Decitabine-primed Tandem CD19/CD20 CAR T Cells Plus Epigenetic Agents in Aggressive r/r B-NHL With Huge Tumor Burden

Study Overview
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Brief Summary
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This open-label, multi-cohorts, phase 1/2 study has the primary objective of comparing decitabine-primed tandem CART 19/20 solo, with decitabine-primed tandem CART 19/20 plus chidamide, decitabine-primed tandem CART 19/20 plus decitabine, and decitabine-primed tandem CART 19/20 plus decitabine+chidamide in patients with aggressive B-NHL who were confirmed as Relapsed and/or Refractory B cell Non-Hodgkin's Lymphoma with hugh tumor burden (Sum of the Product of the perpendicular Diameters for multiple lesions, SPD ≥ 100cm^2 or the largest-diameter of tumor ≥ 10 cm.).

Official Title
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Treatment of Decitabine-primed Tandem Targeting CD19 and CD20 Chimeric Antigen Receptor T Cells Plus Epigenetic Agents in Aggressive Relapsed and/or Refractory Non-Hodgkin's Lymphoma Patients With Huge Tumor Burden

Conditions
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Refractory or Relapsed Aggressive r/r B-NHL With Huge Tumor Burden

Intervention / Treatment
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* Drug: Chidamide
* Drug: Decitabine
* Drug: Chidamide and Decitabine
* Biological: Decitabine-primed Tandem CAR19/20 engineered T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥16 and ≤ 65 years. Sum of the Product of the perpendicular Diameters for multiple lesions, SPD ≥ 100cm^2 or the largest-diameter of tumor ≥ 10cm. Histologically confirmed CD20+ and/or CD19+ aggressive B-cell non-Hodgkin lymphoma (NHL), including the following types defined by the World Health Organization (WHO) 2016: Diffuse large B-cell lymphoma (DLBCL). High grade B-cell lymphoma(HGBL). Other aggressive B-cell lymphoma. Refractory disease or relapse after treatment with ≥2 lines of chemotherapy, including rituximab and anthracycline and either having failed autologous hematopoietic stem cell transplantation (HSCT), being ineligible for autologous HSCT or not consenting to autologous HSCT. We defined chemotherapy-refractory disease as meeting one or more of the following criteria: No response to first-line therapy (primary refractory disease). No response to second-line or later therapy. Progressive disease (PD) as the best response to the most recent therapy regimen. Stable disease (SD) as the best response after at least 2 cycles of the most recent line of therapy with an SD duration of no longer than 6 months from the last dose of therapy. Failure following autologous HSCT was defined as follows: PD or relapsed disease ≤12 months after autologous stem cell transplantation (ASCT) (requires biopsy-proven recurrence in relapsed subjects). No response or relapse after salvage therapy is given post-ASCT. PD or relapse ≥3 months after treatment with targeted CD19 therapy, including CD19 CAR T cells or anti-CD19/anti-CD3. Successful leukapheresis assessment and preculture of T cells. Life expectancy > 3 months. Adequate organ function: Creatinine < 1.6 mg/dL (140 µmol/L) or creatinine clearance ≥60 mL/min. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3× upper limit of the normal range. Bilirubin <2.0 mg/dL unless the subject had Gilbert's syndrome (<3.0 mg/dL). A minimum level of pulmonary reserve defined as ≤ grade 1 dyspnoea and pulse oxygenation > 91% with room air. Cardiac ejection fraction ≥50%, no evidence of pericardial effusion as determined by an echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings. An adequate bone marrow reserve defined as: Absolute neutrophil count (ANC)>1,000/mm3. Absolute lymphocyte count (ALC)≥300/mm3. Platelet count ≥ 50,000/mm3. Haemoglobin > 7.0 mg/dL. Measurable or assessable disease according to the IWG Response Criteria for Malignant Lymphoma (Cheson 2014). Patients in complete remission (CR) with no evidence of disease were not eligible. Informed consent/assent requiring that all patients have the ability to understand and the willingness to provide written informed consent. Exclusion