Safety, Efficacy and Pharmacokinetics of ThisCART19A in Patients With Refractory or Relapsed B Cell Lymphoma

Study Overview
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Brief Summary
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This is a phase 1/2, open-label study to assess the efficacy, safety and pharmacokinetics of ThisCART19A (Allogeneic Anti CD19 CAR-T) in patients with refractory or relapsed CD19 positive B cell Lymphoma.

Detailed Description
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This is a phase 1/2, single-center, nonrandomized, open-label, dose-escalation and dose-expansion study to evaluate the efficacy, safety and pharmacokinetics of ThisCART19A in patients with r/r CD19 positive B cell Lymphoma and identify a treatment regimen most likely to result in clinical efficacy while maintaining a favorable safety profile. AIDS-related B-cell lymphoma were not excluded from this clinical trial. Before initiating ThisCART19A infusion, subjects will be administered lymphodepletion chemotherapy composed of fludarabine、cyclophosphamide and VP-16. At Day 0 of the Treatment Period, subjects will receive an intravenous (IV) infusion of ThisCART19A. All subjects are monitored during the treatment period through Day 42. All subjects who receive a dose of ThisCART19A will be followed up to 2 years.

Official Title
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A Single Dose-escalation and Dose-expansion Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Allogeneic CAR-T Targeting CD19 in Patients With Refractory or Relapsed B Cell Lymphoma.

Conditions
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Refractory or Relapsed B Cell Lymphoma

Intervention / Treatment
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* Drug: ThisCART19A
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years ≤ age ≤ 65 years. Voluntarily sign a documented IRB-approved ICF prior to any screening procedure. Patients with histologically confirmed B-cell NHL defined by the World Health Organization (WHO) 2016, including but not limited to diffuse large B-cell lymphoma (DLBCL), follicular lymphoma transferring to DLBCL, mantle cell lymphoma (MCL), follicular lymphoma 3B (FL-3B), original Mediastinal (thymus) large B-cell lymphoma, high-grade B-cell lymphoma and AIDS-associated B-cell lymphoma. Prior therapy must have included: Anti-CD20 monoclonal antibody and Anthracycline containing chemotherapy regimen. Had available evaluation lesion. ECOG(Eastern Cooperative Oncology Group) ≤ 2 or Karnofsky ≥ 60%. Serum creatinine≤1.5×ULN or creatinine clearance>30 mL/min/1.73 m2. Alanine aminotransferase(ALT)≤5×ULN(Upper limit of normal) and total bilirubin(TBIL)<2.0 mg/dL(for patients with Gilbert heald diseases, live involvement and taking atazanavir or indinavir, TBIL<3.0 mg/dL can be enrolled.) Left ventricular ejection fraction(LVEF)≥40% Absolute neutrophile counts≥1000/mm3 Thrombocyte≥30000/mm3 Total bilirubin(TBIL) ≤ 2.0 mg/dL Confirmed Cluster of differentiation(CD)19 positive by biopsy for the patients who received CD19 target therapy before. Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year. AIDS Related B Cell Lymphoma :HIV virus loading < 200 copy/ml and CD4+T cell counts >200 cells/mm3 within 4 weeks before screening. Patients with TBIL≤ 1.5 mg/dL, Aspartate aminotransferase(AST) and ALT ≤ 3×ULN, and hepatitis B virus(HBV) DNA <2000 IU/ml can be enrolled for HBV positive patients(defined as hepatitis B virus surface antigen(HBsAg) positive and hepatitis B core(HBc)-total positive ) and hepatitis C virus(HCV) positive patients(defined as HCV antibody positive) . Patients with cirrhosis are excluded. Hepatitis B core antibody(HBcAb) positive patients enrolled in this trial have to taking anti-HBV drugs during the whole research. Exclusion Criteria: Known for allergic to the preconditioning measures. Uncontrollable bacterial, fungal, viral infection before enrollment. Patients with pulmonary embolism within 3 months prior enrollment. Intolerable serious cardiovascular and cerebrovascular diseases and hereditary diseases. Imaging confirmed the presence of central nervous system involvement(including primary and secondary) and rapid progressing diseases. Receive allogeneic hematopoietic stem cell transplantation less than 100 days. Systemic steroid use (e.g., prednisone ≥20mg) within 3 days prior to screening. iIntermittent use of topical, inhaled or intranasal steroids recently or currently. Or systemic disease requiring long-term use of immunosuppression drugs. Excluded the patients received Influenza vaccinations within 2 weeks prior to lymphodepletion (Received Severe Acute Respiratory Syndrome-Corona virus disease(SARS-COV)19 vaccines could be included. Received inactivated, live/non-live adjuvant vaccines could be enrolled). Excluded women who are in pregnant or lactating, and female subjects or partners who plan to be pregnant within 1 year after infusion. Male subjects planning pregnancy within 1 year after infusion should be excluded.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ThisCART19A cells infusion<br>In this study, allogeneic anti-CD19 CAR T cells (ThisCART19A) infusion is used to treat patients with r/r B cell Lymphoma. | Drug: ThisCART19A<br>* Single dose of Allogeneic Anti-CD19 CAR T cells (ThisCART19A) will be infused after the lymphodepletion conditioning of Fludarabine, Cyclophosphamide and Etoposide.<br>* Other names: Allogeneic Anti-CD19 CAR T cells;Drug: Fludarabine<br>* Fludarabine is used for lymphodepletion.<br>Drug: Cyclophosphamide<br>* Cyclophosphamide is used for lymphodepletion.<br>Drug: Etoposide<br>* Etoposide is used for lymphodepletion.<br>* Other names: VP-16;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limited toxicity(DLT) observation in patient with r/r B cell Lymphoma | DLT was defined as CAR T cells-related events with onset within first 28 days following infusion. | 28 days | 
| The incidence of all grade TEAEs and ≥3 grade TEAEs | Incidence of treatment-emergent adverse events (TEAEs) and ≥3 grade TEAEs | Up to 2 years after ThisCART19A infusion | 
| Objective Response Rate | the incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as best response to treatment. | Up to 2 years after ThisCART19A infusion | 
| Duration of response (DOR) | DOR is defined as the date of their first CR or PR (which is subsequently confirmed) to PD assessed by investigators and based on the Lugano 2014 assessment criterion for r/r B cell Lymphoma, or death regardless of cause. | Up to 2 years after ThisCART19A infusion | 
| Progress-free survival (PFS) | PFS is defined as the time from the ThisCART19A infusion date to the date of disease progression assessed by investigators and based on the Lugano 2014 assessment criterion, or death any cause. | Up to 2 years after ThisCART19A infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TTR (Time to response) | TTR is defined as the time from ThisCART19A infusion to first assessed CR or PR based on the Lugano 2014 assessment criterion. | Up to 2 years after ThisCART19A infusion | 
| OS (Overall survival) | Overall survival (OS) is defined as the time from the date of lymphodepletion until death from any cause. | Up to 2 years after lymphodepletion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic CAR T，B cell Lymphoma