ARMS - Rapidly Generated Multivirus-Specific CTLs for the Prophylaxis And Treatment of EBV, CMV, Adenovirus, HHV6, and BK Virus

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 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:
NCT01570283
First received: March 27, 2012
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

Subjects have a type of blood cell cancer, other blood disease or a genetic disease for which they will receive a stem cell transplant. The donor of the stem cells will be either the subjects brother or sister, or another relative, or a closely matched unrelated donor. We are asking subjects to participate in this study which tests if blood cells from the subjects donor that have been grown in a special way, can prevent or be a effective treatment for early infection by five viruses - Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus, BK virus (BKV) and human herpes virus 6 (HHV6).

Adenovirus is a virus that usually causes symptoms of a common cold, but can cause serious life-threatening infections in patients who have weak immune systems. It can affect the lungs and cause very serious pneumonia, and can also damage the gut, liver, pancreas and eyes.

CMV can also cause serious infections in patients with weak or suppressed immune systems. It usually affects the lungs, causing a very serious pneumonia, but it can also affect the gut, the liver and the eyes. Approximately 2/3 of normal people harbor this virus in their body. In healthy people CMV rarely causes any problems because the immune system can keep it under control, but after a transplant, the risk of developing CMV disease is much higher because the immune system is so weak.

EBV is the virus that causes glandular fever or kissing disease. It is also a life long infection like CMV that is normally controlled by immune system. When immunity is weak, the virus can become active and cause fevers, enlarged lymph nodes and sometimes a type of cancer called lymphoma.

BKV is a virus that usually causes symptoms of a common cold such as fever and normally does not cause problems. If the immune system is weakened in some way, for example following a bone marrow transplant, then BKV can cause life-threatening infections affecting mainly the kidneys, bladder, and urinary tract.

HHV6 is another virus that infects most people in childhood causing symptoms like fever, diarrhea and rash. Like CMV, EBV, and BKV, HHV6 remains in the body for life and can cause problems when the immune system is weakened. When this occurs the virus can affect many organs including the brain, lungs, heart, kidney and gastrointestinal tract.

We want to see if we can use a kind of white blood cell called T lymphocytes (or T cells) to prevent and treat adenovirus, CMV, EBV, BKV and HHV6 in the early stages of reactivation or infection.

We have grown T cells from the subject's stem cell donor in the laboratory in a way that will train them to recognize the viruses and control them when the T cells are given after a transplant. This treatment with specially trained T cells (also called cytotoxic T cells or "CTLs") has had activity against three of these viruses (CMV, EBV and Adenovirus) in previous studies. In this study we want to see if we increase the number of viruses that can be targeted to include BKV and HHV6 using a simple and fast approach to make the cells.


Condition Intervention Phase
Viral Infection
Biological: Multi-virus-specific cytotoxic T lymphocytes
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: ARMS - Administration Of Rapidly Generated Multivirus-Specific Cytotoxic T-Lymphocytes For The Prophylaxis And Treatment Of EBV, CMV, Adenovirus, HHV6, And BK Virus Infections Post Allogeneic Stem Cell Transplant

Resource links provided by NLM:


Further study details as provided by Baylor College of Medicine:

Primary Outcome Measures:
  • Patients with acute GvHD grades III-IV within 42 days of the last dose of CTLsinfusion [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]
    To determine the feasibility and safety of escalating doses of donor-derived rapidly generated multi-virus-specific cytotoxic T lymphocytes (mCTLs) in patients at risk of developing CMV, adenovirus EBV, HHV6 or BK virus infections after allogeneic stem cell transplant.

  • Patients with grades 3-5 infusion-related adverse events within 30 days of the last CTL dose [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    To determine the feasibility and safety of escalating doses of donor-derived rapidly generated multi-virus-specific cytotoxic T lymphocytes (mCTLs) in patients at risk of developing CMV, adenovirus EBV, HHV6 or BK virus infections after allogeneic stem cell transplant.

  • Patients with grades 4-5 nonhematological adverse events within 30 days of the last CTL dose [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    To determine the feasibility and safety of escalating doses of donor-derived rapidly generated multi-virus-specific cytotoxic T lymphocytes (mCTLs) in patients at risk of developing CMV, adenovirus EBV, HHV6 or BK virus infections after allogeneic stem cell transplant.


