Targeting CD19 and CD22 CAR-T Cells Immunotherapy in Patients With Relapsed or Refractory Acute B Lymphocytic Leukemia

Study Overview
=================
Brief Summary
-----------------
Evaluation the safety,tolerability, preliminary efficacy,and PK/PD of CD19-CD22 CAR-T cells for the treatment of acute B lymphocytic leukemia.

Detailed Description
-----------------
A non randomized study ,plans to enrollment 24 subjects of acute B lymphocytic leukemia .The subjects will divide into low, medium and high dose groups，to evaluate the safety and tolerability of CD19-CD22 CAR - T cells，to evaluate the preliminary efficacy and observe PK/PD parameters of CD19-CD22 CAR -T cells immunotherapy in patients with relapsed or refractory acute B lymphocytic leukemia .

Official Title
-----------------
A Clinical Study to Evaluate the Safety and Effectiveness of CD19- BCMA CAR - T Cells Immunotherapy in Patients With Relapsed or Refractory Acute B Lymphocytic Leukemia

Conditions
-----------------
Acute Lymphocytic Leukemia， B-Cell

Intervention / Treatment
-----------------
* Biological: CD19-CD22 CAR-T cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 6-70 - year - old male or female subjects (including 6 years old and 70 years old, 6-18 subjects use only the recommended dose of treatment); The Clinical diagnosis of recurrent/refractory acute B lymphocytic leukemia, after at least 2 courses of treatment, has not been achieved partial response, still in the continuous phase and progress, including the MRD positive, or recurrent intramedullary patients； Bone marrow samples inspection by using flow cytometry or organization pathology ，the cell membrane surface antigen CD19 and/or CD22 positive； ECOG physical status score of 0 to 2 points; Expected lifetime is more than 12 weeks; The clinical laboratory test results of screening phase meet the following criteria: (7 days before the inspection without blood transfusion) Hb≥60 g/L (allowed to use recombinant human erythropoietin); PLT≥ 50 x 10 ^ 9 / L ; ALC≥0.3×10^9/L; ANC≥0.75×10^9/L (allowed to use granulocyte colony stimulating factor); AST≤3ULN,ALT≤3ULN,TBIL≤2ULN；Ccr≥30 mL/min/1.73 m2； Cardiopulmonary function: left ventricular ejection fraction > 40%; Baseline blood oxygen saturation > 95%; Has a history of allogeneic/allogeneic hematopoietic stem cell transplantation patients: transplantation in 3 months ago, no grade 2 or more active graft versus host disease (GVHD), more than a month without immune inhibitors. Exclusion Criteria: The active hepatitis b, HBV - DNA detection lower limit of the subjects above research center; Hepatitis c virus (HCV) antibody positive and peripheral blood HCV - RNA positive subjects; Antibodies to HIV positive subjects; Early syphilis screening antibody positive; The other clinical significance of active virus, bacterial infection, or failing to control systemic fungal infection; Any instability of systemic disease, including but not limited to, unstable angina, cerebrovascular accident, or transient ischemic (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), New York heart association (NYHA) classification level III or higher congestive heart failure, drug control of serious arrhythmia, liver, kidney or metabolic diseases, as well as the standard treatment cannot control high blood pressure; In past two years, because of autoimmune diseases such as crohn's disease, rheumatoid arthritis and systemic lupus erythematosus (sle), etc.) causing end-organ damage, or need systemic application of immunosuppressive drugs; Had a history of the central nervous system diseases, such as epilepsy, serious brain damage, dementia, Parkinson's disease, psychosis,etc which influence the appraising of test,; Diagnosed with other active malignancy in past five years(the basal or scaly skin cancer, superficial bladder cancer, breast cancer in situ, which has been cured and does not require follow-up treatment are not included ); Known allergic to cyclophosphamide, fluorine dara marina or CAR - T cell s including accessories, DMSO ; Patients with pregnancy or lactation, patients do not want to take effective contraceptive measures within 6months after infusion CAR-T cells; The other situations that researchers determined doesn't fit to participate in this study.

