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

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ClinicalTrials.gov Identifier: NCT05020392
Recruitment Status : Recruiting
First Posted : August 25, 2021
Last Update Posted : October 21, 2021
Sponsor:
Collaborator:
Wuhan Si'an Medical Technology Co., Ltd
Information provided by (Responsible Party):
MEI HENG, 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

Condition or disease Intervention/treatment Phase
Diffuse Large B Cell Lymphoma Mantle Cell Lymphoma Chronic Lymphocytic Leukemia Follicular Lymphoma Burkitt Lymphoma Drug: BTK inhibitor+ Fludarabine + Cyclophosphamide + CAR-T-CD19 Cells Drug: Fludarabine + Cyclophosphamide + CAR-T-CD19 Cells Phase 3

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 retroviral 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : September 14, 2021
Estimated Primary Completion Date : October 13, 2023
Estimated Study Completion Date : October 13, 2024


Arm Intervention/treatment
Experimental: Effective of CAR-T-CD19 cells with concurrent BTK inhibitor
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 lymphodepletion with low dose fludarabine and cyclophosphamide on day -5 to -3, followed by one infusion of CAR-T-CD19 cells (2*10^6 to 4*10^6 cells/kg) on day 0.
Drug: BTK inhibitor+ Fludarabine + Cyclophosphamide + CAR-T-CD19 Cells
BTK inhibitor from enrollment to 90 days after CAR-T-CD19 infusion. Low dose fludarabine and cyclophosphamide on day -5 to -3. CAR-T-CD19 cells (2*10^6 to 4*10^6 cells/kg) on day0.

Active Comparator: Effective of CAR-T-CD19 cells monotherapy
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 lymphodepletion with low dose fludarabine and cyclophosphamide on day -5 to -3, followed by one infusion of CAR-T-CD19 cells (2*10^6 to 4*10^6 cells/kg) on day 0.
Drug: Fludarabine + Cyclophosphamide + CAR-T-CD19 Cells
Low dose fludarabine and cyclophosphamide on day -5 to -3. CAR-T-CD19 cells (2*10^6 to 4*10^6 cells/kg) on day0.




Primary Outcome Measures :
  1. 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. [ Time Frame: within 2 years after infusion ]
    PFS will be assessed from CAR-T cell infusion to death or last follow-up


Secondary Outcome Measures :
  1. 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. [ Time Frame: within 2 years after infusion ]
    ORR will be assessed from CAR-T cell infusion to death or last follow-up (censored).

  2. 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. [ Time Frame: within 2 years after infusion ]
    DOR will be assessed from CAR-T cell infusion to death or last follow-up (censored).

  3. 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. [ Time Frame: within 2 years after infusion ]
    OS will be assessed from CAR-T cell infusion to death or last follow-up (censored).

  4. Event-free survival (EFS) of administering CAR- T-CD19 cells or CAR-T-CD19 cells with oral BTK inhibitor in Relapsed/Refractory CD19+ B-cell lymphoma. [ Time Frame: within 2 years after infusion ]
    EFS will be assessed from CAR-T cell infusion to death or last follow-up (censored).

  5. Incidence of Treatment-related Adverse Events [ Time Frame: 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).

  6. 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. [ Time Frame: within 2 years after infusion ]
    CR will be assessed from CAR-T cell infusion to death or last follow-up (censored).

  7. 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. [ Time Frame: within 2 years after infusion ]
    PR will be assessed from CAR-T cell infusion to death or last follow-up.


Other Outcome Measures:
  1. In vivo expansion and survival of CAR-T-CD19 cells [ Time Frame: within 2 years after infusion ]
    Quantity of CAR-T-CD19 CAR copies in bone marrow, peripheral blood and cerebrospinal fluid will be determined by using quantitative polymerase chain reaction.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

    -

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.

    -


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05020392


Contacts
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Contact: Heng Mei 027-8572600 hmei@hust.edu.cn
Contact: Wenjing Luo 15927552323 weerfi@hust.edu.cn

Locations
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China, Hubei
Union Hospital, Huazhong University of Science and Technology Recruiting
Wuhan, Hubei, China, 430022
Contact: Heng Mei, M.D., Ph.D    027-8572600    hmei@hust.edu.cn   
Contact: Wenjing Luo    15927552323    weerfi@hust.edu.cn   
Principal Investigator: Yu Hu, M.D., Ph.D         
Sponsors and Collaborators
Wuhan Union Hospital, China
Wuhan Si'an Medical Technology Co., Ltd
Investigators
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Principal Investigator: Yu Hu Wuhan Union Hospital, China
Additional Information:
Publications:
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Responsible Party: MEI HENG, Proferssor, Cheif Doctor, Wuhan Union Hospital, China
ClinicalTrials.gov Identifier: NCT05020392    
Other Study ID Numbers: auto-CART-CD19 cells and BTKi
First Posted: August 25, 2021    Key Record Dates
Last Update Posted: October 21, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Burkitt Lymphoma
Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia
Leukemia, B-Cell
Epstein-Barr Virus Infections
Herpesviridae Infections
DNA Virus Infections
Virus Diseases
Infections
Tumor Virus Infections
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents