Phase I study of targeted radioimmunotherapy for leptomeningeal cancers using intra-Ommaya 131-I-3F8.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Kramer
Kim
K
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. kramerk@mskcc.org
Humm
John L
JL
Souweidane
Mark M
MM
Zanzonico
Pat B
PB
Dunkel
Ira J
IJ
Gerald
William L
WL
Khakoo
Yasmin
Y
Yeh
Samuel D
SD
Yeung
Henry W
HW
Finn
Ronald D
RD
Wolden
Suzanne L
SL
Larson
Steven M
SM
Cheung
Nai-Kong V
NK
D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology* / Q000493:pharmacokinetics; D058846:Antibodies, Monoclonal, Murine-Derived; D002528:Cerebellar Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000276:immunology*; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics; D007223:Infant; D007457:Iodine Radioisotopes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008527:Medulloblastoma / Q000000981:diagnostic imaging / Q000276:immunology / Q000532:radiotherapy; D008577:Meningeal Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009447:Neuroblastoma / Q000000981:diagnostic imaging / Q000276:immunology / Q000532:radiotherapy; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging
C419226:3F8 antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; D000922:Immunotoxins; D007457:Iodine Radioisotopes