Blinatumomab for CNI-Resistant/Intolerant SRNS in Children

Phase 1

Recruiting

• Conditions: CNI-resistant Steriod Resistant Nephrotic Syndrome; CNI-intolerent; Steriod Resistant Nephrotic Syndrome
• Interventions: Drug: Blinatumomab Treatment

• Registration Number: NCT06607991
• Lead Sponsor: The Children's Hospital of Zhejiang University School of Medicine

Brief Summary

This clinical trial aims to evaluate the safety and effectiveness of Blinatumomab in treating children with calcineurin inhibitor (CNI)-resistant or intolerant, steriod-resistant nephrotic syndrome (SRNS). The study will involve administering a short course of low-dose Blinatumomab to pediatric patients who have not responded to CNI treatments or are unable to tolerate them. The goal is to assess whether Blinatumomab can reduce proteinuria and induce remission in these children, potentially offering a new therapeutic option for those with limited treatment alternatives.

Detailed Description

Nephrotic syndrome (NS) in children is characterized by excessive proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Steroid-resistant nephrotic syndrome (SRNS) occurs in about 15-20% of children with NS, with a poor response to steroid therapy. SRNS can further be complicated by resistance or intolerance to calcineurin inhibitors (CNI), commonly used as first-line therapies. This study aims to explore the use of Blinatumomab, a bispecific T-cell engager targeting CD19-positive B cells, in treating children with CNI-resistant or intolerant hormone-resistant nephrotic syndrome.

The study will follow a single-center, open-label design, enrolling 6 pediatric patients between the ages of 2 and 17. These patients will receive two 5-day courses of low-dose Blinatumomab administered intravenously. Outcomes will include the rate of complete or partial remission of proteinuria, safety assessments, and immune marker analysis. By targeting B cells, Blinatumomab may address the underlying immune dysfunction contributing to disease progression in these patients. The study will also evaluate the safety of short-term Blinatumomab use in this pediatric population.

Study Timeline

• Status Verified: 2024-09
• Study First Submitted: 2024-09-18
• Study Start: 2024-09-19
• Study First Submitted QC: 2024-09-19
• Study First Posted: 2024-09-23
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-04
• Primary Completion: 2025-09-19
• Study Completion: 2027-09-18

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 6

Inclusion Criteria

Subjects must meet all of the following criteria to be included in the study:

1. Age between 2 and 17 years, regardless of gender; 2. Meet the KDIGO 2021 definition of steroid-resistant nephrotic syndrome (SRNS) and have received an adequate dose of CNI for more than 6 months without achieving at least partial remission; or have contraindications or i intolerance to CNI use, including:

2. Significant renal impairment with eGFR < 60 mL/min/1.73 m² or acute kidney injury at the time of diagnosis;

3. Renal biopsy showing significant acute or chronic tubular injury (e.g., tubular atrophy or interstitial fibrosis greater than 50%);

4. Elevated urinary β2-microglobulin, α1-microglobulin, or retinol-binding protein levels greater than three times the upper limit of normal;

5. Impaired glucose tolerance;

6. Severe uncontrolled hypertension (systolic and/or diastolic blood pressure ≥ the 95th percentile +12 mmHg for children of the same sex, age, and height, or ≥140/90 mmHg);

7. Concomitant use of medications that have significant interactions with CNIs, resulting in increased toxicity or decreased efficacy;

8. Known allergy to CNIs or any of their components. 3. Renal biopsy prior to screening confirming a diagnosis of minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS); 4. The subject or legal guardian must agree to participate in the study and sign an informed consent form indicating understanding of the purpose and procedures of the study, with the ability to withdraw consent at any time without affecting future medical care.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from the study:

1. eGFR < 60 mL/min/1.73 m² (using the modified Bedside Schwartz formula);
2. Stroke or seizure within 6 months prior to screening, or other active central nervous system disorders;
3. Genetic nephropathy confirmed by genetic testing;
4. Renal biopsy confirming IgA nephropathy, membranous nephropathy, or membranoproliferative glomerulonephritis;
5. Severe congenital heart disease or history of acute myocardial infarction within 6 months, or severe arrhythmias (e.g., frequent multifocal ventricular or supraventricular tachycardia, ventricular tachycardia), or moderate to large pericardial effusion, severe myocarditis, or unstable vital signs requiring vasopressors to maintain blood pressure;
6. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with hepatitis B virus (HBV) DNA levels above the normal range; positive for hepatitis C virus (HCV) antibodies with HCV RNA levels above the normal range; or positive for human immunodeficiency virus (HIV) antibodies, syphilis, or cytomegalovirus (CMV) DNA;
7. Abnormal laboratory values prior to screening: moderate to severe neutropenia (≤1.0×10⁹/L); moderate to severe anemia (hemoglobin <90 g/L); thrombocytopenia (<75×10⁹/L); or liver dysfunction (ALT, AST, or bilirubin greater than 2.5 times the upper limit of normal and persisting for 2 weeks);
8. Subjects with tumors or other life-threatening diseases prior to screening;
9. Positive blood pregnancy test;
10. Participation in other clinical trials within 1 month prior to enrollment;
11. Received rituximab or cyclophosphamide therapy within the past 3 months;
12. Any other condition deemed by the investigator to be unsuitable for participation;
13. Vaccination with live vaccines within 4 weeks prior to screening.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Blinatumomab Treatment	Blinatumomab Treatment	-

Primary Outcome Measures

Name	Time	Method
Effectiveness and safety of Blinatumomab	with 24 weeks of Blinatumomab treatment	Effectiveness: The primary endpoint is the proportion of patients achieving complete or partial remission within 24 weeks of treatment. Complete remission is defined as a urinary protein/creatinine ratio (UPCR) ≤ 200 mg/g for three consecutive days, while partial remission is defined as a ≥ 50% reduction in proteinuria from baseline with a UPCR between 200 and 2000 mg/g.; Safety: Adverse events (AEs) and serious adverse events (SAEs) will be monitored and classified according to the CTCAE v5.0. This includes events such as cytokine release syndrome, fever, headache, and potential neurotoxicity.

Secondary Outcome Measures

Name	Time	Method
long-term efficacy of Blinatumomab and Immunological Markers	with 52 weeks of Blinatumomab	Secondary Outcome Measures: Long-term Efficacy: Maintenance of remission at 52 weeks will be evaluated, along with the time to remission and the duration of remission.; Immunological Markers: Changes in CD19+ B cell counts, particularly depletion and subsequent recovery of B cell populations, will be monitored.; Recurrence of Disease: The time to first relapse and the proportion of patients who relapse during the 52week follow-up period will be analyzed.

Trial Locations

Locations (1)

Children's Hospital, Zhejiang University School of Medicine; 🇨🇳 Hangzhou, Zhejiang, China