Immunological Tolerance in Patients With Mismatched Kidney Transplants

Sponsor

University of California, Los Angeles (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05806749

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study seeks to determine if administration of the drug belumosudil (KD025) will be safe and improve transplant tolerance in subjects undergoing combined 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.

Condition or Disease	Intervention/Treatment	Phase
End Stage Kidney Disease Immunological Tolerance Kidney Transplant Failure and Rejection Chronic Kidney Diseases	Combination Product: Donor CD34+, CD3+. and belumosudil	Phase 1

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 TLI and 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regimen has not been successful in allowing recipients of HLA single haplotype matched allografts to be completely withdrawn from immunosuppression in spite of increasing the dose of infused CD34 and CD3 cells.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 total lymphoid irradiation. An infusion of at least 8 X106 (target ≥ 10 X 106) donor CD34 cells/kg recipient weight and of at least 10 X106 (target 100 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. 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

May 1, 2023

Anticipated Primary Completion Date :

Apr 1, 2025

Anticipated Study Completion Date :

Apr 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Immune tolerance in mismatched kidney transplant recipient Our goal is to establish this regimen as a novel, safe and effective approach for induction of transplant tolerance in HLA single haplotype-matched related and HLA mismatched unrelated recipients of combined HSCT/KT. Patients will undergo conditioning with rATG and TLI, followed by infusion of hematopoeitic stem cells from the same donor, a triple immunosuppressive regimen, and receive belumosudil following the kidney transplant. 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.	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.

Arm

Intervention/Treatment

Experimental: Immune tolerance in mismatched kidney transplant recipient

Our goal is to establish this regimen as a novel, safe and effective approach for induction of transplant tolerance in HLA single haplotype-matched related and HLA mismatched unrelated recipients of combined HSCT/KT. Patients will undergo conditioning with rATG and TLI, followed by infusion of hematopoeitic stem cells from the same donor, a triple immunosuppressive regimen, and receive belumosudil following the kidney transplant. 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.

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.

Outcome Measures

Primary Outcome Measures

Determine impact of treatment regimen on patient and kidney allograft survival [12 months]
Measure percentage of patients alive and percentage of patients with a functioning graft at 12 months

Secondary Outcome Measures

Determine probability of successful withdrawal of immunosuppression [18 months]
Measure percentage of patients who are successfully withdrawn from mycophenolate at 12 months and from tacrolimus at 18 months
Determine risk of kidney allograft rejection [36 months]
To determine the percentage of subjects with graft rejection within 36 months post-HPSC infusion defined as (1) meets Banff criteria for rejection on biopsy performed to confirm clinical suspicion of rejection or (2) clinical suspicion of rejection demonstrating response to corticosteroids in absence of biopsy when confirmatory biopsy contraindicated or declined.
Determine risk of acute and/or chronic graft vs host disease [36 months]
To determine percentage of patients who develop acute and/or chronic graft vs host disease within 36 months.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Recipient Inclusion Criteria:

Age 18 and older
Receiving an HLA single haplotype-matched related living donor or 0-3 antigen (at A, B, C, DR) HLA mismatched unrelated living donor combined kidney and hematopoietic stem cell transplant (the first six subjects will be HLA single haplotype-matched; the final two subjects may be either HLA single-haplotype-matched or 0-3 antigen (at A, B, C, DR) HLA mismatched)
Agreement to participate in the study and ability to give informed consent
Meets institutional criteria for kidney and allogeneic HSC transplant
Resides or is willing to stay within 3 hours distance from UCLA Medical Center by ground transportation for the first six months post-kidney transplant
No known contraindication to administration of rATG or radiation
If a patient is a female of reproductive potential (i.e. no documented absence of ovaries or uterus, history of tubal ligation, or post-menopausal status) patient must be confirmed not pregnancy by a serum or urine pregnancy test and must agree to practice a reliable form of contraception including hormonal treatments, barrier methods or intrauterine device for duration of the study
Males of reproductive age must consent to use reliable and effective methods to avoid pregnancy
Karnofsky Performance Score (KPS) ≥ 70
Adequate cardiac function defined as left ventricular ejection fracture (LVEF) ≥ 40% by MUGA (Multi Gated Acquisition) scan or echocardiogram
Adequate pulmonary function defined as FVC and DLCO of ≥ 50% of predicted
Adequate liver function defined as total bilirubin ≤ 1.5 times the upper limit of normal and AST/ALT ≤ 2.0 times the upper limit of normal
Adequate social support based on evaluation by the UCLA renal transplant team licensed clinical social worker
Negative test for COVID 19 by RT -PCR and/or have received COVID 19 vaccinations

