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

Study Overview
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Brief Summary
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The purpose of this study is to determine the clinical benefit and characterize the safety profile of tabelecleucel for the treatment of Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV+ PTLD) in the setting of (1) solid organ transplant (SOT) after failure of rituximab and rituximab plus chemotherapy or (2) allogeneic hematopoietic cell transplant (HCT) after failure of rituximab.

Detailed Description
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This is a multicenter, open-label, phase 3 study to assess the efficacy and safety of tabelecleucel for the treatment of EBV+ PTLD in the setting of SOT after failure of rituximab and rituximab plus chemotherapy (SOT cohort) or HCT after failure of rituximab (HCT cohort). Enrollment will be preceded by confirmation of availability of partially human leukocyte antigen (HLA) matched and restricted tabelecleucel for the participant. Study procedures and product administration will be the same for each cohort. Tabelecleucel will be administered in cycles lasting 5 weeks (35 days). During each cycle, participants will receive intravenous tabelecleucel at a dose of 2×10^6 cells/kg on Days 1, 8, and 15, followed by observation through Day 35. Treatment will continue until maximal response, unacceptable toxicity, initiation of non protocol therapy, or failure of tabelecleucel with up to 2 different HLA restrictions (SOT cohort) or up to 4 different HLA restrictions (HCT cohort). The study includes a total of 5 years of follow-up for disease and survival status. This protocol has been amended to include the HCT cohort from clinical study ATA129-EBV-301 (NCT03392142). NOTE, 29 April 2020: Enrollment is temporarily paused at study site/locations with status active, not recruiting due to COVID-19 restrictions.

Official Title
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Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Subjects With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease After Failure of Rituximab or Rituximab and Chemotherapy

Conditions
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Epstein-Barr Virus+ Associated Post-transplant Lymphoproliferative Disease (EBV+ PTLD), Solid Organ Transplant Complications, Lymphoproliferative Disorders, Allogeneic Hematopoietic Cell Transplant, Stem Cell Transplant Complications

Intervention / Treatment
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* Biological: tabelecleucel


Participation Criteria
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Eligibility 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 (PET)-diagnostic computed tomography (CT), except when contraindicated or mandated by local practice, then magnetic resonance imaging (MRI) may be used.For subjects with treated central nervous system (CNS) disease, a head CT and/or brain/spinal MRI 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 subgroup A or HCT cohort) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (SOT subgroup B) for treatment of PTLD. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged ≥ 16 years; Lansky score ≥ 20 for subjects < 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 subject underwent transplant must be in morphologic remission Adequate organ function Absolute neutrophil count ≥ 1000/μL, (SOT cohort) or ≥ 500/μL (HCT cohort), with or without cytokine support 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 subject 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 [CTCAE], version 5.0) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin each < 5 × the upper limit of normal; however, ALT, AST, and total bilirubin each ≤ 10 × 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 Subject or subject's representative is willing and able to provide written informed consent Exclusion Criteria: Burkitt lymphoma, classical Hodgkin lymphoma, or any T cell lymphoma 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 subject is actively receiving CNS-directed chemotherapy (systemic or intrathecal) or radiotherapy at enrollment. NOTE:Subjects with previously treated CNS PTLD may enroll if CNS-directed therapy is complete. Suspected or confirmed grade ≥ 2 graft-versus-host disease (GvHD) 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: 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 Epstein-Barr virus cytotoxic T lymphocytes 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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SOT cohort -Subgroup A<br>Participants who have failed rituximab will receive IV tabelecleucel. | Biological: tabelecleucel<br>* Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.<br>* Other names: EBV-CTL;|
| Experimental: SOT cohort -Subgroup B<br>Participants who have failed both rituximab and chemotherapy will receive IV tabelecleucel. | Biological: tabelecleucel<br>* Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.<br>* Other names: EBV-CTL;|
| Experimental: HCT cohort<br>Participants who have failed rituximab will receive IV tabelecleucel. | Biological: tabelecleucel<br>* Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.<br>* Other names: EBV-CTL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) in the SOT or HCT cohort |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) in SOT and HCT cohorts separately |  | 2 years | 
| ORR and DOR in SOT and HCT cohorts combined |  | 2 years | 
| Rates of complete response (CR) and partial response (PR) |  | 2 years | 
| Time to response |  | 2 years | 
| Time to best response |  | 2 years | 
| Overall survival (OS) |  | 2 years | 
| Rates of allograft loss or rejection episodes (SOT cohort) |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epstein-Barr Virus (EBV)-associated Lymphoproliferative Disease (LPD), Epstein-Barr Virus (EBV), Cytotoxic T lymphocyte (CTL), Cancer After Transplant, Kidney transplant, Renal transplant, Liver transplant, Heart transplant, Lung transplant, Intestinal transplant, Pancreas transplant, Post-transplant Lymphoma, Solid Organ Transplant (SOT), Bone Marrow Transplant Complications, Epstein-Barr Virus-specific Cytotoxic T Lymphocytes (EBV-CTL), Hematopoietic Cell Transplant (HCT), Hematopoietic Stem Cell Transplantation (HSCT), Allogeneic Hematopoietic Cell Transplant, Allogeneic, Off-The-Shelf T-cell Immunotherapy