A Study to Evaluate Tabelecleucel in Participants With Epstein Barr Virus (EBV) Associated Diseases

An Open-label, Single-arm, Multicohort, Phase 2 Study to Assess the Efficacy and Safety of Tabelecleucel in Subjects With Epstein Barr Virus Associated Diseases (EBVision)

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

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 [cohort closed for enrollment after completion of stage1]
• EBV+ post-transplant 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 which occurs at 12 (± 1) months after Cycle 1 Day 1 for adults, and 24 (± 1) months after Cycle 1 Day 1 for pediatric participants. 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 relevant 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.

Inclusion Criteria:

• Diagnosis of EBV+ disease.
• Eastern Cooperative Oncology Group performance status ≤ 3 for participants aged ≥ 16 years; Lansky score ≥ 20 for participants from ≥ 1 year to < 16 years.
• 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:

• For participants with CNS PTLD:

  • 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.
  • 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.
  • Participant may have systemic and CNS disease or CNS disease only.

Exclusion Criteria:

• Currently active Burkitt, T-cell, natural killer/T-cell lymphoma/LPD, Hodgkin, plasmablastic, transformed lymphoma, active hemophagocytic lymphohistiocytosis, or other malignancies requiring systemic therapy.

• Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment, or known history of human immunodeficiency virus (HIV) infection.

• Suspected or confirmed Grade ≥ 2 acute graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research (CIBMTR) consensus grading system or extensive chronic GvHD per National Institutes of Health (NIH) consensus criteria at the time of the enrollment.

• Need for vasopressor or ventilatory support at the time of enrollment.

• Prior therapy (in order of increasing washout period) prior to enrollment as follows:

  • Within 4 weeks or 5 half-lives (whichever is shorter) for any investigational product and/ or any chemotherapy (systemic or intrathecal), targeted small molecule therapy, or antibody/biologic therapy. Note: prior anti-CD20 antibody use is permitted within the washout period if a subsequent disease response assessment indicates disease progression.
  • Within 8 weeks: prior tabelecleucel (> 8 weeks prior to enrollment) is permitted if response was obtained or if usual protocol-directed therapeutic options were not exhausted, for cellular therapies (chimeric antigen receptor therapies directed at T-cells or T-cell subsets, donor lymphocyte infusion, other CTLs or virus-specific T-cells); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab).
  • Any prior treatment with EBV-CTLs with the exception of tabelecleucel as above

• Women who are breastfeeding or pregnant.

• Unwilling to comply with protocol specified contraceptive/reproductive restrictions from enrollment through 90 days after the last treatment.

• Inability or unwillingness to comply with all study procedures.

• Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (for participants with CNS disease, protocol-specified dexamethasone is permitted and concludes by the time of enrollment).

• Any conditions that may put the study outcomes at undue risk (life expectancy < 60 days or any life-threatening illness, medical condition, or organ system dysfunction).