Specific Cytotoxic T-Lymphocytes, EBV-positive Lymphoma, GRALE

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Baylor College of Medicine
Sponsor:
Collaborators:
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Helen Heslop, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT01555892
First received: March 13, 2012
Last updated: May 9, 2014
Last verified: May 2014
  Purpose

Subjects have a type of lymph gland disease called Hodgkin or non-Hodgkin Lymphoma or 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.

Some patients with Lymphoma or T/NK-lymphoproliferative disease or CAEBV show signs of virus that is 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 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. We want to see if special white blood cells, called GRALE T cells, that have been trained to kill EBV infected cells can survive in the blood and affect the tumor.

We have used this sort of therapy to treat a different type of cancer that occurs after bone marrow or solid organ transplant called post transplant lymphoma. In this type of cancer the tumor cells have 9 proteins made by EBV on their surface. We grew T cells in the lab that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However, in HD and NHL, T/NK-lymphoproliferative disease, and CAEBV, the tumor cells and B cells only express 4 EBV proteins. In a previous study, we made T cells that recognized all 9 proteins and gave them to patients with HD. Some patients had a partial response to this therapy but no patients had a complete response. We then did follow up studies where we made T cells that recognized the 2 EBV proteins seen in patients with lymphoma, T/NK-lymphoproliferative disease and CAEBV. Those proteins are called LMP-1 and LMP-2. The cells are called LMP-specific cytotoxic T-Lymphocytes (CTLs). We have treated over 45 people on those studies. About 63% of those patients who had disease at the time they got the cells had responses including some patients with complete responses. This study will expand on those results and we will try and make the T cells in the lab in a simpler faster way. We will also make T cells that will still see the LMP proteins but also 2 other EBV proteins called EBNA-1 and BARF. These cells are called GRALE T cells. These GRALE CTLs are an investigational product not approved by the FDA.

The purpose of this study is to find the largest safe dose of LMP-specific cytotoxic GRALE T cells created using this new manufacturing technique. We will learn what the side effects are and to see whether this therapy might help patients with HD or NHL or EBV associated T/NK-lymphoproliferative disease or CAEBV.


Condition Intervention Phase
Hodgkin's Disease
Non-Hodgkin's Lymphoma
Lymphoproliferative Disease
Lymphoma
Biological: LMP, BARF1 & EBNA1 specific CTLs: A
Biological: LMP, BARF1 & EBNA1 specific CTLs : B
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Administration of Rapidly Generated LMP, BARF1 And EBNA1 Specific Cytotoxic T-Lymphocytes To Patients With EBV-Positive Lymphoma

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Assessment of toxicity of escalating doses of LMP, BARF1 and EBNA1 CTLs [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    To determine the safety of escalating doses of 2 intravenous injections of autologous rapid LMP, BARF1 and EBNA1 specific cytotoxic T-lymphocytes (CTL) in patients with EBV-associated Hodgkin's Disease or non-Hodgkin's lymphoma or T/NK-lymphoproliferative disease and CAEBV.


Secondary Outcome Measures:
  • Determine survival and immune function of LMP/BARF1/EBNA1-specific cytotoxic T-lymphocyte lines [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    To determine the survival and the immune function of LMP/BARF1/EBNA1-specific cytotoxic T-lymphocyte lines

  • Assess anti-viral and anti-tumor effects of LMP/BARF1/EBNA1-specific CTL [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    To assess the anti-viral and anti-tumor effects of LMP/BARF1/EBNA1--specific CTL

  • Obtain preliminary information on safety and response to extended dosage regimen [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    To obtain preliminary information on the safety and response to an extended dosage regimen.


Estimated Enrollment: 136
Study Start Date: January 2013
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LMP, BARF1 & EBNA1 specific CTLs: A

Group A: Patients in second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiple relapsed patients in remission who are at a high risk of relapse) or any patient with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated.

Each group will have the dose escalation done separately. Two patients will be entered at the starting dose level. Each patient will receive 2 injections, 14 days apart, according to the dosing schedules. If there are no dose limiting toxicities, the escalation will continue at the pre-specified dose levels.

Biological: LMP, BARF1 & EBNA1 specific CTLs: A

Dose Level 1: 2 x 10^7 cells/ m2; 2 x 10^7 cells/m2

Dose Level 2: 2 x 10^7 cells/m2; 1 x 10^8 cells/m2

Dose Level 3: 1 x 10^8 cells/m2; 2 x 10^8 cells/m2

Other Name: LMP, BARF1 and EBNA1 specific CTLs
Experimental: LMP, BARF1 & EBNA1 specific CTLs : B

Group B: Patients in remission or with minimal residual disease (MRD) status after autologous or syngeneic SCT.

