NCT_ID: NCT05806749
Clinical Trial Link
Brief Summaries
| Sequence: | 30516456 |
| Description | 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. |
Studies
| Study First Submitted Date | 2023-02-01 |
| Study First Posted Date | 2023-04-10 |
| Last Update Posted Date | 2023-04-10 |
| Start Month Year | May 1, 2023 |
| Primary Completion Month Year | April 2025 |
| Verification Month Year | April 2023 |
| Verification Date | 2023-04-30 |
| Last Update Posted Date | 2023-04-10 |
Detailed Descriptions
| Sequence: | 20554788 |
| 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regimen has not been successful in allowing recipients of HLA single haplotype matched allografts to be completely withdrawn from immunosuppression in spite of increasing the dose of infused CD34 and CD3 cells.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. |
Facilities
| Sequence: | 198453698 |
| Name | University of California, Los Angeles |
| City | Los Angeles |
| State | California |
| Zip | 90095 |
| Country | United States |
Facility Contacts
| Sequence: | 27922890 | Sequence: | 27922891 |
| Facility Id | 198453698 | Facility Id | 198453698 |
| Contact Type | primary | Contact Type | backup |
| Name | Dana Levin-Lopez, MPH | Name | Jenny Lester, MPH |
| dlevinlopez@mednet.ucla.edu | jlester@mednet.ucla.edu | ||
| Phone | 310-794-8893 | Phone | 3107949728 |
Facility Investigators
| Sequence: | 18217885 |
| Facility Id | 198453698 |
| Role | Principal Investigator |
| Name | Neil Kogut, MD |
Browse Interventions
| Sequence: | 95208360 | Sequence: | 95208361 | Sequence: | 95208362 | Sequence: | 95208363 |
| Mesh Term | Belumosudil | Mesh Term | Protein Kinase Inhibitors | Mesh Term | Enzyme Inhibitors | Mesh Term | Molecular Mechanisms of Pharmacological Action |
| Downcase Mesh Term | belumosudil | Downcase Mesh Term | protein kinase inhibitors | Downcase Mesh Term | enzyme inhibitors | Downcase Mesh Term | molecular mechanisms of pharmacological action |
| Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Conditions
| Sequence: | 51742454 | Sequence: | 51742455 | Sequence: | 51742456 | Sequence: | 51742457 |
| Name | End Stage Kidney Disease | Name | Immunological Tolerance | Name | Kidney Transplant Failure and Rejection | Name | Chronic Kidney Diseases |
| Downcase Name | end stage kidney disease | Downcase Name | immunological tolerance | Downcase Name | kidney transplant failure and rejection | Downcase Name | chronic kidney diseases |
Id Information
| Sequence: | 39817056 |
| Id Source | org_study_id |
| Id Value | Mismatch-Tolerance |
Countries
| Sequence: | 42216025 |
| Name | United States |
| Removed | False |
Design Groups
| Sequence: | 55163204 |
| Group Type | Experimental |
| Title | Immune tolerance in mismatched kidney transplant recipient |
| Description | 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. |
Interventions
| Sequence: | 52064133 |
| Intervention Type | Combination Product |
| Name | Donor CD34+, CD3+. and belumosudil |
| Description | 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. |
Keywords
| Sequence: | 79167342 | Sequence: | 79167343 | Sequence: | 79167344 | Sequence: | 79167345 | Sequence: | 79167346 | Sequence: | 79167347 |
| Name | Immunological Tolerance | Name | Kidney Transplant | Name | Tolerance | Name | End Stage Kidney Disease | Name | End Stage Renal Disease | Name | Chronic Kidney Disease |
| Downcase Name | immunological tolerance | Downcase Name | kidney transplant | Downcase Name | tolerance | Downcase Name | end stage kidney disease | Downcase Name | end stage renal disease | Downcase Name | chronic kidney disease |
Design Outcomes
| Sequence: | 175989624 | Sequence: | 175989625 | Sequence: | 175989626 | Sequence: | 175989627 |
| Outcome Type | primary | Outcome Type | secondary | Outcome Type | secondary | Outcome Type | secondary |
