An Exploratory Study to Evaluate the Safety and Efficacy of Universal STAR-T Cell Injection in Subjects With Autoimmune Kidney Diseases
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Type, severity, and frequency of adverse events (AEs)
研究概览
简要总结
This is an investigator initiated, single-arm, open-label, dose-escalation study to explore the preliminary efficacy, safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the universal STAR-T cell injection which is a CD19 and BCMA bispecific CAR-T cells in patients with autoimmune kidney diseases. Approximately 10-24 adult participants diagnosed as IgA nephropathy and primary membranous nephropathy will be enrolled. Three dose levels (1.5 E6 STAR-T cells/kg, 3.0 E6 STAR-T cells/kg and 4.5 E6 STAR-T cells/kg) will be established in this study, and the universal STAR-T cell will be administered as a single intravenous infusion. A recommended dose will be selected for subsequent dose-expansion studies to evaluate the safety and efficacy of universal STAR-T cell injection in participants with autoimmune kidney diseases based on the safety, PK results, and preliminary efficacy data. This study includes the screening period (D-28 to D-6), pre-clearance treatment and observation period (D-5 to D-1), cell infusion and main study endpoint observation period (D0 to W12 after infusion), and extended follow-up period (W12 to W104).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet all the following inclusion criteria to be enrolled in this study:
- •Age 18-65 years (inclusive), gender (no gender restriction);
- •Previous diagnosis of IgA Nephropathy (IgAN) or Primary Membranous Nephropathy (PMN)：
- •IgA Nephropathy (IgAN): Renal biopsy confirmed as IgAN, and meets any one of the following criteria:
- •Treatment-refractory IgAN: Previously received RAAS inhibitors or SGLT2 inhibitors or endothelin receptor antagonists (ERA) or mineralocorticoid receptor antagonists (MRA) for at least 12 weeks, and combined with/or sequentially added at least one immunosuppressant or biologic agent for ≥3 months, with 24-hour urinary protein ≥1.0 g or 24-hour urine protein/creatinine ratio (UPCR) ≥0.8 g/g;
- •eGFR decreased by ≥50% within the past 3 months, and acute kidney injury (AKI) is excluded;
- •Unable to tolerate conventional treatment, may be considered for enrollment after full evaluation by the investigator.
- •Primary Membranous Nephropathy (PMN): Renal biopsy confirmed as PMN, and anti-phospholipase A2 receptor antibody (anti-PLA2R) is positive, and meets any one of the following criteria for relapsed or refractory PMN:
- •Refractory PMN: Received hormone combined with cyclophosphamide or calcineurin inhibitor (CNI) or rituximab for ≥6 months, and meets any one of the following:(a) Anti-PLA2R persistently high titer >50 RU/mL;(b) Persistent 24-hour urinary protein >3.5 g/d, and reduction <50% during treatment;(c) Unable to tolerate the above immunosuppressive therapy, or discontinued due to severe adverse reactions;
- •Relapsed PMN: After achieving complete remission, 24-hour urinary protein re-increased to >3.5 g/d;
- •Function of vital organs meets the following requirements:
- •Bone marrow function must satisfy:(a) Neutrophil count ≥1.0×10⁹/L (without colony-stimulating factor treatment within 2 weeks prior to testing, except for disease-induced neutropenia);(b) Hemoglobin ≥60 g/L;(c) Platelet count ≥30×10⁹/L;
- •Liver function:(a) ALT ≤3×ULN (elevations due to disease are excluded);(b) AST ≤3×ULN (elevations due to disease are excluded);(c) TBIL ≤1.5×ULN (elevations due to disease are excluded);
- •Kidney function: Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (calculated by CKD-EPI formula);
- •Coagulation function: International Normalized Ratio (INR) ≤1.5×ULN, Prothrombin Time (PT) ≤1.5×ULN;
- •Cardiac function: Hemodynamically stable;
- •Female subjects of childbearing potential and male subjects whose partners are of childbearing potential must agree to use medically accepted contraceptive measures or abstinence during the study and for 24 months after cell infusion; female subjects of childbearing potential must have a negative serum HCG test within 7 days prior to enrollment and must not be lactating:
- •Voluntarily participate in this clinical study and sign the informed consent form.
