FDA Puts Clinical Hold on Tabelecleucel in EBV+ PTLD, ATA3219 in Lymphoma

The clinical hold for tab-cel follows a complete response letter (CRL) that the FDA issued in January 2025, which identified Good Manufacturing Practices (GMP) compliance issues associated with a pre-license inspection of a third-party manufacturing facility.

The FDA has placed a clinical hold on the investigational new drug applications for tabelecleucel (tab-cel; Ebvallo) in Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease (PTLD) and ATA3219 in non-Hodgkin lymphoma and systemic lupus erythematosus, according to a news release from the developer, Atara Biotherapeutics, Inc.¹

Patients who are currently enrolled on trials assessing tab-cel or ATA3219 and determined to potentially derive clinical benefit from these agents may be eligible to continue study therapy based on ongoing study programs. Investigators have paused screening and enrollment of new patients as part of both programs.

The clinical hold for tab-cel follows a complete response letter (CRL) that the FDA issued in January 2025, which identified Good Manufacturing Practices (GMP) compliance issues associated with a pre-license inspection of a third-party manufacturing facility.² This CRL did not highlight any deficiencies related to the manufacturing, efficacy, or safety of tab-cel in EBV-positive lymphoproliferative disease.

According to the FDA, the starting materials associated with the production of ATA3219 are impacted by the compliance issues at the same third-party facility that the CRL referenced. Developers have spoken and aligned with the regulatory agency regarding the next steps for lifting the clinical holds.

“We intend to work closely with the FDA to address these issues as expeditiously as possible. We are encouraged with ongoing correspondence with the agency and a potential path to submitting the necessary data to release the clinical hold,” Cokey Nguyen, PhD, president and chief executive officer at Atara, stated in the press release.¹ “Patient safety remains our priority and maintaining the highest standards for our programs.”

Tab-cel

The FDA previously accepted a biologics license application (BLA) for tab-cel as a treatment for those with EBV-positive PTLD in July 2024.³ Supporting data for the BLA came from the phase 3 ALLELE trial (NCT03394365). Investigators presented updated findings from the ALLELE trial at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.⁴

At the time of analysis, tab-cel produced an objective response rate (ORR) of 50.7%across the overall population. Additionally, the median duration of response (DOR) was 23 months, and the median overall survival (OS) was 18.4 months.

Safety findings were comparable with prior reports of the agent. There were no treatment-emergent adverse effects (TEAEs) that were associated with tab-cel, and investigators observed no instances of cytokine release syndrome, tumor flare or infusion reactions, or immune effector cell-associated neurotoxicity syndrome.

ATA3219

Developers designed ATA3219 to use off-the-shelf allogenic EBV-sensitized T cells that express a second-generation CD19 CAR construct.⁵ It features a 1XX signaling domain that may optimize expansion while mitigating T-cell exhaustion.

Investigators assessed treatment with ATA3219 among patients with relapsed/refractory B-cell non-Hodgkin lymphoma as part of a phase 1 trial (NCT06256484). In this open-label study, patients were assigned to receive a single intravenous infusion of ATA3219 at one of 4 dose levels.⁶

The trial’s primary end points were the incidence and severity of TEAEs, incidence and severity of AEs of special interest, dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose. Secondary end points included the maximum observed plasma concentration of ATA3219, ORR, complete response rate, time to response, DOR, and OS.

Patients 18 years and older with histologically confirmed relapsed/refractory B-cell non-Hodgkin lymphoma per 2022 revised World Health Organization classification of lymphoid neoplasms defined as large B-cell lymphoma, grade 3b follicular lymphoma, or mantle cell lymphoma were eligible for enrollment on the trial.

References

1. Atara Biotherapeutics provides update on clinical programs related to EBVALLO™ (tabelecleucel) and ATA3219. News release. Atara Biotherapeutics, Inc. January 21, 2025. Accessed January 21, 2025. https://tinyurl.com/ywmbn5md
2. Atara Biotherapeutics provides regulatory and business update on EBVALLO™ (tabelecleucel). News release. Atara Biotherapeutics, Inc. January 16, 2025. Accessed January 21, 2025. https://tinyurl.com/2sutywn9
3. Atara Biotherapeutics announces U.S. FDA acceptance and priority review of the Biologics License Application for tabelecleucel (tab-cel®) for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease. News Release. Atara Biotherapeutics, Inc. July 17, 2024. Accessed January 21, 2025. https://tinyurl.com/4h4wps4j
4. Updated results of phase 3 ALLELE study presented at 66th American Society of Hematology Annual Meeting confirm efficacy, safety and durability of novel allogeneic cell therapy tabelecleucel in relapsed or refractory Epstein-Barr virus positive post-transplant lymphoproliferative disease (EBV+ PTLD). News release. Pierre Fabre Pharmaceuticals Inc. December 9, 2024. Accessed January 21, 2025. https://tinyurl.com/vksjmpb8
5. Pipeline: ATA3219. Atara Biotherapeutics, Inc. Accessed January 21, 2025. https://tinyurl.com/434pb5md
6. A study to evaluate the safety and preliminary efficacy of ATA3219 in participants with relapsed/​refractory B-cell non-Hodgkin lymphoma. ClinicalTrials.gov. Updated December 6, 2024. Accessed January 21, 2025. https://tinyurl.com/bdh7bj2e