Acute Lymphoblastic Leukemia, B-precursor, Non-Hodgkin Lymphoma, B-cell
Conditions
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).
Interventions
BIOLOGICALCD19 CAR T cells
Autologous T cells activated and transduced with a chimeric antigen receptor targeting CD19
Sponsors
Sheba Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 50 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with treatment related adverse events as assessed by CTCAE v4. | 2 years | — |
| 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 |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Cytokine levels in the peripheral blood of the patients | 30 days | Measurement of cytokines in the blood of participants following CAR T cell administration |
Countries
Israel
Contacts
Primary ContactAmos Toren, MD,Phd
Backup ContactElad Jacoby, MD
Outcome results
None listed