Clinical trial NCT05020392: Autologous Cells Derived Anti-CD19 CAR-Engineered T Cells With Concurrent BTK Inhibitor for B Cell Lymphoma
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Diffuse Large B Cell Lymphoma
Burkitt Lymphoma
Follicular Lymphoma
Chronic Lymphocytic Leukemia
Mantle Cell Lymphoma
Lead sponsor: Wuhan Union Hospital, China
Sponsor class: OTHER
Collaborators: name: Wuhan Si'an Medical Technology Co., Ltd
First posted: 2021-08-25
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

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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.

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Primary outcomes:
measure: Incidence of Treatment-related Adverse Events
timeFrame: within 2 years after infusion
Secondary outcomes:
measure: 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.
timeFrame: within 2 years after infusion
measure: 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.
timeFrame: within 2 years after infusion
measure: 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.
timeFrame: within 2 years after infusion
measure: PFS will be assessed from CAR-T cell infusion to death or last follow-up
timeFrame: within 2 years after infusion
measure: 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.
timeFrame: within 2 years after infusion
measure: 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.
timeFrame: within 2 years after infusion
Other outcomes:
measure: In vivo expansion and survival of CAR-T-CD19 cells
timeFrame: within 2 years after infusion
Locations:
city: Wuhan
country: China
facility: Union Hospital, Huazhong University of Science and Technology
state: Hubei
Study officials:
affiliation: Wuhan Union Hospital, China
name: Yu Hu
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
citation: Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014 Feb;74(2):263-71. doi: 10.1007/s40265-014-0178-8.