The surpass trial: a phase 2/3 registrational trial of ELA026 in subjects with treatment-Naïve secondary hemophagocytic lymphohistiocytosis

Abstract

Abstract Background/Significance: Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory condition where the immune system overreacts, attacking healthy tissues, and causing severe organ damage. It is most often triggered by malignancies (mHLH), infections, rheumatological diseases, or other predisposing conditions. Of these subtypes, mHLH is the deadliest with a mortality rate of approximately 50% at 8-weeks. ELA026 is a monoclonal antibody directed against signal regulatory protein-α/β1/γ that is designed to deplete the pathologically hyperactivated T cells and myeloid cells that fuel the clinical sequelae of this disease. In the phase 1b portion of ELA026-CP002 (NCT05416307), ELA026 demonstrated an encouraging safety profile and 100% survival rate at 8-weeks in treatment-naïve (TN)/early refractory mHLH patients. Study Design/Methods: SURPASS is an open-label, single-arm, multicenter, historical control registrational trial in adults (≥18 years) and pediatrics (≥6 years) with sHLH. Cohort A will enroll adults with TN mHLH diagnosed by HLH-2004 criteria (primary cohort; N=60 of which N=47 will be lymphoma-associated (LA)-HLH). Cohort B will enroll adults with TN sHLH diagnosed by HLH-2004 criteria not triggered by malignancy, adults with TN mHLH diagnosed by OHI index criteria but not meeting HLH-2004 diagnostic criteria, and ≥6 to 17 years old sHLH diagnosed by HLH-2004 criteria due to any trigger (exploratory cohort; N=30). The study will include a 12-week treatment period followed by a safety follow-up and assessment of long-term survival. Extended ELA026 treatment is permitted in patients deriving ongoing clinical benefits. The primary endpoint is overall survival (OS) at 8-weeks from diagnosis in subjects with TN LA-HLH who have received ELA026. Key secondary endpoints include additional measures of OS, HLH response, and safety. Exploratory endpoints include tumor response, biomarker response and frequency of HLH-related genes. This study will be conducted at approximately 35 sites globally. Enrollment is anticipated to begin in 2025. Study results will support the registration of ELA026 in sHLH.