Universal STAR-T Cell Injection in Autoimmune Kidney Diseases

Official title

An Exploratory Study to Evaluate the Safety and Efficacy of Universal STAR-T Cell Injection in Subjects With Autoimmune Kidney Diseases

Overview

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).

Interventions

• Biological Universal STAR-T Cell
  There are three dose levels of STAR-T cells injection(1.5 E6 STAR-T cells/kg, 3.0 E6 STAR-T cells/kg and 4.5 E6 STAR-T cells/kg) .

Primary outcome measures

• Type, severity, and frequency of adverse events (AEs) [Time frame: AEs will be observed until 24 weeks after STAR-T cells injection and extended to 104 weeks.]
• Incidence of Dose-Limiting Toxicities (DLTs). [Time frame: Within 28 days after START-T cells infusion.]
• Remission rates of IgAN at the week 12 and week 24 [Time frame: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively]
• Remission rates of PMN at the week 12 and week 24 [Time frame: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively]

Secondary outcome measures (12)

• Changes in 24-hour UPCR from baseline in IgAN and PMN participants [Time frame: 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 [Time frame: 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 [Time frame: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively]
• Changes in serum biomarkers from baseline in IgAN participants [Time frame: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively]
• Changes in serum biomarkers from baseline in PMN participants [Time frame: From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively]
• Maximum Plasma Concentration of Universal STAR-T Cells (Cmax) [Time frame: 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. [Time frame: 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 [Time frame: Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.]
• Change in PD Biomarkers [Time frame: Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.]
• Changes in B cells in peripheral blood [Time frame: Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks]
• Change in plasma cells in peripheral blood [Time frame: Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks.]
• Anti-Drug Antibodies (ADA) against universal STAR-T cells [Time frame: Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks]

Eligibility criteria

Inclusion criteria

• 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:

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• 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; 4. 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: 5. Voluntarily participate in this clinical study and sign the informed consent form.

Exclusion criteria

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Guangdong Provincial People's Hospital. — Guangdong

Identifiers

NCT: NCT07746453 · YTS209-004

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