ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02287311
Recruitment Status : Recruiting
First Posted : November 10, 2014
Last Update Posted : August 10, 2018
Sponsor:
Collaborators:
Center for Cell and Gene Therapy, Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Information provided by (Responsible Party):
Rayne Rouce, Baylor College of Medicine

Brief Summary:

The subject has a type of lymph gland disease called Hodgkin Disease (HD) or non-Hodgkin Lymphoma (NHL), T/NK-lymphoproliferative disease or severe chronic active Epstein Barr Virus (CAEBV) which has come back, is at risk of coming back, or has not gone away after treatment, including the best treatment we know for these diseases. This research study uses special immune system cells called LMP, BARF-1 and EBNA1- specific cytotoxic T lymphocytes (MABEL CTLs).

Some patients with Lymphoma, T/NK-lymphoproliferative disease, or CAEBV show signs of a virus called Epstein Barr virus (EBV) that causes mononucleosis or glandular fever ("mono" or the "kissing disease") before or at the time of their diagnosis. EBV is found in 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. 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 treatment more urgently. To address these issues, the T cells in the current study were made in the laboratory in a simpler, faster, and safer way. The T cells we have made will still see LMP proteins but also two other EBV proteins called EBNA-1 and BARF. These cells are called MABEL CTLs. In order 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 or NHL, T/NK-lymphoproliferative disease and severe chronic active Epstein Barr Virus (CAEBV). We will search the bank to find a MABEL CTL line that is a partial match with the subject.


Condition or disease Intervention/treatment Phase
Hodgkin Disease Non-Hodgkin Lymphoma Severe Chronic Active Epstein Barr Virus T/NK-lymphoproliferative Disease Biological: MABEL CTLs Drug: Cyclophosphamide Drug: Fludarabine Phase 1

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 trains 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : February 2015
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Group A: MABEL CTLs

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.

Biological: MABEL CTLs

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.

Other Names:
  • LMP, BARF-1 and EBNA1 specific cytotoxic T lymphocytes
  • MABEL Cytotoxic T cells

Drug: Cyclophosphamide

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.

Other Name: Cytoxan

Drug: Fludarabine

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.

Other Name: Fludara

Experimental: Group B: 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.

Biological: MABEL CTLs

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.

Other Names:
  • LMP, BARF-1 and EBNA1 specific cytotoxic T lymphocytes
  • MABEL Cytotoxic T cells

Drug: Cyclophosphamide

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.

Other Name: Cytoxan

Drug: Fludarabine

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.

Other Name: Fludara

Experimental: Group C: 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.

Biological: MABEL CTLs

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.

Other Names:
  • LMP, BARF-1 and EBNA1 specific cytotoxic T lymphocytes
  • MABEL Cytotoxic T cells

Drug: Cyclophosphamide

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.

Other Name: Cytoxan

Drug: Fludarabine

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.

Other Name: Fludara




Primary Outcome Measures :
  1. Number of patients with a dose-limiting toxicity (DLT) [ Time Frame: 8 weeks ]
    To evaluate the safety of administering escalating doses of banked allogeneic, partially HLA-matched rapid EBV specific T cells.


Secondary Outcome Measures :
  1. percent of patients whose best response is either complete remission or partial remission [ Time Frame: 8 weeks ]
    To measure anti-tumor and anti-viral effects of ESTs



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

SCREENING

  1. 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, or
    • 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

    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)
  2. EBV positive tumor
  3. Weighs at least 12kg
  4. Informed consent (and assent as applicable) obtained from patient/guardian.

TREATMENT

  1. 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, or
    • 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

    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)
  2. EBV positive tumor
  3. Patients with life expectancy greater than or equal to 6 weeks.
  4. Patients with bilirubin less than or equal to 3x upper limit of normal
  5. AST less than or equal to 5x upper limit of normal
  6. Hgb more than 8.0 (may be a transfused value).
  7. Patients with a creatinine less than or equal to 2x upper limit of normal for age
  8. Pulse oximetry of > 90% on room air
  9. Patients should have been off other investigational therapy for 30 days prior to infusion.
  10. Patients with a Karnofsky/Lansky score of more than or equal to 50.
  11. 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.
  12. Informed consent (and assent as applicable) obtained from patient/guardian.

Exclusion Criteria:

TREATMENT

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02287311


Contacts
Contact: Rayne H Rouce, MD 832-824-4716 rouce@bcm.edu
Contact: Amy Reyna 832-824-1904 axreyna1@texaschildrens.org

Locations
United States, Texas
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen E Heslop    832-824-4662    hheslop@bcm.edu   
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Rayne H Rouce, MD    832-824-4716    rouce@bcm.edu   
Sponsors and Collaborators
Baylor College of Medicine
Center for Cell and Gene Therapy, Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Investigators
Principal Investigator: Rayne H Rouce, MD Baylor College of Medicine

Responsible Party: Rayne Rouce, Instructor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT02287311     History of Changes
Other Study ID Numbers: H-35253 MABEL
MABEL ( Other Identifier: Baylor College of Medicine )
First Posted: November 10, 2014    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 2018

Keywords provided by Rayne Rouce, Baylor College of Medicine:
EBV positive diseases
cytotoxic T lymphocytes

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Hodgkin Disease
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents