Biological Therapy in Treating Patients at High-Risk or With Lymphoma, Lymphoproliferative Disease, or Malignancies

Study Overview
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Brief Summary
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The purpose of this phase I/II trial is to study the side effects and best dose of biological therapy to treat patients at high-risk or with Epstein-Barr virus-associated lymphoma or lymphoproliferative disease.

Official Title
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An Evaluation of the Toxicity and Therapeutic Effects of Epstein-Barr Virus-Immune T-Lymphocytes Derived From a Normal HLA-Compatible or Haplotype-Matched Donor in the Treatment of EBV-Associated Lymphoproliferative Diseases or Malignancies and Patients With Detectable Circulating Levels of EBV DNA Who Are at High Risk for EBV-Associated Lymphoproliferative Diseases

Conditions
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EBV-induced Lymphomas, EBV-associated Malignancies, Transplant Patients With EBV Viremia at High Risk of Developing a Recurrent EBV Lymphoma

Intervention / Treatment
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* Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma, or other EBV-associated malignancy OR Severely immunocompromised patients who develop blood levels of EBV DNA exceeding 500 copies/ml DNA, and are therefore at high risk for developing an EBV LPD It is expected that five types of patients afflicted with EBV-associated lymphomas or lymphoproliferative diseases will be referred and will consent to participate in this trial. These are: Patients developing or at risk for EBV lymphomas or lymphoproliferative disorders following an allogeneic marrow transplant. Patients developing or at risk for EBV lymphomas or lymphoproliferative disorders following an allogeneic organ transplant. Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a consequence of the profound acquired immunodeficiency induced by HIV. Patients who develop EBV lymphomas or lymphoproliferative diseases as a consequence of profound immunodeficiencies associated with a congenital immune deficit or acquired as a sequela of anti-neoplastic or immunosuppressive therapy. 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: Moribund patients who, by virtue of heart, kidney, liver, lung, or neurologic dysfunction not related to lymphoma, are unlikely to survive the 6-8 weeks required for in vitro generation and expansion of the EBV-specific T cells to be used for therapy and the subsequent 3 weeks required to achieve an initial assessment of the effects of infusions of EBV-specific T cells. Pregnancy does not constitute a contraindication to infusions of EBV-specific T cells.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EBV+ PTLD-HCT R/R Rituximab (Tab-cel Only)<br>Patients with Epstein-Barr virus positive (EBV+) posttransplant lymphoproliferative disorders (PTLD) following hematopoietic cell transplant (HCT) who were relapse/refractory (R/R) to rituximab will receive IV infusion of tabelecleucel (tab-cel) at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ PTLD-SOT R/R Rituximab + Chemo (Tab-cel Only)<br>Patients with EBV+ PTLD following solid organ transplant (SOT) who were R/R to rituximab and chemotherapy will receive IV infusion of tabelecleucel at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ AID-LPD (Tab-cel Only)<br>Patients with EBV+ acquired immunodeficiency (AID) lymphoproliferative disorder (LPD) will receive IV infusion of tabelecleucel at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ LMS (Tab-cel Only)<br>Patients with EBV+ leiomyosarcoma (LMS) will receive IV infusion of tabelecleucel at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ NPC (Tab-cel Only)<br>Patients with EBV+ nasopharyngeal carcinoma (NPC) will receive IV infusion of tabelecleucel at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ PTLD-HCT R/R Rituximab (EBV-CTLs Only)<br>Patients with EBV+ following PTLD HCT who were R/R to rituximab or rituximab naive will receive IV infusion of transplant donor-derived EBV-cytotoxic T lymphocytes (CTLs) at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ PTLD-SOT R/R Rituximab + Chemo (EBV-CTLs Only)<br>Patients with EBV+ PTLD following SOT who were R/R to rituximab and chemotherapy will receive IV infusion of transplant donor-derived EBV-CTLs at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ Viremia (EBV-CTLs Only)<br>Patients with EBV+ viremia will receive IV infusion of transplant donor-derived EBV-CTLs at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ PID-LPD (Tab-cel or EBV-CTLs)<br>Patients with EBV+ primary immunodeficiency (PID) LPD will receive IV infusion of tabelecleucel or transplant donor-derived EBV- CTLs at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|
| Experimental: EBV+ Lymphoma (Tab-cel or EBV-CTLs)<br>Patients with EBV+ lymphoma will receive IV infusion of tabelecleucel or transplant donor-derived EBV-CTLs at 1-5 × 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. | Biological: Epstein-Barr virus-specific cytotoxic T lymphocytes (EBV-CTLs)<br>* 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.<br>* Other names: transplant donor-derived EBV-CTLs;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | 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. | From Day 1 through 251.1 months after Day 1 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | The OS is defined as the time from the first dose of tabelecleucel or EBV-CTLs to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. | From Day 1 through 251.1 months after Day 1 dose | 
