Human CD19 Targeted T Cells Injection(CD19 CAR-T) Therapy for Relapsed and Refractory B-cell Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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A Phase Ⅱ Clinical Study Evaluating the Efficacy and Safety of Human CD19 Targeted T Cells Injection (CD19 CAR-T) Therapy for R/R B-NHL. Patients will be given a conditioning chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of CD19 CAR+ T cells.

Detailed Description
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Subjects with relapsed and refractory B-cell non-Hodgkin's lymphoma would be selected if subjects meet all criteria evaluated by physical exams, blood tests, electrocardiograph, computedtomography （CT）/magnetic resonance Imaging(MRI)/positron emission tomography（PET）, tumor assessments, etc. Subjects would be hospitalized to receive the infusion of CD19 CAR+ T cells after lymphodepleting regimen, with the observation and evaluation of efficacy and safety.

Official Title
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A Phase Ⅱ Clinical Study Evaluating the Efficacy and Safety of Human CD19 Targeted T Cells Injection (CD19 CAR-T) Therapy for Relapsed and Refractory B-cell Non-Hodgkin's Lymphoma

Conditions
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B-cell Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Human CD19Targeted T Cells Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:Subjects with relapsed/refractory B-cell non-Hodgkin's lymphoma Age≥18 years old，gender is not limited; Expected survival > 12 weeks; ECOG score 0-2; B-cell non-Hodgkin's lymphoma confirmed by cytology or histopathology according to the 2016 World Health Organization (WHO) classification and diagnostic criteria, including: diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed filter Alveolar lymphoma (TFL) and high-grade B-cell lymphoma (HGBCL); Pathology demonstrated that B-cell non-Hodgkin's lymphoma and who meet one of the following conditions: Relapsed and refractory B-cell non-Hodgkin's lymphoma, after standard first-line treatment and at least 2 courses of second-line treatment without remission and relapse (the previous use of CD20-targeted drugs and anthracyclines were needed); Relapse of B-cell non-Hodgkin lymphoma after stem cell transplantation, regardless of previous treatments. The venous access required for collection can be established and leukepheresis can be carried according to the judgement of investigators, satisfying hemoglobin≥80g/L, neutrophils ≥1.0×10^9/L, platelets ≥75×10^9 / L; According to the Lugano 2014 criteria, there should be at least one measurable tumor lesion; Liver, kidney and cardiopulmonary functions meet the following requirements: Serum creatinine≤1.5×ULN or creatinine clearance rate≥50mL/min (GockcroftGault formula); Cardiac ejection fraction >50%, no clinically significant pericardial effusion detected, no clinically significant pleural effusion detected; Baseline blood oxygen saturation>92%; Total bilirubin≤1.5×ULN(Gilbert syndrome≤5×ULN); ALT and AST≤3×ULN (AST and ALT ≤5×ULN in patients with liver metastases); Able to understand and sign the Informed Consent Document. Exclusion Criteria:Any one of the following conditions cannot be selected as a subject： Malignant tumors other than diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed follicular lymphoma (TFL), and high-grade B-cell lymphoma (HGBCL) within 5 years prior to screening, in addition to adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical resection, ductal carcinoma in situ after radical resection and thyroid cancer after radical resection ; Subjects with positive Hepatitis B surface antigen(HBsAg) or Hepatitis B core antibody (HBcAb) and positive peripheral blood hepatitis B virus (HBV) DNA titers (higher than the upper limit of the normal range of the investigative site); Hepatitis C virus (HCV) antibody positive and peripheral blood HCV RNA positive; Human Immunodeficiency Viral (HIV) antibody positive; syphilis positive; Any uncontrolled systemic diseases, including but not limited to active infection (except for localized infection), uncontrolled angina, cerebrovascular accident, or transient cerebral ischemic (within 6 months prior to screening), myocardial infarction (within 6 months prior to screening), congestive heart failure (New York heart association (NYHA) classification ≥ III), need drug therapy of severe arrhythmia, liver, kidney, or metabolic disease; Any other uncontrolled active disease that precludes participation in the trial; Any circumstances that the investigator believes will compromise the safety of the subject or interfere with the purpose of the study; Pregnant or lactating woman, or planned pregnancy during treatment or within 1 year after treatment, or male subject whose partner plans to have a pregnancy within 1 year after cell transfusion; Active or uncontrollable infection requiring systemic therapy within 14 days prior to enrollment (except uncomplicated urinary tract infection or upper respiratory tract infection); Subjects who were receiving systemic steroid treatment within 14 days before enrollment and who were judged by the investigator to require long-term use of systemic steroid therapy during treatment (except inhalation or topical use); or subjects who received any systemic anti-tumor therapy ( except for local anti-tumor therapy) ; Subjects who have received CAR-T treatment or other gene-modified cell therapy before enrollment; Patients with symptoms of central nervous system or brain metastasis or have received treatment for central nervous system or brain metastasis (radiotherapy, surgery or other treatment) within 3 months before enrollment; Subjects who have a disease that affects the signing of written informed consent or who are unable to comply with research procedures; or who are unwilling or unable to comply with research requirements; Subjects who are considered unsuitable to participate in this trial by the investigator.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Human CD19 Targeted T Cells Injection<br>Single administration：2.0×10^6 CAR+T/kg | Drug: Human CD19Targeted T Cells Injection<br>* A single dose of predetermined level CAR-positive T cells will be infused.<br>* Other names: CD19 CAR-T;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) at 3 months post infusion | ORR is defined as proportion of subjects who achieved Partial remission(PR) or better at 3 months (D90±7) post infusion as assessed by an independent review committee (IRC) based on Lugano 2014 criteria. | 3 months post infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of remission (DOR) after administration | DOR refers to the time from the first assessment of complete response or partial response to the first assessment of disease progression or death from any cause. | 2 years post infusion | 
| Progression-free Survival (PFS) after administration | PFS refers to the time from the start of cell infusion to the first assessment of tumor progression or death from any cause. | 2 years post infusion | 
| Overall Survival (OS) after administration | OS refers to the time from cell infusion to death due to any cause. | 2 years post infusion | 
| Disease control rate (DCR) | The best overall response is the ratio of partial response(PR) or complete response(CR) or stable disease(SD) patients to the total number of cases. | 2 years post infusion | 
| Safety evaluation | The occurrence and outcome of adverse events evaluated by physical examination, laboratory examination, electrocardiogram, imaging scan, etc. | 2 years post infusion | 
| Pharmacokinetic (PK) parameters: Maximum CAR level inperipheral blood | The highest concentration of Human CD19 Targeted T Cells Injection amplified in peripheral blood after infusion (Cmax) . | 2 years post infusion | 
| Pharmacokinetics(PK) parameters: Time to peak CAR level in blood (Tmax) | The time to reach the highest concentration of Human CD19 Targeted T Cells Injection in peripheral blood after infusion (Tmax) . | 2 years post infusion | 
| Pharmacokinetics(PK) parameters: 28-day Area under the curve of the CAR level in blood(AUC0-28) | The 28-day area under the curve of Human CD19 Targeted T Cells Injection in peripheral blood after infusion（AUC0-28d）. | 2 years post infusion | 
| Pharmacodynamic (PD) parameters | The clearance degree of CD19 positive B cells in peripheral blood at respective time point. | 2 years post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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B-cell non-Hodgkin's Lymphoma, CD19, CAR-T, Relapsed/Refractory