The Safety and Efficacy of CART-19 Cells in B-cell Acute Lymphoblastic Leukemia (B-ALL).

Study Overview
=================
Brief Summary
-----------------
This is a study for patients who have been previously treated for B-ALL. The purpose of this study is to determine the safety and feasibility of CART-19 cells to the patients with relapsed and refractory CD19+ B-ALL.

Detailed Description
-----------------
Subjects will be staged and the suitability of their T cells for CART-19 manufacturing will be determined at entry phase,. Subjects will be collected large numbers of peripheral blood mononuclear cells (PBMC) for CART-19 manufacturing. The T cells will be purified from the PBMC, transduced with CART-19 lentiviral vector, expanded in vitro and then administered to subjects. Subjects will have blood tests to assess safety and efficacy, and persistence of the CART-19 cells at regular intervals through four weeks after their last infusion of the study. Following the 6 months of intensive follow-up, subjects will be evaluated quarterly for two years with a physical examination, blood tests, bone marrow aspirate, minimal residual disease (MRD) and persistence of CART-19. Following this evaluation, subjects will be evaluated health problems every year for an additional thirteen years.

Official Title
-----------------
The Safety and Efficacy of CART-19 Cells in Relapse and Refractory Patients With CD19+ B-cell Acute Lymphoblastic Leukemia.

Conditions
-----------------
B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Biological: CART-19 cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 4 years to 70 years, expected survival > 3 months CD19 positive B-cell acute lymphoblastic leukemia Karnofsky Performance Status (KPS) >70 Relapsed after allogeneic or autologous stem cell transplantation (SCT); Cardiac function: 1-2 levels; Liver: TBIL≤3 Upper Limit of Normal (ULN)，aspartate aminotransferase (AST) ≤2.5 ULN，ALT ≤2.5 ULN; kidney: Cr≤1.25 ULN; bone marrow: White Blood Cell (WBC) ≥ 3.0×109/L, Hb ≥90 g/L, Platelet (PLT) ≥ 80×109/L） No serious allergic constitution No other serous diseases that conflicts with the clinical program No other cancer history No serious mental disorder Informed consent is signed by a subject or his lineal relation. Exclusion Criteria: Pregnant or lactating women; (female participants of reproductive potential must have a negative serum or urine pregnancy test) Uncontrolled active infection, HIV infection, syphilis serology reaction positive Active hepatitis B or hepatitis C infection Recent or current use of glucocorticoid or other immunosuppressor With severe cardiac, liver, renal insufficiency, diabetes and other diseases Transaminase >2.5 ULN, Bilirubin >3 ULN，Creatinine>1.25 ULN Participate in other clinical research in the past three months; previously treatment with any gene therapy products Researchers think of that does not fit to participate in the study, or other cases that affect the clinical trial results

Ages Eligible for Study
-----------------
Minimum Age: 4 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CART-19<br>patients will receive a pre-conditioning with cyclophosphamide and fludarabine before infusion of CART-19 cells. The CART-19 cells are to be administered on day0,day1,day2. | Drug: Cyclophosphamide<br>* patients will receive a standard pre-conditioning regime with cyclophosphamide 0.8-1.0g/m2/day IV for 2 days(Day-5 to day-4).<br>Drug: Fludarabine<br>* Fludarabine 25mg/m2/day IV for 3 days (Day-5 to day-3).<br>Biological: CART-19 cells<br>* CART-19 cells will be administered using a split dose on day0(10%), 1(30%), and 2(60%) after completion of the chemotherapy.<br>* Other names: CD19 specific Chimeric Antigen Receptor T-cells;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| safety as assessed by the occurrence of study related adverse events. | monitor the occurrence of study related adverse events. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| efficacy | anti-tumor activity of CART-19 cells will be determined in a follow-on study | 2 years | 
| duration of CART-19 | Determine duration of in vivo survival of CART-19 cells. | 2 years |