Phase 3 Multicenter Study of Tabelecleucel in Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease Post-Rituximab Failure

Trial ID: 2024-516622-57-00
Protocol: ATA129-EBV-302
Sponsor: Pierre Fabre Medicament

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Diseases & Conditions

Post transplant lymphoproliferative disorder Epstein-Barr virus associated lymphoproliferative disorder

Objectives

The primary objective of this study is to determine the clinical benefit of **tabelecleucel** (ATA129; allogeneic Epstein-Barr virus specific cytotoxic T lymphocytes [EBV-CTLs]) by measuring the objective response rate (ORR) in subjects with Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease (EBV+ PTLD). This evaluation is conducted across several cohorts: solid organ transplant (SOT) subjects who have failed rituximab treatment, including those ineligible for chemotherapy (SOT-R-Ci) and those who received rituximab plus chemotherapy (SOT-R+C), as well as allogeneic hematopoietic cell transplant (HCT) subjects who have failed rituximab treatment. Additionally, a combined population of SOT-R-Ci, SOT-R+C, and HCT subjects who received a commercial product or a product manufactured using a comparable process version (PV) is assessed. The clinical relevance of this objective lies in its potential to provide a therapeutic option for patients with limited treatment alternatives following the failure of standard therapies.

Secondary objectives include:

Evaluating the duration of response (DOR) in the SOT and HCT cohorts separately.
Assessing ORR and DOR in the SOT and HCT cohorts combined.
Evaluating ORR and DOR in subjects who received a commercial product or a product manufactured using a comparable PV in the SOTR-Ci and SOT-R+C combined, and separately, HCT.
Evaluating DOR in a combined population (SOT-R-Ci, SOT-R+C, and HCT) who received a commercial product or a product manufactured using a comparable PV.
Assessing rates of complete response (CR) and partial response (PR).
Evaluating time to response and time to best response.
Assessing overall survival (OS).
Evaluating graft status in SOT subjects only.
Characterizing the safety profile of tabelecleucel in this subject population.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic efficacy and safety of tabelecleucel, offering insights into its potential role in managing EBV+ PTLD post-transplantation.

Participants

The clinical trial involves a total of **48 participants** diagnosed with **Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease** (EBV+ PTLD). The study population includes both **males and females** of any age, encompassing a broad age range. Participants were selected based on their prior solid organ transplant (SOT) or allogeneic hematopoietic cell transplant (HCT) and subsequent treatment failure with rituximab or rituximab plus chemotherapy. The trial includes individuals with a performance status of ≤ 3 for those aged 16 years and older, and a Lansky score of ≥ 20 for those under 16 years. Participants are required to have adequate organ function and measurable, FDG-avid systemic disease. The trial population is considered vulnerable, and the selection process ensures the availability of appropriate partially HLA-matched and restricted tabelecleucel. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is a **Phase 3** study designed to evaluate the efficacy of **tabelecleucel**, an advanced therapy medicinal product, in subjects with **Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease** (EBV+ PTLD) following the failure of rituximab or rituximab plus chemotherapy. The trial employs an open-label design and involves multiple centers. The primary objective is to determine the clinical benefit of tabelecleucel as measured by the objective response rate (ORR) in different cohorts, including solid organ transplant (SOT) and allogeneic hematopoietic cell transplant (HCT) recipients. The trial is expected to run from June 2020 to June 2027, with participants involved for a maximum treatment period of 35 days.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior SOT or HCT, biopsy-proven EBV+ PTLD, and treatment failure of rituximab. The screening will also ensure the availability of appropriate partially HLA-matched tabelecleucel. Following the screening, participants will receive the investigational product via **intravenous use**. Follow-up visits will be scheduled to monitor the response to treatment and assess any adverse events. The end-of-study visit will conclude the participant's involvement, evaluating the overall treatment efficacy and safety.

Participants are expected to remain in the study for the duration of the treatment period unless conditions arise that necessitate early termination. Such conditions include significant adverse reactions, withdrawal of consent, or any medical reasons deemed appropriate by the investigator. The trial's primary endpoint is the ORR, while secondary endpoints include duration of response (DOR), overall survival (OS), and rates of complete and partial responses. The study aims to provide valuable insights into the therapeutic potential of tabelecleucel for patients with EBV+ PTLD who have limited treatment options.

Treatment

The clinical trial involves the administration of **tabelecleucel**, an advanced therapy investigational medicinal product classified as a somatic cell therapy medicinal product. Tabelecleucel is provided as a **dispersion for injection** with a concentration ranging from 2.8 × 10^7 to 7.3 × 10^7 cells/mL. The active substance, tabelecleucel, is an allogeneic Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) therapy. The pharmaceutical form is a dispersion for injection, and the route of administration is **intravenous use**. The maximum daily dose is 2 million organisms, with a total maximum dose of 36 million organisms over a treatment period not exceeding 35 days. The product is manufactured by Pierre Fabre Medicament and Atara Biotherapeutics Inc., and it is designated as an orphan drug under the designation number EU/3/16/1627.

In addition to the experimental treatment, the study may involve the use of standard-of-care therapies such as rituximab or rituximab combined with chemotherapy, depending on the cohort and prior treatment failures. These non-experimental treatments serve as comparator therapies to evaluate the clinical benefit of tabelecleucel in subjects with Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) following solid organ or allogeneic hematopoietic cell transplant. Participant compliance with the dosing schedule and administration will be monitored throughout the trial to ensure adherence to the protocol.

