Safety and Efficacy of BiTE in Desensitization Therapy for Highly Sensitized Kidney Transplant Candidates With cPRA ≥ 90%
试验速览
- 阶段
- 4 期
- 状态
- 尚未招募
- 入组人数
- 20
- 主要终点
- Percentage of participants achieving the predefined composite desensitization response
研究概览
简要总结
This study is a prospective, open-label, two-arm exploratory clinical trial aimed at evaluating the safety and efficacy of Bispecific T-cell Engager (BiTE) therapies in refractory, highly sensitized kidney transplant candidates. Patients with end-stage renal disease (ESRD) who have a calculated panel reactive antibody (cPRA) ≥ 90% and have waited for a transplant for over 5 years, despite receiving standard desensitization therapies (e.g., IVIG, plasmapheresis, rituximab), will be enrolled.
A total of 20 participants will be randomized in a 1:1 ratio to receive either Blinatumomab (a CD19×CD3 BiTE) or Teclistamab (a BCMA×CD3 BiTE). The primary objective is to evaluate the desensitization response rate, defined as the reduction of cPRA to < 20% or by ≥ 50% from baseline, assessed at multiple time points up to 1 year post-treatment. Secondary objectives include assessing the safety profile (such as the incidence of Cytokine Release Syndrome [CRS] and neurotoxicity), the extent of CD19+ B cell depletion, and the proportion of participants who successfully undergo kidney transplantation within 1 year.
详细描述
Background:
Kidney transplantation is the optimal treatment for end-stage renal disease (ESRD). However, highly sensitized patients with a calculated panel reactive antibody (cPRA) ≥ 90% face significant barriers to finding a compatible donor and have a higher risk of antibody-mediated rejection (AMR). Standard desensitization protocols, primarily utilizing intravenous immunoglobulin (IVIG) and plasmapheresis (PLEX), often fail to achieve long-term reductions in human leukocyte antigen (HLA) antibodies because they do not adequately deplete memory B cells and long-lived plasma cells. Bispecific T-cell Engagers (BiTEs) such as Blinatumomab (CD19×CD3) and Teclistamab (BCMA×CD3) directly recruit endogenous T cells to eliminate B cells and plasma cells, respectively. This study investigates whether these targeted therapies can provide a deeper and more sustained desensitization for refractory transplant candidates, bridging them to a successful transplant.
Study Design:
This is a single-center, prospective, non-blinded, two-arm exploratory trial conducted at West China Hospital, Sichuan University. Twenty eligible patients will be enrolled and randomly assigned (1:1) via block randomization (block size of 4) to either the Blinatumomab arm or the Teclistamab arm.
Interventions:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Male or female participants aged 18 to 65 years.
- •Diagnosis of end-stage kidney disease and being evaluated for or awaiting kidney transplantation.
- •Calculated panel-reactive antibody level (cPRA) ≥90% and a kidney transplant waiting time of ≥5 years.
- •Previous treatment with a conventional desensitization regimen based on intravenous immunoglobulin and/or plasma exchange, with or without rituximab, with traceable medical records.
- •Persistent cPRA ≥90% or unacceptable HLA antibodies after conventional desensitization, resulting in failure to meet the immunological criteria for kidney transplantation.
- •Adequate nonrenal organ function to tolerate the study treatment, including left ventricular ejection fraction >50%, resting oxygen saturation >94%, AST and ALT <3 times the upper limit of normal, total bilirubin <34.2 μmol/L, and no active infection.
- •Ability to understand the study procedures, provide written informed consent, and comply with study treatment and follow-up requirements.
排除标准
- •Inability to understand or comply with the study protocol or follow-up schedule.
- •Known or suspected hereditary complement deficiency.
- •Clinically significant central nervous system disease, including epilepsy, psychotic disorder, organic brain syndrome, cerebrovascular accident, encephalitis, central nervous system vasculitis, or cranial neuropathy requiring intervention.
