CAR-T-19 Injection in the Treatment of CD19-positive Relapsed/Refractory B-ALL

Study Overview
=================
Brief Summary
-----------------
This is a phase II clinical study to evaluate the safety and efficacy of CAR-T-19 injection in the treatment of CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia.

Detailed Description
-----------------
This is a multiple-center, single-arm, open-label study. After meeting the eligibility criteria and enrolling on the trial, patients will undergo leukapheresis for collection of autologous lymphocytes, patients will then proceed to lymphodepleting chemotherapy with cyclophosphamide 300mg/m^2 and fludarabine 30mg/m^2 for 3 consecutive days followed by the infusion of CD19 CAR T-cells at a target dose of 1.5 x10^6 cells/kg（range 0.5-1.5×10^6 cells/kg）.

Official Title
-----------------
Phase II Clinical Study of CAR-T-19 (Anti-CD19 Single-chain Antibody Chimeric Antigen Receptor T Cell) Injection in the Treatment of CD19-positive Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia(B-ALL) Under 25 Years of Age (Inclusive)

Conditions
-----------------
Relapsed B-cell Acute Lymphoblastic Leukemia, Refractory B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
-----------------
* Biological: CAR-T-19 cell injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Voluntary participation in clinical trial, The Participants or his legal guardian is fully understands this clinical trial and signs the Informed Consent Form (ICF); Willing to follow and be able to complete all trial procedures; Age<25 years old at the time of screening, regardless of gender; Bone marrow examination confirmed the diagnosis of B-ALL, and meet one of the following conditions： Relapsed B-ALL：1）Relapse within 12 months of the first remission；2）Relapse after first-line/multi-line salvage chemotherapy；3） recurrence after autologous or allogeneic hematopoietic stem cell transplantation(HSCT)； Refractory B-ALL：1）failed to achieve complete remission after 2 cycles of standard induction chemotherapy；2）failed to achieve complete remission after first-line/multi-line salvage chemotherapy; Ph+ALL patients are eligible：1）Relapsed or refractory after receiving at least two Tyrosine kinase inhibitors (TKI) treatments；If Ph+ALL patients with t315i mutation are resistant to first- and second-generation TKIs, in the absence of effective TKI therapy, patients are not required to receive at least two TKIs；2）cannot tolerate TKI treatment；3）Presence of contraindications to TKI therapy. Bone marrow (BM) or peripheral blood (PB) tumor cells were measured to express CD19 within 3 months prior to screening; Bone marrow blasts ≥ 5% at screening; Adequate organ function and must meet the following criteria： Alanine aminotransferase (ALT) ≤ 5 ×Upper limit of normal value(ULN)；Total serum bilirubin ≤ 2.0 ×ULN(（for Gilbert syndrome, total bilirubin≤3.0×ULN)；in non-oxygen state, No > grade 1 dyspnea, Blood oxygen saturation > 95%；left ventricular ejection fraction(LVEF) ≥ 50%；Serum creatinine≤1.5 × ULN； Karnofsky（age≥16 years）performance status≥70 or Lansky（age<16 years）performance status≥50； Life expectancy ≥ 12 weeks; Adequate venous access (for apheresis or venous blood collection) and no other contraindications to apheresis; Negative blood/urine pregnancy test in women of childbearing potential before apheresis and within 3 days prior to cell infusion, and any male and female patients of childbearing potential must agree to use an effective method of contraception throughout the study and for at least 2 years after CAR-T-19 infusion. In the judgment of the investigator, a patient of childbearing potential means that he/she is biologically capable of having children and having a normal sexual life； For Participants who have previously undergone allogeneic hematopoietic stem cell transplantation, CAR-T-19 cell preparation is performed using their previous donor peripheral blood， and the donor needs to meet the following conditions：1）Have donated bone marrow/hematopoietic stem cells as a transplant donor for the patient；2）Age ≥8 years at screening；3）Voluntary participation in clinical studies; the donor (and legal guardian, if applicable) am fully aware of and informed about this trial and have signed an informed consent form (ICF); Willing to follow and be able to complete all trial procedures；4）Have adequate venous access (for apheresis or venous blood collection) and no other contraindications to apheresis. Exclusion Criteria: Isolated extra-medullary disease relapse; Participants with genetic syndromes, Patients with Down Syndrome will not be excluded; Participants with Burkitt's lymphoma/leukemia ; Received the following anti-tumor therapy before screening：1）Received any chemotherapy, targeted therapy, etc. within 4 weeks；2）Radiotherapy within 14 days；3）Intrathecal treatment within 7 days；4）Receive TKI treatment within 3 days；5）Receive short-acting cytotoxic or antiproliferative drugs within 3 days; Participants with a history of other malignant tumors or other malignant tumors at the same time (excluding fully treated cervical carcinoma in situ, basal cell or squamous epithelial cell skin cancer, local prostate cancer after radical resection, thyroid cancer, ductal carcinoma in situ after radical resection); Any of the following applies:1）Hepatitis B surface antigen (HBsAg) positive or hepatitis B virus DNA(HBV DNA) quantity is higher than the upper limit of normal value；2）Hepatitis C virus antibody (HCV Ab) is positive and HCV RNA quantification is higher than the upper limit of normal values;3）Positive for human immunodeficiency virus antibody (HIV-Ab);4）EB virus DNA quantification is higher than the upper limit of normal values;5）Cytomegalovirus DNA quantification is higher than the upper limit of normal values; have or suspected to have fungal, bacterial, viral or other infections that are uncontrollable or require intravenous treatment; Participants who have received HSCT within 3 months before screening or Presence of grade 2 to 4 active graft-versus-host disease (GVHD), and those who have received systemic drug therapy for GVHD within 4 weeks before infusion; Participants who have been treated with systemic glucocorticoids within 1 week before blood collection, physiological replacement doses of steroids are allowed; Long-acting Granulocyte Colony-Stimulating Factor(G-CSF) is prohibited within 21 days and short-acting G-CSF is prohibited within 7 days before screening; Participants with active central nervous system disease; Active central nervous system leukemia at screening; Those who have received CAR-T therapy with any target; Allergy to albumin and aminoglycoside antibiotics; Received live vaccine within 6 weeks before screening; Participants after organ transplantation (except hematopoietic stem cell transplantation); participated in other interventional clinical studies (received active trial drug treatment) within 3 months before screening, or intend to participate in another clinical trial or receive another anti-tumor therapy; Other investigators deem it inappropriate to participate in the study.

