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

Background: Epstein-Barr virus (EBV), a member of the herpesvirus family, normally infects individuals in early adolescence and results in either asymptomatic infection or infectious mononucleosis. Following a lytic primary infection, EBV latently infects B-cells with control of latent infection primarily relying on T-cell function. 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 that occurs following solid organ transplant (SOT) is also called EBV⁺ post-transplant lymphoproliferative disorder (EBV⁺PTLD).

Current treatments for EBV⁺PTLD following SOT include reduction in immunosuppression (RIS), use of off-label rituximab alone or in combination with multi-agent chemotherapy (CT). Challenges with current treatments include lack of response, relapse, potential for graft rejection, short- and long-term toxicity and high mortality rates. These challenges highlight a clear unmet need for patients who fail or relapse after initial treatment with rituximab.

Tabelecleucel is an off-the-shelf, allogeneic EBV-specific T-cell immunotherapy generated from healthy donors. Tabelecleucel is selected for each patient from a library of T cells using the most appropriate HLA restriction to address the patient's disease and has been evaluated in clinical studies (NCT00002663, NCT01498484, NCT02822495). 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 a multicenter, open label, phase-3 study of tabelecleucel for solid organ transplant subjects with EBV⁺PTLD after failure of rituximab or rituximab and chemotherapy.

Study Design and Methods: This multicenter, open label, single arm, phase 3 study is designed to determine the clinical benefit of tabelecleucel in subjects with EBV⁺PTLD following SOT after failure of (1) rituximab monotherapy or (2) rituximab plus chemotherapy (NCT03394365). Key inclusion criteria include a diagnosis of locally-assessed, biopsy-proven EBV⁺PTLD and treatment failure of rituximab or rituximab plus concurrent or sequential chemotherapy. Exclusion criteria include untreated central nervous system (CNS) PTLD or CNS PTLD where treatment is not yet complete or subjects with suspected or confirmed grade > 2 graft-vs-host disease.

Tabelecleucel is partially matched to each patient from a library of HLA-characterized tabelecleucel using 1 EBV HLA restriction allele and at least 1 other matched HLA allele. Tabelecleucel is administered in cycles lasting 5 weeks (35 days). During each cycle, subjects receive intravenous (IV) tabelecleucel at a dose of 2 × 10⁶ cells/kg on days 1, 8, and 15, followed by observation through day 35. At the end of each cycle, each subject's response will undergo clinical and radiographic assessment by the investigator based on Lugano response criteria (Cheson et al, 2014). Subjects' responses to tabelecleucel are evaluated by investigators to determine treatment duration and evaluate HLA restriction based on the tabelecleucel-treatment algorithm. Treatment with tabelecluecel is continued until maximal response, unacceptable toxicity, initiation of non-protocol therapy, or failure in response to tabelecluecel with up to 2 different HLA restrictions. After treatment is completed or discontinued, subjects are assessed for disease response every 3 months, up to 24 months from cycle 1 day 1, and every 6 months thereafter up to 5 years from cycle 1 day 1 for survival status. The primary endpoint of the study is overall response rate (ORR) following the administration of tabelecleucel.