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Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1 And EBNA1 Specific CTL, EBV-Positive Lymphoma (MABEL) (MABEL)

Primary Purpose

Hodgkin Disease, Non-Hodgkin Lymphoma, Severe Chronic Active Epstein Barr Virus

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

MABEL CTLs

Cyclophosphamide

Fludarabine

About this trial

This is an interventional treatment trial for Hodgkin Disease focused on measuring EBV positive diseases, cytotoxic T lymphocytes

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

SCREENING

Any patient regardless of age or sex, with diagnosis of either:
- EBV positive Hodgkin's lymphoma
- EBV Positive non-Hodgkin's Lymphoma (regardless of histologic subtype)
- EBV (associated)-T/NK-lymphoproliferative disease
- Severe Chronic Active EBV (CAEBV) -- CAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV
- Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, smooth muscle tumors, etc.)
AND
- in first or subsequent relapse (Group A)
- with active disease persisting despite therapy (Group B)
- with active disease if immunosuppressive chemotherapy is contraindicated e.g. patients who develop Hodgkin disease after solid organ transplantation or if the lymphoma is a second malignancy e.g. a Richter's transformation of CLL. (Group C)
EBV positive tumor
Weighs at least 12kg
Informed consent (and assent as applicable) obtained from patient/guardian.

TREATMENT

Any patient regardless of age or sex, with diagnosis of either:
- EBV positive Hodgkin's lymphoma
- EBV Positive non-Hodgkin's Lymphoma (regardless of histologic subtype)
- EBV (associated)-T/NK-lymphoproliferative disease
- Severe Chronic Active EBV (CAEBV) -- CAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV
- Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, smooth muscle tumors, etc.)
AND
- in first or subsequent relapse (Group A)
- with active disease persist despite therapy (Group B)
- with active disease if immunosuppressive chemotherapy is contraindicated e.g. patients who develop Hodgkin disease after solid organ transplantation or if the lymphoma is a second malignancy e.g. a Richter's transformation of CLL. (Group C)
EBV positive tumor
Patients with life expectancy greater than or equal to 6 weeks
Patients with bilirubin less than or equal to 3x upper limit of normal
AST less than or equal to 5x upper limit of normal
Hemoglobin greater than or equal to 7.0 (may be a transfused value)
Patients with a creatinine less than or equal to 2x upper limit of normal for age
Pulse oximetry of > 90% on room air
Patients should have been off other investigational therapy for 30 days prior to infusion.
Patients with a Karnofsky/Lansky score of more than or equal to 50.
Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom.
Informed consent (and assent as applicable) obtained from patient/guardian.

Exclusion Criteria:

TREATMENT

Pregnant or lactating
Severe intercurrent infection
Current use of systemic corticosteroids more than 0.5 mg/kg/day
Patients receiving ATG, Campath, or other immunosuppressive T cell monoclonal antibodies within 30 days.

Sites / Locations

Houston Methodist HospitalRecruiting
Texas Children's HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Group A: MABEL CTLs

Group B: MABEL CTLs

Group C: MABEL CTLs

Arm Description

Patients with 1st or subsequent relapse. Three different dosing schedules will be evaluated. Two to four patients will be evaluated on each dosing schedule. Each patient will receive 2 injections, 14 days apart. If the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide (Cytoxan) and Fludarabine before s/he receives MABEL CTLs.

Patients with persistent active disease despite therapy. Three different dosing schedules will be evaluated. Two to four patients will be evaluated on each dosing schedule. Each patient will receive 2 injections, 14 days apart. If the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide (Cytoxan) and Fludarabine before s/he receives MABEL CTLs.

Patients with active disease if immunosuppressive chemotherapy is contraindicated. Three different dosing schedules will be evaluated. Two to four patients will be evaluated on each dosing schedule. Each patient will receive 2 injections, 14 days apart. If the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide (Cytoxan) and Fludarabine before s/he receives MABEL CTLs.

Outcomes

Primary Outcome Measures

Number of patients with a dose-limiting toxicity (DLT)

To evaluate the safety of administering escalating doses of banked allogeneic, partially HLA-matched rapid EBV specific T cells.

Secondary Outcome Measures

percent of patients whose best response is either complete remission or partial remission

To measure anti-tumor and anti-viral effects of ESTs

Full Information

NCT ID

NCT02287311

First Posted

November 6, 2014

Last Updated

January 13, 2023

Sponsor

Baylor College of Medicine

Collaborators

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital Research Institute

1. Study Identification

Unique Protocol Identification Number

NCT02287311

Brief Title

Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1 And EBNA1 Specific CTL, EBV-Positive Lymphoma (MABEL)

Acronym

MABEL

Official Title

ADMINISTRATION OF MOST CLOSELY MATCHED THIRD PARTY RAPIDLY GENERATED LMP, BARF1 and EBNA1 SPECIFIC CYTOTOXIC T-LYMPHOCYTES TO PATIENTS WITH EBV-POSITIVE LYMPHOMA AND OTHER EBV-POSITIVE MALIGNANCIES