| Measure | Determine impact of treatment regimen on patient and kidney allograft survival | Measure | Determine probability of successful withdrawal of immunosuppression | Measure | Determine risk of kidney allograft rejection | Measure | Determine risk of acute and/or chronic graft vs host disease |
| Time Frame | 12 months | Time Frame | 18 months | Time Frame | 36 months | Time Frame | 36 months |
| Description | Measure percentage of patients alive and percentage of patients with a functioning graft at 12 months | Description | Measure percentage of patients who are successfully withdrawn from mycophenolate at 12 months and from tacrolimus at 18 months | Description | 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. | Description | To determine percentage of patients who develop acute and/or chronic graft vs host disease within 36 months. |
Browse Conditions
| Sequence: | 191761048 | Sequence: | 191761049 | Sequence: | 191761050 | Sequence: | 191761051 | Sequence: | 191761052 | Sequence: | 191761053 | Sequence: | 191761054 | Sequence: | 191761055 | Sequence: | 191761056 | Sequence: | 191761057 | Sequence: | 191761058 | Sequence: | 191761059 |
| Mesh Term | Kidney Diseases | Mesh Term | Renal Insufficiency, Chronic | Mesh Term | Kidney Failure, Chronic | Mesh Term | Urologic Diseases | Mesh Term | Female Urogenital Diseases | Mesh Term | Female Urogenital Diseases and Pregnancy Complications | Mesh Term | Urogenital Diseases | Mesh Term | Male Urogenital Diseases | Mesh Term | Renal Insufficiency | Mesh Term | Chronic Disease | Mesh Term | Disease Attributes | Mesh Term | Pathologic Processes |
| Downcase Mesh Term | kidney diseases | Downcase Mesh Term | renal insufficiency, chronic | Downcase Mesh Term | kidney failure, chronic | Downcase Mesh Term | urologic diseases | Downcase Mesh Term | female urogenital diseases | Downcase Mesh Term | female urogenital diseases and pregnancy complications | Downcase Mesh Term | urogenital diseases | Downcase Mesh Term | male urogenital diseases | Downcase Mesh Term | renal insufficiency | Downcase Mesh Term | chronic disease | Downcase Mesh Term | disease attributes | Downcase Mesh Term | pathologic processes |
| Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-list | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor | Mesh Type | mesh-ancestor |
Sponsors
| Sequence: | 47920921 |
| Agency Class | OTHER |
| Lead Or Collaborator | lead |
| Name | University of California, Los Angeles |
Central Contacts
| Sequence: | 11922070 | Sequence: | 11922071 |
| Contact Type | primary | Contact Type | backup |
| Name | Ruth Wynne Jones | Name | Dana Levin-Lopez, MPH |
| Phone | 310-825-3377 | Phone | 3107948893 |
| rwynnejones@mednet.ucla.edu | dlevinlopez@mednet.ucla.edu | ||
| Role | Contact | Role | Contact |
Design Group Interventions
| Sequence: | 67628243 |
| Design Group Id | 55163204 |
| Intervention Id | 52064133 |
Eligibilities
| Sequence: | 30515237 |
| Gender | All |
| Minimum Age | 18 Years |
| Maximum Age | N/A |
| Healthy Volunteers | No |
| Criteria | 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 |
| Adult | True |
| Child | False |
| Older Adult | True |
Calculated Values
| Sequence: | 254066227 |
| Number Of Facilities | 1 |
| Registered In Calendar Year | 2023 |
| Were Results Reported | False |
| Has Us Facility | True |
| Has Single Facility | True |
| Minimum Age Num | 18 |
| Minimum Age Unit | Years |
| Number Of Primary Outcomes To Measure | 1 |
| Number Of Secondary Outcomes To Measure | 3 |
Designs
| Sequence: | 30264270 |
| Allocation | N/A |
| Intervention Model | Single Group Assignment |
| Observational Model | |
| Primary Purpose | Treatment |
| Time Perspective | |
| Masking | None (Open Label) |
Responsible Parties
| Sequence: | 28644551 |
| Responsible Party Type | Principal Investigator |
| Name | Neil Kogut |
| Title | Adjunct Assistant Professor |
| Affiliation | University of California, Los Angeles |