safety and efficacy of metabolically armed cd19 car-t cells (meta10- 19) in the treatment of r/r b-all clinical research

Conditions: B-cell Acute Lymphoblastic Leukemia

Summary: 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.

Keywords: meta10-19 car-t cells therapy r/r b-all