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

February 2015 (undefined)

Primary Completion Date

February 2024 (Anticipated)

Study Completion Date

March 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Baylor College of Medicine

Collaborators

Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital Research Institute

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The subject has a type of cancer or lymph gland disease associated with a virus called Epstein Barr Virus (EBV), which has come back, is at risk of coming back, or has not gone away after standard treatments. This research study uses special immune system cells called LMP, BARF-1 and EBNA1- specific cytotoxic T lymphocytes (MABEL CTLs). Some patients with Lymphoma (such as Hodgkin (HD) or non-Hodgkin Lymphoma (NHL)), T/NK-lymphoproliferative disease, or CAEBV, or solid tumors such as nasopharyngeal carcinoma (NPC), smooth muscle tumors, and leiomyosarcomas show signs of a virus called EBV before or at the time of their diagnosis. EBV causes mononucleosis or glandular fever ("mono" or the "kissing disease"). EBV is found in the cancer cells of up to half the patients with HD and NHL, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some immune system cells (in CAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. EBV is also found in the majority of NPC and smooth muscle tumors, and some leiomyosarcomas. We want to see if special white blood cells (MABEL CTLs) that have been trained to kill EBV infected cells can survive in your blood and affect the tumor. In previous studies, EBV CTLs were generated from the blood of the patient, which was often difficult if the patient had recently received chemotherapy. Also, it took up to 1-2 months to make the cells, which is not practical when a patient needs more urgent treatment. To address these issues, the MABEL CTLs were made in the lab in a simpler, faster, and safer way. The MABEL CTLs will still see LMP proteins but also two other EBV proteins called EBNA-1 and BARF. To ensure these cells are available for use in patients in urgent clinical need, we have generated MABEL CTLs from the blood of healthy donors and created a bank of these cells, which are frozen until ready for use. We have previously successfully used frozen T cells from healthy donors to treat EBV lymphoma and virus infections and we now have improved our production method to make it faster. In this study, we want to find out if we can use banked MABEL CTLs to treat HD, NHL, T/NK-lymphoproliferative disease, CAEBV, NPC, smooth muscle tumors or leiomyosarcoma. We will search the bank to find a MABEL CTL line that is a partial match with the subject. MABEL CTLs are investigational and not approved by the Food and Drug Administration.

Detailed Description

A healthy donor has given blood to make LMP/BARF1/EBNA-1 MABEL CTLs in the lab. We made the cells by first growing a special type of cells called activated T cells to stimulate the T cells. We then added specially produced mixtures of proteins that include the LMP, EBNA1 and BARF proteins. These were used to stimulate T cells. As the T cells grew, we added some of the healthy donor cells expressing these proteins to stimulate them. We also added a cell called K562 that has had new genes put inside it so it expresses proteins that stimulate the immune system to encourage the T cells to grow. K562 cells are cancer cells that have been treated with radiation so they cannot grow. This stimulation trained the MABEL CTLs to kill cells with EBV proteins on their surface. These cells were grown and frozen. For the subject's treatment, the MABEL CTLs will be thawed and infused into the subject over 1-10 minutes. Initially, two doses of MABEL CTLs will be given two weeks apart. Subjects may be eligible to receive additional doses of the MABEL CTLs up to 6 times. All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital. Medical tests before treatment: Before being treated, the subject will receive a series of standard medical tests: Physical exam; Blood tests to measure blood cells, kidney and liver function; Tumor measurements by routine imaging studies: Computer Tomogram (CT), Magnetic Resonance Imaging (MRI), or Positron Emission Tomography (PET/CT); Pregnancy test for females who are able to have children. Several studies suggest that the infused T cells need room to be able to proliferate and accomplish their functions and that this may not happen if there are too many other T cells in circulation. Because of that, if the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide (Cytoxan) and fludarabine before s/he receives MABEL CTLs. Medical tests during and after treatment: Blood tests to measure blood cells, kidney and liver function; Imaging study 8 weeks after the 1st CTL infusion. If the subject receives additional doses they will also have an imaging study at 1 to 3 months after their final dose. Subjects will either be seen in the clinic or will be contacted by research staff yearly for 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hodgkin Disease, Non-Hodgkin Lymphoma, Severe Chronic Active Epstein Barr Virus, T/NK-lymphoproliferative Disease, Nasopharyngeal Carcinoma, Smooth Muscle Tumor

Keywords

EBV positive diseases, cytotoxic T lymphocytes

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

42 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group A: MABEL CTLs

Arm Type

Experimental

Arm Description

Arm Title

Group B: MABEL CTLs

Arm Type

Experimental

Arm Description

Arm Title

Group C: MABEL CTLs

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

MABEL CTLs

Other Intervention Name(s)

LMP, BARF-1 and EBNA1 specific cytotoxic T lymphocytes, MABEL Cytotoxic T cells

Intervention Description

Dose escalation: DL1:2x10^7 cells/m2+2x10^7 cells/m2 DL2:2x10^7cells/m2+5x10^7 cells/m2 DL3:5x10^7 cells/m2+1x10^8 cells/m2 *Doses are based on total CD3+cells/m2 Patients with active disease that have apparent clinical benefit at the 8 wk post 1st infusion (6 wks after 2nd infusion) or subsequent evaluations may receive up to 6 additional doses of CTLs at intervals at least 6 wks apart, each of which will consist of the same cell number as their second injection or below the original dose if there is not enough product available for the original dose. Patients may receive lymphodepleting chemotherapy (Cy/Flu) before additional infusions. Patients cannot receive additional doses until the initial safety profile is completed at 6 wks following the second infusion.

