Safety and Efficacy of BiTE in Desensitization Therapy for Highly Sensitized Kidney Transplant Candidates With cPRA ≥ 90%
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.
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
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:
Arm 1 (Blinatumomab): Administered intravenously. Cycle 1 consists of 9 µg/day for 4 consecutive days (Days 1-4). Following a 7-day interval, Cycle 2 consists of 9 µg/day for another 4 consecutive days (Days 12-15).
Arm 2 (Teclistamab): Administered subcutaneously using a step-up dosing schedule to mitigate Cytokine Release Syndrome (CRS) risk. Cycle 1 involves 0.06 mg/kg on Day 1 and 0.3 mg/kg on Day 2. Following a 7-day interval, Cycle 2 involves a target dose of 1.5 mg/kg on Day 10.
Study Objectives & Endpoints:
Primary Endpoint: Desensitization response rate evaluated at 1, 2, 3, 6, and 12 months post-treatment. A positive response is defined as a reduction of cPRA from >90% to <20% (or a ≥50% decrease from baseline), or the conversion of positive HLA antibodies to negative, or a ≥50% reduction in Mean Fluorescence Intensity (MFI) to a predefined threshold.
Secondary Endpoints:
Safety and tolerability, including the incidence and severity of CRS, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), infections, and neutropenia.
Changes in peripheral blood lymphocyte subsets, with a specific focus on CD19+ B cell depletion and recovery trends.
Duration of sustained low cPRA levels. Proportion of patients receiving a kidney transplant within 1 year.
Safety Monitoring:
Given the mechanism of action of BiTEs, strict monitoring for adverse events like CRS and ICANS is integrated into the protocol, utilizing ASTCT consensus grading standards. Treatment algorithms for managing severe events (e.g., using tocilizumab or corticosteroids) are predefined. An independent Data and Safety Monitoring Board (DSMB) consisting of multidisciplinary experts will oversee the study. The protocol includes strict stopping rules for severe toxicities, such as ≥ Grade 3 CRS/ICANS refractory to standard treatment, severe infections, or treatment-related mortality, to ensure patient safety throughout the trial.
Type d'étude
Inscription (Estimé)
Phase
- Phase 4
Contacts et emplacements
Coordonnées de l'étude
- Nom: Chenliang Xu, Master of Clinical Medicine
- Numéro de téléphone: +86 17208274528
- E-mail: fancyplain@163.com
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
La description
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: Bispecific T cell engager treatment group1：Blinatumomab group
BiTE (CD19 x CD3 Bispecific Antibody)
|
Blinatumomab is a CD19×CD3 bispecific T-cell engager (BiTE) administered via intravenous infusion.
This intervention utilizes a specific low-dose, short-course exploratory regimen tailored for non-oncology kidney transplant candidates to safely deplete B cells and reduce HLA antibodies.
The treatment consists of two cycles separated by a 7-day interval.
In Cycle 1 (Days 1-4), patients receive a continuous infusion of 9 µg/day for 4 consecutive days, with a total target dose of 35 µg for the cycle.
Following the 7-day interval, Cycle 2 (Days 12-15) is administered with the identical regimen of 9 µg/day for 4 consecutive days.
|
|
Expérimental: Bispecific T cell engager treatment group2：Teclistamab group
BiTE (BCMA x CD3 Bispecific Antibody)
|
Teclistamab is a BCMA×CD3 bispecific T-cell engager (BiTE) administered via subcutaneous injection.
To mitigate the early risk of cytokine release syndrome (CRS), this intervention employs a strictly defined step-up dosing schedule.
The treatment involves two cycles separated by a 7-day interval.
Cycle 1 (Days 1-2) begins with a step-up dose of 0.06 mg/kg on Day 1, followed by 0.3 mg/kg on Day 2. After the 7-day interval, Cycle 2 (Days 10-11) is initiated, during which a target dose of 1.5 mg/kg is administered on Day 10.
