PD1-CD19-CART in Patients With r/r B-cell Lymphoma

Study Overview
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Brief Summary
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This is an open label, single-site, dose-escalation study in up to 25 participants with relapse/refractory B-NHL. This study aims to evaluate the safety and efficacy of the treatment with PD1-CD19-CART.

Detailed Description
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PD1-CD19-CART is a kind of chimeric antigen T cell targeting CD19 with both CD19-CAR gene integration and also PD1 knockout by one-step gene-editing. After completion of study treatment, subject participation for this study will be followed up to 15 years post T cell infusion.

Official Title
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a Safety and Efficacy Evaluation of PD1-CD19-CART in Patients With Relapse/Refractory B-cell Lymphoma

Conditions
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B-cell Lymphoma

Intervention / Treatment
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* Biological: PD1 specific integrated anti-CD19 Chimeric Antigen Receptor T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have the capacity to give informed consent; ALL patients with the age between 18 and 70 years old; Expected survival >3 moths; With no severe heart and lung disease; Previously confirmed diagnosis as CD19+ NHL within 6 months; Hematological index as following, white blood cell (WBC)≥1.5×10^9/L，absolute neutrophil count (ANC) ≥0.8×10^9/L, Platelet count≥50×109/L, Hemoglobin (Hgb) ≥ 90mg/L, lymphocyte count≥ 0.4×10^9/L； Blood biochemical index as no more than 1.5* ULN, including total bilirubin (TBIL), transglutaminase (AST), alanine aminotransferase (AST), Creatinine (SCr), Urea in patients with no tumor metastasis in liver and kidney; Blood biochemical index no more than 5* ULN in patients with tumor metastasis in liver and kidney; With a stable cardiac function, the left ventricular ejection fraction (LVEF) ≥ 55%; Virological tests were negative for EBV, CMV, HIV, TP and HCV; a negative HBV DNA test is acceptable if HBsAg is positive; ECOG <2; Relapsed or refractory (r/r) NHL including, Diffuse large B cell lymphoma(DLBCL, NOS), stage Ⅲ-Ⅳ;Primary mediastinal large B-cell lymphoma (PMBL), stage Ⅲ-Ⅳ; High grade B-cell lymphoma (HGBL), stage Ⅲ-Ⅳ; Mantle cell lymphoma (MCL), stage Ⅲ-Ⅳ; follicular lymphoma (FL), stage Ⅲ-Ⅳ and with aggression. r/r NHL defined as following, demonstrate disease that persists or relapse after achieving complete response (CR) after > 2 cycles of standard chemotherapy, or relapse after autologous hematopoietic stem cell transplantation (auto-HSCT), or not achieving CR after auto-HSCT. Exclusion Criteria: Pregnant or lactating women; With a pregnancy plan in the next 2 years; Prior treatment of anti-GVHD therapy; Acceptance of allogeneic stem cell transplant (ASCT); Isolated extramedullary relapse of ALL; Severe mental disorders, active autoimmune diseases, active infectious diseases, severe cardiovascular diseases; Partial prothrombin time or activated partial thromboplastin time or international standardized ratio > 1.5*ULN without anticoagulant treatment; History of other type of maligant tumors; Any circumstances that possibly increase the risk of subjects or interfere with study results, which judged by investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Interventional Model Description: Patients will receive one of the three doses of 2*10^6/kg, 4*10^6/kg,6*10^6/kg.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PD1-CD19-CART<br>Patients undergo leukapheresis. Patients will receive a lymphodepletion chemotherapy with cyclophosphamide and fludarabine before CART infusion. A dose of PD1-CD19-CART will be infused on day 0. | Biological: PD1 specific integrated anti-CD19 Chimeric Antigen Receptor T Cells<br>* Gene editing autologous T cells with anti-CD19 ScFv expression and knockout of PD1<br>* Other names: PD1-CD19-CART;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | MTD will be determined based on DLTs observed during the first 28 days of study treatment. | up to 28 days after T cell infusion | 
| RP2D | RP2D will be determined based on MTD and efficiency during the first 28 days of study treatment. | up to 28 days after T cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | Proportion of patients in whom a response among complete response and partial response as defined by standard disease-specific criteria, will be observed. | Baseline up to 3 months after T cell infusion | 
| Progress free survival (PFS) | Assessed using modified Lugano classification response criteria for lymphoma (2014) | Baseline up to 3 months after T cell infusion |