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Cyclophosphamide

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Fludarabine phosphate

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Alkylating Agents

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

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

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

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.

Chidamide

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.

Fludarabine and cyclophosphamide

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.

Anti-CD19 CAR-T cells

Weidong Han, Ph.D

Liang Wang

Wei Zhang, Ph.D

Zhitao Ying, Ph.D

Yuhua Li, Ph.D

Qingqing Cai, Ph.D

Liang Huang, Ph.D

Heng Mei, Ph.D

Aibin Liang, Ph.D

Ting Niu, Ph.D

Caixia Li, Ph.D

Huilai Zhang, Ph.D

Wenbin Qian, Ph.D

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.

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.

Chidamide Bridging for CAR-T Therapy

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

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. In the chidamide bridging group, the timing of secondary biopsy was arranged at least 6 times' chidamide therapy and before CAR-T infusion.

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.

AE is defined as any adverse medical event from the time between the date of randomization and the date of 12 months after CAR-T infusion. AE may be an adverse sign (including abnormal laboratory tests, etc.), symptom, or illness that is not related to the purpose of medication and is time-related to drug use, regardless of causality to the drug, such as long-term cytopenia, cytokine release syndrome, neurotoxicity, etc.

ORR was defined as the percentage of subjects who achieved complete response or partial response assessed by investigators and based on the Lugano 2014 assessment criterion. All subjects who do not meet objective response criteria by the data analysis deadline will be considered nonresponders. The source of this endpoint will only include the assessment of response obtained after CAR-T infusion and prior to any additional antitumor therapy.

CRR was defined as the percentage of subjects who achieved a CR assessed by investigators and based on the Lugano 2014 assessment criterion.

RFS was defined as the time between the date of CAR-T infusion and the date of first lymphoma recurrence (local, regional, distant metastasis) or death (whatever the cause) for subjects who received complete response after CAR-T infusion. For participants who remained alive and whose disease had not recurred, RFS was censored on the date of last visit/contact with disease assessments.

OS was defined as the time between the date of CAR-T infusion and death from any cause.

Chinese PLA General Hospital

Director of Biotherapeutic Department

Lymphoma, B-Cell

B-cell Lymphoma

patients will receive a lymphodepletion chemotherapy prior to CAR T cell infusion

iPD1 CD19 eCAR T cells are administrated in a 3-day split-dose regimen （d0, 30%; d1, 30%; d2, 40%）.

CAR T cell dose escalation: 1×10\^5 /kg，1×10\^6 /kg，3×10\^6 /kg，and 6×10\^6 CAR T cells/kg

iPD1 CD19 eCAR T cells

Fludarabine 25 mg/m2 d1-3; cyclophosphamide 250 mg/m2 d1-3. Lymphodepletion chemotherapy is completed 1 to 4 days before CAR T cell infusion

Jun Zhu, MD

Zhitao Ying, MD

Xiaoyu Xiang, PhD

PD1 pathway is critical in determining the response to CAR T cell therapy. Emerging data suggested that Inhibition of PD1 could enhance the efficacy of CAR T cell therapy. iPD1 CD19 eCAR T cells is an enhanced version of the classical 2nd generation anti-CD19 4-1BB-costimulatory chimeric antigen receptor engineered T cells with cell-intrinsic PD1 inhibition by incorporation of a PD1 shRNA-expressing cassette in the CAR lentivector. This design will enhance the anti-tumor activities of CAR T cells by inhibiting PD1 induction after CAR T cell activation. This pilot, single arm, one center, dose-escalation, open label study is to determine the safety and efficacy of iPD1 CD19 eCAR T cells in relapsed or refractory CD19 positive lymphoma.

Subjects will be given a lymphodepletion chemotherapy comprised of Fludarabine and cyclophosphamide prior to CAR T cell infusion. The chemotherapy is completed 1 to 4 days before the first dost of iPD1 CD19 eCAR T cells.

Safety and Efficacy of iPD1 CD19 eCAR T Cells in Relapsed or Refractory B-cell Lymphoma

Pilot Study of Autologous Anti-CD19 4-1BB CAR T Cells With Cell-intrinsic PD1 Inhibition in Relapsed or Refractory B-cell Lymphoma

incidents of treatment related adverse events per NCI CTCAE V4.0

The efficacy of infusion of iPD1 CD19 eCAR T cells is assessed according to the standardized response criteria for malignant lymphoma (Cheson BD, JCO, 2007), which is defined as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD).

Overall survival is defined as the time from receiving iPD1 CD19 eCAR T cells infusion to death for any cause.

Progression-free survival (PFS) is defined as the time from receiving iPD1 CD19 eCAR T cell infusion to disease progression or death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Chidamide Bridging for CAR-T Therapy	NCT05370547	Non Hodgkin's L...	Chidamide Fludarabine and... Anti-CD19 CAR-T...	16 Years - 75 Years	Chinese PLA General Hospital
Safety and Efficacy of iPD1 CD19 eCAR T Cells in Relapsed or Refractory B-cell Lymphoma	NCT03208556	Relapsed or Ref...	iPD1 CD19 eCAR ... Fludarabine and...	18 Years - 70 Years	Peking University

Spots Global Cancer Trial Database for fludarabine and cyclophosphamide