Phase IIa Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRz and 4-Signaling Domains in Patients With Chemotherapy Relapsed or Refractory CD19+ Lymphomas
Condition: Non-Hodgkins Lymphoma (NHL) Patients, With CD19+B Cell Lymphomas
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Intervention: CART-19
Intervention description: Single infusion of CART-19 cells administered by i.v. injection (total dose of 1 - 5 x108 CART-19 cells, calculated as a range of 2-50% transduced cells in total cells).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 63.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Phase IIa study to estimate the efficacy of a single infusion of autologous T cells
      expressing CD19 chimeric antigen receptors expressing tandem TCR and 4-1BB (TCR /4-1BB)
      costimulatory domains (referred to as CART-19 or CTL019 cells) in non-Hodgkins Lymphoma (NHL)
      patients. The duration of active protocol intervention is approximately 24 months from
      screening visit. The protocol will require approximately 48 months to complete.
    

Eligibility criteria:

        Inclusion Criteria

          -  Male or female subjects with CD19+ B cell lymphomas with no available curative
             treatment options (such as autologous or allogeneic SCT) who have a limited prognosis
             (several months to <2 year survival) with currently available therapies will be
             enrolled. The study will enroll 51 evaluable subjects as follows:

          -  CD19+ Lymphoma

        Cohort A Subjects:

        a. Follicular lymphoma, previously identified as CD19+ i. At least 2 prior chemotherapy or
        immunochemotherapy regimens (not including single agent monoclonal antibody therapy) ii.
        Patients who progress within 2 years after second or higher line of therapy will be
        eligible. For instance, patients who have progression of lymphoma < 2 years after second or
        greater line therapy, but who have responded to their most recent treatment (3rd line or
        higher) will be eligible. Patients may have progression, stable disease or responding
        disease at the time of enrollment.

        iii. Patients with a history of large cell transformation are eligible. b. Mantle cell
        lymphoma, previously identified as CD19+ i. Beyond 1st CR with relapsed disease,
        progressive disease during first line rituximab-chemotherapy combination, or persistent
        disease after first line rituximab-chemotherapy combination and not eligible or appropriate
        for conventional allogeneic or autologous SCT.

        ii. Relapsed after prior autologous SCT. c. Diffuse large B cell lymphoma, previously
        identified as CD19+ i. Residual disease after primary therapy and not eligible for
        autologous SCT ii. Relapsed or persistent disease after prior autologous SCT iii. Beyond
        1st CR with relapsed or persistent disease and not eligible or appropriate for conventional
        allogeneic or autologous SCT iv. Patients with an antecedent history of follicular lymphoma
        or CLL/SLL are eligible.

        Cohort B Subjects:

        a. Diffuse large B cell lymphoma, previously identified as CD19+ CD19 i. Residual disease
        after primary therapy and not eligible for autologous SCT ii. Relapsed or persistent
        disease after prior autologous SCT iii. Beyond 1st CR with relapsed or persistent disease
        and not eligible or appropriate for conventional allogeneic or autologous SCT iv. Patients
        with an antecedent history of follicular lymphoma or CLL/SLL are eligible.

        v. Patients with T cell/histiocyte-rich disease as confirmed by surgical pathology report

        Cohort C Subjects:

        a. Diffuse large B cell lymphoma, previously identified as CD19+ i. Residual disease after
        primary therapy and not eligible for autologous SCT ii. Relapsed or persistent disease
        after prior autologous SCT iii. Beyond 1st CR with relapsed or persistent disease and not
        eligible or appropriate for conventional allogeneic or autologous SCT iv. Patients with an
        antecedent history of follicular lymphoma or CLL/SLL are eligible.

          -  Age ≥18 years

          -  Creatinine < 1.6 mg/dL

          -  ALT/AST < 3x upper limit of normal

          -  Bilirubin <2.0 mg/dL, unless subject has Gilbert's Syndrome (<3.0 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:

               1. Have no active GVHD and require no immunosuppression

               2. Are more than 6 months from transplant

          -  Measurable or assessable disease according to the "Revised Response Criteria for
             Malignant Lymphoma" (Cheson et al., J. Clin. Onc., 1999)108. Patients in complete
             remission with no evidence of disease are not eligible.

          -  Performance status (ECOG) 0 or 1.

          -  Left Ventricle Ejection Fraction (LVEF) > 40% confirmed by ECHO/MUGA

          -  Written informed consent is given. Successful T cell test expansion (first 10
             subjects).

        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
             pregnancy test at enrollment. A urine pregnancy test will be 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. For additional details regarding use of steroids

          -  Any uncontrolled active medical disorder that would preclude participation as
             outlined.

          -  Class III/IV cardiovascular disability according to the New York Heart Association
             Classification (see Appendix 1).

          -  HIV infection.

          -  Patients with active CNS involvement by malignancy. Patients with prior CNS disease
             that has been effectively treated will be eligible providing treatment was >4 weeks
             before enrollment

          -  Patients in complete remission with no assessable disease.

          -  Patients with a known history or prior diagnosis of optic neuritis or other
             immunologic or inflammatory disease affecting the central nervous system.