The Safety and Efficacy of BRL-201 in the Treatment of r/r B Lymphocyte Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This is a multi-center, single-arm, open-label clinical study, and the sample size is set to 12-18 subjects.

Detailed Description
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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.

Official Title
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A Phase I/II Clinical Study of the Safety and Efficacy of CD19-targeted Non-viral PD1 Site-specific Integrated CAR-T Cell Injection (BRL-201) in the Treatment of Relapsed or Refractory B Lymphocyte Non-Hodgkin Lymphoma

Conditions
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Non-hodgkin Lymphoma,B Cell

Intervention / Treatment
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* Drug: CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing to participate in this clinical study and sign an informed consent form; Age ≥ 18 years old; Estimated survival time ≥ 3 months; 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; 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); Relapsed or refractory diseases; Subjects who must receive adequate prior therapy; Absence of invasion of central nervous system (CNS) lymphoma by cranial magnetic resonance imaging (MRI); Hematological parameters meeting the requirements; Blood biochemistry meeting the requirements; LVEF ≥ 55%; No severe pulmonary disorders; Toxic reactions induced by prior anti-lymphoma therapy must be stable and resolved to grade ≤ 1; Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1; Patients with physical conditions for apheresis of peripheral blood; 16 . Willing to abide by the rules formulated in the study protocol. Exclusion Criteria: Pregnant or lactating women; Subjects who previously received allogeneic cell therapies, including allogeneic stem cell transplant; Subjects who previously received anti-CD19 targeted therapy, except those who receive BRL-201 and are eligible to receive reinfusion in this study; Prior treatment with any CAR-T cell product or other genetically modified T cell therapies; History of Richter's transformation of chronic lymphocytic leukemia (CLL); 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; 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; Severe mental disorders; history of CNS disorders (e.g., epileptic seizure, cerebrovascular ischemia/hemorrhage, dementia, cerebellar diseases, or any CNS-involved autoimmune disorders); 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; Primary immunodeficiency; History of other malignancies; 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; History of deep venous thrombosis or pulmonary embolism within 6 months before enrollment; 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; 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; 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; Conditions (e.g., intestinal obstruction or vascular compression) requiring emergency treatment due to tumor masses; History of severe immediate hypersensitivity to any drug to be used in this study; Vaccination of live vaccines, excluding corona virus disease 2019 (COVID-19) vaccines, within ≤ 6 weeks before the start of the pretreatment regimen; Any circumstances that possibly increase the risk of subjects or interfere with the study results as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Total target count of CD3+CAR+ viable cells
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BRL-201 A<br>Total target count of CD3+CAR+ viable cells | Drug: CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* Other names: BRL-201;|
| Experimental: BRL-201 B<br>Total target count of CD3+CAR+ viable cells | Drug: CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* Other names: BRL-201;|
| Experimental: BRL-201 C<br>Total target count of CD3+CAR+ viable cells | Drug: CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* CD19-targeted non-viral PD1 site-specific integrated CAR-T cell injection<br>* Other names: BRL-201;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DLT | The number and severity of dose-limiting toxicity (DLT) events | Within 28 Days After BRL-201 Infusion | 
| AEs | The total number, incidence, and severity of AEs | Up to 24 Months After BRL-201 Infusion | 
| RP2D | The recommended phase 2 dose | Within 28 Days After BRL-201 Infusion |