Carfilzomib and Belatacept for Desensitization

Study Overview
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Brief Summary
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Some kidney transplant candidates have a very low chance of getting a kidney transplant because their immune systems are highly sensitized to most kidney donors. Being highly sensitized means that they will likely have to wait a long time (more than 5 years) before an acceptable donor is found for them or, they never receive a compatible donor, and die while on the kidney transplant waitlist. The purpose of this study is to find out whether two drugs, carfilzomib (Kyprolis®),and belatacept (Nulojix®), can make these kidney transplant candidates less sensitized, and make it easier and quicker to find a kidney donor for them.

Detailed Description
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This study will enroll 15 eligible participants, 18 to 65 years of age, with end stage renal failure on dialysis who are on the waiting list for a deceased donor transplant with calculated panel reactive antibodies (cPRA) ≥99.9% or >98% (with >5 years of waiting time) or, those with cPRA >98% and an human leukocyte antigen (HLA)-incompatible approved living donor who have not received a transplant after 1 year in a paired kidney exchange program. The study will evaluate whether the study treatment is safe and can lower the participant's immune system's sensitization to kidney donors, making it easier to find a well-matched kidney for them. Participants in the study will be enrolled in two consecutive Cohorts of 5 and 10 patients respectively. The total duration of participation in the study will be 76 weeks for Cohort 1 and 68 weeks for Cohort 2. Participants who undergo kidney transplantation while enrolled in the study will undergo an additional 52 weeks of follow up post-transplant. The duration of participation for living donors is one study visit. Their participation in the study ends upon completion of this study visit.

Official Title
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Measuring the Impact of Carfilzomib and Belatacept on Allogeneic Desensitization in Prospective Kidney Transplant Recipients (ITN089ST)

Conditions
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Highly Sensitized Prospective Kidney Transplant Recipients

