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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

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:

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.
-

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

NCT ID

NCT05020392

First Posted

August 19, 2021

Last Updated

July 23, 2023

Sponsor

Wuhan Union Hospital, China

Collaborators

Wuhan Si'an Medical Technology Co., Ltd

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

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

Arm Title

Effective of CAR-T-CD19 cells monotherapy

Arm Type

Active Comparator

Arm Description

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

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

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

hmei@hust.edu.cn

First Name & Middle Initial & Last Name or Official Title & Degree

Wenjing Luo

Phone

15927552323

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

hmei@hust.edu.cn

First Name & Middle Initial & Last Name & Degree

Wenjing Luo

Phone

15927552323

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

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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