Autologous Cells Derived Anti-CD19 CAR-Engineered T Cells With Concurrent BTK Inhibitor for B Cell Lymphoma

Study Overview
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Brief Summary
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This is a single-center, open-label and pragmatic clinical trial to evaluate the primary efficacy and safety of anti-CD19 chimeric antigen receptor (CAR)-modified T cells (CART-CD19) with concurrent BTK inhibitor in patients with relapsed or refractory B cell lymphoma

Detailed Description
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Anti-CD19 chimeric antigen receptor (CAR) T-cell has shown dramatical efficacy in B cell malignancies. And Bruton tyrosine kinase (BTK) inhibitor agents have been validated as an effective drug to treat B cell malignancies. Combined therapies comprising ibrutinib (a BTK inhibitor) and anti-CD19 CAR-T cells in patients with CLL after ibrutinib failure are considered feasible and safe. Ibrutinib is the first-generation BTK inhibitror and Zanubrutinib is the second-generation BTK inhibitor. Orelabrutinib is a newly developed BTK inhibitor with high selectivity and have received its approval in China. Autologous cells derived T cells are purified and transduced with a lentiviral vector encoding the humanized CD19 scFv. To evaluate whether the addition of BTK inhibitor (Ibrutinib, Zanubrutinib and Orelabrutinib) in anti-CD19 CAR-T cells therapy would further improve efficacy and safety, we intend to conduct this pragmatic clinical trial.

Official Title
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Efficacy and Safety of Autologous Cells Derived Anti-CD19 CAR-Engineered T Cells With Concurrent BTK Inhibitor for B Cell Lymphoma：a Single-center, Open-label, Pragmatic Clinical Trial

Conditions
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Burkitt Lymphoma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells
* Drug: Fludarabine-based chemotherapy + CAR-T-CD19 Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 years and ≤70 years. Expected survival over 6 months. Eastern Cooperative Oncology Group score≤ 2. Diagnosed pathologically and histologically CD19+B cell lymphoma, including mantle cell lymphoma, chronic lymphocytic leukemia, follicular cell lymphoma, Burkitt lymphoma and diffuse large B cell lymphoma. Patients have failed at least 1 line of prior therapy Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form. - Exclusion Criteria: Investigators judge the patients with gastrointestinal lymph node and/or central nervous system involvement who may be at high-risk of receiving CAR-T-CD19 cell treatment. Existing or preexisting CNS conditions, such as epileptic seizures, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any CNS related autoimmune diseases. Patients with graft-versus-host reaction and need immunosuppressive agents, or patients with autoimmune diseases. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within five years. History of Richter's syndrome. History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease. Patients who are pregnant or breast-feeding. Patients with any one of the following terms: A. Creatine >2.5mg/dl (221.0umol/L). B. Alanine aminotransferase/aspartate aminotransferase >3 times the upper limit of normal (ULN). C. Total bilirubin>2.0 mg/dl (34.2umol/L). Major surgery within 4 weeks of randomization. Systemic steroids are used within 2 weeks before apheresis (Except for those who are using inhaled steroids recently or currently). Patients receive cytotoxic chemotherapy or radiotherapy within 21 days before enrollment (Tyrosine kinase inhibitors or other targeted therapies can be used two weeks before lymphodepleting chemotherapy). Prior treatment with any gene therapy product. Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV) infection. Systemic fungal, bacterial, viral, or other infection that is not controlled. The absolute value of lymphocytes was too low to manufacture CAR-T cells. Other conditions considered inappropriate by the researcher. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study was a pragmatic clinical trial in which patients were divided into two groups, one receiving anti-CD19 CAR-T cells infusion, the other group receiving anti-CD19 CAR-T cells infusion and concurrent oral BTK inhibitor.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Effective of CAR-T-CD19 cells with concurrent BTK inhibitor<br>After enrollment, all subjects will receive oral BTK inhibitor immediately and BTK inhibitor treatment will continue for up to 90 days (or longer for who are benefiting from BTK inhibitor) after CAR-T-CD19 infusion. Eligible patients will undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) for CAR T-cell production. Upon successful generation CAR-T-CD19 product, participants will receive fludarabine-based lymphodepletion chemotherapy, followed by infusion of CAR-T-CD19 cells (2*10^6 cells/kg) on day 0 and day 1 respectively. | Drug: BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells<br>* BTK inhibitor from enrollment to more than 90 days after CAR-T-CD19 infusion. Fludarabine-based lymphodepletion chemotherapy was followed by CART19 infusion at a dose of 1x10^6/kg on day 0 and day 1 respectively.<br>|
| Active Comparator: Effective of CAR-T-CD19 cells monotherapy<br>Eligible patients will undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) for CAR T-cell production. Upon successful generation CAR-T-CD19 product, participants will receive fludarabine-based lymphodepletion chemotherapy, followed by infusion of CAR-T-CD19 cells (2*10^6 cells/kg) on day 0 and day 1 respectively. | Drug: Fludarabine-based chemotherapy + CAR-T-CD19 Cells<br>* Fludarabine-based lymphodepletion chemotherapy was followed by CART19 infusion at a dose of 1x10^6/kg on day 0 and day 1 respectively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events | Therapy-related adverse events (AE), including severe adverse events (SAE) and laboratory outliers with clinical significance, will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). | within 2 years after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) of administering CAR-T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory B cell lymphoma. | ORR will be assessed from CAR-T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Duration of Response (DOR) of administering CAR- T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory CD19+ B-cell lymphoma. | DOR will be assessed from CAR-T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Overall survival (OS) of administering CAR- T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory CD19+ B-cell lymphoma. | OS will be assessed from CAR-T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| PFS will be assessed from CAR-T cell infusion to death or last follow-up | Progress-free survival (PFS) of administering CAR- T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory CD19+ B-cell lymphoma. | within 2 years after infusion | 
| Complete response rate (CR) of administering CAR-T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory B cell lymphoma. | CR will be assessed from CAR-T cell infusion to death or last follow-up (censored). | within 2 years after infusion | 
| Partial response rate (PR) of administering CAR-T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory B cell lymphoma. | PR will be assessed from CAR-T cell infusion to death or last follow-up. | within 2 years after infusion |