ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma

Study Overview
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Brief Summary
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This is a single center, open-label, 3+3 dose escalation, phase 1 study to evaluate the efficacy and safety of ET019003-T cells therapy for patients with relapsed/refractory CD19+ acute lymphoblastic leukemia and lymphoma.

Detailed Description
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ET019003-T cells is a human anti-CD19 CAR-T cells by fusing the anti-CD19 antibody Fab domain with the transmembrane and intracellular domains from the γδTCR, which can avoid mispairing with the T cell's endogenous αβTCR chains. Meanwhile, an independent ET190L1-CSR(Chimeric Signaling Receptor) is added to ET019003-T cells in trans, which can bind CD19 to activate a novel costimulatory domain to further promote T cell proliferation and persistence. The trial is conducted to explore the safety and efficacy of ET019003-T cells in CD19+ Leukemia and Lymphoma.

Official Title
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Safety and Efficiency Study of ET019003-T Cells in Relapsed/Refractory CD19+ B-Cell Leukemia and Lymphoma

Conditions
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Leukemia, Lymphoma

Intervention / Treatment
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* Drug: ET019003-T Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient or his or her legal guardian voluntarily participates in and signs an informed consent form. Male or female, aged 18 to 75 years (including 18 and 75 years old). Pathologically confirmed CD19+ B-cell malignancies, and patients met the following criteria for refractory or relapsed B-cell malignancies. A. Refractory/relapsed B-cell lymphoblastic leukemia (meeting one of the following) i. Recurrence within 6 months after first remission. ii. Primary refractory disease which cannot achieve complete remission (CR) after 2 cycles of standardized chemotherapy regimen. iii. Failure to achieve CR or relapse after one line or multiple lines of salvage chemotherapy. iv. Not suitable for hematopoietic stem cell transplantation (HSCT), or abandon HSCT due to various restrictions, or relapse after HSCT. B. Refractory/relapsed B-cell lymphoma (Meeting 1 of the first 3 items plus item 4) i. Tumor shrinkage less than 50% or disease progression after 4 cycles of standard chemotherapy. ii. Achieved CR after standard chemotherapy, but relapsed within 6 months. iii. Two or more relapses after CR. iv. Subjects must have received adequate treatment in the past, including anti-CD20 monoclonal antibody and combination chemotherapy with anthracyclines. Having a measurable or evaluable lesion: A. Patients with lymphoma require a single lesion≥15mm or 2 or more lesions≥10mm. B. Patients with leukemia require persistent positive or positive relapse of bone marrow MRD. Patient's main organs functioning well: A. Liver function: ALT/AST ≤ 3 times the upper limit of normal (ULN) and total bilirubin≤2 times ULN. B. Renal function: Creatinine < 220μmol/L. C. Pulmonary function: Indoor oxygen saturation≥95%. D. Cardiac Function: Left ventricular ejection fraction (LVEF) ≥ 50%. ≥ 2 weeks since prior therapy at the time of enrollment, and the toxicity related to previous treatments returned to < grade 1 (except for low grade toxicity such as alopecia). ECOG score≤ 2. Estimated survival time≥3 months. Exclusion Criteria: Women who are pregnant or breastfeeding. Women of child-bearing potential and all male participants can't use effective methods of contraception for at least 12 months following infusion. Patients fail to collect enough PBMC. Patients with other uncontrolled diseases, such as active infections. Active hepatitis B or active hepatitis C. Known HIV positive patients. Patients with active autoimmune diseases requiring systemic immunosuppressive therapy. Participants with other active malignancies (except non-melanoma skin cancer and cervical cancer) within 3 years. Patients with severe mental disorder or disorders of consciousness. Patients who need immediate treatment to control tumor progression or relieve tumor burden. Patients participated in other clinical treatments within 6 weeks. Patients with drug addiction. Patients with poor treatment compliance.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: This study was a single-center, open-label, single-arm, non-randomized,3+3 dose escalation clinical trial.18 patients are separated into 9 leukemia and 9 lymphoma. Each disease has 3 groups by infusion dose level. Each dose group has 3 patients.If no DLT emerges in the group, then the next group uses the subsequent higher dose. If DLT emerges in a single subject in any dose level, 3 more subjects will be enrolled to the same dose level.The maximum dose could be extended.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ET019003-T Cells<br>The trial will enroll 9 patients with leukemia and 9 patients with lymphoma. Each disease has 3 dose-levels. | Drug: ET019003-T Cells<br>* Fludarabine 25 mg/day on day -5, -4 and -3; Cyclophosphamide 250 or 300 mg/day on day -5, -4 and -3; ET019003-T Cells on day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-related Adverse Events | Therapy-related adverse events will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0). | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Remission Rate(ORR) of ET019003-T cells in Leukemia and Lymphoma | ORR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Overall survival(OS) of ET019003-T cells in Leukemia and Lymphoma | OS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Progress-free survival(PFS) of ET019003-T cells in Leukemia and Lymphoma | PFS will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| duration of Response(DOR) of ET019003-T cells in Leukemia and Lymphoma | DOR will be assessed from the first CAR-T cell infusion to death or last follow-up (censored). | 3 years | 
| Rate of ET019003-T cells in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) rate of ET019003-T cells were determined by means of flow cytometry. | 3 years | 
| Quantity of ET019003-T CAR copies in bone marrow cells and peripheral blood cells | In vivo (bone marrow and peripheral blood) quantity of ET019003-T CAR copies copies were determined by means of qPCR. | 3 years |