Treatment of Refractory/Relapsed Non-Hodgkin Lymphoma With TriCAR-T_CD19

Study Overview
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Brief Summary
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This is a single arm, open-label, single-center, phase 1/2 study, to determine the safety and efficacy of TriCAR-T-CD19, an autologous tri-functional anti-CD19 chimeric antigen receptor (CAR)-positive T cell therapy, in refractory/Relapsed Non-Hodgkin Lymphoma (NHL).

Detailed Description
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The tri-functional anti-CD19 chimeric antigen receptor contains an anti-CD19 scFv, a PD-L1 blocker, and a cytokine complex, enabling the TriCAR-T-CD19 to simultaneously targeting the CD19 positive NHL，blocking the inhibitory PD-L1 signal and stimulating T/NK cell activation and expansion.

Official Title
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TriCAR-T-CD19 Adoptive Immunotherapy for CD19-positive Refractory/Relapsed Non-Hodgkin Lymphoma

Conditions
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Non-hodgkin Lymphoma,B Cell

Intervention / Treatment
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* Biological: TriCAR-T-CD19


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must personally sign and date the consent form before initiating any study specific procedures or activities; All subjects must be able to comply with all the scheduled procedures in the study; Histologically or cytologically confirmed CD19 positive non-Hodgkin lymphoma; Chemotherapy-refractory disease, defined as one or more of the following: Relapsed in 6 months after most recent therapy; Progressive disease in the standard R-CHOP or CHOP chemotherapy; Disease progression or relapsed in ≤12 months of ASCT (must have biopsy proven recurrence in relapsed subjects); If salvage therapy is given post-ASCT, the subject must have had no response to or relapsed after the last line of therapy. No available standard therapy; At least one measurable lesion per revised IWG Response Criteria; Aged 18 to 68 years; Expected survival ≥12 weeks; Eastern cooperative oncology group (ECOG) performance status of ≤2; Systematic usage of immunosuppressive drug or corticosteroid must have been stopped for more than 4 weeks; All other treatment induced adverse events must have been resolved to ≤grade 1; Laboratory tests must fulfill the following criteria: ANC ≥ 1000/uL, HGB >70g/L, Platelet count ≥ 50,000/uL, Creatinine clearance ≤1.5 ULN, Serum ALT/AST ≤2.5 ULN, Total bilirubin ≤1.5 ULN (except in subjects with Gilbert's syndrome); Female must be not pregnant during the study. Exclusion Criteria: History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years; History of allogeneic stem cell transplantation; Prior other CAR therapy or other genetically modified T cell therapy; Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV antimicrobials for management. Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment; Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of CNS lymphoma, cerebrospinal fluid malignant cells or brain metastases; Lactating women; Active infection with hepatitis B (HBsAG positive) or hepatitis C virus (anti-HCV positive); Subjects need systematic usage of corticosteroid; History of any gene therapy; Subjects need systematic usage of immunosuppressive drug; Known history of infection with HIV; Planed operation, history of other related disease, or any other related laboratory tests restrict patients for the study; Other reasons the investigator think the patient may not be suitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 68 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: TriCAR-T-CD19<br>Tri-functional anti-CD19 chimeric antigen receptor transduced autologous T cells will be administered intravenously | Biological: TriCAR-T-CD19<br>* A conditioning chemotherapy regimen of fludarabine and cyclophosphamide will be administered followed by a single infusion of CAR transduced autologous T cells administered intravenously at a target dose of 0.5-1 x 10^6 CAR+ T cells/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety (Incidence of treatment-related adverse events as assessed by CTCAE v4.0) | Incidence of treatment-related adverse events as assessed by CTCAE v4.0 | 30 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response rate[CR] (Complete response rate per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma) | Complete response rate per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma | 12 months | 
| Partial response rate [PR] (Partial response rate per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma) | Partial response rate per the revised International Working Group (IWG) Response Criteria for Malignant Lymphoma | 12 months | 
| Duration of Response （The time from response to relapse or progression） | The time from response to relapse or progression | 12 months | 
| Progression Free Survival（The time from the first day of treatment to the date on which disease progresses.） | The time from the first day of treatment to the date on which disease progresses. | 12 months | 
| Overall Survival（The number of patient alive, with or without signs of cancer） | The number of patient alive, with or without signs of cancer | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD19, CAR-T, TriCAR-T-CD19, non-Hodgkin lymphoma, NHL