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

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05020392
• Other study ID #: auto-CART-CD19 cells and BTKi
• Status: Recruiting
• Phase: Phase 3
• Start date: September 14, 2021
• Est. completion date: October 13, 2024

Study information

• Verified date: July 2023
• Source: Wuhan Union Hospital, China
• Contact: Heng Mei
• Phone: 027-8572600
• Email: hmei[@]hust.edu.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 24
• Est. completion date: October 13, 2024
• Est. primary completion date: October 13, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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. -

Related Conditions & MeSH terms

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

Intervention

Drug:
• BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells
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.
• Fludarabine-based chemotherapy + CAR-T-CD19 Cells
Fludarabine-based lymphodepletion chemotherapy was followed by CART19 infusion at a dose of 1x10^6/kg on day 0 and day 1 respectively.

Locations

Country	Name	City	State
China	Union Hospital, Huazhong University of Science and Technology	Wuhan	Hubei

Sponsors (2)

Lead Sponsor	Collaborator
Wuhan Union Hospital, China	Wuhan Si'an Medical Technology Co., Ltd

Country where clinical trial is conducted

China, 

References & Publications (3)

Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014 Feb;74(2):263-71. doi: 10.1007/s40265-014-0178-8. — View Citation

Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, Lacey SF, Melenhorst JJ, McGettigan SE, Cook DR, Zhang C, Xu J, Do P, Hulitt J, Kudchodkar SB, Cogdill AP, Gill S, Porter DL, Woyach JA, Long M, Johnson AJ, Maddocks K, Muthusamy N, Levine BL, June CH, Byrd JC, Maus MV. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016 Mar 3;127(9):1117-27. doi: 10.1182/blood-2015-11-679134. Epub 2016 Jan 26. — View Citation

Gauthier J, Hirayama AV, Purushe J, Hay KA, Lymp J, Li DH, Yeung CCS, Sheih A, Pender BS, Hawkins RM, Vakil A, Phi TD, Steinmetz RN, Shadman M, Riddell SR, Maloney DG, Turtle CJ. Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure. Blood. 2020 May 7;135(19):1650-1660. doi: 10.1182/blood.2019002936. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	In vivo expansion and survival of CAR-T-CD19 cells	Quantity of CAR-T-CD19 CAR copies in bone marrow, peripheral blood and cerebrospinal fluid will be determined by using quantitative polymerase chain reaction.	within 2 years after infusion
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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