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Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies

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ClinicalTrials.gov Identifier: NCT01498484
Recruitment Status : Completed
First Posted : December 23, 2011
Results First Posted : October 21, 2022
Last Update Posted : October 21, 2022
Sponsor:
Collaborator:
Memorial Sloan Kettering Cancer Center
Information provided by (Responsible Party):
Atara Biotherapeutics

Tracking Information
First Submitted Date  ICMJE December 21, 2011
First Posted Date  ICMJE December 23, 2011
Results First Submitted Date  ICMJE June 30, 2022
Results First Posted Date  ICMJE October 21, 2022
Last Update Posted Date October 21, 2022
Actual Study Start Date  ICMJE December 2011
Actual Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2022)
Objective Response Rate (ORR) [ Time Frame: From Day 1 through 65.3 months after Day 1 dose ]
The ORR is defined as percentage of participants with best overall response of complete remission/response (CR) or partial remission/response (PR) based on investigator's assessment. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR is complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of the affected tissues when indicated, lasting for at least 3 weeks following completion of a cycle of tabelecleucel; and PR is a 50 % or greater reduction in the size of all lymphomatous lesions as determined by computed tomography (CT) or magnetic resonance imaging (MRI) measurements of tumor volume, which was maintained for at least 3 weeks following completion of a cycle of tabelecleucel. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR is clearance of EBV without subsequent development of EBV+ LPD; and PR is at least a 10-fold decrease in EBV DNA levels.
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2011)
efficacy [ Time Frame: 3 weeks ]
The responses of the clinically and/or radiologically evident EBV LPD or malignancies will be identified three weeks post-infusion cycle as complete remission, partial remission, stable disease, or no response with disease progression.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2022)
  • Overall Survival (OS) [ Time Frame: From Day 1 through 65.3 months after Day 1 dose ]
    The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.
  • OS Rate at 12 Months [ Time Frame: From Day 1 through 12 months after Day 1 dose ]
    Percentage of participants with OS at 12 months are reported. The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.
  • OS Follow-up Time [ Time Frame: From Day 1 through 65.3 months after Day 1 dose ]
    The OS follow-up time are reported. The OS is defined as the time from the first dose of tabelecleucel to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.
  • Time to Response (TTR) [ Time Frame: From Day 1 through 65.3 months after Day 1 dose ]
    The TTR is defined as the time from the date of the first dose of tabelecleucel to the date of a PR or CR, whichever occurred first. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR is defined as complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of the affected tissues when indicated, lasting for at least 3 weeks following completion of a cycle of tabelecleucel; and a PR is defined as a 50 % or greater reduction in the size of all lymphomatous lesions as determined by CT or MRI scan measurements of tumor volume, which was maintained for at least 3 weeks following completion of a cycle of tabelecleucel. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR is defined as clearance of EBV without subsequent development of EBV+ LPD; and PR is defined as at least a 10-fold decrease in EBV DNA levels.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2011)
remaining EBV-LPD free [ Time Frame: 6 months ]
Complete remission: Complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of affected tissues when indicated, lasting for at least three weeks following completion of a course of cell infusions.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Therapeutic Effects of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies
Official Title  ICMJE A Phase II Study of the Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From a Normal HLA-Compatible Or Partially-Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies
Brief Summary This is a Phase II trial to evaluate the efficacy and safety of human leukocyte antigen (HLA) partially-matched third-party allogeneic Epstein-Barr virus cytotoxic T lymphocytes (EBV-CTLs) for the treatment of EBV-induced lymphomas and EBV-associated malignancies.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • EBV-induced Lymphomas
  • EBV-associated Malignancies
  • Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma
Intervention  ICMJE Biological: EBV-specific T cells (EBV-CTLs)
EBV-CTLs are cytotoxic T lymphocytes that specifically kill cells presenting EBV protein antigens including EBV-transformed B lymphocytes responsible for EBV-associated lymphomas and lymphoproliferative disorders.
Other Names:
  • tabelecleucel
  • tab-cel®
  • ATA129
Study Arms  ICMJE
  • Experimental: HCT EBV+ PTLD R/R Rituximab
    Patients with Epstein-Barr virus positive (EBV+) posttransplant lymphoproliferative disorders (PTLD) hematopoietic cell transplant (HCT) who were relapse/refractory (R/R) to rituximab will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: SOT EBV+ PTLD R/R Rituximab
    Patients with EBV+PTLD solid organ transplant (SOT) who were R/R to rituximab or R/R to rituximab and chemotherapy will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After 3 week observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ AID-LPD
    Patients with EBV+ acquired immunodeficiency (AID) lymphoproliferative disorder (LPD) will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ PID-LPD
    Patients with EBV+ primary immunodeficiency (PID) LPD will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ Viremia
    Patients with EBV+ viremia will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ Leiomyosarcoma
    Patients with EBV+ leiomyosarcoma (LMS) will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ Lymphoma
    Patients with EBV+ lymphoma will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ NPC
    Patients with EBV+ nasopharyngeal carcinoma (NPC) will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
  • Experimental: EBV+ Other Solid Tumor
    Patients with EBV+ other solid tumors will receive IV infusion of tabelecleucel 2 × 10^6 T-cells/kg on Days 1, 8, and 15 and will be observed for 3 weeks. After the observation period, additional courses (2 courses) may have been provided in the absence of disease progression or unacceptable toxicity.
    Intervention: Biological: EBV-specific T cells (EBV-CTLs)
Publications * Prockop S, Doubrovina E, Suser S, Heller G, Barker J, Dahi P, Perales MA, Papadopoulos E, Sauter C, Castro-Malaspina H, Boulad F, Curran KJ, Giralt S, Gyurkocza B, Hsu KC, Jakubowski A, Hanash AM, Kernan NA, Kobos R, Koehne G, Landau H, Ponce D, Spitzer B, Young JW, Behr G, Dunphy M, Haque S, Teruya-Feldstein J, Arcila M, Moung C, Hsu S, Hasan A, O'Reilly RJ. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest. 2020 Feb 3;130(2):733-747. doi: 10.1172/JCI121127.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 10, 2019)
87
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2011)
58
Actual Study Completion Date  ICMJE July 2019
Actual Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma or other EBV-associated malignancy.

