanne L. Wolden, Steven M. Larson, Nai-Kong V. Cheung

From the Departments of Pediatrics, Nuclear Medicine, Neurosurgery, Pathology, and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Kim Kramer, MD, Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, 1275 York Ave, Box 429, New York, NY 10021; e-mail: kramerk{at}mskcc.org

Purpose Tumors metastasizing to the CNS and leptomeninges (LM) are associated with significant mortality. We tested the toxicity, pharmacokinetics, and dosimetry of intraventricular iodine-131–labeled monoclonal antibody 3F8 (¹³¹I-3F8) targeting GD2-positive CNS/LM disease in a phase I clinical trial.

Patients and Methods Adequate CSF flow was determined by pretreatment indium-111-DTPA studies. Fifteen patients received a tracer (1 to 2 mCi) and therapeutic injection (10 to 20 mCi) of intra-Ommaya ¹³¹I-3F8. ¹³¹I-3F8 pharmacokinetics were studied by serial CSF and blood samplings. Dosimetry was based on pharmacokinetics and region of interest (ROI) analyses on whole-body gamma camera scans. Tumor response was determined by clinical, radiographic, and cytologic criteria.

Results Total absorbed CSF dose was 1.12 to 13.00 Gy by sampling and 1.00 to 13.70 Gy by ROI data. Average dosimetry ratio (Gy/mCi) of the therapy/tracer administration was 0.88 (± 0.58) and 1.08 (± 0.66) based on CSF pharmacokinetics and ROI analysis, respectively. CSF half-life by sampling was 3 to 12.9 hours. Toxicities included self-limited headache, fever, and vomiting. Dose-limiting toxicity was reached at the 20-mCi dose, when transient elevations in intracranial pressure and chemical meningitis were seen. Three of 13 assessable patients achieved objective radiographic and/or cytologic responses. No late toxicities have been seen in two patients who remain in remission off therapy for more than 3.5 years.

Conclusion Intra-Ommaya ¹³¹I-3F8 was generally well tolerated; the maximum-tolerated dose was 10 mCi. A high CSF-to-blood ratio was achieved. Tracer studies reliably predicted the therapeutic dose to the CSF. Radioimmunoconjugates targeting GD2 may have clinical utility in the treatment of CNS/LM malignancies.

Supported by National Cancer Institute Grant No. CA72868, the Robert Steel Foundation, Catie Hoch Foundation, Katie's Find A Cure Fund, Pediatric Cancer Foundation, and The Leptomeningeal Research Fund.

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

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