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Phase I/II Study of the Administration of Multi-Virus-Specific Cytotoxic T Lymphocytes Expressing CD19 Chimeric Receptors for Prophylaxis or Therapy of Relapse of CD19 Positive Malignancies Post Hematopoietic Stem Cell Transplantation


Phase 1/Phase 2
N/A
N/A
Open (Enrolling)
Both
Stem Cell Transplant, Acute Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Non Hodgkin's Lymphoma

Thank you

Trial Information

Phase I/II Study of the Administration of Multi-Virus-Specific Cytotoxic T Lymphocytes Expressing CD19 Chimeric Receptors for Prophylaxis or Therapy of Relapse of CD19 Positive Malignancies Post Hematopoietic Stem Cell Transplantation


The donor gave us blood to make CD19 chimeric receptor trivirus specific T cells in the
laboratory. These cells were grown and frozen for the subject. To make these special T cells
we grow them with stimulator cells. Stimulator cells are also made from the donor's blood
but they are irradiated so that they can no longer grow. Stimulator cells have been infected
with viruses so that they carry proteins from 3 viruses (CMV, adenovirus, and EBV). These
cells are cultured with the T cells so that they can learn to see and attack cells infected
with CMV, EBV and adenovirus.

To get the CD19 antibody to attach to the surface of the T cell, we inserted the antibody
gene into the T cell. This is done with a virus called a retrovirus that has been made for
this study and will carry the antibody gene into the T cell. This virus also helps us find
the T cells in the blood after we inject them. Once we make sufficient numbers of T cells we
freeze the cells and test them to make sure they kill CD19+ tumors cells and cells infected
with CMV, EBV and adenovirus. Once testing is completed the cells will be ready to give to
the subject.

Because the subject will have received cells with a new gene in them the subject will be
followed for a total of 15 years to see if there are any long term side effects of gene
transfer.

When the subjects enroll on this study, they will be assigned a dose of CD19 chimeric
receptor trivirus specific T cells.

The subject will be given an injection of cells into the vein through an IV line at the
assigned dose. Before the subjects receive the injection, they may be given a dose of
diphenhydramine (Benadryl) and acetaminophen (Tylenol). The injection will take about 20
minutes. We will follow the subject in the clinic after the injection for up to 3 hours. The
treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital
or The 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.

Medical tests during and after treatment—

The subject will receive standard medical tests when they are getting the infusions and
after:

Physical exams Blood tests to measure blood cells, kidney and liver function.

To learn more about the way the CD19 chimeric receptor trivirus specific T cells are working
and how long they last in the body, extra blood will be drawn.

This blood may be drawn from a central line if the subject has one. On the day the subject
receives the cells, blood will be taken before the cells are given and 3 hours afterwards.
Other blood will be drawn one week, 2 weeks, 4 weeks, 6 weeks and 8 weeks after the
infusion, then at Months 3, 6, 9 and 12. Then blood will be drawn every 6 months for 4
years, then yearly for a total of 15 years (up to 30 blood collections). If the subject
receives the cells at a time when sensitive tests indicate relapse or a high risk of
relapse, they will have additional reviews and blood tests to monitor these tests and look
for relapse.

The total blood drawn during the participation in this study will not exceed 300 teaspoons.
No more than 10 teaspoons or 1/2 teaspoon per 2.2 pounds of body weight (whichever is
lesser) will be drawn at each collection. This volume is considered safe, but may be
decreased if the subject has a low red blood cell count (anemic).

If the subject has bone marrow studies in the first year after completing treatment on this
study, we may ask to have a sample (about 1 teaspoon) of bone marrow to look for CD19
chimeric receptor T cells for research purposes.

Patients will receive supportive care for acute or chronic toxicity, including blood
components or antibiotics, and other intervention as appropriate.

