EBV-associated Malignancies, EBV-induced Lymphomas, Transplant Patients With EBV Viremia at High Risk for Developing a Recurrent EBV Lymphoma
Conditions
Keywords
EBV-specific T-cell lines, 11-130
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.
Interventions
BIOLOGICALEBV-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.
Sponsors
Memorial Sloan Kettering Cancer Center
Atara Biotherapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
Yes
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 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 | 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 | 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) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HCT EBV+ PTLD R/R Rituximab Participants with EBV+ PTLD HCT who were R/R to rituximab received IV infusion of tabelecleucel 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 and were 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. | 25 |
| SOT EBV+ PTLD R/R Rituximab Participants with EBV+PTLD SOT who were R/R to rituximab or R/R to rituximab and chemotherapy received IV infusion of tabelecleucel 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 and were 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. | 10 |
| EBV+ Lymphoma Participants with EBV+ lymphoma received IV infusion of tabelecleucel 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 and were 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. | 25 |
| EBV+ NPC Participants with EBV+ NPC received IV infusion of tabelecleucel 2 × 10\^6 T-cells/kg on Days 1, 8, and 15 and were 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. | 14 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Death | 6 | 3 | 1 | 1 | 0 | 0 | 10 | 1 | 0 |
| Overall Study | Other | 5 | 2 | 0 | 0 | 1 | 0 | 3 | 0 | 1 |
| Overall Study | Physician Decision | 3 | 2 | 1 | 1 | 0 | 0 | 8 | 13 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | HCT EBV+ PTLD R/R Rituximab | SOT EBV+ PTLD R/R Rituximab | EBV+ Lymphoma | EBV+ NPC | Total |
|---|---|---|---|---|---|
| Age, Customized <18 years | 5 Participants | 4 Participants | 2 Participants | 2 Participants | 13 Participants |
| Age, Customized >=18 years | 20 Participants | 6 Participants | 23 Participants | 12 Participants | 61 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 0 Participants | 3 Participants | 3 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 19 Participants | 10 Participants | 21 Participants | 11 Participants | 61 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 5 Participants | 11 Participants | 17 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) White | 17 Participants | 9 Participants | 15 Participants | 1 Participants | 42 Participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 15 Participants | 4 Participants | 37 Participants |
| Sex: Female, Male Male | 14 Participants | 3 Participants | 10 Participants | 10 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 46 / 87 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 46 / 87 |
Outcome results
Primary
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.
Time frame: From Day 1 through 65.3 months after Day 1 dose
Population: Full analysis set included all participants who received at least one dose of tabelecleucel.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HCT EBV+ PTLD R/R Rituximab | Objective Response Rate (ORR) | 68.0 Percentage of participants |
| SOT EBV+ PTLD R/R Rituximab | Objective Response Rate (ORR) | 50.0 Percentage of participants |
| EBV+ Lymphoma | Objective Response Rate (ORR) | 16.0 Percentage of participants |
| EBV+ NPC | Objective Response Rate (ORR) | 14.3 Percentage of participants |
Secondary
OS Follow-up Time
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 frame: From Day 1 through 65.3 months after Day 1 dose
Population: Full analysis set included all participants who received at least one dose of tabelecleucel.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HCT EBV+ PTLD R/R Rituximab | OS Follow-up Time | 23.33 Months |
| SOT EBV+ PTLD R/R Rituximab | OS Follow-up Time | 14.88 Months |
| EBV+ Lymphoma | OS Follow-up Time | 7.20 Months |
| EBV+ NPC | OS Follow-up Time | 16.0 Months |
Secondary
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 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 frame: From Day 1 through 12 months after Day 1 dose
Population: Full analysis set included all participants who received at least one dose of tabelecleucel. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HCT EBV+ PTLD R/R Rituximab | OS Rate at 12 Months | 68.0 Percentage of participants |
| SOT EBV+ PTLD R/R Rituximab | OS Rate at 12 Months | 60.0 Percentage of participants |
| EBV+ Lymphoma | OS Rate at 12 Months | 50.3 Percentage of participants |
| EBV+ NPC | OS Rate at 12 Months | 77.9 Percentage of participants |
Secondary
Overall Survival (OS)
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 frame: From Day 1 through 65.3 months after Day 1 dose
Population: Full analysis set included all participants who received at least one dose of tabelecleucel. Participants who were lost to follow-up or still alive were censored on the last known-to-be-alive date.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HCT EBV+ PTLD R/R Rituximab | Overall Survival (OS) | NA Months |
| SOT EBV+ PTLD R/R Rituximab | Overall Survival (OS) | 14.9 Months |
| EBV+ Lymphoma | Overall Survival (OS) | 12.3 Months |
| EBV+ NPC | Overall Survival (OS) | NA Months |
Secondary
Time to Response (TTR)
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.
Time frame: From Day 1 through 65.3 months after Day 1 dose
Population: Full analysis set included all participants who received at least one dose of tabelecleucel. Participants who achieved CR or PR were analyzed for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| HCT EBV+ PTLD R/R Rituximab | Time to Response (TTR) | 1.77 Months |
| SOT EBV+ PTLD R/R Rituximab | Time to Response (TTR) | 3.32 Months |
| EBV+ Lymphoma | Time to Response (TTR) | 2.28 Months |
| EBV+ NPC | Time to Response (TTR) | 1.76 Months |