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

Primary Purpose

Diffuse Large B Cell Lymphoma, Burkitt Lymphoma, Follicular Lymphoma

Status
Recruiting
Phase
Phase 3
Locations
China
Study Type
Interventional
Intervention
BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells
Fludarabine-based chemotherapy + CAR-T-CD19 Cells
Sponsored by
Wuhan Union Hospital, China
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B Cell Lymphoma

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

    -

Sites / Locations

  • Union Hospital, Huazhong University of Science and TechnologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Effective of CAR-T-CD19 cells with concurrent BTK inhibitor

Effective of CAR-T-CD19 cells monotherapy

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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).
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).
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).
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.
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).
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.

Full Information

First Posted
August 19, 2021
Last Updated
July 23, 2023
Sponsor
Wuhan Union Hospital, China
Collaborators
Wuhan Si'an Medical Technology Co., Ltd
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1. Study Identification

Unique Protocol Identification Number
NCT05020392
Brief Title
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

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 14, 2021 (Actual)
Primary Completion Date
October 13, 2023 (Anticipated)
Study Completion Date
October 13, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Wuhan Union Hospital, China
Collaborators
Wuhan Si'an Medical Technology Co., Ltd

4. Oversight

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

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B Cell Lymphoma, Burkitt Lymphoma, Follicular Lymphoma, Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
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)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Effective of CAR-T-CD19 cells with concurrent BTK inhibitor
Arm Type
Experimental
Arm Description
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.
Arm Title
Effective of CAR-T-CD19 cells monotherapy
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
BTK inhibitor+ Fludarabine-based chemotherapy + CAR-T-CD19 Cells
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Fludarabine-based chemotherapy + CAR-T-CD19 Cells
Intervention Description
Fludarabine-based lymphodepletion chemotherapy was followed by CART19 infusion at a dose of 1x10^6/kg on day 0 and day 1 respectively.
Primary Outcome Measure Information:
Title
Incidence of Treatment-related Adverse Events
Description
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).
Time Frame
within 2 years after infusion
Secondary Outcome Measure Information:
Title
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.
Description
ORR will be assessed from CAR-T cell infusion to death or last follow-up (censored).
Time Frame
within 2 years after infusion
Title
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.
Description
DOR will be assessed from CAR-T cell infusion to death or last follow-up (censored).
Time Frame
within 2 years after infusion
Title
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.
Description
OS will be assessed from CAR-T cell infusion to death or last follow-up (censored).
Time Frame
within 2 years after infusion
Title
PFS will be assessed from CAR-T cell infusion to death or last follow-up
Description
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
Title
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.
Description
CR will be assessed from CAR-T cell infusion to death or last follow-up (censored).
Time Frame
within 2 years after infusion
Title
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.
Description
PR will be assessed from CAR-T cell infusion to death or last follow-up.
Time Frame
within 2 years after infusion
Other Pre-specified Outcome Measures:
Title
In vivo expansion and survival of CAR-T-CD19 cells
Description
Quantity of CAR-T-CD19 CAR copies in bone marrow, peripheral blood and cerebrospinal fluid will be determined by using quantitative polymerase chain reaction.
Time Frame
within 2 years after infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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. -
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Heng Mei
Phone
027-8572600
Email
hmei@hust.edu.cn
First Name & Middle Initial & Last Name or Official Title & Degree
Wenjing Luo
Phone
15927552323
Email
weerfi@hust.edu.cn
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yu Hu
Organizational Affiliation
Wuhan Union Hospital, China
Official's Role
Principal Investigator
Facility Information:
Facility Name
Union Hospital, Huazhong University of Science and Technology
City
Wuhan
State/Province
Hubei
ZIP/Postal Code
430022
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Heng Mei, M.D., Ph.D
Phone
027-8572600
Email
hmei@hust.edu.cn
First Name & Middle Initial & Last Name & Degree
Wenjing Luo
Phone
15927552323
Email
weerfi1211@hust.edu.cn
First Name & Middle Initial & Last Name & Degree
Yu Hu, M.D., Ph.D

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32076701
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.
Results Reference
background
PubMed Identifier
26813675
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.
Results Reference
background
PubMed Identifier
24464309
Citation
Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014 Feb;74(2):263-71. doi: 10.1007/s40265-014-0178-8.
Results Reference
background
Links:
URL
https://ashpublications.org/blood/article/136/Supplement%201/39/470300/Transcend-CLL-004-Phase-1-Cohort-of-Lisocabtagene?searchresult=1
Description
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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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