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Percentage of participants achieving the predefined composite desensitization response
Délai: 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:
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.) |
At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Percentage reduction from baseline in calculated panel-reactive antibody level
Délai: At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
Percentage reduction will be calculated as: (Baseline cPRA - cPRA at the assessment timepoint) / baseline cPRA × 100%. A positive value indicates a reduction, whereas a negative value indicates an increase.HLA antibodies will be assessed using a single-antigen bead assay, and cPRA will be calculated based on unacceptable HLA antigens. The percentage reduction from baseline will be calculated at each assessment timepoint. |
At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
|
Absolute change from baseline in calculated panel-reactive antibody level
Délai: At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
Absolute change will be calculated as cPRA at the assessment timepoint minus baseline cPRA. A negative value indicates a reduction from baseline. Results will be reported separately at Months 1, 2, 3, 6, and 12. HLA antibody specificities will be determined using a single-antigen bead assay. cPRA will be calculated based on prespecified unacceptable HLA antigens and the HLA antigen frequencies of the reference donor population. The absolute difference between cPRA at each assessment and baseline cPRA will be calculated. |
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
Délai: At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
The change will be calculated as the maximum MFI at each assessment minus the baseline maximum MFI. A negative value indicates a reduction in HLA class I antibody strength. Maximum MFI will be used as the prespecified participant-level summary when multiple antibody specificities are present. HLA-A, HLA-B, and HLA-C antibodies will be measured using a single-antigen bead assay. For each participant, the highest MFI among all baseline unacceptable HLA class I antibody specificities will be identified, and the MFI of the same antibody specificity will be followed at each assessment. |
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
Délai: At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
Change will be calculated as the maximum MFI at each assessment minus the baseline maximum MFI. A negative value indicates a reduction in antibody strength. HLA-DR, HLA-DQ, and HLA-DP antibodies will be measured using a single-antigen bead assay. The highest MFI among all baseline unacceptable HLA class II antibody specificities will be identified for each participant, and the same antibody specificity will be followed over time. |
At baseline and at 1, 2, 3, 6, and 12 months after treatment
|
|
Number of participants receiving kidney transplantation within 12 months after treatment
Délai: Within 12 months after the first administration of study treatment
|
The number of participants who undergo kidney transplantation within 12 months after the first administration of study treatment will be reported. Participants who receive a donor offer or matching assessment without undergoing transplantation will not be counted. Kidney transplantation will be confirmed using transplant waiting-list records, donor-matching information, crossmatch results, hospitalization records, and operative records. |
Within 12 months after the first administration of study treatment
|
|
Change from baseline in peripheral blood CD19-positive B-cell absolute count
Délai: At baseline, at protocol-specified assessments during treatment, and at 1, 2, 3, 6, and 12 months after treatment
|
Change will be calculated as the CD19-positive B-cell absolute count at each assessment minus the baseline count. The magnitude of B-cell reduction, nadir, and recovery pattern will be evaluated. Peripheral blood CD19-positive B-cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: During treatment and at 1, 2, 3, 6, and 12 months after treatment
|
CD19-positive B-cell depletion is defined as an absolute peripheral blood CD19-positive B-cell count <10 cells/μL. The number of participants meeting the depletion criterion at each assessment will be reported. Peripheral blood CD19-positive B-cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment
|
Change will be calculated as the CD3-positive T-cell absolute count at each assessment minus the baseline count. Peripheral blood CD3-positive T-cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment
|
Change from baseline in the CD4-positive T-cell absolute count will be calculated at each assessment. Peripheral blood CD4-positive T-cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment
|
Change from baseline in the CD8-positive T-cell absolute count will be calculated at each assessment. Peripheral blood CD8-positive T-cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: At baseline, during treatment, and at 1, 2, 3, 6, and 12 months after treatment
|
Change from baseline in natural killer cell absolute count will be calculated at each assessment. Peripheral blood CD3-negative CD16-positive and/or CD56-positive natural killer cell absolute counts will be measured using multiparameter flow cytometry. |
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
Délai: From the first dose through 30 days after the last dose
|
