Safety and Efficacy of Metabolically Armed CD19 CAR-T Cells (Meta10- 19) in the Treatment of r/r B-ALL Clinical Research

Study Overview
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Brief Summary
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A Study of Metabolically Armed CD19 CAR-T Cells Therapy for Patients With Relapsed and/or Refractory B-cell Acute Lymphoblastic Leukemia

Detailed Description
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This is a single arm , open-label study. This study is indicated for relapsed and/or refractory CD19+ B-cell Acute Lymphoblastic Leukemia . The selections of dose levels and the number of subjects are based on clinical trials of similar foreign products. Main research objectives: To evaluate the safety and efficacy of metabolically armed CD19 CAR-T Cells in the treatment of r/r B-ALL. Secondary research objectives: A. To evaluate the pharmacokinetic (PK) and pharmacodynamics(PD) characteristics of metabolically armed CD19 CAR-T Cells after infusion. B. To evaluate tumor remission after infusion of metabolically armed CD19 CAR-T Cells.

Official Title
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Safety and Efficacy of Metabolically Armed CD19 CAR-T Cells (Meta10- 19) in the Treatment of r/r B-ALL Clinical Research

Conditions
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B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Metabolically Armed CD19 CAR-T cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient or his/her guardian voluntarily signed the informed consent； Patients with relapsed and refractory B-cell Acute Lymphoblastic Leukemia. Definition of relapsed or refractory B-ALL (meeting one of the following conditions): 2 or more relapses; Bone marrow relapsed after allo-HSCT and prepared to infuse Meta10-19 more than 6 months after allo-HSCT ; CR not achieved after standardized chemotherapy; Philadelphia-chromosome-positive (Ph+) patients who are ineffective or intolerant to first- and second-generation tyrosine kinase inhibitor (TKI) treatments, or who have contraindications to tyrosine kinase inhibitors; The number of primordial cells (lymphoblast and prolymphocyte) in bone marrow is ≥ 5% CD19 expression was positive by biopsy or flow cytometry (accept the results of this peripheral blood mononuclear cells collection or previous Class A tertiary hospital before this peripheral blood collection); Expected survival time greater than 12 weeks The baseline ECOG score was 0 or 1； Organ function： Kidney function: Serum creatinine ≤1.5 times ULN, or； The glomerular filtration rate (eGFR) estimated by MDRD formula was ≥60m/min/1.73m2；[eGFR=186×（age）-0.203×SCr-1.154（mg/dl），for females, the result was ×0.742]； Liver function： ALT≤5 times ULN, and; Patients with total bilirubin ≤2.0mg/dl, except those with Gilbert-Meulengracht syndrome. Patients with Gilbert-.Meulengracht syndrome with total bilirubin ≤3.0 times ULN and direct bilirubin ≤1.5 times ULN were included. Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment. Hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (MUGA) and LVEF ≥45％; Patients using the following drugs must meet the following conditions: Steroid: Therapeutic doses of steroids must be discontinued 2 weeks prior to Meta10-19 infusion. However, physiological replacement doses of steroids are permitted, hydrocortisone or its equivalent < 6-12mg/mm2/ day； Immunosuppressive agent: Any immunosuppressive drug must be stopped ≥4 weeks before the informed consent is signed; Anti-proliferative therapy other than preconditioning chemotherapy is discontinued within 2 weeks prior to Meta10-19 infusion； Treatment for CNS disease must be stopped 1 week before Meta10-19 infusion (e.g., intrathecal methotrexate) The patient has recovered from the toxicity of the previous treatment, that is, the CTCAE toxicity grade is less than 1 (The exception is specific toxicity of grade 2 or less, such as hair loss, which the researchers have determined is not recoverable in a short period of time) is suitable for pretreatment chemotherapy and CAR-T cell therapy; Women of childbearing age and all male patients must consent to use an effective contraception for at least 12 months after Meta10-19 infusion and until two consecutive PCR tests show no more CAR-T cells in vivo. Exclusion Criteria: Patients with isolated extramedullary relapse; Patients with confirmed diagnosis of Burkitt's lymphoma/ leukemia; Patients who had received prophylaxis for CNS leukemia within 1 week prior to Meta10-19 infusion; Patients with present or history of central nervous system diseases such as seizures disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement; Patients with history of allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 6 months prior to Meta10-19 infusion; Patients who had received chemotherapy other than preconditioning chemotherapy within 2 weeks prior to Meta10-19 infusion ; Patients who participated in other clinical trials within 30 days prior to enrollment; Patients with active hepatitis B (defined as hepatitis B surface antigen positive or hepatitis B core antibody positive, concomitant hepatitis B virus DNA level > 1000 copies/ml) or hepatitis C (HCV RNA positive); Patients with HIV antibody positive or treponema pallidum antibody positive; Patients with uncontrolled acute life-threatening bacterial, viral or fungal infections (e.g. positive blood cultures ≤72 hours before Meta10-19 infusion) Patients with unstable angina pectoris and/or myocardial infarction within 6 months prior to enrollment； Patients with history of other malignancies, but the following conditions can be enrollment: Adequately treated basal or squamous cell carcinoma (requiring adequate wound healing before signing informed consent); Carcinoma in situ (DCIS) of cervical or breast cancer, which has been treated therapeutically, has shown no signs of recurrence for at least 3 years prior to the signing of the informed consent； The primary malignancy has been completely resected and in complete remission for ≥5 years。 Women who are pregnant or breastfeeding (pregnancy tests for women of childbearing age are positive); Patients with active neuroautoimmune or inflammatory conditions (e.g. Guillian-Barre syndrome, amyotrophic lateral sclerosis); Other conditions that the investigator considered should not be enrolled in this clinical study, such as poor compliance.

Ages Eligible for Study
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Minimum Age: 3 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administration of Metabolically Armed CD19 CAR-T cells<br>Patients undergo leukapheresis. Patients will receive a lymphodepletion chemotherapy with cyclophosphamide and fludarabine before CAR-T cells infusion. A dose of metabolically armed CD19 CAR-T cells will be infused on day 0. | Drug: Metabolically Armed CD19 CAR-T cells<br>* Each subject receive metabolically armed CD19 CAR-T cells by intravenous infusion.<br>* Other names: Meta10-19;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD | Determine the Maximal Tolerable Dose(MTD) | MTD will be determined based on DLTs observed during the first 28 days of study treatment | 
| Objective response rate (ORR) | Measure Tumor response rate (including CR and PR) | Within 3 months following infusion of Meta10- 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics | The number of CAR-T cells in peripheral blood was measured to evaluate the persistence of CAR-T cells | Up to 12 months after CAR-T treatment | 
| Pharmacodynamics | Peak level of cytokines in peripheral blood | Up to 28 days after infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meta10-19, CAR-T Cells Therapy, r/r B-ALL