IgA Nephropathy (IgAN), Primary Membranous Nephropathy
Conditions
Keywords
IgA Nephropathy, Primary Membranous Nephropathy, CD 19, BCMA, Safety, Efficacy
Brief summary
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
BIOLOGICALUniversal 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) .
Sponsors
Guangdong Provincial People's Hospital
China Immunotech (Beijing) Biotechnology Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must meet all the following inclusion criteria to be enrolled in this study: 1. Age 18-65 years (inclusive), gender (no gender restriction); 2. 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: 1. 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; 2. eGFR decreased by ≥50% within the past 3 months, and acute kidney injury (AKI) is excluded; 3. 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: 1. 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; 2. Relapsed PMN: After achieving complete remission, 24-hour urinary protein re-increased to \>3.5 g/d; 3. Function of vital organs meets the following requirements: <!-- --> 1. 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; 2. 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); 3. Kidney function: Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² (calculated by CKD-EPI formula); 4. Coagulation function: International Normalized Ratio (INR) ≤1.5×ULN, Prothrombin Time (PT) ≤1.5×ULN; 5. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Type, severity, and frequency of adverse events (AEs) | 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). | 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 | 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 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 24-hour urine sample will be collected and UPCR will be measured. |
| 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 | 24-hour urine sample will be collected and urinary protein excretion will be measured. |
| 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 | eGFR will be measured to evaluate kidney fucntion |
| Changes in serum biomarkers from baseline in IgAN participants | From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively | Biomarkers include serum albumin, Gd-IgA1, C3, C4 and Immunoglobulins. |
| Changes in serum biomarkers from baseline in PMN participants | From enrollment to the end of treatment at 12 weeks and 24 weeks, respectively | Biomarkers include serum albumin, anti-PLA2R, C3, C4 and Immunoglobulins. |
| Maximum Plasma Concentration of Universal STAR-T Cells (Cmax) | Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks. | To evaluate the maximum observed plasma concentration of Universal STAR-T Cells |
| 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. | To evaluate the time to reach the maximum observed plasma concentration of Universal STAR-T Cells. |
| 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. | To evaluate the total systemic exposure to Universal STAR-T Cells over time. |
| Change in PD Biomarkers | Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks. | PD Biomarkers include serum serum cytokine concentrations, such as IL-1β, IL-2、IL-6, IL-8, TNF-α, and IFN-γ, using validated ELISA kits |
| Changes in B cells in peripheral blood | Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks | Evaluation of PD effects of Universal STAR-T Cells via serial quantification of CD19-positive B cells in peripheral blood, expressed as cells per microliter (cells/μL). Measurement will be performed using flow cytometry according to standardized laboratory protocols |
| Change in plasma cells in peripheral blood | Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks. | Evaluation of PD effects of Universal STAR-T Cells via serial quantification of plasma cells in peripheral blood, expressed as cells per microliter (cells/μL). Measurement will be performed using flow cytometry according to standardized laboratory protocols.T |
| Anti-Drug Antibodies (ADA) against universal STAR-T cells | Up to 24 weeks (Core Analysis Period); Extended observation up to 104 weeks | To evaluate the development of anti-drug antibodies (ADA) against allogeneic universal STAR-T cells in peripheral blood |
Countries
China
Contacts
CONTACTXueqing Yu, MD
CONTACTLi Fan, MD
Outcome results
None listed