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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


Phase 1/Phase 2
N/A
N/A
Open (Enrolling)
Both
Viral Infection

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Trial Information

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


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.

This is a dose escalation study. This means that at the beginning, patients will be started
on the lowest dose (1 of 3 different levels, 2-4 patients at each dose level) of T cells and
followed for 42 days for dose limited toxicity evaluations. The decision whether it is safe
to escalate to next dose level or not will be made after at least two patients have finished
their 42 days. 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 T cell injections will be
stopped.

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.


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
9. AST
10. Serum creatinine
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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Patients with acute GvHD grades III-IV within 42 days of the last dose of CTLsinfusion

Outcome Description:

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.

Outcome Time Frame:

42 days

Safety Issue:

Yes

Principal Investigator

Helen Heslop, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine

Authority:

United States: Institutional Review Board

Study ID:

H-29966 ARMS

NCT ID:

NCT01570283

Start Date:

September 2012

Completion Date:

December 2016

Related Keywords:

  • Viral Infection
  • post allogeneic hematopoietic stem cell transplant
  • cytotoxic T lymphocytes
  • Cytomegalovirus
  • CMV
  • adenovirus
  • Epstein-Barr virus
  • EBV
  • Human polyomavirus type I
  • BK virus
  • Human herpesvirus 6
  • HHV6
  • Adenoviridae Infections
  • Virus Diseases

Name

Location

Texas Children's HospitalHouston, Texas  
The Methodist HospitalHouston, Texas  77030