A Phase 1 Dose Escalation Study Of Tb-403 In Pediatric Relapsed Or Refractory Medulloblastoma, Neuroblastoma, Ewing Sarcoma, Or Alveolar Rhabdomyosarcoma.

Abstract Background: TB-403 is a monoclonal antibody directed against placental growth factor (PlGF). In medulloblastoma (MB), PlGF promotes tumor progression by activating downstream pathways that promote cell proliferation, cell survival and metastasis. Elevation in PlGF expression, or its receptor neuropilin 1 (Nrp1), is found in tumor samples in a variety of small round blue cell tumors, including MB, neuroblastoma (NB), Ewing sarcoma (ES), and alveolar rhabdomyosarcoma (ARMS). Additionally, pre-clinical studies have shown that TB-403 inhibits primary tumor growth and spinal metastasis in mice with orthotopic MB grafts, and that mice treated with TB-403 survive significantly longer than untreated animals. PlGF is expressed across human MB subtypes, and high expression of the PlGF receptor Nrp1 correlates with poor overall survival. Objective: Evaluate the safety and maximum tolerated dose (MTD) of TB-403 administered as a single agent during cycle 1 of therapy in children with relapsed or refractory MB, NB, ES or ARMS and measure pharmacokinetics (PK). Methods: A phase 1, open-label, multicenter, dose escalation study of TB-403 in pediatric subjects with relapsed or refractory MB, NB, ES or ARMS. The study involved 4 dose levels (20 mg/kg, 50 mg/kg, 100 mg/kg, 175 mg/kg) using a 3+3 dose escalation scheme. A treatment cycle was 28 days. Subjects received 2 doses of TB-403 (on Days 1 and 15) per cycle unless they experienced toxicity. After cycle 1, temozolomide or etoposide could be added at the investigator's discretion. The primary objective was to determine the MTD of TB-403 monotherapy during a dose-limiting toxicity (DLT) assessment period or 1 cycle. The secondary and exploratory objectives included PK and plasma biomarkers respectively of TB-403 administered as a single agent or in combination with chemotherapy. For subjects who continued TB-403 treatment after the DLT assessment period, we evaluated preliminary efficacy. Results: Fifteen subjects enrolled; 3 to DL1 (Dose Level 1), 3 to DL2, 6 to DL3 and 3 to DL4. All subjects received 2 doses of TB-403 in cycle 1. Five serious treatment emergent adverse events were reported in 3 patients. None of these were considered serious unexpected adverse drug reactions. Conclusion: TB-403 was shown to be safe at all dose levels evaluated without reaching a MTD in pediatric subjects. Initial results look encouraging for incurable relapsed disease. Citation Format: Giselle L. Saulnier Sholler, Dan G. Duda, Genevieve Bergendahl, David Ebb, Matija Snuderl, Theodore W. Laetsch, Jennifer Michlitsch, Derek Hanson, Michael Isakoff, Kevin Bielamowicz, Jacquline Kraveka, Peter Carmeliet, Andy De Deene, Rakesh K. Jain. A phase 1 dose escalation study of TB-403 in pediatric relapsed or refractory medulloblastoma, neuroblastoma, Ewing sarcoma, or alveolar rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT015.