ALPHA3: A pivotal phase 2 study of first-line (1L) consolidation with cemacabtagene ansegedleucel (cema-cel) in patients (pts) with large B-cell lymphoma (LBCL) and minimal residual disease (MRD) after response to standard therapy.
Background: R-CHOP as 1L therapy for LBCL has a cure rate of ~60%. However, ~10% of pts are refractory (Coiffier, NEJM 2002) and ~30% of responders relapse within 2 years (Maurer, J Clin Oncol 2014). Autologous CAR T cell therapies have revolutionized treatment of relapsed/refractory (R/R) LBCL and are considered standard 2L treatment due to improved overall survival (OS; Westin, NEJM 2023) but may not be an option due to aggressive disease, pt comorbidities, access barriers, and/or manufacturing issues/delays. Identifying responders to 1L therapy at high risk of relapse and rapidly administering an off-the-shelf CAR T cell therapy for remission consolidation may improve outcomes. Presence of circulating tumor DNA–based MRD, measured by PhasED-Seq, at the end of 1L therapy is highly prognostic for relapse (Roschewski, Hematol Oncol 2023). Cema-cel is an immediately available, off-the-shelf, HLA-unmatched allogeneic CD19 CAR T cell product made using Cellectis technologies. A phase 1 study of cema-cel in pts with R/R LBCL showed safety and efficacy comparable to that of autologous CAR T cell therapies (Locke, J Clin Oncol 2023). We describe the design of the pivotal ALPHA3 phase 2 study of cema-cel, the first randomized, open‑label study to assess a CAR T cell therapy as a consolidation strategy in pts with detectable MRD measured by PhasED‑Seq after standard 1L immunochemotherapy. Methods: ALPHA3 (NCT06500273) will evaluate efficacy and safety of cema-cel with 1 of 2 lymphodepletion (LD) regimens compared to standard-of-care (SOC) observation in pts with LBCL who are in response at the end of 1L therapy but test MRD+. Key eligibility criteria include histologically confirmed LBCL, completion of a full course of standard 1L therapy, ECOG PS 0/1, and adequate organ function. The study will consist of a 2-part seamless design. In Part A (currently enrolling), pts will be randomized to SOC observation or to 1 of 2 treatment arms (cema-cel [120×106 CAR T cells] following 3-day LD with fludarabine [30 mg/m2/day] and cyclophosphamide [300 mg/m2/day] with/without the anti-CD52 monoclonal antibody, ALLO-647 [30 mg/day]). Part A will conclude with an interim analysis to select the optimal LD regimen. Part B will assess efficacy of the selected regimen vs observation. The primary endpoint 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. The study will enroll ~240 pts across ~50 sites at academic- and community-based centers. Site activation is ongoing; sites outside the US are being considered. The study was initiated in June 2024 with accrual into 2026. ©American Society of Hematology (2024). Reused with permission.
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Author Details
Jason Westin
The University of Texas MD Anderson Cancer Center, Houston, TX
Abstract Details
Meeting
2025 ASCO Annual Meeting
Session Type
Poster Session
Session Title
Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia
Track
Hematologic Malignancies
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