Each group will have the dose escalation done separately. Two patients will be entered at the starting dose level. Each patient will receive 2 injections, 14 days apart, according to the dosing schedules. If there are no dose limiting toxicities, the escalation will continue at the pre-specified dose levels.

Biological: LMP, BARF1 & EBNA1 specific CTLs : B

Dose Level 1: 2 x 10^7 cells/ m2; 2 x 10^7 cells/m2

Dose Level 2: 2 x 10^7 cells/m2; 1 x 10^8 cells/m2

Dose Level 3: 1 x 10^8 cells/m2; 2 x 10^8 cells/m2


Detailed Description:

Subjects will give blood for investigators to make LMP/BARF1/EBNA-1 (GRALE) CTLs in the lab. These cells will be grown and frozen for the subject.

Patients will be started on the lowest dose (1 of 3 different levels) of GRALE T cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 3 dose levels are studied. If the side effects are too severe, the dose will be lowered or the GRALE T cell injections will be stopped.

The GRALE T cells will then be thawed and injected into the subject over 2-10 minutes. Initially, two doses of GRALE T cells will be given 2 weeks apart.

If after the 2nd infusion there is a reduction in the size of the lymphoma on CT or MRI scan as assessed by a radiologist, the subject can receive additional doses of the GRALE T cells if they wish (up to 6 times). Follow up testing will be collected just like after the 1st infusion. CT scans, MRI, or nuclear imaging will be collected 1-3 months after the final infusion.

All of the treatments will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.

We will follow the subjects after the injections. They will either be seen in the clinic or the subject will be contacted by a research nurse yearly for 5 years. To learn more about the way the T cells are working in the body, extra blood will be taken before each infusion and then at 2,4 and 6 weeks and 3,6,9 and 12 months after each infusion (8 times). The blood may be drawn from the central line at the time of the regular blood tests. We will use this blood to see how long the GRALE T cells last and to look at the immune response to the subjects cancer. One additional blood sample might be drawn 3 to 4 days after the infusion.

Subjects will be on study for approximately 5 years. If they receive additional doses of the GRALE T cells as described above, they will be followed until 5 years after the last dose of GRALE T-cells.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria at time of Procurement

Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma, (regardless of the histological subtype) or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic Active EBV (CAEBV)

In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients in remission who have a high risk of relapse) OR any patient with primary disease or in first remission 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 A)

OR

In remission or with minimal residual disease status after autologous or syngeneic stem cell transplantation (SCT). (Group B)

  • EBV positive tumor
  • Weighs at least 12kg
  • Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.

Inclusion Criteria at time of Infusion

Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma (regardless of histologic subtype), or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic Active EBV (CAEBV) and

In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients in remission who have a high risk of relapse) OR any patient with primary disease or in first remission 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 A)

OR

In remission or with minimal residual disease status after autologous or syngeneic SCT. (Group B)

  • EBV positive tumor (can be pending at this time)
  • Patients with life expectancy > 6 weeks.
  • Patients with bilirubin < 3x upper limit of normal, AST < 5x upper limit of normal, and Hgb > 8.0 (may be a transfused value).
  • Patients with a creatinine < 2x upper limit of normal for age
  • Pulse oximetry of > 90% on room air
  • Patients should have been off other investigational therapy for 4 weeks prior to entry in this study.
  • Patients with a Karnofsky/Lansky score of > 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 explained to, understood and signed by patient/guardian. Patient/guardian given copy of informed consent.

    • 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

Exclusion Criteria at Time of Procurement

- Active infection with HIV, HTLV, HBV, HCV (can be pending at this time)

Exclusion Criteria at Time of Infusion

  • Pregnant or lactating
  • Severe intercurrent infection.
  • Current use of systemic corticosteroids > 0.5 mg/kg/day
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01555892

Contacts
Contact: Helen E Heslop, MD 832-824-4662 hheslop@bcm.edu
Contact: Vicky Torrano 832-824-7821 vxtorran@txch.org

Locations
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen E Heslop, MD    832-824-4662    hheslop@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen E Heslop, MD    832-824-4662    hheslop@bcm.edu   
Contact: Vicky Torrano    832-824-7821    vxtorran@txch.org   
Sponsors and Collaborators
Baylor College of Medicine
Texas Children's Hospital
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
Principal Investigator: Helen E Heslop, MD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Helen Heslop, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT01555892     History of Changes
Other Study ID Numbers: H-29617-GRALE, GRALE, P50CA126752
Study First Received: March 13, 2012
Last Updated: May 9, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
EBV
Hodgkin's Lymphoma
Non-Hodgkin's Lymphoma
Lymphoma Relapse
Autologous or Syngeneic Stem Cell Transplant
T/NK-lymphoproliferative disease
LMP
BARF1
EBNA1

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Lymphoma
Hodgkin Disease
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on September 18, 2014