NCT05370547

Chidamide Bridging for CAR-T Therapy

A Multiple Center Study on NOXA Expression-guided Randomized Chidamide Bridging Intervention in CAR-T Treated NHL Patients

• Status: Unknown
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Sponsor: Chinese PLA General Hospital · Academic / Other
• Sex: All
• Age: 16 Years – 75 Years
• Healthy volunteers: Not accepted

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.

Detailed description

Background: CAR-T cell therapy has been shown to be superior to conventional therapy in patients with r/r B-cell NHL. 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. The investigators used genome-wide CRISPR/Cas9 to screen for CAR T-resistant cells and identified low NOXA expression as associated with CAR-T resistance. NOXA protein is a member of the Bcl2 protein family, which plays a critical role in P53-dependent apoptosis. The 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. Through the verification of nearly 40 clinical samples previously treated with CAR-T, the investigators found that low NOXA expression was associated with poor prognosis. Meanwhile, animal experiments demonstrated that HDACi can up-regulate the expression of NOXA in tumor cells and significantly improve the efficacy of CAR-T therapy by reducing the incidence of resistance. The research was published in Signal Transduction and Targeted Therapy in 2022. Objective: The primary objective of the study was to evaluate whether chidamide bridging intervention improved clinical response to CAR-T in patients with r/r B-cell NHL. A secondary objective was to evaluate the safety of bridging therapy with chidamide and subsequent CAR-T infusion in above patients. The exploratory objective was to investigate the effect of chidamide intervention on NOXA expression. Design: This is a multicenter, prospective, controlled, open-label, phase Ⅰ/Ⅱ study. 120 patients with r/r B-cell NHL will be enrolled. Biopsy was performed before peripheral blood mononuclear cell (PBMC) collection, and NOXA expression level was detected by immunohistochemistry (IHC). Patients with high NOXA expression (IHC score \> 4) were treated with conventional CAR-T process (n=60), including PBMC collection, bridging therapy (without chidamide), fludarabine and cyclophosphamide (FC) regimen conditioning, CAR-T cell infusion, efficacy evaluation and follow-up; Patients with low NOXA expression (IHC score 0 - 4) were randomly assigned 1:1 to conventional CAR-T group as mentioned earlier (n=30) or CAR-T group containing chidamide bridging therapy (n=30). The bridging therapy regimen containing chidamide was divided into monotherapy and combination therapy. Chidamide combination intervention can be used in cases of high tumor burden, rapid progression of disease, symptoms of compression, involvement of specific sites or organs, and other burden reduction that need to be addressed. 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. In this study, commercial CAR-T cells (mainly Relma-cel, with Axi-cel or other commercial CAR-T cells also acceptable) or experimental CAR-T cells targeted at CD19 were acceptable. If feasible, for the group with low NOXA expression, a secondary biopsy was performed at the same site to detect changes in NOXA expression before CAR-T infusion.

Conditions

• Non Hodgkin's Lymphoma

Interventions

Type	Name	Description
DRUG	Chidamide	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.
DRUG	Fludarabine and cyclophosphamide	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.
BIOLOGICAL	Anti-CD19 CAR-T cells	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.

Timeline

• Start date: 2022-05-25
• Primary completion: 2024-06-30
• Completion: 2025-06-30
• First posted: 2022-05-11
• Last updated: 2024-03-06

Locations

13 sites across 1 country: China