Secondary Outcome Measures:
  • Assessment of viral load response to the CTL infusion [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    Assess the effect of the CTL infusion on viral load, reconstitution of antiviral immunity post-infusion, and clinical responses

  • Reconstitution of antiviral immunity [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Assessment of Reconstitution of antiviral immunity


Estimated Enrollment: 24
Study Start Date: September 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Multi-virus-specific cytotoxic T lymphocytes
Multivirus-specific T cells will be thawed and given by intravenous injection.
Biological: Multi-virus-specific cytotoxic T lymphocytes

The feasibility and safety of 3 different dose levels will be evaluated and will determine the maximum tolerated dose (MTD) level.

A minimum of 10 patients will be treated with total six patients accrued at the MTD level for a total of 16 for Phase I. At most there will be 2 cohorts at each level and no more than 2 subjects in each cohort.

Dose Level One: 5x10^6 mCTLs/m2

Dose Level Two: 1x10^7 mCTLs/m2

Dose Level Three: 2x10^7 mCTLs/m2

There may be an option of administering 2 additional doses (at the same level the patient was receiving), 28 days after the first dose, in subjects that have a partial response after one dose or who receive other therapy that may affect the persistence or function of the infused CTL.


Detailed Description:

To make the CTLs we mixed the subjects donors' cells with small pieces of proteins, called peptides that come from adenovirus, CMV, EBV, BKV and HHV6. These peptides stimulate donor T cells that react against the viruses to grow and train the donor T cells to kill cells that are infected with CMV, EBV, adenovirus, BKV and HHV6. Once we made sufficient numbers of T cells, we tested them to make sure they would target the cells infected with these viruses but not the normal cells. Then we froze the cells.

When we think the subject needs them, the subject's donor's CTL cells will be thawed and injected into the intravenous line. To prevent an allergic reaction, prior to receiving the CTLs the subject may be given diphenhydramine (Benadryl) and acetaminophen (Tylenol). After the subject receives the cells we will monitor the levels of these five viruses in the blood. We will also take blood to see how long the T cells we gave the subject are lasting in the body.

If the CTL infusion has helped the subjects infection or if they have had a treatment, for example with steroid drugs that might have destroyed the T cells the subject was given, then they are allowed to receive up to 2 more doses of the cells.

The first part of this study was a dose escalation study. That means that at the beginning, patients were started on the lowest dose (1 of 3 different levels) of T cells. Once that dose schedule was proven safe, the next group of patients were started at a higher dose. This process continued until all 3 dose levels were studied. We have now seen that all three dose levels are safe. We would now like to enroll more patients at the highest dose level to get more information about how the T cells work.

Subjects will continue to be followed by their transplant doctors after the injection. The subject will either be seen in the clinic or they will be contacted by a research nurse to follow up for this study every week for 6 weeks then at 8 week and 3, 6 and 12 months. The subject may have other visits for their standard care. Subjects will also have regular blood tests done to follow their counts and the viral infection. To learn more about the way the T cells are working in the body, up to an extra 30-40 ml (6-8 teaspoons) of blood will be taken before the infusion and then at 1, 2, 4, 5, 6 and 8 weeks and 3 months. Blood should come from the central intravenous line, and should not require extra needle sticks.

If subjects experience a positive response or are taking medicines (such as steroids) that may affect how long T cells stay in the body, they may be able to receive up to two additional doses of the T cells at the same initial dose level from 28 days after their initial dose. After each T-cell infusion, they will be monitored as described above.

Study Duration: Subjects will be on study for approximately one year. If they receive additional doses of the T cells as described above, they will be followed until 1 year after their last dose of T-cells.

  Eligibility

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

Inclusion Criteria:

Patients will be eligible following any type of allogeneic transplant to receive CTLs as prevention or for early reactivations as defined below.

