Clinical Study of ET019002-T Cell Therapy for Refractory/Relapsed B-Cell Malignancies

Study Overview
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Brief Summary
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This study is to determine the safety, including potential dose limiting toxicities, and efficiency of ET019002-T cells and the duration of in vivo survival of ET019002-T cells in patients with relapsed/refractory B-Cell Malignancies.

Detailed Description
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ET019002-T cell therapy is a novel chimeric T-cell therapy platform that in preclinical studies, functionally matches the efficacy of CAR-T cells, but dramatically reduces the release of cytokines upon killing of target-positive tumors.The arm of the study is experimental i.v. arm:ET019002-T cells administered by intravenous (IV) infusion.The intervention is ET019002-T cells(Autologous T cells transduced with lentivirus encoding an anti-CD19 (ET019002)-expression construct).

Official Title
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The Clinical Study of Structurally Optimized ET019002-T Cell Therapy for Refractory/Relapsed B-Cell Malignancies

Conditions
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B-Cell Malignancies

Intervention / Treatment
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* Biological: Low dose ET019002- T Cells
* Biological: Middle dose ET019002- T Cells
* Biological: High dose ET019002- T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed B cell malignancies including: B-cell Acute Lymphoblastic Leukemia (B-ALL) and B cell lymphomas (DLBCL、FL、MZL、LPL、HCL、CLL、BL、MCL) Refractory/Relapsed B cell malignancies: Age 6-80 years, male or female Nidus could be evaluated: minimum diameter of single nidus ≥10mm, and/or tumor cells in bone marrow ≥ 5% ECOG≤2 points Function of main organs or tissues were functional: Liver - ALT/AST≤3 normal upper limit, Serum total bilirubin (TBIL) ≤2 normal upper limit; Kidney - glomerular filtration rate (GFR) > 60 mL/min/1.73 m2 or serum creatinine in normal range; Lunge - carbon monoxide diffusion capacity (DLCO) or forced expiratory volume in 1s (FEV) >45% estimate; Heart - left ventricular ejection fraction (LVEF) ≥50% Expecting life span ≥3 months No chemotherapy, radiation therapy or immunotherapy in 2 weeks before enrollment Fertile females/males consented to use contraceptives during participation of the trial Patient or his/her custodia could understand and is willing to sign the written consent Exclusion Criteria: Pregnancy or lactation Couldn't use contraceptives during participation of the trial Couldn't collect enough monocyte Active and/or severe infection HIV infection, active Hepatitis B or Hepatitis C infection Had active autoimmune disease Had non-melanoma skin carcinoma (NMSC) or Carcinoma in situ (e.g. cervix, bladder, galactophore) Obvious clinical encephalopathy or novel neuron function damage Organ failure: Heart - upper than NYHA level III or had uncontrolled malignant arrhythmia; Liver - upper than level III of Wuhan conference classification; Kidney - kidney failure stage3 or worse Using immunosuppressive drugs or adreno-cortical hormone (ACH) within two weeks of enrollment Insufficient T cell number or T cell transfection rate Needed urgent disease controlling due to tumor load Patients had biological treatment, immunotherapy or radiation therapy within 6 weeks prior to enrollment or are currently under these treatment Substance abuse or drug addiction lack of compliance, communication deficit or other unaccommodated situations

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 80 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: The low dose group<br> | Biological: Low dose ET019002- T Cells<br>* ET019002- T Cells are autologous T cells transduced expressing a novel anti-CD19 (ET019002) chimeric antigen receptor,and are administered by intravenous infusion with the dose of 0.75×10*6/kg.<br>|
| Experimental: The middle dose group<br> | Biological: Middle dose ET019002- T Cells<br>* ET019002- T Cells are autologous T cells transduced expressing a novel anti-CD19 (ET019002) chimeric antigen receptor,and are administered by intravenous infusion with the dose of 1.5×10*6/kg.<br>|
| Experimental: The high dose group<br> | Biological: High dose ET019002- T Cells<br>* ET019002- T Cells are autologous T cells transduced expressing a novel anti-CD19 (ET019002) chimeric antigen receptor,and are administered by intravenous infusion with the dose of 3.0×10*6/kg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | A dose limiting toxicity is defined as any toxicity that is considered to be primarily related to the ET019002T-cells,which is irreversible or life threatening or CTCAE Grade 3-5. | Up to 12 weeks. | 
| Tmax of serum cytokine levels | Cytokins as measured by CBA-Bioplex Multiplex Immunoassays will be presented as time to peak level. | Up to 12 weeks. | 
| Time to baseline for serum cytokine levels | Inceases or decreases in the amout of cytokine produced compared to baseline at time points measured up to 24 weeks since dosing. | Up to 12 weeks. | 
| Toxicity profile of ET019002T-cell treatment | Frequency of treatment-related adverse events that occurred at any time from the first day of infusion that are possibly, likely, or definitely related to the study, including infusion related toxicity and ET019002 T cell related toxicity. Include but not limited to: Fever, chills, nausea, vomiting, jaundice and other gastrointestinal symptoms; Fatigue, hypotension, respiratory distress; Tumor lysis syndrome; Cytokine release syndrome; Neutropenia, thrombocytopenia; Liver and kidney dysfunction. Assessed at all visits. | Up to 2 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of disease response | Rate of disease response assessed by lugano cliassification.Response rates will be estimated as CR,PR,SD,PD. | Up to 12 weeks. | 
| Progression free survival(PFS) | Progression free survival(PFS) denotes the chances of staying free of disease progression for patients after treatment. | Up to 2 years. | 
| Time to baseline for B cell level | B cell level as measured by Bio-Plex Multiplex Immunoassays will be presented. | Up to 2 years. |