Phase 1 study of intraventricular 131I-omburtamab targeting B7H3 (CD276)-expressing CNS malignancies

Kim Kramer, Neeta Pandit-Taskar, Brian H Kushner, Pat Zanzonico, John L Humm, Ursula Tomlinson, Maria Donzelli, Suzanne L Wolden, Sophia Haque, Ira Dunkel, Mark M Souweidane, Jeffrey P Greenfield, Satish Tickoo, Jason S Lewis, Serge K Lyashchenko, Jorge A Carrasquillo, Bae Chu, Christopher Horan, Steven M Larson, Nai-Kong V Cheung, Shakeel Modak, Kim Kramer, Neeta Pandit-Taskar, Brian H Kushner, Pat Zanzonico, John L Humm, Ursula Tomlinson, Maria Donzelli, Suzanne L Wolden, Sophia Haque, Ira Dunkel, Mark M Souweidane, Jeffrey P Greenfield, Satish Tickoo, Jason S Lewis, Serge K Lyashchenko, Jorge A Carrasquillo, Bae Chu, Christopher Horan, Steven M Larson, Nai-Kong V Cheung, Shakeel Modak

Abstract

Background: The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies.

Patients and methods: We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease.

Results: Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included < grade 4 self-limited headache, vomiting or fever, and biochemical abnormalities. Grade 3/4 thrombocytopenia was the most common hematologic toxicity. Recommended phase 2 dose was 1850 MBq/injection. The median radiation dose to the CSF and blood by sampling was 1.01 and 0.04 mGy/MBq, respectively, showing a consistently high therapeutic advantage for CSF. Major organ exposure was well below maximum tolerated levels. In patients developing antidrug antibodies, blood clearance, and therefore therapeutic index, was significantly increased. In patients receiving cRIT for neuroblastoma, survival was markedly increased (median PFS 7.5 years) compared to historical data.

Conclusions: cRIT with 131I-omburtamab is safe, has favorable dosimetry and may have a therapeutic benefit as adjuvant therapy for B7-H3-expressing leptomeningeal metastases.

Trial registration: clinicaltrials.gov NCT00089245, August 5, 2004.

Keywords: B7H3; CNS metastases; CNS tumors; Omburtamab; Radioimmunotherapy.

Conflict of interest statement

MSK has institutional financial interests related to this research in the form of intellectual property rights and equity interests in Y-Mabs, the company licensing the intellectual property from MSK. N.K. Cheung (NKC) reports receiving commercial research grants from Y-Mabs Therapeutics and Abpro-Labs Inc.; holding ownership interest/equity in Y-Mabs Therapeutics Inc. and Abpro-Labs and owning stock options in Eureka Therapeutics. NKC and KK are inventors and owners of issued patents licensed by MSK to YMabs Therapeutics. KK holds ownership interest/equity in Y-Mabs Therapeutics Inc. NKC is a consultant/advisory board member for Abpro-Labs and Eureka Therapeutics. SM Larson (SML) reports: receiving commercial research grants from Genentech, Wilex, Telic and Regeneron; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc.; holding stock in Imaginab. SML is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samos Inc. and Elucida Oncology Inc. SML is or has been a consultant to Cynvec, Lilly, Prescient, Advanced Innovative Partners, Gershon Lehrman, Progenics and Janssen Pharmaceuticals. Jorge A Carasquillo reports other support from Y-Mabs Therapeutics. Mark M Souweidane reports other support from Aesculap. Kim Kramer, Serge Lyashchenko, and Shakeel Modak are consultants to Y-Mabs Therapeutics Inc. Shakeel Modak is a consultant to Illumina. Omburtamab was licensed to Y-Mabs Therapeutics by MSK in 2015. This clinical trial was not sponsored by Y-Mabs Therapeutics.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
124-I-omburtamab whole-body positron emission tomography (PET) scans obtained approximately 4 h, 24 h and 48 h following a single injection of 74 MBq intraventricular 124-I-omburtamab, demonstrating activity throughout the ventricles, the sac and over the convexities

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