the safety and efficacy of brl-201 in the treatment of r/r b lymphocyte non-hodgkin lymphoma

Conditions: Non-hodgkin Lymphoma,B Cell

Summary: this is a multi-center, single-arm, open-label clinical study, and the sample size is set to 12-18 subjects.

this is a multi-center, single-arm, open-label clinical study, and the sample size is set to 12-18 subjects. based on the "3 + 3" dose escalation design principle, subjects will be divided into 3 groups from low dose to high dose in sequence (group a; group b; group c. additional subjects will be enrolled into the rp2d group to ensure that 6-9 efficacy-evaluable subjects are available in the rp2d group before entering the phase ii study.

Eligibility criteria:
inclusion criteria: 1. willing to participate in this clinical study and sign an informed consent form; 2. age ≥ 18 years old; 3. estimated survival time ≥ 3 months; 4. presence of at least one measurable lesion as assessed according to lugano classification 2014 for response assessment in lymphomas (i.e., the cross-sectional images obtained by ct show that the long diameter of lymph node lesions is \> 15 mm or the long diameter of extranodal lesions is \> 10 mm, and fdg-pet scan results are positive). lesions, for which radiotherapy was provided, can be regarded as measurable lesions only if there is an unequivocal progression after radiotherapy; 5. histopathologically confirmed aggressive b-nhl; positive expression of cd19 in tumors detected by immunohistochemistry or flow cytometry; pathological types of b-nhl (according to who lymphoma classification 2016); 6. relapsed or refractory diseases; 7. subjects who must receive adequate prior therapy; 8. absence of invasion of central nervous system (cns) lymphoma by cranial magnetic resonance imaging (mri); 9. hematological parameters meeting the requirements; 10. blood biochemistry meeting the requirements; 11. lvef ≥ 55%; 12. no severe pulmonary disorders; 13. toxic reactions induced by prior anti-lymphoma therapy must be stable and resolved to grade ≤ 1; 14. eastern cooperative oncology group (ecog) performance status score of 0-1; 15. patients with physical conditions for apheresis of peripheral blood; 16 . willing to abide by the rules formulated in the study protocol. exclusion criteria: 1. pregnant or lactating women; 2. subjects who previously received allogeneic cell therapies, including allogeneic stem cell transplant; 3. subjects who previously received anti-cd19 targeted therapy, except those who receive brl-201 and are eligible to receive reinfusion in this study; 4. prior treatment with any car-t cell product or other genetically modified t cell therapies; 5. history of richter's transformation of chronic lymphocytic leukemia (cll); 6. presence of uncontrollable fungal, bacterial, viral, or other infections requiring systemic therapy. patients can be enrolled if the simple urinary tract infection or pharyngitis responds to treatment; 7. subjects with positive hepatitis b surface antigen (hbsag) or hepatitis b core antibody (hbcab) and peripheral blood hbv dna titer higher than the upper limit of detection; hepatitis c virus (hcv) antibody positive and peripheral blood hcv rna positive; human immunodeficiency virus (hiv) antibody positive; syphilis test positive; 8. severe mental disorders; history of cns disorders (e.g., epileptic seizure, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any cns-involved autoimmune disorders); 9. active autoimmune disorders requiring immunotherapy, including but not limited to end organ damages caused by autoimmune disorders (e.g., crohn's disease, rheumatoid arthritis, and systemic lupus erythematosus) in the past 2 years, or requiring systemic application of immunosuppressive drugs or other drugs for systemic control of diseases; 10. primary immunodeficiency; 11. history of other malignancies; 12. patients with severe cardiovascular disorders, including but not limited to those with lymphoma infiltration in the cardiac atrium or ventricles and those with a history of myocardial infarction, cardioangioplasty or stent implantation, unstable angina, or other clinically significant heart diseases within 12 months before enrollment; 13. history of deep venous thrombosis or pulmonary embolism within 6 months before enrollment; 14. patients who are receiving oral anticoagulant therapy; prothrombin time (pt), activated partial thromboplastin time (aptt), or international normalized ratio (inr) \> 1.5 × uln without anticoagulant therapy; 15. presence of any indwelling tube or catheter (e.g., tube or catheter for percutaneous nephrostomy, indwelling catheter, or catheter in pleural cavity/peritoneal cavity/pericardium). dedicated central venous access catheters (e.g., port-a-cath or hickman catheter) are permitted; 16. lymphoma cells detected in cerebrospinal fluid, presence of brain metastases, history of cns lymphoma, or history of lymphoma cells detected in cerebrospinal fluid or brain metastases; 17. conditions (e.g., intestinal obstruction or vascular compression) requiring emergency treatment due to tumor masses; 18. history of severe immediate hypersensitivity to any drug to be used in this study; 19. vaccination of live vaccines, excluding corona virus disease 2019 (covid-19) vaccines, within ≤ 6 weeks before the start of the pretreatment regimen; 20. any circumstances that possibly increase the risk of subjects or interfere with the study results as judged by the investigator.