Summary

Location
at Sacramento, California and other locations
Dates
study started
estimated completion
Principal Investigator
by Mehrdad Abedi, MD

Description

Summary

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

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

Details

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 106 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.

Keywords

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 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) Virus Diseases Primary Immunodeficiency Diseases Immunologic Deficiency Syndromes Tabelecleucel EBV+ PID LPD EBV+ AID LPD EBV+ PTLD CNS EBV+ sarcoma, including LMS CAEBV/ HLH

Eligibility

You can join if…

  • 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 × 103/mL, neutrophils < 1 × 103/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 × 103/mL, neutrophils < 1 × 103/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

You CAN'T join if...

  • 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

Locations

  • University of California Davis Comprehensive Cancer Center (Adults and Pediatrics) accepting new patients
    Sacramento California 95817 United States
  • Children's Hospital of Orange County (Pediatrics [up to 25 years old]) accepting new patients
    Orange California 92868 United States

Lead Scientist at UC Davis

  • Mehrdad Abedi, MD
    Professor, Hematology and Oncology. Authored (or co-authored) 61 research publications.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Atara Biotherapeutics
Links
Sign up for this study
ID
NCT04554914
Phase
Phase 2
Study Type
Interventional
Last Updated