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: TheALPHA3 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.

Westin:AbbVie/GenMab: Consultancy; Nurix: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Morphosys/Incyte: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Regeneron: Consultancy; Pfizer: Consultancy. Herrera:Allogene Therapeutics: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy, Research Funding; Regeneron: Consultancy; Caribou Biosciences: Consultancy; Seattle Genetics: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; KiTE Pharma: Research Funding; Adicet Bio: Consultancy; Gilead Sciences: Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Genmab: Consultancy; AstraZeneca: Consultancy, Research Funding. Lynch:TG Therapeutics: Research Funding; Rapt: Research Funding; Abbvie: Consultancy; Merck: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Research Funding; SeaGen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Foresight Diagnostics: Consultancy; Baye: Research Funding; Cyteir: Research Funding. Abramson:Merck: Research Funding; Cellectis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Epizyme Inc: Consultancy; Mustang Bio: Research Funding; Seagen Inc.: Research Funding; Interius BioTh: Consultancy; Incyte Corporation: Consultancy; Genmab US Inc: Consultancy; Genentech, a member of the Roche Group: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy; BeiGene Ltd: Consultancy; Caribou Biosciences Inc: Consultancy; Century Therapeutics: Consultancy; AbbVie Inc: Consultancy; Foresight Diagnostics: Consultancy. Matasar:Genmab: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria; AstraZeneca: Honoraria; IMV Therapeutics: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; ADC Therapeutics: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Merck: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy, Honoraria, Research Funding; Kite: Honoraria; Pfizer: Honoraria; Epizyme: Honoraria; GM Biosciences: Consultancy, Research Funding; BMS/Celgene: Honoraria; Takeda: Honoraria. Skarbnik:Genmab: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Verastem: Honoraria, Research Funding; Novartis: Honoraria; Acerta Pharma: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; SeaGen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Honoraria; Beigene: Honoraria, Speakers Bureau. Iragavarapu:Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; MorphoSys: Research Funding; Regeneron Pharmaceuticals: Research Funding; Century Pharma: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Janssen Pharmaceuticals: Research Funding. Essell:Canopy Care: Current equity holder in private company; Genmab: Speakers Bureau; AbbVie: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Kite: Speakers Bureau. Hunter:Notable Labs: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; In8 Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Merchant:IMMpact Bio: Research Funding; Innate Pharma: Research Funding; Amgen: Consultancy; BMS: Speakers Bureau; Oncovalent: Consultancy, Research Funding; Genmab: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Varadarajan:Cadmon Pharmaceuticals: Consultancy; Novartis: Consultancy. Tandra:Seattle Genetics: Speakers Bureau. Patel:KITE: Speakers Bureau; ADAPTIVE: Speakers Bureau; GENMAB: Speakers Bureau; PFIZER: Speakers Bureau. Behl:Geron: Consultancy; Cairo Science: Consultancy; First Thoughts: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; ANCO: Honoraria; Karyopharm: Speakers Bureau; My Cancer Haven: Membership on an entity's Board of Directors or advisory committees. Sharman:AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly and Company: Consultancy, Honoraria, Other: Anciliarry supplies, transportation, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria. Yimer:AbbVie: Speakers Bureau; Amgen: Speakers Bureau; Genmab: Speakers Bureau; BeiGene: Speakers Bureau; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Karyopharm: Speakers Bureau; G1 Therapeutics: Speakers Bureau. Gandhi:Janssen Oncology Ad Board 5/2023: Membership on an entity's Board of Directors or advisory committees; Sanofi Ad Board 12/2022: Membership on an entity's Board of Directors or advisory committees. Farhadfar:BMS: Research Funding; NMDP: Research Funding; Incyte: Consultancy, Speakers Bureau; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Blood and Marrow Clinical Trial Network (BMT CTN): Other: Medical Monitor; Chronic GVHD Consortium: Other: DSMB Member; Sanofi: Consultancy. Bartlett:Washington University School of Medicine: Current Employment; ADC Therapeutics: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees. Latif:Amgen: Other: DMC chair. Caimi:Abbvie: Consultancy, Research Funding; Abcon therapeutics: Current equity holder in private company; Genentech: Research Funding; Recordati: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Genmab: Research Funding; SOBI: Honoraria; BMS: Honoraria; Novartis: Honoraria; Synthekine: Honoraria; Luminary Therapeutics: Membership on an entity's Board of Directors or advisory committees. Yared:AAACTT: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; University of Maryland: Current Employment. Feng:Allogene Therapeutics: Current Employment, Current equity holder in private company. Navale:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Arcutis Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Amgen: Current equity holder in publicly-traded company; Sana Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Ghatta:ALLOGENE: Current Employment; QRD Pharma LLC: Current equity holder in private company. Le Gall:Allogene Therapeutics: Current Employment; Instil Bio: Ended employment in the past 24 months; ALLO: Current equity holder in publicly-traded company; TIL: Current equity holder in publicly-traded company. Roberts:Allogene Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company; Instil Bio Inc: Current equity holder in publicly-traded company. Burke:Novartis: Consultancy; BeiGene: Consultancy; Genmab: Consultancy; Foresight Diagnostics: Consultancy; SeaGen: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; Eli Lilly and Company: Honoraria, Other: Food/Beverage ; Genentech/Roche: Consultancy; Regeneron: Consultancy; Kymera: Consultancy; Nurix: Consultancy; Abbvie: Consultancy; Adaptive Biotechnologies: Consultancy.