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

A Multicenter, Prospective, One-arm Clinical Study

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.

Study Overview

• Status: Recruiting
• Conditions: Antibody-mediated Rejection; Kidney Tranplant
• Intervention / Treatment: Drug: Daratumumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jianyong Wu, MD; Phone Number: 86-571-87236189; Email: wujianyong1964@zju.edu.cn
• Study Contact Backup: Name: Yu Cui, MD; Phone Number: 86-571-87236992; Email: cuiyu@zju.edu.cn

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • 79# Qingchun Road
      • Contact: Jianyong Wu, MD; Phone Number: 86-0571-87236189; Email: wujianyong1964@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Voluntary signing of written informed consent
2. Age ≥ 18 years old
3. ≥ 180 days after living donor kidney or DD donor kidney transplantation
4. EGFR ≥ 30mL/min/1.73 m2 (CKD-EPI formula)
5. Pre stored and/or newborn DSA (HLA antibody)

Exclusion Criteria:

1. Patients participating in another clinical trial
2. Age less than 18 years old
3. Female subjects are pregnant or breastfeeding, or do not receive appropriate contraceptive measures
4. ABO incompatibility transplantation

5. 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

6. Receive anti acute rejection treatment within 3 months before screening
7. 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
8. Total bilirubin>2 times the upper normal limit, alanine aminotransferase and aspartate aminotransferase>2.5 times the upper normal limit
9. Hemoglobin<8 g/dL
10. Thrombocytopenia: Platelets<100 × 109/L
11. Leukopenia: White blood cells<3 × 109/L, neutropenia: neutrophils<1.5 × 109/L
12. Hypogammaglobulinemia: Serum IgG<400 mg/dL
13. Eliminate active viral, bacterial, or fungal infections
14. Excluding Active Malignant Diseases with Intensive Immunosuppressive Therapy
15. Latent or active tuberculosis
16. Inoculate live vaccine within 6 weeks after screening
17. History of alcohol or illicit drug abuse
18. Serious medical or mental illness that may affect participation in the study
19. Active hepatitis B virus infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Patient with CaAMR; 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; 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.; Other Names: CD38 monoclonal antibody

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Zhejiang University
• Investigators: Principal Investigator: Jianyong Wu, MD, The First Affiliated Hospital of Medicine College, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2023
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): August 30, 2024

Study Registration Dates

• First Submitted: March 29, 2023
• First Submitted That Met QC Criteria: June 21, 2023
• First Posted (Actual): June 22, 2023

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Antineoplastic Agents; Daratumumab
• Other Study ID Numbers: IIT20220103C-R1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The investigators will disclose our research protocol, the clinical outcome of the investigator, and the original data of the participants can be obtained by contacting the investigator.
• IPD Sharing Time Frame: 6 months after the end of the study
• IPD Sharing Access Criteria: Contact the investigator to obtain via email
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No