Pb2328: trial in progress: athena-1 – a phase 1 study to assess safety and tolerability of regn5837 in combination with odronextamab in patients with relapsed/refractory aggressive b-cell non-hodgkin lymphoma

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Many patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) are unable to tolerate, access, or benefit from intensive chemo-therapeutic approaches or cellular therapies and will invariably relapse; therefore, novel approaches are urgently required. Odronextamab (REGN1979) is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that elicits T-cell-mediated cytotoxicity of malignant B cells. In the ELM-2 Phase 2 study (NCT03888105), odronextamab monotherapy has shown a manageable safety profile with encouraging efficacy in heavily pre-treated patients with R/R B-NHL (Kim W-S, et al. Blood. 2022;140(Suppl 1):1070–1; Kim TM, et al. Blood. 2022;140(Suppl 1):2280–2). REGN5837 is a hinge-stabilized, human CD28×CD22 IgG4-based bispecific antibody that provides a co-stimulatory signal (signal 2). When combined with odronextamab (signal 1), REGN5837 improved anti-tumor efficacy and survival in in vivo diffuse large B-cell lymphoma tumor models via enhanced T-cell expansion (Wei J, et al. Sci Transl Med. 2022;14(670):eabn1082). We hypothesize that combining REGN5837 with odronextamab may deepen and extend anti-tumor activity in patients with aggressive lymphoma. Aims: The primary objective of this study is to assess the safety and tolerability of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. Methods: ATHENA-1 (NCT05685173) is a Phase 1, open-label, first-in-human study of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. During induction, odronextamab and REGN5837 will be administered weekly over 21-day cycles. To mitigate potential cytokine release syndrome events, odronextamab will be introduced with step-up dosing as a monotherapy, followed by introduction of REGN5837 on Cycle 2 Day 15 with step-up dosing. Maintenance will consist of 28-day cycles (odronextamab and REGN5837 administration on Day 1, 15). Patients who achieve a sustained complete response (≥9 months) will have study drug(s) administration changed to once every 4 weeks. Patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status ≤1, with adequate organ function, and have CD20+ aggressive B-NHL that progressed after ≥2 lines of systemic therapy containing at least an anti-CD20 antibody and an alkylating agent, with or without prior chimeric antigen receptor T cell therapy. Exclusion criteria include prior allogeneic stem cell transplant, organ transplant, or CD20xCD3 bispecific antibodies, or mantle cell lymphoma or central nervous system lymphoma. All patients will provide informed consent. Primary endpoints are incidence of dose-limiting toxicities and the incidence and severity of treatment-emergent adverse events. Secondary endpoints include pharmacokinetics of odronextamab and REGN5837, anti-drug antibody incidence, objective response rate, complete response rate, duration of response, progression-free survival, and overall survival. Results: Enrollment is planned to open in early 2023. Summary/Conclusion: This Phase 1, open-label, first-in-human study will assess the safety and tolerability of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. Keywords: Monoclonal antibody, Phase I, Bispecific, Non-Hodgkin’s lymphoma