Chidamide Bridging for CAR-T Therapy

NCT05370547 | Recruiting Phase 1 DMC

• 1 other identifier: CHN-PLAGH-BT-071
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 13

Brief Summary

The previous research suggests that the low expression of NOXA protein may be an important biomarker for the treatment of drug resistance of chimeric antigen receptor-T (CAR-T) cells. Up regulating the expression of NOXA through histone deacetylase inhibitor (HDACi) can improve drug resistance and significantly improve the therapeutic effect of CAR-T cells. This study will enroll approximately 120 subjects with recurrent or refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL). Those with high expression of NOXA will receive conventional CAR-T treatment (without chidamide bridging), and those with low expression of NOXA will be randomly assigned 1:1 to those without or containing chidamide bridging. The purpose of this study was to evaluate the clinical response and safety of chidamide bridging.

Conditions

Non Hodgkin's Lymphoma

Keywords

CAR-T; NOXA; Chidamide

Outcome Measures

Primary Outcomes (1)

• Percentage of participants with progression-free survival (PFS) at 6 months after CAR-T infusion among all participants

  PFS is defined as the time between the date of CAR-T infusion and disease progression or death from any cause. At the time of statistical analysis of study endpoints, there were no PFS events, and data were truncated as the date of the last objective tumor evaluation. Patients who were lost to follow-up or withdrew informed consent will be included in the end point evaluation, with data truncated as the date of the last objective tumor evaluation.

  6 months

Secondary Outcomes (7)

• Incidence of adverse events (AE) of chidamide bridging and subsequent CAR-T infusion arm

  12 months

• Participants with objective response rate (ORR) at 3 months after CAR-T infusion among all participants

  3 months

• Participants with complete response rate (CRR) at 3 months after CAR-T infusion among all participants

  3 months

• Percentage of participants with recurrence-free survival (RFS) at 6 months after CAR-T infusion among all participants

  6 months

• Percentage of participants with RFS at 12 months after CAR-T infusion among all participants

  12 months

Other Outcomes (1)

• Effect of chidamide intervention on NOXA expression

  an average of 4 weeks

Study Arms (3)

high NOXA expression

EXPERIMENTAL

NOXA IHC score \> 4; Bridging therapy was allowed but not containing chidamide; n=60.

Drug: Fludarabine and cyclophosphamide; Biological: Anti-CD19 CAR-T cells

low NOXA expression and no chidamide intervention

EXPERIMENTAL

NOXA IHC score \< 4; Bridging therapy was allowed but not containing chidamide; n=30.

Drug: Fludarabine and cyclophosphamide; Biological: Anti-CD19 CAR-T cells

low NOXA expression and chidamide intervention

EXPERIMENTAL

NOXA IHC score \< 4; Bridging therapy containing chidamide alone or combination; n=30.

Drug: Chidamide; Drug: Fludarabine and cyclophosphamide; Biological: Anti-CD19 CAR-T cells

Interventions

Chidamide DRUG

1. Chidamide monotherapy mode: Chidamide was administered for at least 6 times after leukapheresis, 10mg oral D1-4, 20mg oral D7 every 3 days to the beginning day of FC conditioning. 2. Chidamide combination mode: The combination of one or more of the following drugs in addition to chidamide is permitted: glucocorticoids, BTK inhibitors, chemotherapy, other previously used resistance drugs, etc.

Also known as: HDACi

low NOXA expression and chidamide intervention

Fludarabine and cyclophosphamide DRUG

Patients should be received FC regimen conditioning 3 to 5 days prior to CAR-T cell infusion. The recommended regimen is intravenous fludarabine (25-30 mg/m\^2) and cyclophosphamide (250-500 mg/m\^2) daily for 3 consecutive days. The clinician may also adjust the cleansing regimen according to the patient's actual situation.

Also known as: FC regimen

high NOXA expression; low NOXA expression and chidamide intervention; low NOXA expression and no chidamide intervention

Anti-CD19 CAR-T cells BIOLOGICAL

A single infusion of CAR-transduced autologous T cells administered intravenously at a target dose of 100 × 10\^6 for Relma-cel or 2 × 10\^6/kg for Axi-cel. Other commercial CAR-T doses are determined by specific drug infusion instructions. The dose of experimental CAR-T was determined by the investigator. Infusion volume was calculated based on CAR-T cell density and recommended dose.

Also known as: Relma-cel, Axi-cel, Other commercial CAR-T cells, Experimental CAR-T cells

high NOXA expression; low NOXA expression and chidamide intervention; low NOXA expression and no chidamide intervention

