Summary

The purpose of this study is to assess the efficacy and safety of tabelecleucel in
participants with Epstein-Barr virus (EBV) associated diseases.

Objectives

This is a multicenter, multicohort, open label, single-arm, Phase 2 study to assess the
efficacy and safety of tabelecleucel for the treatment of EBV-associated diseases in
participants who are newly diagnosed or relapsed/refractory to prior treatment. Newly
diagnosed or relapsed/refractory participants will be enrolled in one of the following
cohorts:

- EBV+ lymphoproliferative disease (LPD) in the setting of primary immunodeficiency (PID)
(PID LPD)

- EBV+ LPD in the setting of acquired (non-congenital) immunodeficiency (AID) (AID LPD)

- EBV+ posttransplant lymphoproliferative disorder involving the central nervous system
(CNS PTLD)

- EBV+ PTLD where standard first line therapy (rituximab or chemotherapy) is not
appropriate, including CD20 negative disease

- EBV+ sarcomas, including leiomyosarcoma (LMS)

- Chronic active EBV (CAEBV) and EBV+ hemophagocytic lymphohistiocytosis (HLH) (CAEBV/HLH
cohort)

Tabelecleucel will be administered in cycles lasting for 35 days. During each cycle,
participants will receive tabelecleucel at a dose of 2 x 10^6 cells/kg intravenously (IV)
weekly for 3 weeks, followed by observation through Day 35. Treatment will continue until
maximal disease progression, unacceptable toxicity, or initiation of nonprotocol therapy for
the underlying disease. For EBV+ sarcoma cohort, treatment will continue until disease
progression, unacceptable toxicity, or up to 24 months from first dose. Participants who fail
to respond to initial tabelecleucel treatment may continue tabelecleucel with a different
human leukocyte antigen (HLA) restriction (termed a Restriction Switch), if available;
administration of tabelecleucel with up to 4 different HLA restrictions is allowed for any
participant.

Participants will complete a safety follow-up visit at 30 days after the last dose.
Participants without documented disease progression will be assessed every 3 months after the
safety follow-up visit for continued evaluation of disease response until the end of study
(EOS) visit at 24-month after first dose. Participants with disease progression any time
prior to the EOS visit will continue to be followed every 3 months for survival status until
the EOS visit.

An adaptive 2-stage design will be used for each cohort in this study. For each cohort,
approximately 8 participants will be enrolled in Stage 1. The decision to move to Stage 2
enrollment will be based on an interim analysis of the first 8 evaluable participants in the
cohort using investigator's assessment (per defined radiologic, clinical, and/or laboratory
response criteria). The number of participants enrolled in Stage 2 for each cohort will
depend on the number of observed responders in Stage 1.

Eligibility

1. Diagnosis of EBV+ disorder
2. Eastern Cooperative Oncology Group performance status <= 3 for participants aged >= 16 years; Lansky score >= 20 for participants from 1 year to < 16 years
3. Adequate organ function test results, unless organ dysfunction is considered to be due to the underlying EBV-associated disease by the investigator Cohort-specific Inclusion Criteria:
4. For participants with PID LPD:
5. Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
6. Participant must have systemic measurable disease and/ or CNS measurable disease
7. Definitive therapy (eg, allogeneic HCT, gene therapy) for the underlying PID is planned
8. Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
9. For participants with AID LPD:
10. Newly diagnosed or relapsed/refractory LPD confirmed by biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF
11. Participant must have systemic measurable disease and/ or CNS measurable disease
12. Participants who are human immunodeficiency virus positive (HIV+) must meet both of the following criteria: Have an HIV viral load assessed by reverse transcription-polymerase chain reaction (RT-PCR) below the lower limit of detection and CD4 >= 50 cells/µL within 6 months prior to the first dose of tabelecleucel
13. Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
14. For participants with CNS PTLD:
15. Newly diagnosed or relapsed/refractory EBV+ CNS PTLD histologically confirmed by biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF
16. Participant may have systemic and CNS disease or CNS disease only
17. Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
18. For participants with EBV+ PTLD, where standard first line therapy (rituximab and/or chemotherapy) is not appropriate, including CD20-negative disease:
19. Newly diagnosed, biopsy-proven EBV+ PTLD
20. Ineligible for standard first-line therapy for EBV+ PTLD, as determined by the investigator
21. Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used.
22. For participants with sarcoma, including LMS:
23. Newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma. Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ sarcoma, as determined by the investigator.
24. Biopsy-proven EBV+ sarcoma
25. Measurable disease using diagnostic PET/CT and/or MRI following RECIST 1.1 criteria
26. For participants with CAEBV:
27. Newly diagnosed or previously treated CAEBV
28. Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
29. At least 3 active clinical findings (per Kimura H, et al. Front Immunol. 2017;8:1867) as: Fever >= 38.5°C; splenomegaly, lymphadenopathy, and/or hepatomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin < 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 × 10^3/mL); hypogammaglobulinemia; hemophagocytosis; hepatitis; neuropathy; rash; and hydroa vacciniforme
30. For participants with EBV+ viremia with HLH:
31. Newly diagnosed or previously treated EBV+ viremia with HLH
32. A molecular diagnosis consistent with HLH-2004 trial (per Henter JI, et al. Pediatr Blood Cancer. 2007;48:124-31) OR 5 or more of the clinical symptoms (per Jordan MB, et al. Blood. 2011;118:4041-4052): Fever >= 38.5°C; splenomegaly; cytopenia affecting at least 2 or 3 lineages in the peripheral blood (hemoglobin < 9 g/dL, platelets < 100 × 10^3/mL, neutrophils < 1 × 10^3/mL); hypertriglyceridemia (fasting >= 265 mg/dL) and/or hypofibrinogenemia (<= 150 mg/dL); hemophagocytosis in bone marrow, spleen, lymph nodes, or liver; low or absent natural killer cell (NK-cell) activity; ferritin >= 500 ng/mL; and elevated soluble CD25

Treatment Sites in Georgia