Novel Anti-CD19 Universal CAR-T Cells for r/r CD19+ B-ALL

Study Overview
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Brief Summary
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This is a single-arm, single-center, open-labeled clinical study to evaluate the safety and efficacy of UCAR-T Cells injection for patients with relapsed/refractory(r/r) B-cell Acute Lymphoblastic Leukemia(B-ALL).

Detailed Description
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Although the anti-CD19 CAR-T cell therapies have gained significant clinical outcome in patients with r/r B-ALL，autologous CAR-T is not feasible for some patients. To make further improvement, the investigators are going to conduct a clinical trial using universal CAR-T(UCAR-T) cells targeting CD19 for r/r B-ALL patients. After enrollment, patients will get a 3-5 days lymphodepletion therapy, then the UCAR-T Cells will be infused by vein. Subjects will be followed for safety and efficacy up to 12 weeks. For those with a durable remission 12 weeks after infusion, the follow-up will last for at least 12 months for disease control.

Official Title
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An Investigator-initiated Trial to Evaluate the Efficacy and Safety of Anti-CD19 Universal CAR-T Cells in the Treatment of Relapsed/Refractory(r/r) CD19+ B-cell Acute Lymphoblastic Leukemia(B-ALL)

Conditions
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B-cell Acute Lymphoblastic Leukemia, B-ALL

Intervention / Treatment
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* Biological: UCAR-T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged 2-75 years; A definite diagnosis of relapsed/refractory B-ALL and a percentage of primitive/naive lymphocytes >5% in bone marrow at baseline (flow cytometry); CD19 expression was positive in bone marrow or peripheral blood tumor cells; ECOG score 0-2 points; Expected survival time ≥3 months; Adequate liver, kidney, heart and lung function; Patients who have recovered from acute toxic effects of prior chemotherapy should be excluded from the trial at least one week apart; Women of childbearing age have negative blood pregnancy test before the start of the trial, and agree to take effective contraceptive measures during the trial until the last follow-up; male subjects with partners of childbearing potential agree to take effective contraceptive measures during the trial until the last follow-up; Voluntarily sign the informed consent. Exclusion Criteria: Presence of other concurrent active malignancy; People with severe mental disorders; A history of any of the following genetic disorders, such as Fanconi anemia, Schu-Day syndrome, Gerstmann syndrome, or any other known bone marrow failure syndrome; Acute GVHD of grade II-IV or extensive chronic GVHD; Had grade III-IV heart failure or myocardial infarction, cardiac angioplasty or stenting, unstable angina pectoris, or other clinically prominent heart disease within one year prior to enrollment; The presence of any indwelling catheter or drainage (e.g., percutaneous nephrostomy, indwelling catheter, bile drainage, or pleural/peritoneal/pericardial catheter), except for patients who are permitted to use dedicated central venous catheters; A history or disease of the central nervous system(CNS), such as seizure disease, cerebrovascular ischemia/bleeding, dementia, cerebellar disease, or any autoimmune disease involving the CNS; Human immunodeficiency virus (HIV) seropositivity; Hepatitis B surface antigen positive or hepatitis B core antibody positive, and HBV-DNA positive; Patients with hepatitis C (HCV-RNA quantitative test results positive); Or the presence of other serious active viral or bacterial infections or uncontrolled systemic fungal infections; Patients with severe history of allergy or allergic constitution; A history of autoimmune diseases (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus erythematosus) leading to end-organ damage or requiring systemic immunosuppressive/systemic disease modulating drugs within the past 2 years; Had or is suffering from interstitial lung disease (e.g., pneumonia, pulmonary fibrosis); Had undergone other clinical trials in the 4 weeks prior to participating in this trial; Poor compliance due to physiological, family, social, geographical and other factors, unable to cooperate with the study protocol and follow-up plan; For patients contraindicated with cyclophosphamide and fludarabine chemotherapy; Subjects requiring systemic corticosteroid therapy (prednisone ≥5mg/ day or equivalent dose of another corticosteroid) or other immunosuppressive agents within 1 month after UCAR-T cell reinfusion, except for adverse events; Receiving donor lymphocyte infusion within 6 weeks before enrollment; Pregnant and lactating women; Any other condition that the investigator deemed inappropriate for inclusion.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Assigned Interventions<br>Subjects who meet the enrollment conditions will receive intravenous infusion of UCAR-T Cells after lymphodepletion. | Biological: UCAR-T Cells<br>* UCAR-T Cellswill be administered by vein. The trial includes two portions. The first portion is a3+3dose escalation study, in which three dose groups are set:Dose level one:1×10^6 cells/kg;Dose level two:2×10^6 cells/kg;Dose level three:5×10^6 cells/kg. Each dose group requires at least three subjects. The trial will start from dose level one. The second portion includes a dosage extended cohort and will start after the finish of the3+3dose escalation study. Twelve subjects will get infusion of UCAR-T Cells at the best dose verified in the first portion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) | Neurotoxicity and/or CRS≥G3. | Up to 28 days after infusion | 
| Incidence of Treatment Related adverse events (AEs) | The frequency, severity, and laboratory findings of all adverse events/serious adverse events are included. | Up to 12 months after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of CAR-T cells | The persistence over time of CAR-T cells in the peripheral blood as determined by flow cytometry and qPCR. | Up to 24 weeks after infusion | 
| Objective response rate (ORR) | Patients who achieve CR(complete response) or CRi after infusion | At 4,8,12 weeks after infusion | 
| Progression-free survival (PFS) | Progression-free survival (PFS) is the time between the time a patient with tumor disease receives treatment and the time between the observation of disease progression or death from any cause. | Up to 24 weeks after infusion | 
| Overall survival (OS) | Overall survival (OS) is the time from randomization to death from any cause. | Up to 24 weeks after infusion | 
| Duration of remission (DOR) | Duration of remission (DOR) is the time from the first detection of CR or PR to the discovery of PD. | Up to 24 weeks after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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universal CAR-T(UCAR-T), CD19