ALPHA3, a Pivotal Phase 2 Study of First-Line Consolidation with Cemacabtagene Ansegedleucel (Cema-Cel) in Patients with Large B-Cell Lymphoma and Minimal Residual Disease after Response to Standard Therapy

Introduction: R-CHOP is expected to cure approximately 60% of patients with large B-cell lymphoma (LBCL) as first-line (1L) therapy. In addition to ~10% of patients with LBCL refractory to 1L therapy (Coiffier B, et al. N Engl J Med 2002), approximately 30% of patients who achieve 1L treatment response relapse within 2 years (Maurer MJ, et al. J Clin Oncol 2014). Autologous chimeric antigen receptor (CAR) T cell therapies have changed the treatment paradigm of relapsed or refractory (R/R) disease in patients with early relapse (<12 mo after a complete response) and are considered a standard second-line treatment due to improved overall survival (OS; Westin J, et al. N Engl J Med 2023). Nevertheless, autologous CAR T cell therapies are often not an option because of aggressive disease biology at recurrence, patient comorbidities, patient barriers to accessing specialized centers administering these therapies, and/or manufacturing issues and delays; furthermore, many patients may require additional bridging or salvage chemotherapy prior to receiving autologous CAR T cell therapy. Therefore, outcomes may be improved by identifying those patients who achieve response after 1L treatment but have a high risk of relapse, and by rapidly administering an off-the-shelf CAR T cell therapy for remission consolidation. The presence of circulating tumor DNA–based minimal residual disease (MRD), as measured by the PhasED-Seq technology (PhasED-Seq), at the conclusion of 1L treatment has demonstrated promise as a highly prognostic indicator for relapse (Roschewski M, et al. Hematol Oncol 2023). Cema-cel is an immediately available, off-the-shelf, human leukocyte antigen–unmatched allogeneic CD19 CAR T cell product that utilizes Cellectis technologies. A phase 1 study of cema-cel in patients with R/R LBCL showed safety and efficacy comparable with that of autologous CAR T cell therapies (Locke FL, et al. Hematol Oncol 2023). Herein, we describe the design of the pivotal ALPHA3 (NCT06500273) phase 2 study of cema-cel, the first randomized, open‑label study to assess a CAR T cell therapy as a consolidation strategy in patients with detectable MRD measured by PhasED‑Seq after standard 1L immunochemotherapy.

Methods: The ALPHA3 study is designed to evaluate the efficacy and safety of cema-cel with 1 of 2 different lymphodepletion regimens as compared to standard-of-care observation in patients with LBCL who are in response at the conclusion of 1L therapy but test MRD+ by PhasED-Seq. Key eligibility criteria include histologically confirmed LBCL (diffuse LBCL [DLBCL] not otherwise specified, Epstein-Barr virus+ DLBCL, DLBCL with IRF4/MUM1 rearrangement; high-grade B-cell lymphoma; primary mediastinal B-cell lymphoma), completion of a full course of standard 1L therapy (eg, R-CHOP, Pola-R-CHP, DA-EPOCH-R), Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. The study will consist of a 2-part seamless design. In Part A, patients will be randomized to the standard-of-care observation arm or to 1 of 2 treatment arms (cema-cel [120×10⁶ CAR T cells] following a 3-day lymphodepletion regimen with fludarabine [30 mg/m²/day] and cyclophosphamide [300 mg/m²/day] administered with or without the anti-CD52 monoclonal antibody, ALLO-647 [30 mg/day]). Part A will conclude with an interim analysis that will support selection of the most appropriate lymphodepletion regimen for Part B. In Part B, the efficacy of the selected regimen as compared with observation will be assessed. The primary endpoint of the study is event-free survival per independent review committee (IRC), with hierarchical testing of key secondary endpoints of progression-free survival per IRC and OS. Other secondary endpoints include MRD clearance, safety of cema-cel and ALLO-647, and disease outcomes after subsequent therapy. Approximately 240 patients will be enrolled across ~50 sites at both academic and community-based centers. Site activation is ongoing, and sites outside the United States are being considered. The study was initiated in June 2024 and plans to accrue into 2026.