The number of participants experiencing at least one CRS event will be reported. Each participant will be summarized according to the maximum CRS grade experienced during the study. Time to onset, duration, management, and outcome will also be recorded. CRS will be diagnosed and graded according to the ASTCT consensus grading criteria based on fever, hypotension, vasopressor requirement, and oxygen requirement. |
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
Délai: From the first dose through 30 days after the last dose
|
The number of participants experiencing at least one ICANS event will be reported. Each participant will be summarized according to the maximum ICANS grade, with clinical manifestations, onset, duration, management, and outcome recorded. ICANS will be assessed using neurological examination, the Immune Effector Cell-Associated Encephalopathy score, and electroencephalography or neuroimaging when clinically indicated. Events will be graded according to the ASTCT criteria. |
From the first dose through 30 days after the last dose
|
|
Number of participants with treatment-emergent infections
Délai: From the first dose through 12 months after treatment
|
The number of participants experiencing at least one infection will be reported. Infection site, pathogen, maximum CTCAE grade, opportunistic infection status, requirement for intravenous anti-infective treatment or hospitalization, and outcome will be recorded. Infections will be identified based on clinical manifestations, physical examination, microbiological testing, culture, imaging, and laboratory findings, and will be graded according to CTCAE version 5.0. |
From the first dose through 12 months after treatment
|
|
Number of participants with serious adverse events
Délai: From the first dose through 12 months after treatment
|
Serious adverse events include events resulting in death, life-threatening events, hospitalization or prolonged hospitalization, persistent or significant disability, and other medically important serious events. The number of participants with at least one serious adverse event will be reported. Serious adverse events will be collected through participant reports, clinical observation, hospitalization records, physical examinations, and laboratory assessments and will be classified according to standard serious adverse event criteria. |
From the first dose through 12 months after treatment
|
|
Number of participants with neutropenia as assessed by CTCAE version 5.0
Délai: From the first dose through 12 months after treatment
|
The number of participants with at least one post-treatment absolute neutrophil count below the laboratory lower limit of normal will be reported. Each participant will be summarized according to the maximum CTCAE grade. Absolute neutrophil count will be measured using complete blood counts, and neutropenia will be graded according to CTCAE version 5.0. |
From the first dose through 12 months after treatment
|
Collaborateurs et enquêteurs
Parrainer
Publications et liens utiles
Publications générales
- Leon J, Aubert O, Devriese M, Alameda F, Charbonnier S, Fourgeaud J, Blein T, Nguyen TN, Troger A, Chhun S, Roelens M, Usureau C, Gons C, Roger C, Burger C, Le Stang MB, Cotteret C, Timsit MO, Fillatreau S, Rabant M, Taupin JL, Talbot A, Suarez F, Anglicheau D, Zuber J. B-cell maturation antigen-Targeted T-cell Engager Therapy Combined with B-cell Depletion for Treatment of Refractory HLA Sensitization. Kidney Int. 2026 Jun;109(6):1148-1154. doi: 10.1016/j.kint.2026.01.020. Epub 2026 Feb 13.
- Chandramohan D, Adisa O, Patel D, Ware E, Eleti N, Agarwal G. Outcomes of Kidney Transplantation in Highly HLA-Sensitized Patients Treated with Intravenous Immuno-Globulin, Plasmapheresis and Rituximab: A Meta-Analysis. Life (Basel). 2024 Aug 10;14(8):998. doi: 10.3390/life14080998.
- Anwar IJ, DeLaura IF, Gao Q, Ladowski J, Jackson AM, Kwun J, Knechtle SJ. Harnessing the B Cell Response in Kidney Transplantation - Current State and Future Directions. Front Immunol. 2022 Jun 9;13:903068. doi: 10.3389/fimmu.2022.903068. eCollection 2022.
- Subklewe M, Magno G, Gebhardt C, Bucklein V, Szelinski F, Arevalo HJR, Hanel G, Dorner T, Zugmaier G, von Bergwelt-Baildon M, Skapenko A, Schulze-Koops H. Application of blinatumomab, a bispecific anti-CD3/CD19 T-cell engager, in treating severe systemic sclerosis: A case study. Eur J Cancer. 2024 Jun;204:114071. doi: 10.1016/j.ejca.2024.114071. Epub 2024 Apr 22.
- Bucci L, Hagen M, Rothe T, Raimondo MG, Fagni F, Tur C, Wirsching A, Wacker J, Wilhelm A, Auger JP, Pachowsky M, Eckstein M, Alivernini S, Zoli A, Kronke G, Uderhardt S, Bozec A, D'Agostino MA, Schett G, Grieshaber-Bouyer R. Bispecific T cell engager therapy for refractory rheumatoid arthritis. Nat Med. 2024 Jun;30(6):1593-1601. doi: 10.1038/s41591-024-02964-1. Epub 2024 Apr 26.
- Bhoj VG, Kaminski M, Zhao H, Jackson K, Wang W, Liu C, Montgomery RA, Ali N, Mangiola M, Spitzer TR, Safa K, Pattanayak V, Taj R, Chiu J, Bui TM, Sonnenberg EM, Markmann JF, Milone MC, June CH, Siegel DL, Fraietta JA, Gonzalez V, Locci M, Palmer M, Monos D, Hwang WT, Sledge T, Bridges ND, Goldstein JS, Odim J, Sweet SC, Besharatian BD, Hussain SM, Brown NK, Kamoun M, Garfall AL, Naji A. Kidney Transplantation in Two Highly Sensitized Candidates after CAR T-Cell Therapy. N Engl J Med. 2026 Jun 4;394(21):2117-2125. doi: 10.1056/NEJMoa2513428.
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Estimé)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- WestChina-BITE-KT
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Informations sur les médicaments et les dispositifs, documents d'étude
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