Criteria: Patients with definite involvement of the gastrointestinal tract. Endoscopy should be performed to confirm gastrointestinal involvement in suspected patients. However, patients with central nervous system (CNS) involvement were cautiously enrolled in this clinical study. Detection of a clear HAMA effect in patients with prior CD19 CAR T cell treatment failure or recurrence, or negative tumour puncture detection of CD19 and CD20. Pregnant or lactating women. Uncontrolled active bacterial or viral infection (active hepatitis B or hepatitis C infection, HIV infection) or treponema pallidum infection. Class III/IV cardiovascular disability according to the New York Heart Association Classification and a cardiac ejection fraction ≥50%. History of allo-HSCT. Requirement for urgent therapy due to tumour mass effects such as respiratory obstruction or blood vessel compression. Current or expected need for systemic corticosteroid therapy. Any organ failure. Patients with a second tumour requiring therapy or intervention. Eastern Cooperative Oncology Group (ECOG) performance status score between 0 and 2. Subjects considered unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or comply with the study requirements for participation according to the investigator's judgement.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Decitabine-primed Tandem CAR19/20 engineered T cells<br>Tandem dual Specificity targeting CD19 and CD20 decitabine-primed CAR-T cells can recognize and kill the CD19 negative malignant cells through recognition of CD20 and improve the possibility of killing lymphoma tumor cells. | Biological: Decitabine-primed Tandem CAR19/20 engineered T cells<br>* Tandem CAR19/20 engineered T cells<br>* Other names: cohort 1;|
| Experimental: Decitabine-primed Tandem CAR19/20 engineered T cells plus chidamide<br>Chidamide is a novel and orally active benzamide class of HDAC inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, which can Induce tumor-cell apoptosis, suppress cell proliferation and enhance immune surveillance. | Drug: Chidamide<br>* Chidamide will be added 1 month after responding to CART cells infusion<br>* Other names: cohort 2;Biological: Decitabine-primed Tandem CAR19/20 engineered T cells<br>* Tandem CAR19/20 engineered T cells<br>* Other names: cohort 1;|
| Experimental: Decitabine-primed Tandem CAR19/20 engineered T cells plus decitabine<br>Decitabine is an investigational (experimental) drug that works by depleting DNA methyltransferase 1(DNMT1), which can increase tumor antigens and HLA expression, enhances antigen processing, promotes T cell infiltration, and boosts effector T cell function. | Drug: Decitabine<br>* Decitabine will be added 1 month after responding to CART cells infusion<br>* Other names: cohort 3;Biological: Decitabine-primed Tandem CAR19/20 engineered T cells<br>* Tandem CAR19/20 engineered T cells<br>* Other names: cohort 1;|
| Experimental: Decitabine-primed Tandem CAR19/20 engineered T cells plus chidamide+decitabine<br>The combination of chidamide and decitabine can increase tumor antigens and HLA expression, enhances antigen processing, promotes T cell infiltration, and boosts effector T cell function, induce tumor-cell apoptosis, suppress cell proliferation and enhance immune surveillance | Drug: Chidamide and Decitabine<br>* Both chidamide and decitabine will be added 1 month after responding to CART cells infusion<br>* Other names: cohort 4;Biological: Decitabine-primed Tandem CAR19/20 engineered T cells<br>* Tandem CAR19/20 engineered T cells<br>* Other names: cohort 1;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events after intervention | Safety Outcome | 12 months | 
| Progression Free Survival |  | 2 years | 
| Duration of Response |  | 2 years | 
| Overall Survival |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate Outcome Measure | ORR assess by investigators per the 2014 Lugano classification rate of subjects achieved objective response in all evaluable subjects | 2 years | 
| Intervention treatment-related adverse events (AEs) | Incidence, nature, and severity of adverse events graded according to the NCI CTCAE v5.0 | 12 months |