Fatal Adverse Event Leads Allogene to Discontinue Novel Monoclonal Antibody, Adjust Cema-Cel Trial Protocol for Large B-Cell Lymphoma

Allogene Therapeutics has announced a key change to its Phase II ALPHA3 clinical trial (NCT06500273) evaluating cemacabtagene ansegedleucel (cema-cel) as a first-line consolidation therapy for large B-cell lymphoma (LBCL).

The company made the decision after a grade 5 adverse event (AE) involving the death of a patient that was attributed to immunosuppression from ALLO-647 rather than cema-cel. The death occurred in the arm using fludarabine and cyclophosphamide (FC) plus ALLO-647.

In response, Allogene has discontinued further enrollment in that arm and will proceed using standard FC lymphodepletion alone. The company has decided to discontinue development of the novel monoclonal antibody entirely as a result of the patient death. The change was made in consultation with the FDA, the study’s Data and Safety Monitoring Board, and the Steering Committee.¹

Details of the Fatal AE

The grade 5 AE occurred on day 54 post-infusion due to hepatic failure, likely resulting from disseminated adenovirus infection in the context of profound immunosuppression, according to a company press release. Importantly, no cases of adenoviral infection or hepatic failure have been reported in any participants treated with FC lymphodepletion across Allogene’s other trials.¹

Prior Patient Death in Allogene’s Clinical Program

The patient death reported in the ALPHA3 trial is not the first to occur in an Allogene clinical program. In a prior Phase I trial of ALLO-715 for relapsed or refractory multiple myeloma, a patient died from suspected fungal pneumonia eight days post-infusion. That patient had rapidly progressing disease and was treated with cyclophosphamide and ALLO-647 as part of the lymphodepletion regimen. Investigators attributed the death to disease progression and the conditioning regimen, rather than the CAR T-cell product itself.²

“The loss of a patient is always deeply saddening, and we extend our heartfelt condolences to the patient’s family,” said David Chang, MD, PhD, president, CEO, co-founder, Allogene, in a press release. “This event, which prompted an early review of the trial data, compelled us to make a decisive choice—one that may ultimately help bring this potentially life-saving therapy to patients more quickly.”

ALPHA3 Trial Design and Study Endpoints

• The randomized, open-label ALPHA3 trial is evaluating the efficacy and safety of consolidation with cema-cel in approximately 250 patients with LBCL.
• In Part A of the trial, patients with minimal residual disease (MRD) were randomly assigned to receive cema-cel following lymphodepletion with either FC plus ALLO-647, FC alone, or observation per current standard of care.
• The primary endpoint is event-free survival as assessed by an independent review committee.
• Key secondary endpoints include progression-free survival, overall survival, AE incidence and severity (and their relationship to cema-cel and ALLO-647), laboratory toxicities, and MRD clearance.³

What’s Next for ALPHA3 and the Dagger Platform?

Continuing with two arms, the next milestone of the trial will be the futility analysis comparing MRD conversion and is expected take place during the first half of 2026.

According to Allogene, the shift to standard FC represents a broader strategic pivot. ALLO-647 has been removed from all active trials and pipeline programs. The company is now advancing next-generation allogeneic CAR T candidates via its proprietary Dagger Platform Technology, designed to reduce or eliminate the need for traditional lymphodepletion. The platform is currently under evaluation in the ALLO-316 TRAVERSE trial for advanced renal cell carcinoma and the ALLO-329 RESOLUTION trial for autoimmune diseases.¹

“The ability to administer cema-cel following standard FC lymphodepletion in an outpatient setting will simplify study treatment and has the potential to accelerate trial enrollment and streamline regulatory review, ultimately transforming care for patients,” continued Chang, in the press release.

References

1. Allogene Therapeutics Moves Forward with Standard Fludarabine and Cyclophosphamide (FC) Lymphodepletion Regimen in the ALPHA3 Trial for Cemacabtagene Ansegedleucel (Cema-Cel) in First-Line Consolidation for Large B-Cell Lymphoma. Allogene. August 1, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-moves-forward-standard-fludarabine-and
2. Allogene Therapeutics Announces Oral Presentation of Initial Results from its Phase 1 Dose Escalation Study of ALLO-715 in Relapsed/Refractory Multiple Myeloma at the 62nd Annual Meeting of the American Society of Hematology. Allogene. November 4, 2020. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-announces-oral-presentation-initial
3. Consolidation of First-Line MRD+ Remission With Cema-cel in Patients With LBCL (ALPHA3). Clinicaltrials.gov. Accessed August 4, 2025. https://clinicaltrials.gov/study/NCT06500273