Recipient Exclusion Criteria:

ABO incompatibility with donor
Previous solid organ transplant
Multi-organ transplantation
Previous treatment with rATG or a known allergy to rabbit proteins
Previous treatment with belumosudil (KD025)
History of active malignancy within the past 5 years with the exception:
Malignancy treated with curative intent with no known active disease >2 years before the first dose of study treatment and low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Very low risk and low risk cancer adequately treated or on active surveillance
Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ, and DCIS
Pregnant (confirmed by urine or serum pregnancy test) or lactating
Leukopenia (with a white blood cell count < 3,000/µL) or thrombocytopenia (with a platelet count < 100,000/µL)
INR and/or PTT ≥ 1.5X upper limits of institutional normal
Positive HLA DSA
Active bacterial, fungal, mycobacterial, or viral infection (including active hepatitis B and/or C, or West Nile Virus)
Seropositivity for HIV 1, HIV 2, HTLV-1 or HTLV-II
Renal disease with high risk of recurrence (i.e., focal segmental glomerulosclerosis)
Advanced hepatic fibrosis or cirrhosis
Congestive heart failure, symptomatic coronary artery disease, and/or uncontrolled cardiac arrhythmia
Active extra-renal autoimmune disease requiring immunosuppression
Neuropsychiatric or medical illness that precludes the ability to give informed consent and/or places the patient as high risk for non-compliance with the safety monitoring requirements of the study
May not have received immunosuppressive medications within one year of the study treatment. Use of corticosteroids prescribed for a time-limited indication (</= 4 weeks) and stopped at least 4 weeks before the kidney transplant is acceptable.
May not have received immunotherapy or immunomodulatory drugs such as immune checkpoint inhibitors, tumor necrosis factor inhibitors, rituximab, intravenous immune globulin, and interleukin-2 within one year of the study treatment
Current or active abuse of alcohol and/or drugs within the last 6 months
Body Mass Index (BMI) ≥ 40
Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
ESRD patients with the following etiologies
Autoimmune disease including lupus
Vasculitis involving the kidney (such as Wegener's Granulomatosis
Thrombotic Thrombocytopenic Purpura
Alport's syndrome (due to increased risk of developing post-transplant Anti-Glomerular Basement Membrane Disease (Anti-GBM Disease))
HgbA1c ≥10
Prior history of radiation therapy
History of ≥ 20 pack per year smoking. a. Patients must be abstinent from tobacco use for ≥ 6 months prior to transplantation

Donor Inclusion Criteria:

Age 18 or older
HLA single haplotype-matched related living donor or 0-3 Antigen (at A, B, C, DR) HLA mismatched unrelated living donor
Meets institutional criteria for living kidney and allogeneic HSPC transplant donation
Medically fit to tolerate peripheral blood apheresis, including
Weight ≥ 110 pounds
Hemoglobin ≥ 11
White blood cell count ≥ 3,000/µL
Platelets ≥ 120,000/µL
Normal serum chemistry and coagulation parameter studies; or, if abnormal, the changes are not considered clinically significant
Negative test for COVID 19 by RT -PCR and/or have received COVID 19 vaccinations

Donor Exclusion Criteria

ABO incompatibility with recipient
Medically unfit to tolerate peripheral blood apheresis (small body size, poor vascular access, not a suitable candidate for placement of a central catheter, etc.)
Pregnant (confirmed by urine or serum pregnancy test) or lactating
Seropositivity for HIV 1, HIV 2, HTLV-I or HTLV-II
Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C, West Nile Virus)
Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study
History of active malignancy within the past 5 years with the exception:
Adequately managed malignancy within the past two years with low risk of recurrence may be acceptable as per clinician discretion
Adequately managed non-melanoma skin cancer
Adequately managed carcinoma in situ e.g., cervical cancer in situ, and DCIS
No current or recent use of oral anti-coagulants. (For the purpose of this study, recent is defined as less than 60 days prior to apheresis). Aspirin and non-steroidal anti-inflammatory drugs must be stopped 14 days prior to apheresis.
Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data