Universal CAR-T Cells (BRL-301) in Refractory Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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This is an investigator initiated trial to assess the efficacy and safety of BRL-301 in the refractory systemic lupus erythematosus.

Detailed Description
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The study had the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Follow-up.

Official Title
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A Clinical Study on the Safety and Efficacy of BRL-301 (Allogeneic Chimeric Antigen Receptor T Cell Injection Targeting CD19 Gene) in the Treatment of Refractory Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus (SLE)

Intervention / Treatment
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* Biological: BRL-301


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range from 18 to 65 years old (including threshold), regardless of gender; Subjects diagnosed with SLE according to the 2019 EULAR/ACR SLE classification criteria; ANA ≥ 1:80, or positive for anti dsDNA and/or anti Sm antibodies; Routine treatment is ineffective or the disease relapses after remission. Definition of routine treatment: use more than two drugs, including glucocorticoid (more than 1mg/kg/d) and Cyclophosphamide, and any one or more of the following immunomodulatory drugs for more than 6 months: Antimalarial medication, Azathioprine, mycophenolate mofetil, methotrexate, leflunomide, Tacrolimus, Ciclosporin, and biological agents, including rituximab, belizumab, or telitacicept At least one BILAG2004 Class A or two Class B score, or both; SELENA-SLEDAI score ≥ 8 points; The positive expression and expression rate of CD19 on peripheral blood B cells determined by flow cytometry; The functions of important organs meet the following requirements: Bone marrow function needs to meet: White blood cell count ≥ 3 × 109/L; Neutrophil count ≥ 1 × 109/L (no Colony-stimulating factor treatment within 2 weeks before examination); Platelets ≥ 50 × 109/L;d. Hemoglobin ≥ 80g/L Liver function: Alanine Aminotransferase (ALT) ≤ 3 × ULN; Asparagus cochinchinensis transase (AST) ≤ 3 × ULN; Total Bilirubin (TBIL) in serum ≤ 1.5 × ULN (excluding Gilbert syndrome, total bilirubin ≤ 3.0 × ULN); Renal function: Creatinine Clearance Rate (CrCl) ≥ 60 ml/minute (Cockcroft/Fault formula) ; Coagulation function: International Normalized Ratio (INR) ≤ 1.5 × ULN, Prothrombin time (PT) ≤ 1.5 × ULN. Cardiac function: good hemodynamic stability, left ventricular Ejection fraction (LVEF) ≥ 55%; Female patients of childbearing potential and male patients whose female sexual partners are of childbearing age should adopt medically recognized contraceptive measures or abstain from sex within at least 6 months after infusion of BRL-301; female patients of childbearing age should have a negative serum HCG test result within 7 days before study enrollment and be not breastfeeding; Willing to participate in this clinical study, sign an ICF, and complete follow-ups, with good compliance. Exclusion Criteria: Have a serious history of Drug allergy or allergic constitution; Fungi, bacteria, viruses, or other infections that are uncontrollable or require intravenous medication treatment exist or are suspected; Central nervous system disease caused by SLE or not (including epilepsy, psychosis, organic encephalopathy syndrome, cerebrovascular accident, encephalitis, central nervous system Vasculitis); Individuals with relatively serious heart diseases, such as angina pectoris, myocardial infarction, heart failure, and arrhythmia; Subjects with congenital immunoglobulin deficiency; Other malignant tumors (excluding non Melanoma skin cancer, cervical cancer in situ, bladder cancer cancer and breast cancer that have survived for more than 5 years without disease); Subjects with end-stage renal failure; Have received any of the following SLE treatments: Corticosteroid (defined as prednisone or equivalent>20 mg/day) of therapeutic dose were used before enrollment or within 72 hours before BRL-301 infusion. Use any other clinical study drugs for SLE within 4 weeks prior to enrollment. However, if the research treatment period is ineffective or the disease progresses, and at least 3 half-lives have passed before enrollment, enrollment is allowed. Had received anti CD20 monoclonal antibody (such as Rituximab) within 4 weeks before screening, tetaximab within 6 weeks, or belizumab within 12 weeks. Previous CAR-T cell or other genetically modified T Cell therapy. Subjects with positive hepatitis B B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and HBV DNA titer in peripheral blood higher than the upper limit of detection; Patients with positive hepatitis C virus (HCV) antibodies and positive peripheral blood HCV RNA; People who are positive for human immunodeficiency virus (HIV) antibodies; Those who have tested positive for syphilis; Having mental illness and severe cognitive impairment; Those who have participated in other clinical trials within the first 3 months of enrollment; Pregnant or intending to conceive women; Patients who are unsuitable for being included into this study as deemed by the investigator due to other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BRL-301<br>Allogeneic CD19-targeted Chimeric AntigenReceptor (CAR) T Cells | Biological: BRL-301<br>* Single dose of Allogeneic Anti-CD19 CAR T cells will be infused<br>* Other names: Allogeneic Anti-CD19 CAR T cells;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of BRL-301 in refractory systemic lupus erythematosus | Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs as assessed by CTCAE v5.0. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficiency of BRL-301 in refractory systemic lupus erythematosus | Number of patients with SRI-4 response: including SELENA-SLEDAI ≥4-Point improvement, BILAG 2004 with No new A domain score AND no more than 1 new B domain scores, PGA with No worsening (<0.3-point increase) | 3 months | 
| Cellular kinetics | CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood | 12 months |