A Multicenter, Multicohort, Open-Label, Single-Arm per Cohort, Phase II Study to Assess the Efficacy and Safety of Tabelecleucel in Patients with EBV-Associated Diseases Using an Adaptive Two-Stage Study Design

Background

Epstein-Barr virus infection is associated with a variety of life-threatening malignant and non-malignant diseases. In immunocompromised individuals where T-cell function is impaired, loss of immune control of Epstein-Barr virus (EBV) can lead to proliferation of EBV-transformed B cells and result in immunodeficiency-associated lymphoproliferative diseases (IA-LPD). EBV-driven IA-LPDs are a heterogenous group of diseases with variable clinical and pathologic features, including primary immunodeficiency-associated LPD (EBV⁺ PID-LPD), acquired immunodeficiency-associated LPD (EBV⁺ AID-LPD), and post-transplant lymphoproliferative disorder (EBV⁺ PTLD). In addition, EBV-infection of mesenchymal cells can cause sarcomas, including leiomyosarcoma (EBV⁺ sarcoma). In rare instances, EBV viremia (ie, persistent EBV infection) can lead to non-malignant yet life-threatening complications such as chronic active EBV (CAEBV) or hemophagocytic lymphohistiocytosis (HLH).

During the transition from primary EBV infection to latent state, only a subset of viral genes is expressed. The resulting latency proteins are a target of CD8⁺ T cells, making EBV⁺ malignancies good candidates for treatment with EBV-targeted cytotoxic lymphocytes.

Tabelecleucel (tab-cel) is an off-the-shelf, partially human leukocyte antigen (HLA)-matched, allogeneic EBV-specific T-cell immunotherapy generated from screened EBV⁺ donors. Tabelecleucel is characterized by both HLA genotype and HLA restriction, the HLA allele(s) through which tab-cel exerts cytotoxic activity. Tab-cel is selected for each patient from an inventory based on the HLA restriction(s) and partial HLA matching. Initial safety and efficacy data support that tab-cel was well tolerated and showed clinical activity in patients with each of the EBV-associated diseases being proposed in study 205 [Nikiforow S et al. ESMO 2020; Kurlander LS et al. Ann Oncol 2018; Prockop S et al. JCI 2020]. These data encourage investigation to further evaluate the safety and efficacy of tab-cel in these populations.

Study design and objectives

This is a multicenter, multicohort, open-label, single-arm per cohort, phase II study to assess the efficacy and safety of tab-cel in patients with EBV-associated diseases (ATA129-EBV-205). The primary objective of the study is to assess the clinical benefit of tab-cel as measured by objective response rate. This study will also evaluate clinically relevant disease-specific outcomes and will characterize the safety profile of tab-cel in these patient populations.

This study will enroll patients who are relapsed/refractory or newly diagnosed and ineligible for first-line therapy in the following cohorts: EBV⁺ AID-LPD, EBV⁺ PID-LPD, EBV⁺ sarcoma, including LMS, CAEBV/HLH and EBV⁺ PTLD with central nervous system [CNS]-involvement. In addition, a cohort of patients with previously untreated EBV⁺ PTLD where first-line therapy is not appropriate is planned to start enrollment in 2021. A Phase III study of tab-cel for solid organ or allogeneic hematopoietic cell transplant patients with EBV⁺ PTLD after failure of rituximab or rituximab plus chemotherapy (NCT03394365) is ongoing.

Patients in each cohort will receive tab-cel in 35-day cycles. During each cycle, patients will receive intravenous tab-cel at a dose of 2 × 10⁶ cells/kg on days 1, 8, and 15, followed by an observation period through day 35 (Figure 1).

An adaptive two-stage design will be used for each cohort in this study, and for each, a maximum of eight patients will be enrolled in stage 1. The decision to move to stage 2 enrollment for any given cohort will be based on an analysis of the first eight evaluable patients in the cohort using investigator’s assessment (per defined radiologic, clinical, and/or laboratory response criteria). If at least two among the first eight evaluable patients in stage 1 are responders
(ie, complete response or partial response), additional patients may be enrolled in stage 2 of that cohort. The number of patients enrolled in stage 2 will depend on the number of observed responders in stage 1 (Table 1). This design will allow for minimization of the expected number of patients required to evaluate the efficacy of tab-cel in each disease cohort independently.

Figure 1. Study design schema