GZL Sequential CD19/CD22 CAR-T in Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Study Overview
=================
Brief Summary
-----------------
This study intends to use Obinutuzumab, Zanubrutinib, and Lenalidomide sequential CD19/CD22 CAR-T in the treatment of Relapsed or Refractory B-cell Non-Hodgkin Lymphoma patients. The main purpose of this study is to explore a new treatment mode for R/R B-NHL patients and observe the efficacy and safety of this treatment regimen.

Detailed Description
-----------------
The study will start with 2-4 cycles of combination chem-free therapy with obinutuzumab, zanubrutinib and lenalidomide, followed by sequential CAR-T therapy. CAR-T therapy with AZA + FC (Azacitidine +Fludarabine +Cyclophosphamide) conditioning regimen. Targets of CAR-T cells are CD19/CD22. In this clinical trial, ORR, CRR, OS, PFS, AE and other indicators were used to observe the safety and efficacy of this sequential therapy.

Official Title
-----------------
Prospective, Single-center, Single-arm, Open-label Study of Obinutuzumab, Zanubrutinib and Lenalidomide Sequential CD19/CD22 CAR-T in Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Conditions
-----------------
Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Drug: Obinutuzumab
* Drug: Zanubrutinib
* Drug: Lenalidomide
* Drug: CD19/CD22 CAR-T
* Drug: Azacitidine For Injection
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed CD22 + and/or CD19 + aggressive B-cell non-Hodgkin lymphoma (NHL), including the following types as defined by World Health Organization (WHO) 2016: Diffuse large B-cell lymphoma (DLBCL); High grade B-cell lymphoma (HGBL); Primary mediastinal large B-cell lymphoma(PMBCL); T cell/histiocyte-rich large B-cell lymphoma (THRBCL); High grade follicular cell lymphoma Grade 3b (3bFL); Mantle cell lymphoma (MCL) except indolent; Other aggressive B-cell lymphomas. Disease refractory to first-line therapy or early relapse within 12 months of last treatment. Relapse or progressive disease (PD) ≥ 3 months after targeted CD19 therapy including CD19 CAR T cells or anti-CD19/anti-CD3. Successful leukapheresis assessment and T-cell preculture. Life expectancy > 3 months. Appropriate organ function: Creatinine < 1.6 mg/dL (140 µmol/L) or creatinine clearance ≥ 60ml/min; Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < 3 × upper limit of normal; Bilirubin < 2.0 mg/dL unless subject has Gilbert 's syndrome (< 3.0 mg/dL); Pulmonary reserve ≤ Grade 1 dyspnea and SPO2 > 91%; Cardiac ejection fraction ≥ 50% in the absence of oxygen, no evidence of pericardial effusion as determined by echocardiogram (ECHO), and no clinically significant electrocardiogram (ECG) findings. Adequate bone marrow reserve was defined as: Absolute neutrophil count (ANC) > 1000/mm3; Absolute lymphocyte count (ALC) ≥ 300/mm3; Platelet count ≥ 50,000/mm3. Hemoglobin > 7.0 mg/dL. Measurable or evaluable lesions according to IWG response criteria for malignant lymphoma (Cheson 2014). Patients have the ability to understand and are willing to provide written informed consent. Exclusion Criteria: severe liver and kidney dysfunction (alanine aminotransferase, bilirubin, creatinine > 3 times the upper limit of normal); the presence of structural heart disease, and lead to clinical symptoms or abnormal heart function (NYHA ≥ 2); uncontrolled active infection; the presence of other tumors requiring treatment or intervention; the current or expected need for systemic corticosteroid therapy; pregnant or lactating women. Other psychological conditions that prevent patients from participating in the study or signing informed consent; According to the investigator 's judgment, the subject is unlikely to complete all protocol-required study visits or procedures, including follow-up visits, or fail to meet the requirements for participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GZL sequential CD19/CD22 CAR-T<br>Phase I (combined immunotherapy period): 2-4 cycle of combination chem-free therapy with Obinutuzumab, Zanubrutinib and Lenalidomide . Each cycle is 21 days. Phase II (CAR-T therapy): CAR-T therapy with AZA + FC (Azacitidine, Fludarabine and Cyclophosphamide) conditioning regimen. Targets of CAR-T cells are CD19/CD22. | Drug: Obinutuzumab<br>* Obinutuzumab Injection 1000mg ivgtt C1-C4 d1；<br>* Other names: Gazyva;Drug: Zanubrutinib<br>* Zanubrutinib 160mg (2 capsules) oral bid；<br>* Other names: Brukinsa;Drug: Lenalidomide<br>* Lenalidomide 25mg (1 capsule) oral C1-C4 d1-d10.<br>* Other names: Anxian;Drug: CD19/CD22 CAR-T<br>* Targets of CAR-T cells are tandem CD19/CD22. 1 * 10 ^ 7/kg dual-target CAR-T cells were reinfused with 10%, 30% and 60% of the total dose on d1, d2, d3 respectively.<br>Drug: Azacitidine For Injection<br>* Azacitidine For Injection 100mg i.h. d1-d5;<br>* Other names: Anyve;Drug: Fludarabine<br>* Fludarabine 300mg/m2 ivgtt d3-d5;<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Cyclophosphamide 300mg/m2 ivgtt d3-d5.<br>* Other names: Endoxan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) after GZL therapy | the rate of patients who achieved CR or PR after GZL therapy | At the end of GZL therapy (2-4 cycles, each cycle is 21days) | 
| Complete response rate (CRR) after CAR-T | the best rate of patients who achieved CR after CAR-T therapy | Within 3 months after CAR-T therapy | 
| Progression-free survival (PFS) after CAR-T | PFS will be assessed from the GZL combination therapy given to date of progression, relapse, death or end of follow-up. | up to 24 months after the end of last patient's treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events, treatment-related adverse events and serious adverse events | The safety and tolerability of the therapeutic regimen measured by the incidence of Treatment-Emergent Adverse Event. | Initiation of GZL therapy until 30 days after CAR-T therapy | 
| Overall response rate (ORR) after CAR-T | The best rate of patients who achieved CR or PR after CAR-T therapy | Within 3 months after CAR-T therapy | 
| Overall survival (OS) after CAR-T | OS will be assessed from the GZL combination therapy given to date of death or end of follow-up. | up to 24 months after the end of last patient's treatment | 
| Duration of Response(DOR) after CAR-T | DOR will be assessed from the date of CAR-T infusion to the date of progression, relapse, death or end of follow-up | up to 24 months after the end of last patient's treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Humanized anti-CD20 monoclonal antibody, BTK Inhibitor, Immunomodulators, CAR-T