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

NCT ID: NCT01498484

Last Updated: 2022-10-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 87 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-12-31
• Study Completion Date: 2019-07-31

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.

Conditions

EBV-induced Lymphomas; EBV-associated Malignancies; Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

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.

Group Type: EXPERIMENTAL

EBV-specific T cells (EBV-CTLs)

Intervention Type: BIOLOGICAL

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.

Interventions

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.

Intervention Type: BIOLOGICAL

Other Intervention Names

tabelecleucel; tab-cel®; ATA129

Eligibility Criteria

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)

• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Memorial Sloan Kettering Cancer Center

OTHER

Sponsor Role: collaborator

Atara Biotherapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Minoti Hiremath, MD

Role: STUDY_DIRECTOR

Atara Biotherapeutics

Locations

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 31689242 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.mskcc.org/

Memorial Sloan Kettering Cancer Center

Other Identifiers

11-130

Identifier Type: -

Identifier Source: org_study_id