NCT05806749

Immunological Tolerance in Patients With Mismatched Kidney Transplants

Use of the Immunomodulating Agent Belumosudil (KD025) After Combined Kidney and Hematopoeitic Stem Cell Transplantation to Induce Transplant Tolerance: A Pilot Study

• Status: Active Not Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 16 (estimated)
• Sponsor: University of California, Los Angeles · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This study seeks to determine if administration of the drug belumosudil (KD025) will be safe and improve transplant tolerance in subjects undergoing combined Human Leukocyte Antigen (HLA) single haplotype-matched related or 0-3 antigen (at A, B, C, DR) HLA mismatched unrelated living donor kidney and hematopoietic stem cell transplantation.

Detailed description

The goal of achieving transplant tolerance (defined as prolonged graft survival in the absence of immunosuppression) has long been the aspiration of transplant physicians and researchers. Transplant tolerance may be achieved reliably and safely in HLA identical subjects undergoing combined living donor kidney and hematopoietic stem cell utilizing a conditioning regimen of Total Lymphoid Irradiation (TLI) and Rabbit anti-thymocyte globulin (rATG). However, the same treatment regimen has not been successful in allowing recipients of HLA single haplotype matched allografts to be completely withdrawn from immunosuppression in spite of increasing the dose of infused cluster of differentiation (CD) 34 and CD3 cells. This study seeks to determine the safety and efficacy of administering the investigational agent belumosudil to single haplotype- matched or HLA mismatched (0-3 antigen mismatch at HLA A, B, C, DR) subjects undergoing combined kidney and hematopoietic stem cell transplantation conditioned with TLI/rATG. Belumosudil has been shown to be highly active when used in the treatment of steroid refractory chronic graft vs host disease. We hypothesize that belumosudil (KD025) may increase mixed donor chimerism and lead to greater transplant tolerance due to its demonstrated ability to increase the numbers and function of regulatory T cells. The summary of the treatment plan is as follows: Immediately after living donor kidney transplantation, subjects will begin a conditioning regimen of rATG and TLI. An infusion of at least 8 X10\^6 (target ≥ 10 X 10\^6) donor CD34 cells/kg recipient weight and of at least 10 X10\^6 (target 100 X10\^6) donor CD3 cells/kg recipient weight will then be given. A triple immunosuppressive regimen of tacrolimus, corticosteroids, and mycophenolate will be utilized. Corticosteroids will be given on a tapering schedule from day 0 through the first four months. Tacrolimus will be given on a tapering schedule from day 1 through month 18. Mycophenolate will be given at a fixed dose from day 11 through month 12. Subjects will receive belumosudil 200 mg by mouth daily from day 28 following the kidney transplant through month 24. At serial time points, (1) chimerism will be measured in recipient whole blood and leukocyte subsets (2) graft function will be monitored (3) protocol biopsies of the graft will be obtained and (4) a T cell subsets from the peripheral blood including regulatory T cells will be measured. Immunosuppression taper will be stopped and/or immunosuppression will be resumed for any of the following conditions: (1) loss of chimerism (2) clinical or pathological evidence of acute rejection and (3) clinical or pathological evidence of graft vs host disease.

Conditions

• End Stage Kidney Disease
• Immunological Tolerance
• Kidney Transplant Failure and Rejection
• Chronic Kidney Diseases

Interventions

Type	Name	Description
COMBINATION_PRODUCT	Donor CD34+, CD3+. and belumosudil	Immediately after living donor kidney transplantation, subjects will begin a conditioning regimen of rATG and total lymphoid irradiation. An infusion of at least 8 X106 donor CD34 cells/kg recipient weight and of at least 10 X106 donor CD3 cells/kg recipient weight will then be given. A triple immunosuppressive regimen of tacrolimus, corticosteroids, and mycophenolate will be utilized. Corticosteroids will be given on a tapering schedule from day 0 through the first four months. Tacrolimus will be given on a tapering schedule from day 1 through month 18. Mycophenolate will be given at a fixed dose from day 11 through month 12. Subjects will receive belumosudil 200 mg by mouth daily from day 28 following the kidney transplant through month 24.

Timeline

• Start date: 2023-07-07
• Primary completion: 2028-08-01
• Completion: 2028-08-01
• First posted: 2023-04-10
• Last updated: 2025-11-26

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study