The Safety and Efficacy of CD38 Monoclonal Antibody Monotherapy for CaAMR in Renal Transplantation

Study Overview
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Brief Summary
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Renal transplantation is the best choice for the treatment of end-stage renal disease, but the long-term survival of the graft is still remains a challenge. Chronic antibody-mediated rejection (AMR) is the main factor affecting the long-term survival of the graft. There is still no effective treatment for chronic antibody-mediated rejection, even in the active phase (CaAMR). In recent years, new therapeutic drugs based on the generation of DSA and the mechanism of AMR, including protease inhibitor bortezomi, CD20 monoclonal antibody, C5 monoclonal antibody and IL-6 antibody, have not been able to effectively eliminate and inhibit the generation of DSA, nor have they been proved to have a definite effect on AMR. CD38 is a type II transmembrane protein that is highly expressed on plasma cells and NK cells, which are considered to play a key role in the occurrence and development of AMR. Recently, a few cases have reported that CD38 monoclonal antibody combined plasma exchange and/or IVIG may be an effective strategy for the prevention and treatment of AMR, but the effectiveness and safety of daratumumab monotherapy on CaAMR were unknown. This is a multicenter, prospective, single arm clinical study. The study will enroll 15 renal transplant recipients with positive DSA and CaAMR confirmed by biopsy after renal transplantation. According to inclusion and exclusion criteria patients will be screened to participate in the trial.

Detailed Description
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After successful enrollment, the patient will receive daratumumab of 16mg/kg once every two weeks (0-22 weeks) for a total of 12 times, and continue to receive triple immunosuppressive therapy with prednisone, mycophenolic acid, tacrolimus (target valley concentration of 5-7ng/ml) or cyclosporine (target valley concentration of 100-200ng/ml). Peripheral blood samples were collected from 0 to 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) for routine blood tests, liver and kidney function electrolytes, tacrolimus or cyclosporine trough concentrations, HLA antibody quantification (weeks 0, 4, 8, 12, 16, 20, and 24), infection indicators (weeks 0, 8, and 24), immune status assessments (weeks 0, 4, 8, 12, 16, 20, and 24), and biopsy of transplanted kidneys was performed at 24 weeks to assess pathological changes.

Official Title
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A Multicenter, Prospective, One-arm Clinical Study

Conditions
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Antibody-mediated Rejection, Kidney Tranplant

Intervention / Treatment
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* Drug: Daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary signing of written informed consent Age ≥ 18 years old ≥ 180 days after living donor kidney or DD donor kidney transplantation EGFR ≥ 30mL/min/1.73 m2 (CKD-EPI formula) Pre stored and/or newborn DSA (HLA antibody) Exclusion Criteria: Patients participating in another clinical trial Age less than 18 years old Female subjects are pregnant or breastfeeding, or do not receive appropriate contraceptive measures ABO incompatibility transplantation Kidney transplantation biopsy combined with one of the following results: A. T-cell mediated rejection B. New or recurrent severe thrombotic microangiopathy C. Polyomavirus nephropathy Receive anti acute rejection treatment within 3 months before screening Have been treated with other immunomodulatory monoclonal/polyclonal antibodies (such as CD20 antibody, bortezomib, C5 monoclonal antibody, IL-6/IL-6R antibody) within 3 months Total bilirubin>2 times the upper normal limit, alanine aminotransferase and aspartate aminotransferase>2.5 times the upper normal limit Hemoglobin<8 g/dL Thrombocytopenia: Platelets<100 × 109/L Leukopenia: White blood cells<3 × 109/L, neutropenia: neutrophils<1.5 × 109/L Hypogammaglobulinemia: Serum IgG<400 mg/dL Eliminate active viral, bacterial, or fungal infections Excluding Active Malignant Diseases with Intensive Immunosuppressive Therapy Latent or active tuberculosis Inoculate live vaccine within 6 weeks after screening History of alcohol or illicit drug abuse Serious medical or mental illness that may affect participation in the study Active hepatitis B virus infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Each patient received CD38 monoclonal antibody monotherapy
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patient with CaAMR<br>This is a multicenter, prospective, single arm clinical study. The study will enroll 15 renal transplant recipients with positive DSA and CaAMR confirmed by biopsy after renal transplantation. According to inclusion and exclusion criteria patients will be screened to participate in the trial. | Drug: Daratumumab<br>* After successful enrollment, the patient will receive daratumumab of 16mg/kg once every two weeks (0-22 weeks) for a total of 12 times. Peripheral blood samples were collected from 0 to 24 weeks (weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24) for routine blood tests, liver and kidney function electrolytes, tacrolimus or cyclosporine trough concentrations, HLA antibody quantification (weeks 0, 4, 8, 12, 16, 20, and 24), infection indicators (weeks 0, 8, and 24), immune status assessments (weeks 0, 4, 8, 12, 16, 20, and 24), and biopsy of transplanted kidneys was performed at 24 weeks to assess pathological changes.<br>* Other names: CD38 monoclonal antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of donor specific antibody | Donor specific antibody changed 30% based on luminex HLA testing | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of serum creatinine | Creatinine changed by 30% compared to before treatment or returned to baseline level | 6 months | 
| The change of BANFF score | The change of BANFF score, including c, g, ptc score | 6 months | 
| Incidence of treatment-related adverse events | Adverse event monitoring, assessment of labs, monitoring of viral PCRs | 6 months | 
| The change of NK cell count in PBMC | The change of NK cell count in PBMC collected at multiple time points throughout the study | 6 months |