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.
Participants will be enrolled in one of the following cohorts:

- EBV+ lymphoproliferative disease (LPD) in the setting of primary immunodeficiency
(PID) (EBV+ PID LPD) that is relapsed and/or refractory (R/R) or newly diagnosed
where standard first-line therapy is inappropriate

- EBV+ LPD in the setting of acquired (non-congenital) immunodeficiency (AID) (EBV+
AID LPD) that is R/R or newly diagnosed where standard first-line therapy is
inappropriate

- EBV+ posttransplant lymphoproliferative disease (PTLD) involving the central nervous
system (CNS) (EBV+ CNS PTLD) that is R/R or newly diagnosed where standard
first-line therapy is inappropriate

- EBV+ PTLD where standard first-line therapy (rituximab or chemotherapy) is
inappropriate, including cluster of differentiation antigen 20 (CD20)-negative
disease

- EBV+ sarcomas, including leiomyosarcoma (LMS), or smooth muscle tumors that is
rapidly progressive where standard first-line therapy is inappropriate

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 response, 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, two consecutive complete
responses (CRs), or up to 12 months from the 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 four different HLA restrictions is allowed for
any participant.

After treatment is completed or discontinued, participants will complete a safety
follow-up visit at 30 days after the last dose and then will enter a quarterly follow-up
period. 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, 8
evaluable 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) who receive tabelecleucel and have at least 1 valid
postbaseline disease response assessment. The number of participants enrolled in Stage 2
for each cohort will depend on the number of observed responders in Stage 1. Sponsor may
decide not to move forward to Stage 2 in any cohort even if the criteria to move forward
for that cohort are met. The decision not to move forward may also be based on data from
one or other cohorts.

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. R/R or newly diagnosed PID LPD for whom the standard first-line therapy is inappropriate, as determined by investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive cerebrospinal fluid (CSF) cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.
6. Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification (Cheson BD, et al. J Clin Oncol. 2014;27:3059) during or after treatment or failure to achieve a CR or partial response (PR) (defined by Lugano radiographic criteria) after standard first-line therapy
7. Participant may have systemic disease only, systemic and CNS disease, or CNS disease only
8. For participants with AID LPD:
9. R/R or newly diagnosed AID LPD for whom the standard first line therapy is inappropriate, as determined by the investigator. The LPD is confirmed by at least biopsy-proven EBV+ LPD or positive CSF cytology, with or without radiographically measurable intracranial disease, with EBV detected in CSF.
10. Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
11. Participant may have systemic disease only, systemic and CNS disease, or CNS disease only
12. For participants with AID etiology or AID attributable to immunosenescence, objective laboratory evidence of immunodeficiency
13. For participants with CNS PTLD:
14. R/R or newly diagnosed EBV+ CNS PTLD for whom the standard first-line therapy is inappropriate, as determined by the investigator. The CNS PTLD is histologically confirmed by at least biopsy-proven EBV+ CNS PTLD or positive CSF cytology with or without radiographically measurable intracranial disease with EBV detected in CSF.
15. Participants with R/R disease must have had at least one prior line of systemic therapy and one of the following: radiographic disease progression per Lugano Classification during or after treatment or failure to achieve a CR or PR (defined by Lugano radiographic criteria) after standard first-line therapy
16. Participant may have systemic and CNS disease or CNS disease only
17. For participants with EBV+ PTLD, including CD20-negative disease:
18. Biopsy-proven EBV+ PTLD for whom standard first-line therapy (rituximab and/or chemotherapy) is inappropriate, as determined by the investigator
19. Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used
20. For participants with sarcoma, including LMS, or smooth muscle tumors:
21. EBV+ sarcoma or smooth muscle tumor with rapidly progressive disease defined as progressive disease per RECIST 1.1 criteria as documented radiographically within a 6-month interval prior to enrollment
22. Participants with newly diagnosed EBV+ sarcoma for whom the standard first-line therapy is inappropriate, as determined by the investigator
23. Biopsy-proven EBV+ sarcoma meeting one of the criteria's of pathologically confirmed EBV+ Leiomyosarcoma or EBV+ sarcoma or smooth muscle tumor
24. Measurable disease using diagnostic CT and/or MRI following RECIST 1.1 criteria (Eisenhauer et al. 2009. Eur J Cancer 45[2]:228-247)

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