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

Phase 3

Recruiting

• Conditions: Diffuse Large B Cell Lymphoma; Chronic Lymphocytic Leukemia; Mantle Cell Lymphoma; Burkitt Lymphoma; Follicular Lymphoma
• Interventions: Drug: BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells; Drug: Fludarabine-based chemotherapy + CAR-T-CD19 Cells

• Registration Number: NCT05020392
• Lead Sponsor: Wuhan Union Hospital, China

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2021-08-19
• Study First Submitted QC: 2021-08-19
• Study First Posted: 2021-08-25
• Study Start: 2021-09-14
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-23
• Last Update Posted: 2023-07-25
• Primary Completion: 2023-10-13
• Study Completion: 2024-10-13

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Aged ≥ 18 years and ≤70 years.

2. Expected survival over 6 months.

3. Eastern Cooperative Oncology Group score≤ 2.

4. 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.

5. Patients have failed at least 1 line of prior therapy

6. Negativity of blood pregnancy test for woman, and participants use effective methods of contraception until last follow-up.

7. Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.

Exclusion Criteria

1. 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.

2. Existing or preexisting CNS conditions, such as epileptic seizures, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any CNS related autoimmune diseases.

3. Patients with graft-versus-host reaction and need immunosuppressive agents, or patients with autoimmune diseases.

4. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within five years.

5. History of Richter's syndrome.

6. 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.

7. Patients who are pregnant or breast-feeding.

8. 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).

9. Major surgery within 4 weeks of randomization.

10. Systemic steroids are used within 2 weeks before apheresis (Except for those who are using inhaled steroids recently or currently).

11. 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).

12. Prior treatment with any gene therapy product.

13. Active hepatitis B, active hepatitis C, or active human immunodeficiency virus (HIV) infection.

14. Systemic fungal, bacterial, viral, or other infection that is not controlled.

15. The absolute value of lymphocytes was too low to manufacture CAR-T cells.

16. Other conditions considered inappropriate by the researcher.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Effective of CAR-T-CD19 cells with concurrent BTK inhibitor	BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells	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.
Effective of CAR-T-CD19 cells monotherapy	Fludarabine-based chemotherapy + CAR-T-CD19 Cells	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.

Primary Outcome Measures

Name	Time	Method
Incidence of Treatment-related Adverse Events	within 2 years after infusion	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).

Secondary Outcome Measures

Name	Time	Method
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.	within 2 years after infusion	OS will be assessed from CAR-T cell infusion to death or last follow-up (censored).
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.	within 2 years after infusion	DOR will be assessed from CAR-T cell infusion to death or last follow-up (censored).
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.	within 2 years after infusion	ORR will be assessed from CAR-T cell infusion to death or last follow-up (censored).
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.	within 2 years after infusion	PR will be assessed from CAR-T cell infusion to death or last follow-up.
PFS will be assessed from CAR-T cell infusion to death or last follow-up	within 2 years after infusion	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.
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.	within 2 years after infusion	CR will be assessed from CAR-T cell infusion to death or last follow-up (censored).

Trial Locations

Locations (1)

Union Hospital, Huazhong University of Science and Technology; 🇨🇳 Wuhan, Hubei, China