  1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells within 12 months.
  2. Prevention for patients at risk of CMV, adenovirus, EBV, BK virus, or HHV6 infection
  3. Treatment of reactivation or infection which is defined for each virus as below

    • CMV- CMV antigenemia is monitored at least weekly post transplant. Reactivation is defined at CMV antigenemia with <10 leukocytes positive or elevated PCR. If any patient develops CMV antigenemia with >10 leukocytes positive or clinical evidence of CMV infection (defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) either pre or after CTL infusions, standard treatment with Ganciclovir, and/or Foscarnet and Immunoglobulins will be initiated. Patients may receive CTLs for antigenemia or elevated PCR without visceral infection.
    • Adenovirus- Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine or nasopharynx.

    Adenovirus disease will be defined as the presence of adenoviral positivity as detected by culture from more than two sites such as stool or blood or urine or nasopharynx.

    In patients who meet the criteria for disease Cidofovir may be added unless the subject could not tolerate this agent due to nephrotoxicity. Patients may receive CTLs for elevated PCR in blood or stool.

    • EBV- EBV-LPD is defined according to recent guidelines as proven EBV-LPD defined by biopsy or probable EBV-LPD defined as an elevated EBV DNA level associated with clinical symptoms (adenopathy or fever or masses on imaging) but without biopsy confirmation. Patients with EBV DNA reactivation only may receive CTLs on study. Patients with proven or probable EBV-LPD should also receive Rituxan
    • BK virus- Patients post transplant may develop asymptomatic BKV viruria or viremia. BK reactivation will be defined as detection of elevated BK levels by PCR in blood or urine while disease will be defined as detection in multiple sites or in one site with symptoms. Cidofovir has been administered intravenously in a low dose (i.e. up to 1 mg/kg 3 times weekly, without probenecid) or a high dose (ie, 5 mg/kg per week with probenecid) to HSCT patients with BK infections but no randomized trials are available proving its clinical efficacy. In patients who meet the criteria for disease Cidofovir may be added unless the subject could not tolerate this agent due to nephrotoxicity.
    • HHV6- HHV6 reactivation will be defined as detection of elevated HHV6 levels by PCR in blood while disease will be defined as detection in multiple sites or in one site with symptoms. Ganciclovir, Cidofovir, and foscarnet have variable in vitro activity against HHV-6, and may have a role in treating HHV-6-associated disease - hence one or more of these agents will be added in patients with disease.
  4. Treatment may be given to eligible patients with a single or multiple infections. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.
  5. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone.
  6. Karnofsky/Lansky score of ≥ 50
  7. ANC greater than 500/µL.
  8. Bilirubin </= 2x upper limit normal
  9. AST </= 3 x upper limit normal
  10. Serum creatinine </= 2 x upper limit normal
  11. HgB > 8.0
  12. Pulse oximetry of > 90% on room air
  13. Available multivirus-specific CTLs
  14. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).
  15. Written informed consent and/or signed assent line from patient, parent or guardian.

Exclusion Criteria:

  1. Patients receiving ATG, or Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment.
  2. Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.

    Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

  3. Patients who have received donor lymphocyte infusion (DLI) within 28 days.
  4. Patients with active acute GVHD grades II-IV.
  5. Active and uncontrolled relapse of malignancy
  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: NCT01570283

Contacts
Contact: Helen Heslop, MD 832-824-4662 heheslop@txch.org

Locations
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen Heslop, MD    832-824-4662    heheslop@txch.org   
Houston Methodist Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Helen Heslop, MD    832-824-4662    heheslop@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 Heslop, MD Baylor College of Medicine
  More Information

No publications provided

Responsible Party: Helen Heslop, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT01570283     History of Changes
Other Study ID Numbers: H-29966 ARMS, ARMS
Study First Received: March 27, 2012
Last Updated: April 3, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Baylor College of Medicine:
Epstein-Barr virus
BK virus
post allogeneic hematopoietic stem cell transplant
cytotoxic T lymphocytes
Cytomegalovirus
CMV
adenovirus
EBV
Human polyomavirus type I
Human herpesvirus 6
HHV6

Additional relevant MeSH terms:
Adenoviridae Infections
Virus Diseases
DNA Virus Infections

ClinicalTrials.gov processed this record on July 29, 2014