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

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

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.

1. Main research objectives:

   To evaluate the safety and efficacy of metabolically armed CD19 CAR-T Cells in the treatment of r/r B-ALL.
2. 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.

Eligibility Criteria:
Inclusion Criteria:

1. The patient or his/her guardian voluntarily signed the informed consent；
2. Patients with relapsed and refractory B-cell Acute Lymphoblastic Leukemia.

   Definition of relapsed or refractory B-ALL (meeting one of the following conditions):
   1. 2 or more relapses;
   2. Bone marrow relapsed after allo-HSCT and prepared to infuse Meta10-19 more than 6 months after allo-HSCT ;
   3. CR not achieved after standardized chemotherapy;
   4. 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;
   5. The number of primordial cells (lymphoblast and prolymphocyte) in bone marrow is ≥ 5%
3. 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);
4. Expected survival time greater than 12 weeks
5. The baseline ECOG score was 0 or 1；
6. Organ function：

   1. Kidney function:

      Serum creatinine ≤1.5 times ULN, or； The glomerular filtration rate (eGFR) estimated by MDRD formula was ≥60m/min/1.73m2；\[eGFR=186×（age）-0.203×SCr-1.154（mg/dl），for females, the result was ×0.742\]；
   2. 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.
   3. Pulmonary function: ≤CTCAE grade 1 dyspnea and oxygen saturation of blood (SaO2) ≥91% in indoor air environment.
7. Hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (MUGA) and LVEF ≥45％;
8. Patients using the following drugs must meet the following conditions:

   1. 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；
   2. Immunosuppressive agent: Any immunosuppressive drug must be stopped ≥4 weeks before the informed consent is signed;
   3. Anti-proliferative therapy other than preconditioning chemotherapy is discontinued within 2 weeks prior to Meta10-19 infusion；
   4. Treatment for CNS disease must be stopped 1 week before Meta10-19 infusion (e.g., intrathecal methotrexate)
9. 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;
10. 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:

1. Patients with isolated extramedullary relapse;
2. Patients with confirmed diagnosis of Burkitt's lymphoma/ leukemia;
3. Patients who had received prophylaxis for CNS leukemia within 1 week prior to Meta10-19 infusion;
4. 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;
5. Patients with history of allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 6 months prior to Meta10-19 infusion;
6. Patients who had received chemotherapy other than preconditioning chemotherapy within 2 weeks prior to Meta10-19 infusion ;
7. Patients who participated in other clinical trials within 30 days prior to enrollment;
8. 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);
9. Patients with HIV antibody positive or treponema pallidum antibody positive;
10. Patients with uncontrolled acute life-threatening bacterial, viral or fungal infections (e.g. positive blood cultures ≤72 hours before Meta10-19 infusion)
11. Patients with unstable angina pectoris and/or myocardial infarction within 6 months prior to enrollment；
12. Patients with history of other malignancies, but the following conditions can be enrollment:

    1. Adequately treated basal or squamous cell carcinoma (requiring adequate wound healing before signing informed consent);
    2. 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；
    3. The primary malignancy has been completely resected and in complete remission for ≥5 years。
13. Women who are pregnant or breastfeeding (pregnancy tests for women of childbearing age are positive);
14. Patients with active neuroautoimmune or inflammatory conditions (e.g. Guillian-Barre syndrome, amyotrophic lateral sclerosis);
15. Other conditions that the investigator considered should not be enrolled in this clinical study, such as poor compliance.