- •AST, ALT, or GGT >3 times the upper limit of normal, or alkaline phosphatase or total bilirubin >1.5 times the upper limit of normal.
- •Acute myocardial infarction or unstable angina within 6 months before screening, severe cardiac arrhythmia, or New York Heart Association class III or IV heart failure.
- •Uncontrolled acute or chronic disease unrelated to end-stage kidney disease that may impair tolerance to study treatment.
- •Active or uncontrolled infection requiring systemic treatment.
- •Human immunodeficiency virus infection or uncontrolled active hepatitis B or hepatitis C infection.
- •Participation in another interventional clinical study within 3 months before screening or planned concurrent participation in another interventional study.
- •Previous treatment with another T-cell engager or bispecific T-cell-redirecting therapy.
- •Known severe hypersensitivity to blinatumomab, teclistamab, or any of their excipients.
- •Active malignancy.
- •Pregnancy, breastfeeding, or planned pregnancy during the study period.
- •Previous bone marrow transplantation, hematopoietic stem cell transplantation, or solid-organ transplantation other than kidney transplantation.
- •Receipt of a live vaccine within 30 days before screening or planned receipt of a live vaccine during study treatment.
- •Any other clinically significant condition that, in the investigator's judgment, may increase participant risk, interfere with study procedures, or affect safety or efficacy assessments.
结局指标
主要结局
Percentage of participants achieving the predefined composite desensitization response
时间窗: At baseline and at 1, 2, 3, 6, and 12 months after treatment
A composite desensitization response is defined as meeting at least one of the following criteria: 1. cPRA decreases to \<20%; 2. cPRA decreases by ≥50% from baseline; 3. a previously positive HLA antibody becomes negative, defined as an MFI \<1,000; or 4. the MFI of a persistent HLA antibody decreases by ≥50% from baseline or reaches the prespecified threshold. The number and percentage of participants achieving the composite response will be reported at Months 1, 2, 3, 6, and 12 after treatment. (HLA class I and II antibodies and their mean fluorescence intensity will be assessed using a single-antigen bead assay. Calculated panel-reactive antibody levels will be determined based on the unacceptable HLA antigen profile. At each prespecified assessment timepoint, participants will be classified as responders or nonresponders, and the percentage of responders will be reported.)
次要结局
- Percentage reduction from baseline in calculated panel-reactive antibody level(At baseline and at 1, 2, 3, 6, and 12 months after treatment)
- Absolute change from baseline in calculated panel-reactive antibody level(At baseline and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class I antibodies(At baseline and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in the maximum mean fluorescence intensity of unacceptable HLA class II antibodies(At baseline and at 1, 2, 3, 6, and 12 months after treatment)
- Number of participants receiving kidney transplantation within 12 months after treatment(Within 12 months after the first administration of study treatment)
- Change from baseline in peripheral blood CD19-positive B-cell absolute count(At baseline, at protocol-specified assessments during treatment, and at 1, 2, 3, 6, and 12 months after treatment)
- Number of participants achieving peripheral blood CD19-positive B-cell depletion(During treatment and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in peripheral blood CD3-positive T-cell absolute count(At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in peripheral blood CD4-positive T-cell absolute count(At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in peripheral blood CD8-positive T-cell absolute count(At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment)
- Change from baseline in peripheral blood CD3-negative CD16-positive and/or CD56-positive natural killer cell absolute count(At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment)
- Number of participants with cytokine release syndrome as assessed by the ASTCT consensus grading criteria(From the first dose through 30 days after the last dose)
- Number of participants with immune effector cell-associated neurotoxicity syndrome as assessed by the ASTCT consensus grading criteria(From the first dose through 30 days after the last dose)
- Number of participants with treatment-emergent infections(From the first dose through 12 months after treatment)
- Number of participants with serious adverse events(From the first dose through 12 months after treatment)
- Number of participants with neutropenia as assessed by CTCAE version 5.0(From the first dose through 12 months after treatment)
研究者
Turun Song
Associate Chief Physician
West China Hospital