Most Closely HLA-Matched CTLs for Relapsed Epstein Barr Virus(EBV)-Associated Diseases (MALTED)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 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):
Carlos Ramos, Baylor College of Medicine
ClinicalTrials.gov Identifier:
NCT01447056
First received: August 12, 2011
Last updated: July 13, 2014
Last verified: July 2014
  Purpose

Patients have a type of a lymph node cancer called lymphoma, a tumor of the nasal passages called nasopharyngeal carcinoma (NPC), a tumor of a particular type of muscle called leiomyosarcoma (LMS) or a condition called severe chronic active EBV (SCAEBV) syndrome. The disease has come back, may come back or has not gone away after treatment. This voluntary research study uses special immune system cells called LMP-specific cytotoxic T lymphocytes, a new experimental therapy.

Some patients with these diseases show evidence of infection with the virus that causes infectious mononucleosis (called Epstein-Barr virus, or EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of up to half of the patients with lymphomas, and in some cases of NPC and LMS, suggesting that it may play a role in causing these diseases. Those cancer cells (as well as some B cells in SCAEBV) that are 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 T cells, that have been trained to kill cells infected by EBV can survive in the blood and affect the tumor.

This treatment with specially trained T cells has had activity against these viruses when the cells are made from patients with those diseases (or, after bone marrow transplant, from the patient's transplant donor). However, sometimes it is not possible to grow these cells; other times, it may take 2 to 3 months to make the cells, which may be too long when one has an active tumor. We are therefore asking if subjects would like to participate in this study, which tests if blood cells from a donor that is a partial match with the subject (or the transplant donor) that have been grown in the way described above can survive in the blood and affect the disease.

These LMP-specific CTLs are an investigational product not approved by the Food and Drug Administration.


Condition Intervention Phase
Hodgkin Lymphoma
Non-Hodgkin Lymphoma
Lymphoproliferative Disorder
Nasopharyngeal Carcinoma
Leiomyosarcoma
Severe Chronic Active EBV (SCAEBV)
Biological: LMP specific T cells
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Most Closely HLA-Matched Allogeneic LMP1/2-Specific Cytotoxic T Lymphocytes for Treatment of Patients With Relapsed EBV-Associated Diseases

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Patients with dose limiting toxicities after T-cell infusions [ Time Frame: 6 weeks ] [ Designated as safety issue: Yes ]
    To determine the safety of intravenous injections of third-party, partially HLA- matched, allogeneic Epstein Barr Virus (EBV)-specific cytotoxic T-lymphocytes (CTL) in patients with severe chronic active EBV (SCAEBV) infection or EBV-associated Hodgkin or non-Hodgkin lymphomas (HL/NHL), other lymphoproliferative disorders (LPD) or other malignancies (leiomyosarcoma and nasopharyngeal carcinoma)


Secondary Outcome Measures:
  • Safety and response to a repeated dosage regimen [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
    To obtain preliminary information on the safety and response to a repeated dosage regimen.

  • Analysis of immune function of CTLs [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    To determine the survival and the immune function of third-party allogeneic EBV-specific CTL lines

  • Number of patients with an EBV and/or disease response to the CTLs [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
    To assess anti-EBV and anti-tumor effects of third-party partially HLA- matched allogeneic EBV-specific CTL lines.


Estimated Enrollment: 18
Study Start Date: February 2012
Estimated Study Completion Date: February 2021
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LMP Specific T cells
LMP specific T cells will be given by intravenous injection over 1-10 minutes through either a peripheral or a central line and the IV flushed with saline. Then the second product will be given by intravenous injection over 1 to 10 minutes and the IV flushed with saline. The volume of infusion will depend upon the concentration of the cells when frozen, the dose level, and the size of the patient.
Biological: LMP specific T cells

Three dose levels will be evaluated:

Dose Level 1: 2×10^7 cells/m2; Dose Level 2: 1×10^8 cells/m2; Dose Level 3: 2×10^8 cells/m2

If patients have a partial response or have stable disease they will be eligible to receive up to 5 further doses of CTLs, each of which will consist of the same number as their first injection.


Detailed Description:

First, we will search our cell bank to see if there is a CTL line that is a match with the subject and his/her donor. This matching is done using HLA type, which measures 6 proteins on the cell surface. If HLA type has not been previously checked, we will do a blood draw (half to one tablespoon) so that this can be done.

These CTL lines have been made at Baylor College of Medicine from donors for other transplant patients or other normal donors from the National Marrow Donor Program. All donors have been screened in the same way that we screen blood donors. When the CTL lines were made, blood was taken from the donors and used to grow T cells. To do this, we first grew a special type of cells called dendritic cells or monocytes and we put a specially produced human virus (adenovirus) that carries the LMP genes into the dendritic cells or monocytes. They were then used to stimulate T cells. This stimulation trained the T cells to kill cells with LMP on their surface.

