T-cells Expressing Anti-CD19 CAR in Pediatric and Young Adults With B-cell Malignancies

Study Overview
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Brief Summary
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This phase 1 / 2 study will evaluate the response of B-cell malignancies expressing CD19 to autologous T cells transduced with a second generation anti-CD19 chimeric antigen receptor in children and young adults.

Detailed Description
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Autologous T cells transduced with chimeric antigen receptors (CAR) that recognize the CD19 antigen (CD19-CAR T cells) have been used in multiple clinical trials at several institutions worldwide. We established an in-house manufacturing process for CD19-CAR T cells with a CD28 (cluster of differentiation 28) costimulatory domain. Primary Objectives: To study the safety of administration of CAR T cell at the Sheba Medical Center To determine the feasibility and efficacy of administering anti-CD19-CAR T cells in children and young adults with B cell malignancies. Secondary Objectives To study in vivo and in vitro behavior of CAR T cell in patients, including persistence, expansion, cytotoxic potential and exhaustion. To study the cytokine milieu in CAR treated patients. Eligibility Patients 1-50 years of age, with a CD19-expressing B-cell malignancy that has recurred after, or not responded to, one or more standard chemotherapy-containing regimens. Design Peripheral blood mononuclear cells (PBMCs)will be obtained by leukapheresis. Anti-CD19 CAR T cells will be manufactured from fresh autologous PBMCs. PBMC will be cultured in the presence of anti-CD3 (cluster of differentiation 3) antibody and interleukin-2 followed by retroviral vector supernatant containing the anti-CD19 CAR. Total culture time is between 7-10 days. Patients will receive lymphodepleting chemotherapy composed of cyclophosphamide and fludarabine prior to cell infusion, and on day 0 will receive one million CAR T cells per kilogram. Patients will be monitored for toxicity including cytokine release syndrome, hematologic toxicities and B-cell aplasia; for response of their underlying malignancy; and for CAR-T cell persistence in the blood, marrow and cerebral spinal fluid (CSF).

Official Title
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A Phase 1 / 2 Single Arm Study of T-cells Expressing Anti-CD19 Chimeric Antigen Receptor in Pediatric and Young Adult Patients With B-cell Malignancies

Conditions
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Acute Lymphoblastic Leukemia, B-precursor, Non-Hodgkin Lymphoma, B-cell

Intervention / Treatment
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* Biological: CD19 CAR T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with relapsed or refractory B-cell malignancy Age 1-50 years CD19 expression shown by flow cytometry or immunohistochemistry on at least 70% of leukemic blasts / lymphoma cells Adequate CD3 count (above 250 CD3+ cells per microliter blood) Clinical performance status: Patients > 10 years of age: Karnofsky ≥ 50%; Patients ≤ 10 years of age: Lansky scale ≥ 50%. Exception for neurologic symptoms (e.g. paralysis) that are explained by the malignancy. Females of child-bearing potential must have a negative pregnancy test Cardiac function: Left ventricular ejection fraction >45% or shortening fraction >28% For patients following allogeneic bone marrow transplantation - at least 100 days post BMT with no signs or symptoms of active graft-versus-host disease. Key Exclusion Criteria: Hyperleukocytosis (WBC>50,000) or rapidly progressive disease Pregnant or breast-feeding females Hepatic dysfunction, defined as bilirubin > x2 upper normal limit (except when explained by hemolysis or Gilbert) or serum glutamate oxaloacetate transaminase > x25 upper normal limit. Hepatitis B, Hepatitis C or HIV infection. Anti-neoplastic treatment given in the 2 weeks prior to apheresis, with the exception of intrathecal chemotherapy. Active immunosuppressive therapy

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 50 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>All patients will be treated on this single arm | Biological: CD19 CAR T cells<br>* Autologous T cells activated and transduced with a chimeric antigen receptor targeting CD19<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with treatment related adverse events as assessed by CTCAE v4. |  | 2 years | 
| Overall Response Rate | Overall response rate = complete response (CR) + partial response (PR) + complete response with incomplete count recovery (CRi) in leukemia patients; Assessment using bone marrow evaluation for patients with leukemia, and imaging (CT / PET CT) for patients with lymphoma | 28 days | 
| Feasibility of CD19 CAR T cell production as defined by number of products successfully meeting release criteria | For each participant, the feasibility of generating sufficient autologous CAR T cells within 12 days will be evaluated. | 12 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAR T cell persistence as measured by enumeration of CAR T cells in the blood and bone marrow of participants | Enumeration of CAR T cells in the blood and bone marrow of participants | 1 year | 
| T cell activity and exhaustion profile as measured by flow cytometry | Assessment of T cells from peripheral blood by flow cytometry for expression of activation and exhaustion markers. | 3 months | 
| Cytokine levels in the peripheral blood of the patients | Measurement of cytokines in the blood of participants following CAR T cell administration | 30 days |