| OS Rate at 12 Months | Percentage of participants with OS at 12 months are reported. The OS is defined as the time from the first dose of tabelecleucel or EBV-CTLs to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. | From Day 1 through 12 months after Day 1 dose | 
| OS Follow-up Time | The OS at follow-up time are reported. The OS is defined as the time from the first dose of tabelecleucel or EBV-CTLs to the date of death due to any cause. The OS was estimated using Kaplan-Meier method. | From Day 1 through 251.1 months after Day 1 dose | 
| Time to Response (TTR) | The TTR was defined as the time from the date of the first dose of tabelecleucel or EBV-CTLs to the date of a PR or CR, whichever occurred first. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR was 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 or EBV-CTLs; and a PR was 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 or EBV-CTLs. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR was defined as clearance of EBV without subsequent development of EBV+ LPD; and PR was defined as at least a 10-fold decrease in EBV DNA levels. | From Day 1 through 251.1 months after Day 1 dose | 
| Clinical Benefit Rate (CBR) | The CBR was the proportion of participants who have achieved a CR, PR or SD assessed at least 28 days after first dose date of study drug. For participants with clinically and/or radiologically evident EBV LPD or malignancies, CR as complete resolution of all clinical and radiologic evidence of lymphoma, confirmed by biopsy of affected tissues when indicated, lasting for at least 3 weeks following completion of a cycle of tabelecleucel or EBVCTLs; and a PR as a >= 50% reduction in size of all lymphomatous lesions as determined by CT or MRI scan measurements of tumor volume, maintained for at least 3 weeks following completion of a cycle of tabelecleucel or EBV-CTLs. For participants without clinically and/or radiologically evident tumors with increasing levels of EBV DNA, CR as clearance of EBV without subsequent development of EBV+ LPD; and PR as at least a 10-fold decrease in EBV DNA levels. The CBR was included specifically as clinically meaningful for solid tumor, namely LMS. | From Day 1 through 251.1 months after Day 1 dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I adult Hodgkin lymphoma, stage II adult Hodgkin lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, recurrent adult Hodgkin lymphoma, stage IV childhood Hodgkin lymphoma, recurrent/refractory childhood Hodgkin lymphoma, stage I grade 1 follicular lymphoma, stage I grade 2 follicular lymphoma, stage I grade 3 follicular lymphoma, stage I adult diffuse small cleaved cell lymphoma, stage I adult diffuse mixed cell lymphoma, stage I adult diffuse large cell lymphoma, stage I adult immunoblastic large cell lymphoma, stage I adult lymphoblastic lymphoma, stage I adult Burkitt lymphoma, T-cell large granular lymphocyte leukemia, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage III adult diffuse large cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage III adult Burkitt lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage IV adult diffuse small cleaved cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage IV adult diffuse large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage IV adult lymphoblastic lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage III childhood large cell lymphoma, stage IV childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma, recurrent childhood small noncleaved cell lymphoma, recurrent childhood large cell lymphoma, contiguous stage II grade 1 follicular lymphoma, contiguous stage II grade 2 follicular lymphoma, contiguous stage II grade 3 follicular lymphoma, contiguous stage II adult diffuse small cleaved cell lymphoma, contiguous stage II mantle cell lymphoma, contiguous stage II adult diffuse mixed cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, contiguous stage II adult diffuse large cell lymphoma, contiguous stage II adult Burkitt lymphoma, contiguous stage II adult lymphoblastic lymphoma, stage I cutaneous T-cell non-Hodgkin lymphoma, stage II cutaneous T-cell non-Hodgkin lymphoma, stage III cutaneous T-cell non-Hodgkin lymphoma, stage IV cutaneous T-cell non-Hodgkin lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, childhood Burkitt lymphoma, stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma, recurrent childhood lymphoblastic lymphoma, childhood diffuse large cell lymphoma, childhood immunoblastic large cell lymphoma, stage II childhood Hodgkin lymphoma, stage I childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma, stage IV adult Burkitt lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult Burkitt lymphoma, stage I adult T-cell leukemia/lymphoma, stage II adult T-cell leukemia/lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, recurrent adult T-cell leukemia/lymphoma, AIDS-related peripheral/systemic lymphoma, HIV-associated Hodgkin lymphoma, stage I childhood small noncleaved cell lymphoma, stage I childhood large cell lymphoma, stage I mantle cell lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, recurrent mantle cell lymphoma, stage I mycosis fungoides/Sezary syndrome, stage II mycosis fungoides/Sezary syndrome, stage III mycosis fungoides/Sezary syndrome, stage IV mycosis fungoides/Sezary syndrome, recurrent mycosis fungoides/Sezary syndrome, contiguous stage II small lymphocytic lymphoma, contiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, noncontiguous stage II marginal zone lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, stage I marginal zone lymphoma, stage I small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage III marginal zone lymphoma, stage IV small lymphocytic lymphoma, stage IV marginal zone lymphoma, unspecified adult solid tumor, protocol specific, unspecified childhood solid tumor, protocol specific