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A Study to Evaluate Tabelecleucel in Participants With Epstein-barr Virus-associated Diseases

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04554914
Recruitment Status : Recruiting
First Posted : September 18, 2020
Last Update Posted : November 14, 2022
Sponsor:
Information provided by (Responsible Party):
Atara Biotherapeutics

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

Condition or disease Intervention/treatment Phase
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 Biological: Tabelecleucel Phase 2

Expanded Access : An investigational treatment associated with this study is temporarily not available outside the clinical trial.   More info ...

Detailed 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 228 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 14, 2021
Estimated Primary Completion Date : June 2027
Estimated Study Completion Date : May 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Viral Infections

Arms and Interventions
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Arm Intervention/treatment
Experimental: EBV+ PID LPD
Participants with newly diagnosed or relapsed/refractory EBV+ PID LPD will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs
Experimental: EBV+ AID LPD
Participants with newly diagnosed or relapsed/refractory EBV+ AID LPD will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs
Experimental: EBV+ PTLD CNS
Participants with newly diagnosed or relapsed/refractory EBV+ PTLD CNS will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs
Experimental: EBV+ PTLD (ineligible for first-line therapy or CD20 negative)
Participants with EBV+ PTLD where standard first line therapy (rituximab or chemotherapy) is not appropriate, including CD20 negative disease will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs
Experimental: EBV+ sarcoma, including LMS
Participants with newly diagnosed or failed systemic first-line therapy for EBV+ sarcoma will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs
Experimental: CAEBV/ HLH
Participants with newly diagnosed or previously treated CAEBV or EBV viremia with HLH will receive IV tabelecleucel.
 Biological: Tabelecleucel
Tabelecleucel is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ malignancies and diseases.
Other Names:
  • tab-cel®
  • ATA129
  • EBV-CTLs


Outcome Measures
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Primary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Up to 2 years ]
  2. Duration of response (DOR) [ Time Frame: Up to 2 years ]
  3. Progression-free survival (PFS) [ Time Frame: Up to 2 years ]
  4. For EBV+ PID LPD and CAEBV/HLH cohorts who are eligible for allogeneic HCT: Number of participants who reach definitive therapy (ie, allogeneic HCT) for the underlying disease [ Time Frame: Up to 2 years ]
  5. For EBV+ PID LPD and CAEBV/HLH cohorts who are eligible for allogeneic HCT: Time to allogeneic HCT [ Time Frame: Up to 2 years ]
  6. For EBV+ sarcomas, including LMS: Clinical benefit rate [ Time Frame: Up to 2 years ]
  7. For EBV+ sarcomas, including LMS: ORR by immune response evaluation criteria in solid tumors (iRECIST) criteria [ Time Frame: Up to 2 years ]

Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 chemotherapy) is not appropriate, including CD20-negative disease:

    • Newly diagnosed, biopsy-proven EBV+ PTLD
    • 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
    • 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

  • For participants with EBV+ viremia with HLH:

    • 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04554914


Contacts
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Contact: Study Director 650-278-8930 ext option 1 clinicalstudies@atarabio.com

Locations
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Sponsors and Collaborators
Atara Biotherapeutics
Investigators
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Study Director: Justin Wahlstrom, MD Atara Biotherapeutics
More Information
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Responsible Party: Atara Biotherapeutics
ClinicalTrials.gov Identifier: NCT04554914    
Other Study ID Numbers: ATA129-EBV-205
2020-000177-25 ( EudraCT Number )
First Posted: September 18, 2020    Key Record Dates
Last Update Posted: November 14, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Atara Biotherapeutics:
Allogeneic, Off-The-Shelf T-cell Immunotherapy
Epstein-Barr Virus (EBV)
Epstein-Barr Virus-specific Cytotoxic T lymphocyte (EBV-CTL)
Solid Organ Transplant (SOT)
Hematopoietic Cell Transplant (HCT)
Additional relevant MeSH terms:
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Virus Diseases
Epstein-Barr Virus Infections
Leiomyosarcoma
Lymphoproliferative Disorders
Lymphohistiocytosis, Hemophagocytic
Primary Immunodeficiency Diseases
Immunologic Deficiency Syndromes
Infections
Sarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
 Neoplasms
Immune System Diseases
Neoplasms, Muscle Tissue
Lymphatic Diseases
Immunoproliferative Disorders
Herpesviridae Infections
DNA Virus Infections
Tumor Virus Infections
Genetic Diseases, Inborn
Histiocytosis, Non-Langerhans-Cell
Histiocytosis