We then grew these LMP specific CTLs by more stimulation with EBV infected cells (made from the same blood). We also put the adenovirus that carries the LMP genes into these EBV infected cells so that we increased the amount of LMP that these cells had. These EBV infected cells were treated with radiation so they could not grow. Once we made sufficient numbers of T cells, we tested them to make sure they kill cells with LMP on their surface and froze them.

To make sure that these cells won't attack the subject's tissues, we will also test the cells against his/her own cells, which we will grow in the laboratory.

If the level of circulating T-cells in the patient is relatively high, s/he will receive one treatment of cyclophosphamide. This drug will decrease the numbers of the patient's own T-cells before the investigators infuse the LMP-specific cytotoxic T-lymphocytes. If the patient is already receiving chemotherapy, this may not be needed.

The LMP specific CTLs will be thawed and injected IV over 1-5 minutes. Initially, one dose of T-cells will be given. If after the first dose, there is a reduction in the size of the patient's disease, they can receive up to five additional doses of the T-cells if they wish.

This is a dose escalation study, which means that the doses of cells will be increased as more patients are treated, as long as the lower doses are determined to be safe.

  Eligibility

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

INCLUSION CRITERIA:

SCREENING:

  1. Any patient, regardless of age or sex, with one or more of the following EBV-positive or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma - Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma - Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV
  2. Karnofsky/Lansky score 50% or more.
  3. Informed consent explained to and signed by patient or parent/guardian able to give informed consent and given a copy.

TREATMENT:

  1. Any patient, regardless of age or sex, with one or more of the following EBV-positive or associated disorders, regardless of the histological subtype: - Hodgkin lymphoma - Non-Hodgkin lymphoma - Lymphoproliferative disorder - Nasopharyngeal carcinoma - Leiomyosarcoma - Severe chronic active EBV infection syndrome (SCAEBV), defined as high EBV viral load in plasma or PBMC (> 4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV
  2. The disease needs to be in one of the following stages: - At diagnosis or in first relapse AND the patient is unable to receive conventional chemotherapy for his/her condition. - In second or subsequent relapse. - With residual disease after autologous, syngeneic or allogeneic HSCT.
  3. Life expectancy 6 weeks or more.
  4. Tumor tissue is positive for EBV.
  5. Karnofsky/Lansky score 50% or more.
  6. Bilirubin less than 3 less than upper limit of normal (ULN), AST less than 5 less than ULN, Hgb greater than 8.0 g/dL and serum creatinine less than 3 less than ULN
  7. Pulse oximetry of greater than 90% on room air.
  8. If post allogeneic HSCT, patient must not have less than 50% donor chimerism in either peripheral blood or bone marrow.
  9. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone at time of treatment.
  10. Informed consent explained to and signed by patient or parent/guardian able to give informed consent and given a copy.
  11. Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 3 months after the study is concluded. The male partner should use a condom.

EXCLUSION CRITERIA:

SCREENING:

1. Known HIV positivity.

TREATMENT:

  1. Currently receiving any investigational agents or have received any tumor vaccines within previous 4 weeks.
  2. Active acute grade III-IV graft-versus-host disease.
  3. Severe intercurrent infection.
  4. Received alemtuzumab or other anti-T-cell antibody within 28 days.
  5. HIV seropositivity.
  6. Pregnancy (due to unknown effects of this therapy on a fetus) or lactation.
  7. Tumor in a location where enlargement could cause airway obstruction.
  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: NCT01447056

Contacts
Contact: Carlos A Ramos, MD 832-824-4817 caramos@txch.org

Locations
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Carlos A Ramos, MD    832-824-4817    caramos@txch.org   
Principal Investigator: Carlos A Ramos, MD         
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Carlos A Ramos, MD    832-824-4817    caramos@txch.org   
Principal Investigator: Carlos A Ramos, MD         
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: Carlos A Ramos, MD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Carlos Ramos, Assistant Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT01447056     History of Changes
Other Study ID Numbers: H-28361-MALTED, MALTED
Study First Received: August 12, 2011
Last Updated: July 13, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Baylor College of Medicine:
Hodgkin lymphoma
Non-Hodgkin lymphoma
Lymphoproliferative disorder
Nasopharyngeal carcinoma
Leiomyosarcoma
EBV Cytotoxic T Lymphocytes

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Hodgkin Disease
Lymphoma
Carcinoma
Leiomyosarcoma
Nasopharyngeal Neoplasms
Lymphoproliferative Disorders
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Glandular and Epithelial
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Pharyngeal Neoplasms
Otorhinolaryngologic Neoplasms
Head and Neck Neoplasms
Neoplasms by Site
Nasopharyngeal Diseases
Pharyngeal Diseases
Stomatognathic Diseases
Otorhinolaryngologic Diseases

ClinicalTrials.gov processed this record on October 01, 2014