Abstract Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical
Background: ELA026 is a fully human, monoclonal immunoglobulin G1 (IgG1) signal regulatory protein (SIRP)-directed antibody. SIRPs are cell surface proteins expressed on myeloid cells and T cells which are implicated in driving pathology in hemophagocytic lymphohistiocytosis (HLH).
Preclinical studies with ELA026 have demonstrated its ability to induce both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) of human monocytes and ADCC of human SIRP+ activated T lymphocytes. Administration of ELA026 to non-human primates causes a rapid, potent, and reversible reduction of circulating monocyte, granulocyte, and T cell counts. Following washout of ELA026, reconstitution of all affected cell types to predose levels is observed within hours/days, providing evidence that bone marrow hematopoiesis is unaffected. By reducing myeloid-derived antigen presenting cells (monocytes/macrophages) and interferon gamma-producing CD8+ T cells, ELA026 has the potential to halt the initiation and progression of the inflammatory process in sHLH.
This ongoing trial in secondary HLH has now been amended in the USA with planned amendment in Europe to include CAR-T-related HLH, an emerging clinical problem, and to lower the age for inclusion to 6 years.
Aims: Primary objectives are to evaluate the safety of ELA026 and identify a dose for Phase 2/3 testing. Secondary objectives are to determine the efficacy (best response by 4 weeks), characterize the pharmacokinetic (PK) profile and pharmacodynamic (PD) effects, and assess the immunogenicity of ELA026. Efficacy criteria were based on modified HLH-2004 criteria, similar to what were used in a prior pivotal trial for primary HLH (Locatelli F, et al. N Engl J Med. 2020;382(19):1811-22).
Methods: This Phase 1b, open-label, single-arm, multicenter study is investigating the safety, efficacy, PK, and PD of ELA026 following multiple intravenous (IV) doses administered in up to 24 pediatric or adult patients who are treatment naïve or who have relapsed/refractory sHLH regardless of underlying trigger (NCT05416307). Patients must be at least 6 years of age at the time of sHLH diagnosis. Patients are ineligible if they have received hemopoietic stem cell transplantation within 100 days prior to the first dose of ELA026.
This study utilizes an adaptive 3 + 3 design, with an intra-patient dose-escalation phase and a fixed-dose phase. In Cohort 1, after a patient has received 3 daily IV doses at a pharmacologically active dose level, the dose will be escalated until that patient (1) demonstrates monocyte reduction and ferritin biomarker evidence of improvement, (2) develops dose-limiting toxicity; or (3) receives the maximum allowable dose. Biomarker evidence of improvement is defined as monocyte depletion ≥75% from baseline to the end of the dosing interval and serum ferritin reduction ≥20% compared to baseline, if baseline levels are ≥3000 ng/mL, or, if baseline levels are <3000 ng/mL, any decrease in ferritin levels accompanied by improvement in fasting triglyceride levels, coagulation parameters, and/or sIL2 receptor levels compared to baseline.
At the completion of Cohort 1, a Data Monitoring Committee will determine the optimal fixed dose for Cohort 2 to confirm its safety and efficacy. Optional Cohorts 3 and 4 will explore less frequent dosing schedules. Subcutaneous administration also may be evaluated. Total treatment duration is 12 weeks.
Figure
Results: At the completion of Phase 1b, an appropriate dose, route of administration, and dose interval will be determined for a Phase 2/3 trial.
Keywords: Macrophage Activation Syndrome (MAS), EBV, Hemophagocytic Lymphohistiocytosis (HLH)