Chidamide Bridging for CAR-T Therapy

• Status: Recruiting
• Trial end date: 2025-06-30
• Target enrollment: 0
• Participant gender: All

Summary

Chimeric antigen receptor-T (CAR-T) cell therapy has been shown to be superior to conventional therapy in patients with refractory and relapsed B-cell non-Hodgkin's lymphoma. However, prior clinical studies and real-world data suggest that approximately 30-40% of cases of drug resistance still occur after CAR-T cell therapy, and approximately 50-60% of cases have recurrent disease progression over time of infusion. Our previous research suggests that the low expression of NOXA protein may be an important biomarker for the treatment of drug resistance of CAR-T cells. Up regulating the expression of NOXA through histone deacetylase (HDAC) inhibitors can improve drug resistance and significantly improve the therapeutic effect of CAR-T cells. The purpose of this study was to screen the population with low NOXA expression and proposed to receive CAR-T treatment, and to evaluate the safety and effect of intervention containing HDAC inhibitor (chidamide) bridging therapy on CAR-T efficacy.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Chinese PLA General Hospital
• Treatments: Cyclophosphamide; Fludarabine

Criteria

Inclusion Criteria:

1. Age 16-75, male or female;

2. Recurrent or refractory large B-cell lymphoma in adult patients after second-line or more systemic therapy, including diffuse large B-cell lymphoma non-specific type, diffuse large B-cell lymphoma transformed by follicular lymphoma, grade 3b follicular lymphoma, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma with MYC and Bcl-2 and/or Bcl-6 rearrangement (double/triple strike lymphoma);

3. Eastern Cooperative Oncology Group (ECOG) physical status is 0-3;

4. Life expectancy ≥12 weeks;

5. 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;

6. 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

7. 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.

Exclusion Criteria:

1. Patients known to be allergic to the drug Chidamide;

2. Lymphoma involves the central nervous system;

3. Known human immunodeficiency virus (HIV) infection or immunopositive test;

4. 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];

5. Presence of active infectious disease requiring treatment;

6. Received live vaccine within 30 days prior to administration of the study drug;

7. Active autoimmune disease requiring systemic treatment during the past 12 months (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;

8. History of severe allergic reactions;

9. Presence of congestive heart failure or uncontrolled arrhythmias classified by the New York Heart Association as class III-IV;

10. Patients with clinically significant electrocardiogram abnormalities and potential risk of malignant arrhythmias;

11. Clinically significant cardiac events, including unstable angina, acute myocardial infarction, and/or cardiac transmission problems, occurred within 6 months prior to administration;

12. A history of stroke or intracranial hemorrhage within 3 months prior to the date of administration of the study drug;

13. Major surgery or trauma occurred within 28 days prior to the start of treatment, or major side effects have not been recovered;

14. Accompanied by uncontrolled major medical conditions, including, but not limited to, kidney, liver, blood, gastrointestinal, endocrine, pulmonary, neurological, brain or psychiatric disorders;

15. 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;

16. Conditions in which a known mental or physical illness interferes with cooperation with the requirements of the study or disrupts the results or interpretation of the results and, in the opinion of the therapeutic investigator, makes the patient unfit for study participation;

17. There is the situation that the researcher's judgment will interfere with the whole study participation; Situations where there is significant risk to the subject; Or interferes with the interpretation of research data;

18. Pregnant or breast-feeding patients;

19. Inability to swallow and retain oral medications, malabsorption syndrome, diseases that significantly affect gastrointestinal function, total resection of the stomach or small intestine, ulcerative colitis, symptomatic inflammatory bowel disease, partial or complete intestinal obstruction;

20. Use or expect to use any conserved drug during the study period, including a potent CYP3A4 inhibitor or inducer, within 14 days prior to administration of the study drug or within 5 half-life periods, whichever is longer;

21. Inability to understand or unwillingness to sign informed consent.