Intervention / Treatment
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* Biological: carfilzomib
* Biological: belatacept
* Procedure: Bone marrow aspiration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all of the following criteria are eligible for enrollment as study subjects- Subject must be able to understand and provide informed consent End stage renal disease (ESRD) on dialysis United Network for Organ Sharing (UNOS) listed for a kidney transplant with any one of the following: Current calculated panel reactive antibodies (cPRA) ≥ 99.9 percent awaiting deceased donor transplant Current cPRA >98 percent (with >5 years of waiting time) awaiting deceased donor transplant Current cPRA >98 percent with Human Leukocyte Antigen (HLA)-incompatible approved living donor and has not received a transplant after 1 year in a kidney paired exchange program Evidence of established immunity to Epstein-Barr virus (EBV) as demonstrated by serologic testing Negative result of most recent tuberculosis (TB) testing or appropriately completed latent tuberculosis infection (LTBI) therapy. Testing should be conducted using either a purified protein derivative (PPD) or interferon-gamma release assay (i.e. QuantiFERON-TB, T-SPOT.TB). Negative results from tests performed within 12 months prior to study entry are acceptable in the absence of any intervening exposure to TB. Subjects with a positive test result must have completed appropriate therapy for LTBI. Note: LTBI treatment regimens should be among those endorsed by the Centers for Disease Control and Prevention (CDC), url: https://www.cdc.gov/tb/topic/treatment/ltbi.htm Negative Food and Drug Administration (FDA)-approved test for human immunodeficiency virus (HIV) diagnosis (at screening or as documented in medical record, up to 12 months prior to screening) Negative Hepatitis C antibody test at screening or as documented in medical record, up to 12 months prior to screening. --If there is a history of treated hepatitis C or there is a suspected false positive hepatitis C virus (HCV) antibody test, then documentation of two consecutive negative HCV quantitative ribonucleic acid (RNA) polymerase chain reaction (PCR) tests separated by at least 6 months is required Negative result for 2019-novel Coronavirus (2019-nCoV) by real-time reverse transcriptase- polymerase chain reaction (RT-PCR) Subjects must have an echocardiogram within the previous 1 year without any of the following findings: severe left ventricular hypertrophy (LVH) greater than mild LVH accompanied by diastolic dysfunction left ventricular ejection fraction <40 percent pulmonary hypertension defined as right ventricular systolic pressure >35 mm Hg or tricuspid regurgitant velocity >2.8 m/s Female subjects of reproductive potential must have a negative pregnancy test upon study entry All subjects of reproductive potential must agree to use contraception for the duration of the study Subjects must have current vaccinations or documented immunity to: varicella (chickenpox) measles hepatitis B pneumococcus influenza, and varicella zoster (if ≥ 50 years old). Note: If subjects require administration of either live or killed vaccines to meet eligibility requirements, they must wait at least 2 weeks between vaccination and the baseline visit (i.e., at least 4 weeks before initiation of therapy) Living Donor Inclusion Criteria: Living donors must meet all of the following criteria to be eligible- Able to understand and provide informed consent for research Meets United Network for Organ Sharing (UNOS) requirements for kidney organ donation Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study subjects- Inability or unwillingness of a subject to give written informed consent or comply with study protocol Known active current or history of invasive fungal infection, non-tuberculous mycobacterial infection Hepatitis B surface antigen or core antibody positive Serious uncontrolled concomitant major organ disease, excluding kidney failure Chronic respiratory failure Uncontrolled systemic hypertension Previous non-kidney solid organ transplant or bone marrow transplant Any infection requiring hospitalization and intravenous (IV) therapy within 4 weeks of screening or oral therapy within 2 weeks of screening History of positive result for 2019-novel Coronavirus (2019-nCoV) by real-time reverse transcriptase reverse transcriptase-polymerase chain reaction (RT-PCR) Primary or secondary immunodeficiency History of thromboembolism (except thrombosis of dialysis vascular access site) Subjects with myocardial infarction within 12 months of screening or cardiac dysrhythmias uncontrolled by medications History of plasma cell dyscrasia Known bleeding diathesis or coagulation abnormality History of active tuberculosis (TB) (even if treated) Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated cervical cancer in situ Women who are currently pregnant or nursing Alcohol, drug, or chemical abuse within 1 year Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening Current treatment with other biological drug Current treatment with any medication which increases the risk of thromboembolic events including oral contraceptives Currently smoking tobacco Neutropenia (absolute neutrophil count <1000/microliter) or thrombocytopenia (platelet count <100,000/microliter) within 4 weeks prior to screening Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times upper limit of normal (ULN) or total bilirubin ≥ 2 times ULN Past or current medical problems or findings from physical examination or laboratory testing not listed above, which, in the opinion of the investigator, may: pose additional risks from participation in the study interfere with the subject's ability to comply with study requirements, or impact the quality or interpretation of the data obtained from the study. Exclusion Criteria for Living Donors: 1. There are no exclusion criteria for living donors.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (N=5 Subjects)<br>The two investigational agents used in this study are carfilzomib and belatacept. Per protocol, Carfilzomib administered intravenously: Cycle 1 will consist of 2 doses in week 4 (Day 28 and 29). If tolerated, the dose will be increased and administered twice a week in weeks 5 (Day 35 and 36) and 6 (Day 42 and 43). Cycle 2 will consist of a total of 6 doses, administered twice weekly in weeks 12 (Day 84 and 85), 13 (Day 91 and 92) and 14 (Day 98 and 99). Per protocol, Belatacept: -Belatacept will be administered intravenously on days 29 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert. | Biological: carfilzomib<br>* Administered: Intravenously (IV). Carfilzomib is administered intravenously, on two consecutive days, each week for three weeks per cycle. In this study, subjects will receive 2 cycles of carfilzomib. Dosing for each cycle is based on the recommended dosing for carfilzomib monotherapy in the package insert. Carfilzomib is a proteasome inhibitor indicated for the treatment of patients with multiple myeloma. In this study, carfilzomib will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant.<br>* Other names: Kyprolis®;Biological: belatacept<br>* Administered: Intravenously (IV). Belatacept is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. In this study, belatacept will be used in highly sensitized subjects who are awaiting a kidney transplant.<br>* Other names: Nulojix®;Procedure: Bone marrow aspiration<br>* Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 16 weeks after starting the study regimen. In subjects who undergo a kidney transplant during the study, another bone marrow aspiration will be done if it has been >4 weeks since the previous bone marrow aspiration.<br>|
