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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-Hodgkins Lymphoma (NHL) Patients, With CD19+B Cell Lymphomas

Intervention / Treatment
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* Biological: CART-19


Participation Criteria
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Eligibility Criteria
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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: Have no active GVHD and require no immunosuppression 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A<br>murine CART19 | Biological: CART-19<br>* 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).<br>|
| Experimental: Cohort B<br>T cell/histiocyte-rich Diffuse Large B Cell Lymphoma (DLBCL) treated with murine CART19 | Biological: CART-19<br>* 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).<br>|
| Experimental: Cohort C<br>Diffuse Large B Cell Lymphoma (DLBCL) treated with humanized CART19 | Biological: CART-19<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With an Overall Response (i.e. Either Complete Response or Partial Response) Evaluated at Three Months Post Infusion. | Responders will include those patients achieving complete response (CR), complete response unconfirmed (CRu) and partial response (PR) using anatomic imaging such as CT or MRI to assess tumor volume or, in the event of bone marrow involvement, morphologic and immunohistochemical confirmation that the bone marrow infiltrate has been cleared. | 3 months |