Dose Optimization Trial of CD19 Redirected Autologous T Cells
Condition: Adult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL
Intervention: CART-19
Intervention description: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a randomized, open-label, parallel group study to determine the optimal dose of
      CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing
      tandem TCR Zeta and 4-1 BB co-stimulatory domains) of the two dose levels being assessed
      (1-5x10e8 vs. 1-5x10e7 CART-19 cells). This trial will be conducted in two stages.
    

Eligibility criteria:

        Inclusion Criteria

          -  Documented CD19+ CLL or SLL

          -  Successful test expansion of T-cells

          -  At least 2 prior chemotherapy regimens, not including single agent monoclonal antibody
             (rituxan) therapy. Single agent ofatumumab will be counted as a regimen. -Patients
             with high risk disease manifested by deletion chromosome 17p will be eligible if they
             fail to achieve a CR to initial therapy or progress within 2 years of 1 prior regimen.

          -  Patients who progress within 2 years after the second or higher line of therapy will
             be eligible. For instance, patients who had progression < 2 years after second or
             greater line therapy, but who have responded to their most recent treatment (3rd line
             or higher) will be eligible.

          -  Subject is not appropriate candidate for a potentially curative allogeneic SCT due to
             the state of disease, co-morbid illness, lack of an available donor, or patient
             declines Performance status (ECOG) 0 or 1

          -  Age >/= 18 years

          -  Adequate organ system function including:

               1. Creatinine < 1.6 mg/dl

               2. ALT/AST < 3x upper limit of normal

               3. Total 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
             nonmyeloablative) will be eligible if they meet all other inclusion criteria and:

               1. Have no active GVHD and require no immunosuppression

               2. Are more than 6 months from transplant

          -  No contraindications for leukapheresis

          -  Left Ventricular Ejection fraction >40%

          -  Gives voluntary informed consent

        Retreatment Inclusion Criteria

          -  Performance Status 0-1

          -  Adequate organ system function including:

               -  Creatinine < 1.6 mg/dl

               -  ALT/AST < 3x upper limit of normal

               -  Total Bilirubin < 2.0 mg/dl

          -  Subject is not an appropriate candidate for a potentially curative allogeneic SCT due
             to the state of disease, co-morbid illness, lack of an available donor, or patient
             declines.

          -  Left Ventricular Ejection Fraction > 40%

          -  No contraindications for leukapheresis (if required for retreatment)

          -  Gives voluntary informed consent for retreatment

        Exclusion Criteria

          -  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.

          -  Uncontrolled active infection

          -  Active hepatitis B or hepatitis C infection

          -  Concurrent use of systemic steroids or chronic use of immunosuppressant medications.
             Recent or current use of inhaled steroids is not exclusionary. For additional details
             regarding use of steroid and immunosuppressant medications.

          -  Any uncontrolled active medical disorder that would preclude participation as outlined

          -  HIV infection

          -  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.

          -  Class III/IV cardiovascular disability according to the New York Heart Association
             Classification

        Retreatment Exclusion Criteria

          -  Pregnant or lactating women. Female study participants must have a negative serum or
             urine pregnancy test performed within 48 hours before infusion.

          -  Uncontrolled active infection

          -  Active hepatitis or hepatitis infection

          -  Concurrent use of systemic steroids. Recent or current use of inhaled steroids is not
             exclusionary.

          -  Any uncontrolled active medical disorder that would preclude participation as
             outlined.

          -  HIV infection

          -  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 on the retreatment cohort.

          -  Class III/IV cardiovascular disability according to the New York Heart Association
             Classification