Efficacy

The efficacy of **tabelecleucel** in the clinical trial will be assessed primarily through the objective response rate (ORR), which includes complete response (CR) or partial response (PR) following administration of the investigational product. This assessment will be conducted across different analysis cohorts, including solid organ transplant (SOT) and allogeneic hematopoietic cell transplant (HCT) groups, as well as a combined population of SOT-R-Ci, SOT-R+C, and HCT. The ORR will be evaluated after administration of tabelecleucel with up to two different HLA restrictions.

Secondary efficacy endpoints include the duration of response (DOR) in both SOT and HCT cohorts separately and combined, as well as in subjects who received either the commercial product or a product manufactured using a comparable process version (PV). Additional secondary endpoints encompass rates of CR and PR, time to response, time to best response, overall survival (OS), and rates of allograft loss or rejection episodes specifically for the SOT cohort. These parameters will be measured using validated response criteria, such as the Lugano Classification, and will be collected at specified timepoints throughout the trial duration.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of these (SOT cohort); or prior allogeneic HCT (HCT cohort).
A diagnosis of locally-assessed, biopsy-proven EBV+ PTLD.
Availability of appropriate partially HLA-matched and restricted tabelecleucel has been confirmed by the sponsor.
Measurable, 18F-deoxyglucose (FDG)-avid (Deauville score ≥ 3) systemic disease using Lugano Classification response criteria by positron emission tomography -diagnostic computed tomography, except when contraindicated or mandated by local practice, then magnetic resonance imaging may be used. For Participants with treated central nervous system (CNS) disease, head diagnostic computed tomography and/or brain/spinal magnetic resonance imaging as clinically appropriate will be required to follow CNS disease response per Lugano Classification response criteria.
Treatment failure of rituximab or interchangeable commercially available biosimilar monotherapy (SOT-R or HCT cohort) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (SOT-R+C) for treatment of PTLD. Treatment failure is defined based on rituximab response as follows: a. Radiographic disease progression per Lugano Classification following a minimum cumulative dose of 1125 mg/m2 rituximab (typically, 3 weekly doses of 375 mg/m2), or b. Failure to achieve CR or PR, defined by Lugano radiographic criteria, after a minimum cumulative dose of 1500 mg/m2 rituximab (typically, 4 weekly doses of 375 mg/m2), or c. Relapse/progression of PTLD after a response to rituximab (SOT-R or HCT cohort) or rituximab plus chemotherapy (SOT-R+C), defined as radiographic and/or biopsy evidence of relapse/progression consistent with PTLD; if the underlying disease for which the subject underwent allogeneic HCT (HCT cohort) was lymphoma, biopsy confirmation of relapsed EBV+ PTLD is required.
Males and females of any age.
Eastern Cooperative Oncology Group performance status ≤ 3 for Participants aged ≥ 16 years; Lansky score ≥ 20 for Participants < 16 years.
For HCT cohort only: If allogeneic HCT was performed as treatment for an acute lymphoid or myeloid malignancy, the underlying primary disease for which the participant underwent transplant must be in morphologic remission.
Adequate organ function: a. Absolute neutrophil count ≥ 1000/μL (SOT cohort) or ≥ 500/μL (HCT cohort), with or without cytokine support b. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For HCT cohort, platelet count < 50,000/μL but ≥ 20,000/μL, with or without transfusion support, is permissible if the participant has not had grade ≥ 2 bleeding in the prior 4 weeks (where grading of the bleeding is determined per the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0) c. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin each < 5 × the upper limit of normal; however, ALT, AST, and total bilirubin each ≤ 10 × the upper limit of normal is acceptable if the elevation is considered by the investigator to be due to EBV and/or PTLD involvement of the liver as long as there is no known evidence of significant liver dysfunction (e.g., elevated prothrombin time due to liver dysfunction, signs/symptoms of liver dysfunction such as asterixis, or similar).
Participant or participant's representative is willing and able to provide written informed consent.

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Exclusion Criteria

Currently active Burkitt, T cell, NK/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy.
Daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis.
Untreated CNS PTLD or CNS PTLD for which the participant is actively receiving CNS-directed chemotherapy (systemic or intrathecal) or radiotherapy at enrollment. NOTE: Participants with previously treated CNS PTLD may enroll if CNS-directed therapy is complete.
Suspected or confirmed grade ≥ 2 graft-versus-host disease per the Center for International Blood and Marrow Transplant Research consensus grading system at enrollment.
Ongoing or recent use of a checkpoint inhibitor agent (eg, ipilimumab, pembrolizumab, nivolumab) within 3 drug half-lives from the most recent dose to enrollment.
For HCT cohort only: Active adenovirus viremia.
Need for vasopressor or ventilatory support.
Antithymocyte globulin or similar anti-T-cell antibody therapy ≤ 4 weeks prior to enrollment.
Treatment with EBV-CTLs or chimeric antigen receptor T cells directed against B cells within 8 weeks of enrollment (SOT or HCT cohorts); or unselected donor lymphocyte infusion within 8 weeks of enrollment (HCT cohort only).
Female who is breastfeeding or pregnant or female of childbearing potential or male with a female partner of childbearing potential unwilling to use a highly effective method of contraception.
Inability to comply with study-related procedures
Any medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the participant's safety or ability to complete the study.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	15 Jun 2020	4
Belgium	Not Recruiting	15 Jun 2020	4
France	Not Recruiting	15 Jun 2020	8
Italy	Not Recruiting	15 Jun 2020	5
Spain	Recruiting	15 Jun 2020	5