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

Sheba Medical Center300 enrolled

Overview

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.

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: 1. To study the safety of administration of CAR T cell at the Sheba Medical Center 2. To determine the feasibility and efficacy of administering anti-CD19-CAR T cells in children and young adults with B cell malignancies. Secondary Objectives 1. To study in vivo and in vitro behavior of CAR T cell in patients, including persistence, expansion, cytotoxic potential and exhaustion. 2. 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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

300

Conditions

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

Interventions

CD19 CAR T cellsBIOLOGICAL

Autologous T cells activated and transduced with a chimeric antigen receptor targeting CD19

Eligibility

Sex: ALLMin age: 1 YearMax age: 50 Years

Medical Language ↔ Plain English

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

Locations (1)

Chaim Sheba Medical Center

Ramat Gan, Israel

RECRUITING

Outcomes

Primary Outcomes

Number of patients with treatment related adverse events as assessed by CTCAE v4.

Time frame: 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

Time frame: 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.

Time frame: 12 days

Secondary Outcomes

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

Time frame: 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.

Time frame: 3 months

Cytokine levels in the peripheral blood of the patients

Measurement of cytokines in the blood of participants following CAR T cell administration

Time frame: 30 days

Central Contacts

Amos Toren, MD,Phd

CONTACT

03-5302934 amos.toren@sheba.health.gov.il

Elad Jacoby, MD

CONTACT

03-5302934 elad.jacoby@sheba.health.gov.il

Data from ClinicalTrials.gov

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