An Exploratory Clinical Study of Anti-CD19 CAR NK Cell (KN5501) in the Treatment of Relapsed/Refractory Immune Nephropathy

Официальное название

An Exploratory Clinical Study of the Safety and Efficacy of Anti-CD19 Chimeric Antigen Receptor NK Cell Injections (KN5501) in the Treatment of Relapsed/Refractory Immune Nephropathy

Обзор

A single arm, open-label pilot study is designed to determine the safety and effectiveness of anti-CD19 CAR NK cell injection (KN5501) in patients with immune nephropathy. 36 patients are planned to be enrolled in the dose-escalation trial. The primary endpoints are DLT and TEAEs. The secondary endpoints are the overall response rates (ORR) and disease control rate (DCR)

Вмешательства

• Биопрепарат anti-CD19 CAR NK cells
  Patients will receive Fludarabine (30 mg/m2 per day) and Cyclophosphamide (300mg/m2 per day) on day -5, -4, and -3. Multiple doses of anti-CD19 CAR NK cells (KN5501) will infused in each group using the "3 + 3" dose-escalation strategy.

Первичные конечные точки

• Incidence of Dose-Limiting Toxicity (DLT) [Срок оценки: up to 48 weeks after infusion]
• Incidence of Treatment Emergent Adverse Events (TEAEs) [Срок оценки: up to 48 weeks after infusion]

Вторичные конечные точки (4)

• The overall response rate (ORR) [Срок оценки: 1, 3, 6, 12 and 12 months after infusion]
• Disease control rate (DCR) [Срок оценки: 1, 3, 6, 12 and 12 months after infusion]
• B cell depletion rate [Срок оценки: 1, 3, 6, 12 and 12 months after infusion]
• B cell reconstitution [Срок оценки: 1, 3, 6, 12 and 12 months after infusion]

Критерии участия

Common Inclusion Criteria:

• Age: ≥ 18 years old and ≤ 70 years old, male or female;
• Positive CD19 expression in peripheral blood B cells as determined by flow cytometry;
• The functions of important organs meet the following requirements:

• Bone marrow hematopoietic function: a. White blood cell count ≥ 3 x 10\^9/L b. Neutrophil count ≥ 1 x 10\^9/L (no colony-stimulating factor treatment within 2 weeks before examination); c. Hemoglobin ≥60g/L.
• Liver function: ALT ≤ 3 x ULN,AST≤3 x ULN, TBIL≤1.5 x ULN(excluding Gilbert syndrome, total bilirubin ≤ 3.0 x ULN)
• Coagulation function: International standardized ratio (INR) ≤ 1.5 x ULN, prothrombin time (PT) ≤1.5 x ULN.
• Cardiac function: good hemodynamic stability, left ventricular ejection fraction (LVEF) ≥55%.
• Female subjects of childbearing potential and male subjects whose partner is a female of childbearing potential are required to use medically approved contraception or abstain from sex for at least 6 months during and at least 6 months after the end of the study treatment period; female subjects of childbearing potential have had a negative serum HCG test within 7 days prior to study enrollment and are not lactating;
• Voluntarily participate in this clinical study, sign an informed consent form, have good compliance, and cooperate with follow-up.

Criteria for Recurrent/refractory primary membranous nephropathy

• Primary membranous nephropathy diagnosed pathologically by renal biopsy;
• Screening period 24-hour urine protein quantification ≥3.5 g;
• Individuals who have not achieved partial remission (PR) after more than 6 months of treatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/or biologics (including but not limited to anti-CD20 monoclonal antibody); or individuals who have relapsed again after achieving complete remission/partial remission (CR/PR) with treatment (24h urine protein quantification ≥3.5g);
• Glomerular filtration rate (eGFR, CKD-EPI formula) ≥45 ml/min/1.73m2 during the screening period.