Ages Eligible for Study
-----------------
Minimum Age: 6 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: According to the sequence from the low dose group to the high dose group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose Group<br>CD19-CD22 CAR-T cells injection, infused only once,3-6 subjects of low dose group will be intravenously infuse with 0.5×10^6 CAR+T cells/kg. | Biological: CD19-CD22 CAR-T cells<br>* A autologous doping CAR - T cells injection targets with CD19 and CD22，fluorine dara marina injection(30 mg/m2，QD×3d) and cyclophosphamide injection (300 mg/m2，QD×3d)will be used to remove the lymphocyte before infusion CD19-CD22 CAR-T cells .<br>* Other names: Cyclophosphamide injection;|
| Experimental: Middle Dose Group<br>CD19-CD22 CAR-T cells injection, infused only once,3-6 subjects of low dose group will be intravenously infuse with 2×10^6 CAR+T cells/kg. | Biological: CD19-CD22 CAR-T cells<br>* A autologous doping CAR - T cells injection targets with CD19 and CD22，fluorine dara marina injection(30 mg/m2，QD×3d) and cyclophosphamide injection (300 mg/m2，QD×3d)will be used to remove the lymphocyte before infusion CD19-CD22 CAR-T cells .<br>* Other names: Cyclophosphamide injection;|
| Experimental: High Dose Group<br>CD19-CD22 CAR-T cells injection, infused only once,3-6 subjects of low dose group will be intravenously infuse with 5×10^6 CAR+T cells/kg. | Biological: CD19-CD22 CAR-T cells<br>* A autologous doping CAR - T cells injection targets with CD19 and CD22，fluorine dara marina injection(30 mg/m2，QD×3d) and cyclophosphamide injection (300 mg/m2，QD×3d)will be used to remove the lymphocyte before infusion CD19-CD22 CAR-T cells .<br>* Other names: Cyclophosphamide injection;|
| Experimental: Amplification Dose Group<br>CD19-CD22 CAR-T cells injection, infused only once.After determined maximum tolerated dose,15 subjects of amplification dose group will be intravenously infuse with 0.5-5.0×10^6 CAR+Tcells/kg. | Biological: CD19-CD22 CAR-T cells<br>* A autologous doping CAR - T cells injection targets with CD19 and CD22，fluorine dara marina injection(30 mg/m2，QD×3d) and cyclophosphamide injection (300 mg/m2，QD×3d)will be used to remove the lymphocyte before infusion CD19-CD22 CAR-T cells .<br>* Other names: Cyclophosphamide injection;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | Observe wether dose limiting toxicity will happened in dose escalation phase | Form infusion CAR-T cells to 28 days after infusion | 
| ORR | The overall response rate after CD19-CD22 CAR-T Cells immunotherapy | Form infusion CAR-T cells to 2 years after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of various types of adverse recation | According to CTCAE 5.0, record the level , type of adverse events, evaluat the correlation of CD19-CD22 CAR-T cells | Form infusion CAR-T cells to 2 years after infusion | 
| PFS | Progression-free surial | Form infusion CAR-T cells to 2 years after infusion | 
| DOR | Duration of Response | Form infusion CAR-T cells to 2 years after infusion | 
| OS | Overall survival | Form infusion CAR-T cells to subjects died，assessed up to 60 months | 
| Cmax | By measuring the CAR - T cells copy number and the positive rate, peak plasma concentration is determined | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Tmax | The maximum concentration of time | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| AUC（0-720d） | Area under the plasma concentration versus time curve | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Concentration of IL2 level | The levels of cytokines（IL2 ）in peripheral blood | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Concentration of IL6 level | The levels of cytokines（IL6 ）in peripheral blood | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Concentration of IL10 level | The levels of cytokines（IL10 ）in peripheral blood | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Concentration of TNF-α level | The levels of cytokines（TNF-α ）in peripheral blood | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 | 
| Concentration of IFN-γ level | The levels of cytokines（IFN-γ ）in peripheral blood | Before removal of lymphocytes, before CAR - T cells infusion, Day1, Day3, Day5, Day7, Day10, Day14, Day21, Day28, Month2, Month3, Month6, Month9, Month12, Month15, Month18, Month21, Month24 |