PDCT-04. SAFETY AND EFFICACY OF INTRAVENTRICULAR 131I-LABELED MONOCLONAL ANTIBODY 8H9 TARGETING THE SURFACE GLYCOPROTEIN B7-H3 IN PATIENTS WITH CNS/LM DISEASE

Abstract

Tumors metastasizing to the central nervous system (CNS) are associated with significant mortality. Intraventricular 131I-labeled monoclonal antibody targeting tumor associated antigens may eradicate micrometastases. We tested the toxicity and dosimetry of intraventricular 131I-labeled monoclonal antibody 8H9 targeting surface glycoprotein B7-H3 in patients with CNS disease on a phase I/II trial. Adequate CSF flow was determined by 111Indium-DTPA cisternography through intraventricular devices. 131 patients [median age 5.4 years (1.2- 53.6 years)] with primary CNS malignancies or malignancies metastatic to the CNS received 383 injections involving 2 mCi 124I- or 131I-8H9 as a tracer for nuclear imaging and a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9. Pharmacokinetics were studied by serial CSF and blood samplings over 48 hours. Dosimetry was based on pharmacokinetics and ROI analyses on serial scans. Toxicity was defined by CTCAE v3.0. Injections were repeated after 1 month in the absence of serious adverse event or progressive disease. Tumor response was determined by clinical, radiographic, cytologic criteria; overall survival was noted. Injections were well tolerated and routinely administered in the outpatient setting. Rare self-limited adverse events included grade 1 or 2 fever, headache, vomiting, biochemical elevations in AST or ALT [1 injection with grade 3 ALT elevation (dose level 3)]. Although not a dose limiting toxicity, myelosuppression was observed in patients who had received craniospinal radiation. Mean absorbed CSF dose was 104.9 cGy/mCi and 2.6 cGy/mCi to the blood. Of 93 patients treated for metastatic CNS neuroblastoma, an improved overall survival was noted compared to median survival reported with conventional therapies. Intraventricular 131I-8H9 is safe, has favorable CSF and blood dosimetry, and has clinical utility in the treatment of B7-H3 -positive CNS cancers.