Criteria for Relapsed/refractory IgA nephropathy

• Primary IgA nephropathy pathologically confirmed by renal biopsy;
• Treated (ACEI/ARB analogs) for at least 3 months;
• Treatment with hormonal and/or cytotoxic drugs, immunosuppressive therapy, and/or biologics (including, but not limited to anti-CD20 monoclonal antibody) for more than 6 months, 24-hour urine protein quantification ≥ 1.0 g; or rapid progression of renal function (≥ 50% decrease in eGFR within 3 months); or relapse after treatment to achieve complete remission/partial remission (CR/PR) (24-hour urine protein quantification ≥ 1.0 g);
• Glomerular filtration rate (eGFR, CKD-EPI formula) ≥30 ml/min/1.73m2 during the screening period.

Criteria for Relapsed/refractory ANCA-associated vasculitis

• Meets 2022 ACR/EULAR diagnostic criteria for ANCA vasculitis, including microscopic polyangiitis, granulomatous polyangiitis, eosinophilic granulomatous polyangiitis;
• Positive ANCA related antibodies (MPO-ANCA or PR3-ANCA positive);
• Renal biopsy pathology consistent with renal damage in ANCA-associated vasculitis;
• The Birmingham Vasculitis Activity Scale (BVAS) is ≥ 15 points (a total score of 63 points), indicating the activity of the vasculitis condition;
• BVAS score includes at least 2 abnormalities in the renal program;
• Definition of relapse/refractory : ineffective conventional treatment or relapse of disease activity after remission. Definition of routine treatment: use of glucocorticoids (more than 1 mg/kg/d) and cyclophosphamide for ≥3 months, and any of the following immunomodulatory drugs: antimalarial drugs, azathioprine, mycophenolate mofetil, methotrexate, leflunomide, tacrolimus, cyclosporine, as well as biological agents such as rituximab and belimumab;
• Glomerular filtration rate (eGFR, CKD-EPI formula) ≥15 ml/min/1.73m2 during the screening period.

Common exclusion Criteria:

• Individuals with known severe allergic reactions, hypersensitivity, contraindication to any medications during the trial (cyclophosphamide, fludarabine, tozumabs), or subjects with a history of severe allergic reactions;
• Existence or suspicion of uncontrollable or treatable fungal, bacterial, viral or other infections;
• Individuals with central nervous system disorders caused by ADs or not caused by ADs (including epilepsy, psychiatric disorders, organic encephalopathy syndromes, cerebrovascular accidents, 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;
• Subjects with malignant tumors (except for non-melanoma skin cancer and in situ cervical, bladder, and breast cancers that have been disease-free for more than 5 years);
• Subjects with end-stage renal failure;
• Subjects with positive hepatitis 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;
• Subjects with mental illness and severe cognitive impairment;
• Subjects who have received other clinical trial treatment within 3 months;
• Pregnant or intending to conceive women;
• In the opinion of the investigator, there are other reasons why subjects cannot be included in this study.

Exclusion Criteria for Recurrent/refractory primary membranous nephropathy

• Secondary membranous nephropathy (e.g., hepatitis B, systemic lupus erythematosus, drug-associated, malignancy-associated, etc.), or in combination with other renal diseases confirmed by renal biopsy;
• Type 1 or type 2 diabetes.

Exclusion Criteria for Relapsed/refractory IgA nephropathy

• Exclude secondary IgA nephropathy, including but not limited to: anaphylactic purpura, ankylosing spondylitis, systemic lupus erythematosus, desiccation syndrome, viral hepatitis, cirrhosis of the liver, rheumatoid arthritis, and mixed connective tissue disease; or in combination with other renal diseases confirmed by renal biopsy;
• Crescentic nephritis (pathologic diagnosis of >50% crescentic bodies), micrognathic nephropathy with IgA deposition, and other specific types of pathologic or clinical renal disease.

Exclusion Criteria for Relapsed/refractory ANCA-associated vasculitis

• Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2;
• If the patient has alveolar hemorrhage invasive lung ventilation is required, estimated to last longer than the screening period.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shanghai Changhai hospital — Шанхай

Идентификаторы

NCT: NCT06469190 · CHEC2024-188

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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