| Experimental: Cohort 2 (N=10 Subjects)<br>The enrollment of ten additional subjects and dosing regimen is dependent on the results in Cohort 1.° Per protocol, Carfilzomib administered intravenously: Cycle 1 will consist of 2 doses in week 4 (Day 28 and 29). If tolerated, the dose will be increased and administered twice a week in weeks 5 (Day 35 and 36) and 6 (Day 42 and 43). Cycle 2 will consist of a total of 6 doses, administered twice weekly in weeks 12 (Day 84 and 85), 13 (Day 91 and 92) and 14 (Day 98 and 99). Per protocol, Belatacept: -Belatacept will be administered intravenously on days 29 (week 4), 33 (week 5), and weeks 6, 8, 12, 16, then at a lower dose at week 20, 24, 28, 32, 36, 40, 44, 48, 52, and 56. Dosing is based on the recommended dose in the package insert. ° May be modified based on the safety and efficacy analysis of Cohort 1. | Biological: carfilzomib<br>* Administered: Intravenously (IV). Carfilzomib is administered intravenously, on two consecutive days, each week for three weeks per cycle. In this study, subjects will receive 2 cycles of carfilzomib. Dosing for each cycle is based on the recommended dosing for carfilzomib monotherapy in the package insert. Carfilzomib is a proteasome inhibitor indicated for the treatment of patients with multiple myeloma. In this study, carfilzomib will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant.<br>* Other names: Kyprolis®;Biological: belatacept<br>* Administered: Intravenously (IV). Belatacept is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. In this study, belatacept will be used in highly sensitized subjects who are awaiting a kidney transplant.<br>* Other names: Nulojix®;Procedure: Bone marrow aspiration<br>* Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 16 weeks after starting the study regimen. In subjects who undergo a kidney transplant during the study, another bone marrow aspiration will be done if it has been >4 weeks since the previous bone marrow aspiration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects who do not meet a stopping rule for safety and remain free of all of the safety events listed in the outcome description, through Week 20 post treatment initiation or until receiving a transplant, whichever occurs earlier | Proportion of subjects who have not met a subject stopping rule, and remain free of all of the following through Week 20 post treatment initiation or until receiving a transplant, whichever occurs earlier: Grade 3 or higher infusion reaction, Grade 3 or higher infections, and Any malignancy. The study site will grade the severity of adverse events experienced by the study subjects according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (Published November 27, 2017). | Up to 20 weeks post treatment initiation | 
| Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline to Week 20 post treatment initiation | Proportion of subjects who meet any one of the following compared to Baseline (Visit 0): Elimination of one human leukocyte antigen (HLA) antibody at Week 20 (which is Study Week 24) post treatment initiation, 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Week 20 (which is Study Week 24) after starting treatment, and/or Kidney transplant with a previously incompatible donor within 20 weeks after starting treatment without graft loss due to acute antibody mediated rejection occurring within the first four weeks post-transplant and caused by an anamnestic response. | Baseline (Visit 0) to Week 20 post treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects transplanted with a previously incompatible donor within 52 weeks after starting treatment | Clinical outcome measure. Subjects may receive a kidney transplant while in the study, either from a living or deceased donor to whom they were previously compatible, or from a previously incompatible donor in case there is a significant reduction in HLA antibody. | Within 52 weeks post treatment initiation | 
| Proportion of subjects with biopsy-proven acute or chronic antibody mediated rejection (AMR) within 52 weeks post-transplant in subjects who undergo a kidney transplant | Clinical outcome measure. Antibody mediated rejection (AMR) is an important cause of graft loss after organ transplantation and is caused by anti-donor-specific antibodies, especially anti- human leukocyte antigen (HLA) antibodies. | Within 52 weeks post-transplant | 
| Number of biopsy-proven acute or chronic AMR events within 52 weeks post-transplant in subjects who undergo a kidney transplant | Clinical outcome measure. Antibody mediated rejection (AMR) is an important cause of graft loss after organ transplantation and is caused by anti-donor-specific antibodies, especially anti- human leukocyte antigen (HLA) antibodies. | Within 52 weeks post-transplant | 
| Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 20 weeks after starting treatment | A measure of infection-related morbidity. | Within 20 weeks post treatment initiation | 
| Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 52 weeks after starting treatment | A measure of infection-related morbidity. | Within 52 weeks post treatment initiation | 
| Incidence of cytomegalovirus (CMV) infection within 20 weeks after starting treatment | CMV infection confirmed by the presence of detectable CMV in blood by polymerase chain reaction [PCR] diagnostic testing, regardless of whether signs or symptoms are present. | Within 20 weeks post treatment initiation | 
| Incidence of cytomegalovirus (CMV) infection within 52 weeks after starting treatment | CMV infection confirmed by the presence of detectable CMV in blood by polymerase chain reaction [PCR] diagnostic testing, regardless of whether signs or symptoms are present. | Within 52 weeks post treatment initiation | 
| Incidence of cytomegalovirus (CMV) disease within 20 weeks after starting treatment | CMV disease defined by the presence of detectable CMV in the blood and the presence of other clinical manifestations attributable to the CMV virus. | Within 20 weeks post treatment initiation | 
| Incidence of cytomegalovirus (CMV) disease within 52 weeks after starting treatment | CMV disease defined by the presence of detectable CMV in the blood and the presence of other clinical manifestations attributable to the CMV virus. | Within 52 weeks post treatment initiation | 
| Incidence of post-transplant lymphoproliferative disorder (PTLD) | As per diagnosis by local pathologist and treating physician. | Within 52 weeks post-transplant | 
| Mean number of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline | Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). | Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation | 
| Mean proportion of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline | Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). | Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation | 
| Mean percent reduction from Baseline in mean fluorescence intensity (MFI) of the immunodominant Human Leukocyte Antigen (HLA) antibody, Class I and Class II | Mechanistic outcome measure focusing on change in donor specific antibodies (DSA). | Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation | 
| Mean percent reduction from Baseline in mean fluorescence intensity (MFI) of Human Leukocyte Antigen (HLA) antibodies classified by an MFI >10,000 at treatment initiation | Mechanistic outcome measure focusing on change in donor specific antibodies. An MFI of >10,000 reflects a strong DSA intensity. (Reference: A measure of 0 reflects no donor specific antibodies). | Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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calculated panel reactive antibodies (cPRA), desensitization therapy, human leukocyte antigen (HLA) desensitization