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Pilot Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRζ and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma


Phase 1
1 Year
21 Years
Open (Enrolling)
Both
B Cell Leukemia, B Cell Lymphoma

Thank you

Trial Information

Pilot Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRζ and 4-1BB Signaling Domains in Patients With Chemotherapy Resistant or Refractory CD19+ Leukemia and Lymphoma


At entry subjects will be staged and the suitability of their T cells for CART-19
manufacturing will be determined. Subjects who have adequate T cells will be leukapheresed
to obtain large numbers of peripheral blood mononuclear cells (PBMC) for CART-19
manufacturing. The T cells will be purified from the PBMC, transduced with CART-19
lentiviral vector, expanded in vitro and then frozen for future administration. Chemotherapy
will then be given. Following tumor burden reassessment, CART-19 cells will be thawed and
infused.

Subjects will have blood tests to assess safety, and engraftment and persistence of the
CART-19 cells at regular intervals through four weeks after their last infusion of the
study. The subsets of circulating T-cells that contain the CART-19:TCR:4-1BB and
CART-19:TCR only lentiviral vector will be assessed at various times after infusion and
compared to the baseline sample. Following the 6 months of intensive follow-up, subjects
will be evaluated quarterly for two years with a medical history, a physical examination,
and blood tests. Following this evaluation, subjects will enter a roll-over study for
annual follow-up by phone and questionnaire for an additional thirteen years to assess for
the diagnosis of long-term health problems, such as development of new malignancy.

Primary objectives:

1. Determine the safety and feasibility of administration of chimeric antigen receptor T
cells transduced with the anti-CD19 lentiviral vector (referred to as "CART-19" cells).

2. Determine duration of in vivo survival of CART-19 cells. RT-PCR analysis of whole blood
will be used to detect and quantify survival of CART-19 TCR:4-1BB and TCR cells over
time.

Secondary objectives:

1. For patients with detectable disease, measure anti-tumor response due to CART-19 cell
infusions.

2. To determine if the 4-1BB transgene is superior to the TCR only transgene as measured
by the relative engraftment levels of CART-19 TCR:4-1BB and TCR cells over time.

3. For patients with stored or accessible tumor cells (such as patients with active CLL,
ALL, etc) determine tumor cell killing by CART-19 cells in vitro.

4. Determine if cellular or humoral host immunity develops against the murine anti-CD19,
and assess correlation with loss of detectable CART-19 (loss of engraftment).

5. Determine the relative subsets of CART-19 T cells (Tcm, Tem, and Treg)


Inclusion Criteria:



- CD19+ leukemia or lymphoma

- ALL without curative options for therapy, including those not eligible for allogeneic
SCT because of age, comorbid disease, lack of suitable donor or prior SCT.

- Patient may be in any complete response, or

- Patient may have active disease but responding or stable after most recent therapy

- Follicular lymphoma, previously identified as CD19+

- At least 2 prior combination chemotherapy regimens (not including single agent
monoclonal antibody (Rituxan) therapy.

- Stage III-IV disease.

- Less than 1 year between last chemotherapy and progression (i.e. most recent
progression free interval <1 year).

- Disease responding or stable after most recent therapy (chemotherapy, MoAb).

- CLL

- At least 2 prior chemotherapy regimens (not including single agent monoclonal
antibody (Rituxan) therapy.

- Less than 1 year between last chemotherapy and progression (i.e. most recent
progression free interval <1 year).

- Not eligible or appropriate for conventional allogeneic SCT.

- Disease responding or stable after most recent therapy (chemotherapy, MoAb)

- Mantle cell lymphoma

- Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for
conventional allogeneic or autologous SCT.

- Disease responding or stable after most recent therapy (chemotherapy, MoAb).

- Relapsed after prior autologous SCT.

- B-cell prolymphocytic leukemia (PLL) with relapsed or residual disease after at least
1 prior therapy and not eligible for allogeneic SCT.

- Diffuse large cell lymphoma or other high-grade NHL, previously identified as CD19+

- Residual disease after primary therapy and not eligible for autologous SCT.

- Relapsed after prior autologous SCT.

- Beyond 1st CR with relapsed or persistent disease and not eligible or appropriate for
conventional allogeneic or autologous SCT.

- Age 1 to 21 years.

- Expected survival > 12 weeks

- Creatinine < 2.5 mg/dl and less than 2.5x normal for age

- ALT/AST < 3x normal

- Bilirubin <2.0 mg/dl

- Any relapse after prior autologous SCT will make patient eligible regardless of other
prior therapy.

- Patients with relapsed disease after prior allogeneic SCT (myeloablative or
non-myeloablative) will be eligible if they meet all other inclusion criteria and

- Have reverted to recipient hematopoiesis (no evidence of donor cells by STR analysis
on 2 occasions separated by at least 1 month).

- Have no active GVHD and require no immunosuppression

- Are more than 6 months from transplant

- For those patients who require leukapheresis for T cell collection (i.e. no
previously collected product exists), adequate venous access for apheresis or
eligible for appropriate catheter placement, and no other contraindications for
leukapheresis.

- Voluntary informed consent is given.

Exclusion Criteria:

1. Pregnant or lactating women. The safety of this therapy on unborn children is not
known. Female study participants of reproductive potential must have a negative serum
or urine pregnancy test performed within 48 hours before infusion.

2. Uncontrolled active infection.

3. Active hepatitis B or hepatitis C infection.

4. Concurrent use of systemic steroids at the time of cell infusion or cell collection,
or a condition, in the treating physician's opinion, that is likely to require
steroid therapy during collection or after infusion. Steroids for disease treatment
at times other than cell collection or at the time of infusion are permitted. Use of
inhaled steroids is permitted as well.

5. Previously treatment with any gene therapy products.

6. Feasibility assessment during screening demonstrates<30% transduction of target
lymphocytes, or insufficient expansion (<5-fold) in response to CD3/CD28
costimulation.

7. Any uncontrolled active medical disorder that would preclude participation as
outlined.

8. HIV infection.

9. Patients with active CNS involvement with malignancy. Patients with prior CNS
disease that has been effectively treated will be eligible providing treatment was >4
weeks before enrollment

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Number of Participants with Severe/Adverse Events as a Measure of Safety and Tolerability

Outcome Description:

Safety of CAR+ T cell infusion and observed side effects

Outcome Time Frame:

24 weeks

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

10-007706 (CHP959)

NCT ID:

NCT01626495

Start Date:

August 2011

Completion Date:

September 2016

Related Keywords:

  • B Cell Leukemia
  • B Cell Lymphoma
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, B-Cell
  • Lymphoma
  • Lymphoma, B-Cell

Name

Location

CHOP - http://www.chop.edu/service/oncology/pediatric-cancer-research/cart-19-trial.htmlPhiladelphia, Pennsylvania  19104