CD19 Redirected Autologous T Cells

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.

This study is being conducted to determine the optimal dose of autologous CART-19 T cells engineered to express anti-CD19 chimeric antigen receptors in patients with relapsed or refractory CD19 positive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The two dose levels being assessed are 1-5x10e8 versus 1-5x10e7. The trial will be conducted in two stages. In stage I subjects will be randomized into one of the two dose cohort with a1:1 ratio for a total of 12 subjects per dose cohort. Stage II will be to enroll an additional 8 subjects to the selected dose cohort once safety, tolerability and clinical responses have been evaluated to determine the optimal dose cohort.

• Experimental: Target dose of 1-5x10e8
  Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)
  Intervention: Biological: CART-19
• Experimental: Target dose of 1-5x10e7
  Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)
  Intervention: Biological: CART-19

Inclusion Criteria:

• Documented CD19+ CLL or SLL
• Successful test expansion of T-cells (as described in Section 6.1)
• At least 2 prior chemotherapy regimens. At least one fludarabine or other nucleoside analog containing regimen. Chemotherapy in combination with monoclonal antibody (Rituxan) will be considered one prior regimen, but single agent Rituxan will not be considered one prior regimen. Single agent ofatumumbab will be counted as a regimen.
• Less than 2 years between last therapy and progression (e.g. most recent progression free interval 2 years)
• Subject has no available or declines curative treatment options such as allogeneic SCT and has limited prognosis (2 years survival) with currently available therapies
• Expected survival 12 weeks
• Performance status (ECOG) 0 or 1
• Age greater than or equal to 18 years

• Adequate organ system function including:

  1. Creatinine 1.6 mg/dl
  2. ALT/AST 3x upper limit of normal
  3. Direct 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. experienced graft rejection (no evidence of donor cells by STR analysis on 2 occasions separated by at least 1 month)
  2. Have no active GVHD and require no immunosuppression
  3. Are more than 6 months from transplant
• No contraindications for leukapheresis
• Gives voluntary informed consent

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. 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.