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Phase I Study of Activated T-Cells Expressing Second or Third Generation CD19-Specific Chimeric Antigen Receptors for Advanced B-Cell Non-Hodgkin's Lymphoma (SAGAN)


Phase 1
N/A
N/A
Not Enrolling
Both
Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

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Trial Information

Phase I Study of Activated T-Cells Expressing Second or Third Generation CD19-Specific Chimeric Antigen Receptors for Advanced B-Cell Non-Hodgkin's Lymphoma (SAGAN)


Patients will give the investigators blood to make CD19 CD28 (with and without CD137)
chimeric receptor-T cells in the laboratory. These cells will be grown and frozen. To make
the T cells, investigators will take blood (or blood from a donor) and stimulate it with
growth factors to make the T cells grow. To get the CD19 antibody and CD28 (with or without
CD137) to attach to the surface of the T cell, they will insert 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 to find the T cells in
the blood after injecting them; in order to tell them apart investigators have made two
viruses that are slightly different because one has CD137. These two viruses can be told
apart by a special laboratory test. Because the patient will receive cells with a new gene
in them, the patient will be followed for a total of 15 years to see if there are any long
term side effects of gene transfer. If the patient cannot visit the clinic, he or she will
be contacted by the research coordinator or physician.

When subjects enroll on this study, they will be assigned a dose of CD19 chimeric receptor-T
cells. Several studies suggest that the infused T cells need room to be able to proliferate
and accomplish their functions and that this may not happen if there are too many other T
cells in circulation.

Because of that, if the subject's level of circulating T cells is relatively high, they may
receive one treatment of cyclophosphamide (Cytoxan) if the doctor thinks this is
appropriate. This drug will decrease the numbers of the subject's own T cells before
infusion of the CD19 chimeric receptor T cells. If subject is already receiving
chemotherapy, this may not be needed. The investigators would prefer subjects do not receive
other chemotherapy until 6 weeks after cell infusion but they can do so if their doctor
thinks it is medically necessary.

Patients will be given an injection of cells into the vein through an IV at the assigned
dose. The injection will take about 20 minutes. The investigators will follow them in the
clinic after the injection for up to 3 hours. If after a 4-6 week evaluation period after
the infusion, the subject seems to be experiencing a benefit, the subject may be able to
receive up to five additional doses of the T cells if they wish. These additional infusions
would be at least 4-6 weeks apart and at the same dose level received the first time or a
lower dose. The treatment will be given by the Center for Cell and Gene Therapy at Texas
Children's Hospital or The Methodist Hospital.


Inclusion Criteria:



PROCUREMENT

Referred patients (or respective donors) will initially be consented for procurement of
blood for generation of the transduced ATL. Eligibility criteria at this stage include:

- Diagnosis of recurrent aggressive or indolent B-cell lymphoma or CLL, or newly
diagnosed patients unable to receive or complete standard therapy OR diagnosis of
relapsed/refractory aggressive B-cell lymphoma with a treatment plan that will
include high dose therapy and autologous stem cell transplantation.

- CD19-positive tumor (result can be pending at this time).

- Hgb > 8.0

- If pheresis required to collect blood:

- Creatinine<1.5 × upper limit normal

- AST <1.5 × upper limit normal

- PT and APTT <1.5 × upper limit normal

- Informed consent explained to, understood by and signed by patient/guardian (and
donor, where applicable). Patient/guardian given copy of informed consent.

TREATMENT

- Diagnosis of recurrent aggressive or indolent B-cell lymphoma or CLL, or newly
diagnosed patients unable to receive or complete standard therapy OR diagnosis of
relapsed/refractory aggressive B-cell lymphoma with a treatment plan that will
include high dose therapy and autologous stem cell transplantation.

- CD19-positive tumor.

- ANC > 500 and Hgb > 8.0.

- Bilirubin less than 3 times the upper limit of normal.

- AST less than 5 times the upper limit of normal.

- Serum creatinine less than 3 times the upper limit of normal.

- Pulse oximetry of > 90% on room air

- Karnofsky or Lansky score of > 60%.

- Recovered from acute toxic effects of prior chemotherapy at least one week before
entering this study.

- Available autologous or syngeneic activated peripheral blood T cell products (CD28ζ
and CD28/CD137ζ) with more than or equal to 15% expression of CD19.CAR determined by
flow cytometry.

- Life expectancy of greater than 12 weeks.

- 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.

- Patients or legal guardians must sign an informed consent indicating that they are
aware this is a research study and have been told of its possible benefits and toxic
side effects. Patients or their guardians will be given a copy of the consent form.

Exclusion Criteria:

PROCUREMENT

- Active infection requiring antibiotics.

- No history of other cancer (except non-melanoma skin cancer or in situ breast cancer
or cervix cancer) unless the tumor was successfully treated with curative intent at
least 2 years before trial entry.

TREATMENT

- Currently receiving any investigational agents or received any tumor vaccines within
the previous 6 weeks.

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

- Pregnant or lactating.

- Tumor in a location where enlargement could cause airway obstruction.

- Active infection with HIV or HTLV.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Number of patients with dose limiting toxicity (DLT)

Outcome Description:

Toxicity will be evaluated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) scale, version 4. DLT will be defined as any of the following that is NOT (1) pre-existing, or (2) due to infection (to which patients with CLL and NHL are predisposed), or (3) due to underlying malignancy, and that may, after consultation with the FDA when indicated, be considered possibly, probably, or definitely related to the study cellular products: (1) Non-hematologic DLT is any grade 3 or grade 4 non-hematologic toxicity, including allergic reactions to T cell infusions; (2) Hematologic DLT is defined as any grade 4 hematologic toxicity. Patients with evidence of bone marrow disease (metastases or diffuse infiltration) are not evaluable for hematologic dose limiting toxicity.

Outcome Time Frame:

6 weeks

Safety Issue:

Yes

Principal Investigator

Carlos A Ramos, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Baylor College of Medicine

Authority:

United States: Food and Drug Administration

Study ID:

H-31970 SAGAN

NCT ID:

NCT01853631

Start Date:

August 2013

Completion Date:

August 2031

Related Keywords:

  • Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia
  • chronic Lymphocytic Leukemia
  • refractory
  • recurrent
  • aggressive B-cell Lymphoma
  • CD19
  • Non-Hodgkin Lymphoma
  • CD28
  • CD137
  • 4-1BB
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoma, B-Cell

Name

Location

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