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

  • STATUS
    Recruiting
  • End date
    May 11, 2029
  • participants needed
    228
  • sponsor
    Atara Biotherapeutics
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Updated on 11 October 2022
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systemic disease
fever
cancer
rituximab
measurable disease
bone marrow procedure
colony stimulating factor
chemotherapy regimen
cancer chemotherapy
hypogammaglobulinemia

Summary

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

Description

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.

Details
Condition Epstein-Barr Virus (EBV)-Associated Diseases, EBV+ Lymphoproliferative Disease With Primary Immunodeficiency (PID LPD), EBV+ Lymphoproliferative Disease With Acquired (Non-congenital) Immunodeficiency (AID LPD), EBV+ Posttransplant Lymphoproliferative Disease in Central Nervous System (CNS PTLD), EBV+ Post-transplant Lymphoproliferative Disease (EBV+ PTLD), Solid Organ Transplant Complications, Lymphoproliferative Disorders, Allogeneic Hematopoietic Cell Transplant, Stem Cell Transplant Complications, EBV+ Sarcomas, Leiomyosarcoma, Chronic Active Epstein-Barr Virus (CAEBV), Chronic Active Epstein-Barr Virus With Hemophagocytic Lymphohistiocytosis (HLH), Lymphohistiocytosis, Hemophagocytic
Treatment tabelecleucel
Clinical Study IdentifierNCT04554914
SponsorAtara Biotherapeutics
Last Modified on11 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Diagnosis of EBV+ disorder
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 PID LPD
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
Participant must have systemic measurable disease and/ or CNS measurable disease
Definitive therapy (eg, allogeneic HCT, gene therapy) for the underlying PID is planned
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with AID LPD
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
Participant must have systemic measurable disease and/ or CNS measurable disease
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
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with CNS PTLD
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
Participant may have systemic and CNS disease or CNS disease only
Participants with newly diagnosed disease should be ineligible for standard first-line therapy for EBV+ LPD, as determined by the investigator
For participants with EBV+ PTLD, where standard first line therapy (rituximab and/or
Newly diagnosed, biopsy-proven EBV+ PTLD
chemotherapy) is not appropriate, including CD20-negative disease
Ineligible for standard first-line therapy for EBV+ PTLD, as determined by the investigator
Participants must have systemic disease measurable per Lugano Classification criteria, except when contraindicated or mandated by local practice, then MRI may be used
For participants with sarcoma, including LMS
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
Biopsy-proven EBV+ sarcoma
Measurable disease using diagnostic PET/CT and/or MRI following RECIST 1.1 criteria
For participants with CAEBV
Newly diagnosed or previously treated CAEBV
Detectable EBV viremia on at least 2 occasions at a minimum of 90 days apart
For participants with EBV+ viremia with HLH
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
Newly diagnosed or previously treated EBV+ viremia with HLH
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

Exclusion Criteria

Burkitt, T-cell (except in the setting of HLH), natural killer/T-cell lymphoma/LPD, Hodgkin, or transformed lymphoma
Serious known active infections, defined as ongoing uncontrolled adenovirus infection or infections requiring systemic therapy at the time of enrollment
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
Prior therapy (in order of increasing washout period) prior to enrollment as
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 for cellular therapies (EBV-CTLs, chimeric antigen receptor therapies directed at T cells or T-cell subsets, donor lymphocyte infusion, other CTLs); and/or therapies which could impact tabelecleucel function (anti-thymocyte globulin, alemtuzumab)
Unwilling to use protocol specified contraceptive methods
Women who are pregnant or breastfeeding
Ongoing need for daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis (protocol-specified dexamethasone is permitted and concludes by the time of enrollment)
For participants with PID LPD or AID LPD: history of prior allogeneic HCT or solid organ transplant
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