OR

  • Evaluable disease as demonstrated by clinical and/or radiologic studies with current or prior elevated blood levels of EBV DNA exceeding 500 copies/ml by quantitative real time polymerase chain reaction (PCR).

OR

  • Persistent or recurrent elevations in levels of EBV DNA exceeding 500 copies/ml in patients previously treated for EBV-LPD with chemotherapy and/or rituximab who do not yet have clinically or radiologically evaluable disease but are at high risk of disease recurrence.
  • EBV-specific T cells are available for adoptive immune cell therapy from a consenting third party donor. The third party EBV-CTLs to be administered will be selected on the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and 2) that they are restricted by an allele shared with the EBV+ malignancy (if known), or with the donor in HSCT recipients, or patient in organ transplant or immunodeficient patients
  • KPS or Lansky score ≥ 20.
  • A life expectancy of at least 6 weeks.
  • Adequate bone marrow, heart, lung, liver and kidney function at the time of treatment with EBV-specificT cells is initiated, including:

    1. Absolute neutrophil count (ANC) ≥ 1,000/µL, with or without GCSF support
    2. Platelets ≥ 20,000/µL
    3. Creatinine ≤ 2.0mg/dl
    4. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3.0x and total bilirubin < 2.5x the institutional upper limit of normal (ULN)
    5. Stable blood pressure and circulation not requiring pressor support
    6. Adequate cardiac function as demonstrated by EKG and/or echocardiographic evidence (may be performed within 30 days prior to treatment)
  • However, abnormalities of specific organs will not be considered grounds for exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a renal allograft recipient with an EBV LPD may be on dialysis because the allograft was rejected when the immune suppression was stopped as a first approach to treatment of the EBV LPD). At the discretion of the investigator, patients with elevated but stable creatinine will not be precluded from treatment on study.
  • There is no age restriction to eligibility for this protocol.

It is expected that five types of patients afflicted with EBV-associated lymphomas, lymphoproliferative diseases or malignancies will be referred and will consent to participate in this trial. These are:

  1. Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie, marrow, PBSC, or umbilical cord blood).
  2. Patients developing EBV lymphomas or lymphoproliferative disorders following an allogeneic organ transplant.
  3. Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a consequence of the profound acquired immunodeficiency induced by HIV.
  4. Patients who develop EBV lymphomas or lymphoproliferative diseases or other EBV-associated malignancy as a consequence of profound immunodeficiencies associated with a congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive therapy.
  5. Patients who develop other EBV-associated malignancies without pre-existing immune deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma.

Exclusion Criteria:

The following patients will be excluded from this study:

  • Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment
  • Patients who are pregnant
  • Patients with severe comorbidities, not related to their EBV-associated malignancy, that would be expected to preclude their survival for the 6 weeks required to assess response of T cell therapy
  • Patients eligible for MSK protocol #16-803 (EBV-CTL-201)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE Child, Adult, Older Adult
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01498484
Other Study ID Numbers  ICMJE 11-130
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Atara Biotherapeutics
Original Responsible Party Memorial Sloan Kettering Cancer Center
Current Study Sponsor  ICMJE Atara Biotherapeutics
Original Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Memorial Sloan Kettering Cancer Center
Investigators  ICMJE
Study Director: Minoti Hiremath, MD Atara Biotherapeutics
PRS Account Atara Biotherapeutics
Verification Date September 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP