T-cells Expressing Anti-CD19 CAR in Pediatric and Young Adults With B-cell Malignancies
- Conditions
- Acute Lymphoblastic Leukemia, B-precursorNon-Hodgkin Lymphoma, B-cell
- Interventions
- Biological: CD19 CAR T cells
- Registration Number
- NCT02772198
- Lead Sponsor
- Sheba Medical Center
- Brief Summary
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
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).
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 300
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single Arm CD19 CAR T cells All patients will be treated on this single arm
- Primary Outcome Measures
Name Time Method Overall Response Rate 28 days 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
Number of patients with treatment related adverse events as assessed by CTCAE v4. 2 years Feasibility of CD19 CAR T cell production as defined by number of products successfully meeting release criteria 12 days For each participant, the feasibility of generating sufficient autologous CAR T cells within 12 days will be evaluated.
- Secondary Outcome Measures
Name Time Method Cytokine levels in the peripheral blood of the patients 30 days Measurement of cytokines in the blood of participants following CAR T cell administration
CAR T cell persistence as measured by enumeration of CAR T cells in the blood and bone marrow of participants 1 year Enumeration of CAR T cells in the blood and bone marrow of participants
T cell activity and exhaustion profile as measured by flow cytometry 3 months Assessment of T cells from peripheral blood by flow cytometry for expression of activation and exhaustion markers.
Trial Locations
- Locations (1)
Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel