A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disorder (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Abstract

Background In immunocompromised individuals where T-cell function is impaired, EBV-transformed B-cells can proliferate resulting in lymphoproliferative disorders or lymphoma (EBV+LPD). EBV+LPD following solid organ transplant (SOT) is known as EBV+ post-transplant lymphoproliferative disorder (EBV+PTLD). Treatments for EBV+PTLD following SOT include reduction in immunosuppression and off-label rituximab ± multi-agent chemotherapy (CT). Limitations of current EBV+PTLD treatments include lack of response, relapse, potential for graft rejection, short- and long-term toxicity and high mortality, highlighting a clear unmet medical. Tabelecleucel (tab-cel) is an off-the-shelf allogeneic EBV-specific T cell immunotherapy generated from healthy donors that is selected for each patient (pt) from a library of T cells using the most appropriate human leukocyte antigen (HLA) restriction to address the patient's disease. Tab-cel has been evaluated in several clinical studies; One published interim analysis showed that in ALLELE-eligible patients with EBV+PTLD following SOT, the objective response rate (ORR) was 83% (5/6 patients) (Prockop et al, ASH 2017). Here we describe the design of an ongoing study of tab-cel for SOT subjects with EBV+PTLD after failure of rituximab ± CT. Study Design and Methods ALLELE is a multicenter, open-label, single arm, phase 3 study evaluating the clinical benefit of tab-cel in pts with EBV+PTLD following SOT (n=33) after failure of (1) rituximab monotherapy or (2) rituximab plus CT (NCT03394365). Key inclusion criteria are a diagnosis of locally assessed, biopsy-proven EBV+PTLD and failure of rituximab or rituximab plus concurrent/sequential CT. Exclusion criteria include untreated or in-progress treatment of central nervous system PTLD and suspected or confirmed grade >2 graft-vs-host disease. Tab-cel is partially matched to each patient from a library that is HLA-characterized using 1 EBV HLA restriction allele and at least 1 other matched HLA allele. Tab-cel is administered in cycles lasting 5 weeks (35 days). During each cycle, subjects receive intravenous (IV) tab-cel at a dose of 2 × 106 cells/kg on days 1, 8, and 15, followed by observation through day 35. Response per clinical and radiographic assessment are evaluated at the end of each cycle by the investigator and independent review using modified Lugano Classification criteria. Up to 2 different HLA restrictions are allowed per protocol. Treatment is continued until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or failure of the maximum allowable HLA restrictions. After treatment is completed or discontinued, subjects are assessed every 3 months, up to 24 months and every 6 months thereafter up to 5 years for survival status. The primary endpoint of the study is overall response rate (ORR) following the administration of tab-cel.