FDA Lifts Clinical Hold on Tabelecleucel Trial for EBV+ Post-Transplant Lymphoproliferative Disease

FDA

The FDA has lifted the clinical hold on an active investigational new drug application for the tabelecleucel (Ebvallo), allowing the resumption of clinical research for patients with Epstein-Barr virus (EBV)–positive post-transplant lymphoproliferative disease (PTLD) following allogeneic hematopoietic stem cell transplant (HSCT) or solid organ transplant (SOT).¹

The clinical hold was initially imposed in January 21, 2025, and it was linked to GMP compliance concerns identified during a pre-license inspection of a third-party manufacturing facility, which were detailed in a complete response letter (CRL) sent by the FDA on January 16, 2025, in response to a biologics license application (BLA) seeking the approval of tabelecleucel for adult and pediatric patients at least 2 years of age with EBV-positive PTLD who have received at least 1 prior therapy, including an anti-CD20 containing regimen.^2,3

Following submission and review of supplemental data regarding the finished drug product, the FDA has determined that the identified concerns have been sufficiently addressed.¹ As a result, the phase 3 ALLELE trial (NCT03394365) evaluating tabelecleucel in patients with relapsed/refractory EBV-positive PTLD following HSCT or SOT, and a phase 2 multi-cohort, label-expansion study (NCT04554914) investigating the agent in patients with EBV-associated diseases are both allowed to resume.

“We are very pleased to have addressed the FDA’s questions, and this has enabled the FDA to lift the clinical holds,” Cokey Nguyen, PhD, president and chief executive officer of AtaraBiotherapeutics, stated in a news release. “We are working closely with our partner Pierre Fabre Laboratories and our clinical trial sites and anticipate resuming enrollment and treatment of patients as soon as possible.”

Additionally, the FDA has granted a type A meeting to discuss Atara’s proposed strategy to address the deficiencies cited in the CRL and the path forward for the resubmission of the tabelecleucel BLA. The BLA was supported by data from the ALLELE trial.

ALLELE Study Design

The open-label, multicenter ALLELE study is enrolling patients with EBV-associated PTLD following progression on rituximab (Rituxan) or a commercially available biosimilar with or without chemotherapy in the setting of either SOT or HSCT.⁴ Eligible patients must have confirmed availability of partially human leukocyte antigen (HLA)–matched tabelecleucel.

All patients must demonstrate measurable, FDG-avid disease with a Deauville score of at least 3 per Lugano Classification per PET-CT or MRI when clinically appropriate. Central nervous system (CNS) involvement is permitted if imaging confirms measurable disease and CNS-directed therapy has been completed.

The trial includes patients of any sex and age, and patients must have an ECOG performance status of less than 3 for adults or a Lansky score of at least 20 for pediatric patients under 16 years of age. Subjects undergoing HSCT must be in morphologic remission of their primary hematologic malignancy if the transplant was performed for leukemia or lymphoma. Adequate hematologic and liver function are required.

Key exclusion criteria include Burkitt lymphoma, Hodgkin lymphoma, or any T-cell lymphoma; recent high-dose corticosteroid use; active CNS-directed chemotherapy or radiotherapy; and clinically significant graft-vs-host disease (GVHD) for HSCT recipients. Use of checkpoint inhibitors or T-cell–based therapies within 8 weeks of enrollment is not permitted. Patients requiring vasopressor or ventilatory support, or with uncontrolled organ dysfunction, are also excluded.

Patients are being assigned to 1 of the following cohorts: SOT recipients who received rituximab alone (C-SOT-R); SOT recipients who received rituximab and chemotherapy (C-SOT-R+C); or HSCT recipients who received rituximab (C-HCT). All enrolled patients are receiving intravenous tabelecleucel at a dose of 2 × 10⁶ cells/kg on days 1, 8, and 15 of each 35-day cycle. Treatment continues until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or lack of response after up to 2 HLA restrictions in the SOT cohorts or 4 in HSCT cohort.

The trial’s primary objective is to evaluate the clinical benefit and safety of tabelecleucel. Secondary end points include duration of response, overall survival, progression-free survival, and long-term follow-up for disease status over a 5-year period.

References

1. Atara Biotherapeutics provides regulatory updates on EBVALLO™ (tabelecleucel). Atara Bio. News Release May 5, 2025. Accessed May 6, 2025. https://investors.atarabio.com/news-events/press-releases/detail/371/atara-biotherapeutics-provides-regulatory-updates-on
2. Atara Biotherapeutics provides update on clinical programs related to Ebvallo (tabelecleucel) and ATA3219. News release. Atara Biotherapeutics. January 21, 2025. Accessed May 7, 2025. https://investors.atarabio.com/news-events/press-releases/detail/368/atara-biotherapeutics-provides-update-on-clinical-programs
3. Atara Biotherapeutics provides regulatory and business update on EBVALLO (tabelecleucel). News release. Atara Biotherapeutics. January 16, 2025. Accessed May 7, 2025. https://investors.atarabio.com/news-events/press-releases/detail/367/atara-biotherapeutics-provides-regulatory-and-business
4. Tabelecleucel for solid organ or allogeneic hematopoietic cell transplant participants with Epstein-Barr virus–associated post-transplant lymphoproliferative disease (EBV+ PTLD) after failure of rituximab or rituximab and chemotherapy (ALLELE). ClinicalTrials.gov. Updated April 18, 2025. Accessed May 6, 2025. https://clinicaltrials.gov/study/NCT03394365#participation-criteria