排除标准
- •Subjects who meet any of the following exclusion criteria will be excluded from this study:
- •Secondary IgAN, secondary membranous nephropathy;
- •Use of immunosuppressive agents with therapeutic effect on the disease within five half-lives prior to cell infusion, or biologics within 4 weeks;
- •History of severe drug allergy or allergic constitution;
- •Uncontrolled or requiring treatment fungal, bacterial, viral, or other infections;
- •Active tuberculosis at screening;
- •Cardiac insufficiency (NYHA functional class >II), unable to tolerate study lymphodepletion and cell reinfusion;
- •Subjects with congenital immunoglobulin deficiency;
- •History of malignant tumor within the past 5 years that has not yet resolved;
- •Positive for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) with peripheral blood HBV DNA titer above the detection limit; positive for hepatitis C virus (HCV) antibody with peripheral blood HCV RNA positive; positive for human immunodeficiency virus (HIV) antibody; positive for syphilis test;
- •Male and female subjects who plan to conceive during the study period or within 24 months after cell infusion;
- •Subjects whom the investigator deems otherwise unsuitable for inclusion in this study.
研究组 & 干预措施
Universal STAR-T Cell
Three dose levels (1.5 E6 STAR-T cells/kg, 3.0 E6 STAR-T cells/kg and 4.5 E6 STAR-T cells/kg) of universal STAR-T cells will be administered to partcipants.
干预措施: Universal STAR-T Cell (Biological)
结局指标
主要结局
Type, severity, and frequency of adverse events (AEs)
时间窗: AEs will be observed until 24 weeks after STAR-T cells injection and extended to 104 weeks.
Characterization of treatment-emergent adverse events (TEAEs) graded by NCI-CTCAE v6.0, including laboratory abnormalities, vital sign changes, and infusion-related reactions.
Incidence of Dose-Limiting Toxicities (DLTs).
时间窗: Within 28 days after START-T cells infusion.
To assess the safety and tolerability of STAR-T cells and determine the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D). DLTs are defined according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v6.0.
Remission rates of IgAN at the week 12 and week 24
时间窗: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively
Remission include complete remission (CR) or partial remission (PR). (1) Complete remission (CR) is defined as 24-hour urine protein \< 0.5 g, or a 24-hour urine protein-to-creatinine ratio (UPCR) \< 0.5 g/g, accompanied by stable renal function which is defined as a decline in estimated glomerular filtration rate (eGFR) of ≤ 15% from baseline. (2) Partial remission (PR) is defined as 24-hour urine protein or 24-hour UPCR not meeting the CR criteria, but demonstrating a reduction of ≥ 50% from baseline.
Remission rates of PMN at the week 12 and week 24
时间窗: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively
Remission include complete remission (CR) or partial remission (PR). (1) Complete remission (CR) is defined as 24-hour urine protein \< 0.5 g, or a 24-hour urine protein-to-creatinine ratio (UPCR) \< 0.5 g/g, accompanied by stable serum creatinine (defined as a fluctuation of ≤ 15% from baseline), and a serum albumin (ALB) level \> 3.5 g/dL (or 35 g/L). (2) Partial remission (PR) is defined as 24-hour urine protein maintained within the range of 0.5-3.5 g, or 24-hour UPCR maintained within the range of 0.5-3.5 g/g, accompanied by a reduction of ≥ 50% from baseline
次要结局
- Changes in 24-hour UPCR from baseline in IgAN and PMN participants(From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively)
- Changes in 24-hour urinary protein excretion from baseline in IgAN and PMN participants(From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively)
- Changes in kidney function from baseline in IgAN and PMN participants(From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively)
- Changes in serum biomarkers from baseline in IgAN participants(From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively)
- Changes in serum biomarkers from baseline in PMN participants(From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively)
- Maximum Plasma Concentration of Universal STAR-T Cells (Cmax)(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.)
- Time to Reach Maximum Plasma Concentration (Tmax) of Universal STAR-T Cells.(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.)
- Area Under the Plasma Concentration-Time Curve (AUC) of Universal STAR-T Cells(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.)
- Change in PD Biomarkers(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.)
- Changes in B cells in peripheral blood(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks)
- Change in plasma cells in peripheral blood(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.)
- Anti-Drug Antibodies (ADA) against universal STAR-T cells(Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks)
研究者
XueQing Yu
MD
Guangdong Provincial People's Hospital