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

If the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide (Cytoxan) and Fludarabine before s/he receives MABEL CTLs. 3 daily doses of cyclophosphamide (Cy: 500 mg/m2/day) together with fludarabine (Flu: 30 mg/m2) to induce lymphopenia, finishing at least 24 hours before CTL infusion.

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara

Intervention Description

If the patient's level of circulating T cells is relatively high, s/he may require treatment with cyclophosphamide and fludarabine before s/he receives MABEL CTLs. 3 daily doses of cyclophosphamide (Cy: 500 mg/m2/day) together with fludarabine (Flu: 30 mg/m2) to induce lymphopenia, finishing at least 24 hours before CTL infusion.

Primary Outcome Measure Information:

Title

Number of patients with a dose-limiting toxicity (DLT)

Description

To evaluate the safety of administering escalating doses of banked allogeneic, partially HLA-matched rapid EBV specific T cells.

Time Frame

8 weeks

Secondary Outcome Measure Information:

Title

percent of patients whose best response is either complete remission or partial remission

Description

To measure anti-tumor and anti-viral effects of ESTs

Time Frame

8 weeks

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: SCREENING Any patient regardless of age or sex, with diagnosis of either: EBV positive Hodgkin's lymphoma EBV Positive non-Hodgkin's Lymphoma (regardless of histologic subtype) EBV (associated)-T/NK-lymphoproliferative disease Severe Chronic Active EBV (CAEBV) -- CAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, smooth muscle tumors, etc.) AND in first or subsequent relapse (Group A) with active disease persisting despite therapy (Group B) with active disease if immunosuppressive chemotherapy is contraindicated e.g. patients who develop Hodgkin disease after solid organ transplantation or if the lymphoma is a second malignancy e.g. a Richter's transformation of CLL. (Group C) EBV positive tumor Weighs at least 12kg Informed consent (and assent as applicable) obtained from patient/guardian. TREATMENT Any patient regardless of age or sex, with diagnosis of either: EBV positive Hodgkin's lymphoma EBV Positive non-Hodgkin's Lymphoma (regardless of histologic subtype) EBV (associated)-T/NK-lymphoproliferative disease Severe Chronic Active EBV (CAEBV) -- CAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV Other EBV positive malignancies (e.g. nasopharyngeal carcinoma, smooth muscle tumors, etc.) AND in first or subsequent relapse (Group A) with active disease persist despite therapy (Group B) with active disease if immunosuppressive chemotherapy is contraindicated e.g. patients who develop Hodgkin disease after solid organ transplantation or if the lymphoma is a second malignancy e.g. a Richter's transformation of CLL. (Group C) EBV positive tumor Patients with life expectancy greater than or equal to 6 weeks Patients with bilirubin less than or equal to 3x upper limit of normal AST less than or equal to 5x upper limit of normal Hemoglobin greater than or equal to 7.0 (may be a transfused value) Patients with a creatinine less than or equal to 2x upper limit of normal for age Pulse oximetry of > 90% on room air Patients should have been off other investigational therapy for 30 days prior to infusion. Patients with a Karnofsky/Lansky score of more than or equal to 50. Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom. Informed consent (and assent as applicable) obtained from patient/guardian. Exclusion Criteria: TREATMENT Pregnant or lactating Severe intercurrent infection Current use of systemic corticosteroids more than 0.5 mg/kg/day Patients receiving ATG, Campath, or other immunosuppressive T cell monoclonal antibodies within 30 days.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Rayne H Rouce, MD

Phone

832-824-4716

rouce@bcm.edu

First Name & Middle Initial & Last Name or Official Title & Degree

David Allen

Phone

832-824-4391

dlallen@texaschildrens.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Rayne H Rouce, MD

Organizational Affiliation

Baylor College of Medicine

Official's Role

Principal Investigator

Facility Information:

Facility Name

Houston Methodist Hospital

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Helen E Heslop

Phone

832-824-4662

hheslop@bcm.edu

Facility Name

Texas Children's Hospital

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Rayne H Rouce, MD

Phone

832-824-4716

rouce@bcm.edu

12. IPD Sharing Statement

Learn more about this trial

Most Closely Matched 3rd Party Rapidly Generated LMP, BARF1 And EBNA1 Specific CTL, EBV-Positive Lymphoma (MABEL)

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