Eligibility Criteria

• Age: 16 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 16-75, male or female;
• Recurrent or refractory large B-cell lymphoma (LBCL) ,grade 1-3a follicular lymphoma (FL) and mantle cell lymphoma (MCL). Recurrent or refractory disease was defined as progression after systemic treatment with second-line or more lines (including CD20 monoclonal antibody and doxorubicin) or primary resistance (disease progression during first-line treatment or within 6 months after completion of treatment). LBCL includes diffuse large B-cell lymphoma non-specific type (DLBCL-NOS), diffuse large B-cell lymphoma transformed by follicular lymphoma (TFL), grade 3b FL, primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma with MYC and Bcl-2 and/or Bcl-6 rearrangement ( double strike/triple hit lymphoma, DHL/THL);
• Eastern Cooperative Oncology Group (ECOG) physical status is 0-3;
• Life expectancy ≥12 weeks;
• Subjects must be willing to undergo either excised or large-needle lymph node or tissue biopsy, or provide lymph node or tissue biopsy from the most recent available archived tissue for immunohistochemical NOXA testing and pathology review in the study center laboratory;
• There are measurable target lesions;
• CD19 positive;
• Are willing to use contraception according to the following criteria:
• A. Women of reproductive age (15-49 years) must undergo a pregnancy test with negative results within 7 days before starting treatment; B. Women of reproductive age should use effective contraception for at least 120 days after the last dose of the study drug (contraceptive success rate of at least 99%). The subject should communicate with the available contraceptive methods with at least 99% success rate and confirm the understanding of the period; C. Male subjects used effective contraception for at least 93 days after the last dose of study drug (contraceptive success rate of at least 99%). The subject should communicate with the available contraceptive methods with at least 99% success rate and confirm the understanding of the period; D. Infertile women (i.e., surgically sterilized by hysterectomy and/or bilateral oophorectomy or amenorrhea ≥12 months and age \> 45 years) are not subject to conditions A and B above
• Adequate bone marrow and organ functions (normal values shall not be obtained with growth factors, and hemocytopenia caused by lymphoma invasion of bone marrow is not subject to conditions A, B, and C below) :
• A. Neutrophil count (ANC) ≥1.0×10\^9/L; B. Hemoglobin ≥8.0g/dL; C. Platelet count ≥50×10\^9/L; D. Total bilirubin ≤1.5× upper limit of normal value (ULN) (\< 3 TIMES ULN for patients with Gilbert syndrome, cholestasis caused by hilar compression adenosis, biliary obstruction caused by liver involvement or lymphoma); E. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤2.5×ULN or ≤5×ULN when liver invasion is present; F. Creatinine clearance ≥40ml/min using the cockcroft-gault equation or glomerular filtration rate ≥40ml/min/1.73m2 using the modified renal disease diet formula; G. Lipase ≤1.5×ULN.

You may not qualify if:

• Patients known to be allergic to the drug Chidamide;
• Lymphoma involves the central nervous system;
• Known human immunodeficiency virus (HIV) infection or immunopositive test;
• Viral infections that cannot be controlled by antiviral drugs, such as herpetic virus infection, acute or chronic active hepatitis B, acute or chronic active hepatitis C, etc. \[Note: chronic hepatitis B virus (HBV) carriers or non-active hepatitis B surface antigen (HBsAg) positive subjects and HBV-DNA lower than the detection limit can be included in the group; hepatitis C virus (HCV) antibody negative can be enrolled, HCV antibody positive patients need to be tested for HCV-RNA, if negative can be enrolled\];
• Presence of active infectious disease requiring treatment;
• Received live vaccine within 30 days prior to enrollment;
• Active autoimmune disease requiring systemic treatment within 12 months prior to enrollment (i.e., disease-modifying drugs, corticosteroids, or immunosuppressive drugs). Note: Alternative therapies (such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary dysfunction) are not considered a systemic treatment;
• History of severe allergic reactions;
• Presence of congestive heart failure or uncontrolled arrhythmias classified by the New York Heart Association as class III-IV;
• Patients with clinically significant electrocardiogram abnormalities and potential risk of malignant arrhythmias;
• Clinically significant cardiac events, including unstable angina, acute myocardial infarction, and/or cardiac transmission problems, occurred within 6 months prior to enrollment;
• A history of stroke or intracranial hemorrhage within 3 months prior to enrollment;
• Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered;
• Accompanied by uncontrolled major medical conditions, including, but not limited to, kidney, liver, blood, gastrointestinal, endocrine, pulmonary, neurological, brain or psychiatric disorders;
• Current or previous malignancy within 3 years prior to enrollment, excluding cured basal or squamous cell skin cancer, superficial bladder cancer, prostatic intraepithelial tumor and carcinoma in situ of the cervix;

Sponsors & Collaborators

• Chinese PLA General Hospital: lead

Study Sites (13)

Beijing Tongren Hospital, Capital Medical University

Beijing, Beijing Municipality, China

RECRUITING

Peking Union Medical College Hospital

Beijing, Beijing Municipality, China

RECRUITING

Peking University Cancer Hospital

Beijing, Beijing Municipality, China

RECRUITING

Zhujiang Hospital of Southern Medical University

Guangzhou, Guangdong, China

RECRUITING

Sun Yat-Sen University Cancer Hospital

Guangzhou, Guangzhou, China

RECRUITING

Tongji Hospital, Tongji Medical College of HUST

Wuhan, Hubei, China

RECRUITING

Xiehe Hospital, Tongji Medical College of HUST

Wuhan, Hubei, China

RECRUITING

Tongji Hospital of Tongji University

Shanghai, Shanghai Municipality, China

RECRUITING

West China Hospital of Sichuan University

Chengdu, Sichuan, China

RECRUITING

The First Affiliated Hospital of Soochow University

Suzhou, Suzhou, China

RECRUITING

Tianjin Medical University Cancer Institute and Hospital

Tianjin, Tianjin Municipality, China

RECRUITING

The First Affiliated Hospital of Zhejiang University

Hangzhou, Zhejiang, China

RECRUITING

Biotherapeutic Department, Chinese PLA General Hospital

Beijing, China

RECRUITING

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; fludarabine; Cyclophosphamide; CF regimen; relmacabtagene autoleucel

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Weidong Han, Ph.D

  Biotherapeutic Department, Chinese PLA General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Weidong Han, Ph.D

CONTACT

+86-10-55499341; hanwdrsw@sina.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: May 7, 2022
• First Posted: May 11, 2022
• Study Start: May 25, 2022
• Primary Completion: June 30, 2024
• Study Completion: June 30, 2025
• Last Updated: March 6, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (13)