Ages Eligible for Study
-----------------
Maximum Age: 25 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: CAR-T-19 cells<br>CAR-T-19 cells injection: 1.5 x10^6 cells/kg（range 0.5-1.5×10^6 cells/kg） | Biological: CAR-T-19 cell injection<br>* The functional component of CAR-T-19 cell injection is T cells that have been genetically modified to express anti CD19 chimeric antigen receptors.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate(ORR) | ORR included complete response (CR) and CR with incomplete blood count recovery (CRi) as determined by an Independent Review Committee（IRC） assessment. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | ORR at 3 months after CAR-T-19 infusion as assessed by investigator. | 3 months | 
| ORR | ORR at 28 days after CAR-T-19 infusion as assessed by IRC and investigator. | 28 days | 
| Minimal residual disease（MRD） | MRD-negative ORR as assessed by Independent Review Committee (IRC) and investigator. | 3 months | 
| Best overall response (BOR) | BOR as assessed by Independent Review Committee (IRC) and investigator. | 2 years | 
| Duration of response (DOR) | DOR as assessed by Independent Review Committee (IRC) and investigator. | 2 years | 
| Progression Free Survival（PFS） | PFS as assessed by Independent Review Committee (IRC) and investigator. | 2 years | 
| Overall survival (OS) | Overall survival means the time from infusion of CAR-T-19 cells to death of participants from any cause. | 2 yeas | 
| safety | Number of participants with Adverse event (AE). | 2 years | 
| safety | Number of participants with Serious adverse event (SAE) | 2 years | 
| safety | Number of participants with Human anti-mouse antibody (HAMA). | 2 years | 
| Pharmacokinetics (PK) Parameter | Cmax | 2 years | 
| Pharmacokinetics (PK) Parameter | Tmax | 2 years | 
| Pharmacokinetics (PK) Parameter | AUC0-t | 2 years | 
| Pharmacokinetics (PK) Parameter | AUC0-28d | 2 years | 
| Pharmacokinetics (PK) Parameter | t1/2 | 2 years | 
| Pharmacodynamics | The degree of clearance of CD19-positive B cells at different blood collection time points after cell infusion. | 2 years | 
| Serum cytokines | The concentration levels of Interleukin 6（ IL-6）at each time point . | 28 days | 
| Serum cytokines | The concentration levels of tumor necrosis factor -α（ TNF-α） at each time point . | 28 days | 
| Serum cytokines | The concentration levels of Interferon -γ（INF-γ） at each time point . | 28 days |