Universal CAR-T Cells (BRL-301) in Relapse or Refractory Autoimmune Diseases

Sponsor

Bioray Laboratories (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05859997

Collaborator

Shanghai Changzheng Hospital (Other)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is an investigator initiated trial to assess the efficacy and safety of BRL-301 in the relapse or refractory autoimmune diseases of China.

Condition or Disease	Intervention/Treatment	Phase
Systemic Lupus Erythematosus (SLE) Sjogren's Syndrome Diffuse Scleroderma Inflammatory Myopathy ANCA Associated Systemic Vasculitis Antiphospholipid Syndrome	Biological: BRL-301	N/A

Detailed Description

This is an investigator initiated trial to assess the efficacy and safety of BRL-301 in the relapse or refractory autoimmune diseases of China.

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Clinical Study on the Safety and Efficacy of Universal CAR-T Cells (BRL-301) in the Treatment of Relapse or Refractory Autoimmune Diseases

Actual Study Start Date :

Apr 17, 2023

Anticipated Primary Completion Date :

Jul 17, 2024

Anticipated Study Completion Date :

Jul 17, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BRL-301 Allogeneic CD19-targeted Chimeric AntigenReceptor (CAR) T Cells	Biological: BRL-301 Single dose of Allogeneic Anti-CD19 CAR T cells will be infused Other Names: Allogeneic Anti-CD19 CAR T cells

Arm

Intervention/Treatment

Experimental: BRL-301

Allogeneic CD19-targeted Chimeric AntigenReceptor (CAR) T Cells

Biological: BRL-301

Single dose of Allogeneic Anti-CD19 CAR T cells will be infused

Other Names:

Allogeneic Anti-CD19 CAR T cells

Outcome Measures

Primary Outcome Measures

The safety of BRL-301 in relapse or refractory autoimmune diseases [12 months]
Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs as assessed by CTCAE v5.0.

Secondary Outcome Measures

The efficiency of BRL-301 in relapse or refractory autoimmune diseases [3 months]
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)
Cellular kinetics [12 months]
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age range from 18 to 65 years old (including threshold), regardless of gender;
Positive expression 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: a. White blood cell count ≥ 3 × 109/L； b. Neutrophil count ≥ 1 × 109/L (no colony-stimulating factor treatment within 2 weeks before examination); c. Hemoglobin ≥ 60g/L; 2) Liver function: ALT ≤ 3 × ULN； AST≤3 × ULN； TBIL≤1.5 × ULN (excluding Gilbert syndrome, total bilirubin ≤ 3.0 × ULN)； 3) Renal function: creatinine clearance rate (CrCl) ≥ 60 ml/minute (Cockcroft/Fault formula); 4) Coagulation function: International standardized ratio (INR) ≤ 1.5 × ULN, prothrombin time (PT) ≤ 1.5 × ULN； 5) Cardiac function: Good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥ 55%; 4. Female subjects with fertility and male subjects whose partners are women of childbearing age are required to use medically approved contraception or abstinence during the study treatment period and at least 6 months after the end of the study treatment period; Female subjects of childbearing age tested negative for serum HCG within 7 days before enrollment in the study and were not in lactation; 5. Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up.

Criteria for SLE:

Complies with the classification standards of the 2019 European Union Against Rheumatology/American Society of Rheumatology (EULAR/ACR) SLE.
In the moderate to severe active phase of the disease, with SLEDAI ⁃ 2000 score>6.
And at least one British Isle Lupus Rating Group Index (BILAG-2004) Class A (severe manifestation) or two Class B (moderate manifestation) organ scores, or both.
Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab.

Criteria for Sjogren's syndrome with thrombocytopenia:

Meets the 2002 AECG criteria for primary Sjogren's syndrome or the 2016 ACR/EULAR classification criteria.
Diagnosed pSS-TP, platelet count<30 × 10^9/L;
Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab.

Criteria for Diffuse Scleroderma:

Meets the classification criteria for scleroderma according to the 2013 ACR, and conforms to diffuse manifestations;
Concomitant interstitial pneumonia: interstitial changes with ground glass like exudate detected by chest HRCT, and FVC or DLCO<70% predicted value in lung function testing;
Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab.
Definition of progressiveness: a) Definition of skin progression: mRSS increases by>10%; b) The definition of lung disease progression: a 10% decrease in FVC, or a 5% decrease in FVC accompanied by a 15% decrease in DLCO (OMERACT progression).

Criteria for Inflammatory Myopathy:

Classification criteria for inflammatory myopathy in accordance with 2017 EULAR/ACR (including DM, PM, ASS, and NM);
For those with muscle involvement, the MMT-8 score is lower than 142 and at least two abnormalities are found in the following five core measurements (PhGA, PtGA, or extramuscular disease activity score ≥ 2 points; total HAQ score ≥ 0.25; muscle enzyme levels are 1.5 times the upper limit of the normal range) ;
Myositis antibody positive;
Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab.
Progressive definition: rapid progression of interstitial pneumonia in a short period of time;

Criteria for ANCA Associated Vasculitis:

Meets the diagnostic criteria for ANCA vasculitis in 2022ACR/EULAR, including microscopic polyangitis, granulomatous polyangitis, and eosinophilic granulomatous polyangitis.
Positive ANCA related antibodies (MPO-ANCA or PR3-ANCA positive);
The Birmingham Vasculitis Activity Scale (BVAS) is ≥ 15 points (a total score of 63 points), indicating the activity of the vasculitis condition;
There must be at least one main item, at least three secondary items, or at least two renal items, hematuria and proteinuria, in the BVAS evaluation;
Ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: Use of glucocorticoids (above 1mg/Kg/d) and cyclophosphamide, as well as any of the following immunomodulatory drugs for more than 6 months: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab.

Criteria for Antiphospholipid syndrome:

Meets the diagnostic criteria for primary antiphospholipid syndrome revised in Sydney in 2006;
Positive phospholipid antibodies with medium to high titers (IgG/IgM for LA, B2GP1, or acL, tested more than twice within 12 weeks);
Use warfarin anticoagulation or replace the standard treatment of vitamin K antagonist (i.e. maintain the INR required for treatment) or use the standard treatment dose of low molecular weight heparin (LMWH), as well as use of hormones and cyclophosphamide to treat relapse thrombosis;
Catastrophic antiphospholipid syndrome requires the following four criteria: (1) involving three or more organs, systems, and/or tissues; (2) Symptoms appear within 1 week; (3) Histologically confirmed obstruction of small blood vessels in at least one organ or tissue; (4) APL positive;

Exclusion Criteria:

Individuals with a history of severe drug allergies or allergic constitution;
Existence or suspicion of uncontrollable or treatable fungal, bacterial, viral or other infections;
Patients with central nervous system disease diseases caused by or not caused by ADs (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;
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;
The researchers believe that there are other reasons why subjects cannot be included in this study.