For subjects receiving the CTLs for treatment of their disease: If the subject has stable
disease (the tumor did not grow) or there is a reduction in the size of the tumor on imaging
studies or by blood count after the T-cell infusion, the subject can receive up to six
additional doses of the T cells if they wish. After each T-cell infusion, the subject will
be monitored as described above.

Inclusion Criteria


INCLUSION CRITERIA:

Any patient regardless of sex or age with CD19+ B-ALL undergoing allogeneic HSCT (Group
A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL undergoing allogeneic
HSCT (Group B). With minimal residual disease (MRD) or relapse post-HSCT (for the phase I
dose escalation) Any patient regardless of sex or age with CD19+ B-ALL undergoing
allogeneic HSCT (Group A). OR Any patient regardless of sex or age with CD19+ B-CLL or NHL
undergoing allogeneic HSCT (Group B). With minimal residual disease (MRD) or relapse
post-HSCT (for the phase I dose escalation) as evidenced by PCR positivity, specific
cytogenetic abnormalities, an abnormal population on flow cytometry or increased blasts on
bone marrow biopsy or in the peripheral blood.

MRD will be defined as detection in blood or marrow of: 1) Any leukemia specific marker
(such as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre transplant on
a post transplant evaluation 2) A TCR or immune globulin rearrangement known to be a
disease marker for this patient post transplant 3) A leukemia specific phenotype post
transplant at a level of > 0.01% 4) Mixed donor chimerism

OR

With no evidence of ALL or CLL/NHL post-HSCT (to be included in the phase II extension).
Please note that this population will not be enrolled without FDA review and approval of
safety data from Phase I of this protocol.

2) Patients with life expectancy greater than or equal to 6 weeks

3) Patients with a Karnofsky/Lansky score greater than or equal to 50

4) Donor HIV negative

5) Patient or parent/guardian capable of providing informed consent

6) Patients with bilirubin 2x normal or less, AST 3x normal or less, creatinine less than
or equal to 2x normal for age and Hgb greater than 8.0

7) Pulse oximetry of greater than 90% on room air

8) Sexually active patients must be willing to utilize one of the more effective birth
control methods for 6 months after the CTL infusion. The male partner should use a condom.

9) Available allogeneic CD19CAR transduced tri-virus-specific cytotoxic T lymphocytes with
greater than or equal to15% expression of CD19CAR determined by flow-cytometry and greater
than 10% killing of one or more viral antigen pulsed targets in a cytotoxicity assay at an
effector:target ratio of 20:1.*

10) Patients should have been off other investigational antiviral or antitumor therapy for
one month prior to entry in this study.

*Note: Cell dose is based on total cell numbers and not individual antivirus or
antileukemic cell numbers.

EXCLUSION CRITERIA:

1. Severe intercurrent infection

2. Evidence of graft versus host disease >grade II

3. Pregnant or lactating

4. History of hypersensitivity reactions to murine protein-containing products.

5. Currently taking corticosteroids for therapy of GVHD.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Evaluate safety/persistence of escalating doses of allogeneic CMV, EBV and Adenovirus specific CTLs modified to express artificial T-cell receptors targeting CD19 molecule given for prophylaxis, persistence or relapse of high risk B-cell ALL post HSCT

Outcome Time Frame:

6 weeks

Safety Issue:

Yes

Principal Investigator

Catherine M Bollard, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

23637-MULTIPRAT

NCT ID:

NCT00840853

Start Date:

April 2009

Completion Date:

April 2029

Related Keywords:

  • Stem Cell Transplant
  • Acute Lymphoblastic Leukemia (ALL)
  • Chronic Lymphocytic Leukemia (CLL)
  • Non Hodgkin's Lymphoma
  • Stem cell transplant
  • Acute Lymphoblastic Leukemia (ALL)
  • Chronic Lymphocytic Leukemia (CLL)
  • Non Hodgkin's Lymphoma
  • Cytotoxic T lymphocytes
  • CTL
  • CD-19
  • chimeric receptor
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin

Name

Location

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