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

Conditions: Diffuse Large B-cell Lymphoma

Summary: a study of metabolically armed cd19 car-t cells therapy for patients with relapsed and/or refractory diffuse large b-cell lymphoma

this is a single arm, open-label study. this study is indicated for relapsed or refractory cd19+ diffuse large b-cell lymphoma. 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 dlbcl. 2. secondary research objectives: 1. to evaluate the pharmacokinetic (pk) and pharmacodynamics(pd) characteristics of metabolically armed cd19 car-t cells after infusion. 2. to evaluate tumor remission after infusion of metabolically armed cd19 car-t cells.

Eligibility criteria:
inclusion criteria: * the patient or his/her guardian voluntarily signed the informed consent * adult patients clinical diagnosis of relapsed and refractory diffuse large b-cell lymphoma (primary mediastinal large b-cell lymphoma and transformed follicular lymphoma are included) definition of refractory: 1. no response to the last treatment, including: the best response to the last treatment was pd, or ; the best response to the last treatment was sd and the duration was not more than 6 months after the last dose. 2. not suitable for autologous hematopoietic stem cell transplantation (asct), or asct refractory, including: disease progression or recurrence within 12 months or less (recurrence must be confirmed by biopsy) after asct treatment, or; patients accept remedial treatment after asct must have no response or relapse after the last treatment * patients who had previously received ≥2 lines therapy including at least: 1. a chemotherapy regimen containing anthracyclines 2. for patients with transformed dlbcl from follicular lymphoma, they must have previously received chemotherapy for follicular lymphoma and have refractory disease after transformation to dlbcl. * patients with double-strike and triple-strike lymphoma who do not respond to second-line treatment, where double-strike/triple-strike is defined as: detection of lymphoma cells with c-myc gene translocation accompanied by bcl-2 gene translocation or/and bcl-6 gene translocation by chromosome or fish technology. * cd19 expression was positive by immunohistochemistry or flow cytometry (accept the results of this peripheral blood mononuclear cells or previous report from a class a tertiary hospital before peripheral blood collection) * at least one measurable lesion at baseline, according to the initial assessment, staging and response assessment recommendations for hodgkin's and non-hodgkin's lymphoma (2014 edition) * expected survival time greater than 12 weeks * the baseline ecog score was 0 or 1 * organ function: 1. kidney function is defined as: 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 is defined as: 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. * hemodynamic stability was determined by echocardiography or multichannel radionuclide angiography (muga) and lvef ≥45% * 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 in addition to preconditioning chemotherapy 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) * 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 a 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 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 * 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 meta10-19infusion) * 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: 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 * 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.

Keywords: meta10-19 car-t cells therapy r/r dlbcl