Clinical trial NCT05017545: Carfilzomib and Belatacept for Desensitization
Official title: Measuring the Impact of Carfilzomib and Belatacept on Allogeneic Desensitization in Prospective Kidney Transplant Recipients (ITN089ST)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Highly Sensitized Prospective Kidney Transplant Recipients
Keywords: calculated panel reactive antibodies (cPRA)
desensitization therapy
human leukocyte antigen (HLA) desensitization
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
name: Bristol-Myers Squibb
name: PPD Development, LP
name: Rho Federal Systems Division, Inc.
First posted: 2021-08-24
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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 have 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.

Eligibility criteria: Inclusion Criteria:

Individuals who meet all of the following criteria are eligible for enrollment as study subjects-

1. Subject must be able to understand and provide informed consent
2. End stage renal disease (ESRD) on dialysis
3. 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
4. Evidence of established immunity to Epstein-Barr virus (EBV) as demonstrated by serologic testing
5. 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
6. Negative Food and Drug Administration (FDA)-approved test for human immunodeficiency virus (HIV) diagnosis (at screening or as documented in medical record, up to 6 months prior to screening)
7. Negative Hepatitis C antibody test at screening or as documented in medical record, up to 6 months prior to screening.

   --If there is a history of treated hepatitis C then documentation of two consecutive negative HCV quantitative ribonucleic acid (RNA) polymerase chain reaction (PCR) tests separated by at least 6 months is required. Untreated subjects with positive HCV antibody and a single negative HCV quantitative HCV RNA are eligible.
8. Negative result for SARS-CoV-2 by an FDA-authorized molecular diagnostic test. Examples include, but are not limited to RT-PCR, LAMP, TMA, and qSTAR.
9. 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
10. Female subjects of reproductive potential must have a negative pregnancy test upon study entry
11. All subjects of reproductive potential must agree to use contraception for the duration of the study
12. 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-

1. Able to understand and provide informed consent for research
2. 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-

1. Inability or unwillingness of a subject to give written informed consent or comply with study protocol
2. Known active current or history of invasive fungal infection, non-tuberculous mycobacterial infection
3. Hepatitis B surface antigen or core antibody positive
4. Serious uncontrolled concomitant major organ disease, excluding kidney failure
5. Chronic respiratory failure
6. Uncontrolled systemic hypertension
7. Previous non-kidney solid organ transplant or bone marrow transplant
8. Any infection requiring hospitalization and intravenous (IV) therapy within 4 weeks of screening or oral therapy within 2 weeks of screening
9. Primary or secondary immunodeficiency
10. History of thromboembolism (except thrombosis of dialysis vascular access site)
11. Subjects with myocardial infarction within 12 months of screening or cardiac dysrhythmias uncontrolled by medications
12. History of plasma cell dyscrasia
13. Known bleeding diathesis or coagulation abnormality
14. History of active tuberculosis (TB) (even if treated)
15. Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated cervical cancer in situ
16. Women who are currently pregnant or nursing
17. Alcohol, drug, or chemical abuse within 1 year
18. Treatment with any investigational agent within 4 weeks (or 5 half-lives of investigational drug, whichever is longer) of screening
19. Current treatment with other biological drug. If the potential subject receives standard of care antibody treatments for prophylaxis of COVID-19 (permitted in protocol), there must be a minimum interval of 2 weeks after this treatment and before initiation of the study therapy.
20. Current treatment with any medication which increases the risk of thromboembolic events including oral contraceptives
21. Currently smoking tobacco
22. Neutropenia (absolute neutrophil count \<1000/microliter) or thrombocytopenia (platelet count \<100,000/microliter) within 4 weeks prior to screening
23. Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times upper limit of normal (ULN) or total bilirubin ≥ 2 times ULN
24. 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.

Primary outcomes:
measure: Proportion of subjects who do not meet a stopping rule for safety and remain free of all safety events listed in the outcome description, through Week 20 (Cohort 1) post treatment initiation or until receiving a transplant, whichever occurs earlier.
timeFrame: Up to 20 weeks post treatment initiation
measure: Proportion of subjects who do not meet a stopping rule for safety and remain free of all safety events listed in the outcome description, through Week 24 (Cohort 2) post treatment initiation or until receiving a transplant, whichever occurs earlier.
timeFrame: Up to 24 weeks post treatment initiation
measure: 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 - Cohort 1
timeFrame: Baseline (Visit 0) to Week 20 post treatment initiation
measure: Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline to Week 24 post treatment initiation - Cohort 2
timeFrame: Baseline (Visit 0) to Week 24 post treatment initiation
Secondary outcomes:
measure: Proportion of subjects transplanted with a previously incompatible donor within 52 weeks after starting treatment
timeFrame: Within 52 weeks post treatment initiation
measure: 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
timeFrame: Within 52 weeks post-transplant
measure: Number of biopsy-proven acute or chronic AMR events within 52 weeks post-transplant in subjects who undergo a kidney transplant
timeFrame: Within 52 weeks post-transplant
measure: Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 20 weeks after starting treatment - Cohort 1
timeFrame: Within 20 weeks post treatment initiation
measure: Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 24 weeks after starting treatment - Cohort 2
timeFrame: Within 24 weeks post treatment initiation
measure: Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 52 weeks after starting treatment
timeFrame: Within 52 weeks post treatment initiation
measure: Incidence of cytomegalovirus (CMV) infection within 20 weeks after starting treatment (Cohort 1)
timeFrame: Within 20 weeks post treatment initiation
measure: Incidence of cytomegalovirus (CMV) infection within 24 weeks after starting treatment (Cohort 2)
timeFrame: Within 24 weeks post treatment initiation
measure: Incidence of cytomegalovirus (CMV) infection within 52 weeks after starting treatment
timeFrame: Within 52 weeks post treatment initiation
measure: Incidence of cytomegalovirus (CMV) disease within 20 weeks after starting treatment
timeFrame: Within 20 weeks post treatment initiation
measure: Incidence of cytomegalovirus (CMV) disease within 52 weeks after starting treatment
timeFrame: Within 52 weeks post treatment initiation
measure: Incidence of post-transplant lymphoproliferative disorder (PTLD)
timeFrame: Within 52 weeks post-transplant
measure: Mean number of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline (Cohort 1)
timeFrame: Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation
measure: Mean number of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline (Cohort 2)
timeFrame: Baseline (Visit 0), Weeks 16, 24, and 52 post treatment initiation
measure: Mean proportion of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline (Cohort 1)
timeFrame: Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation
measure: Mean proportion of Human Leukocyte Antigen (HLA) antibodies eliminated, compared to Baseline (Cohort 2)
timeFrame: Baseline (Visit 0), Weeks 16, 24, and 52 post treatment initiation
measure: Mean percent reduction from Baseline in mean fluorescence intensity (MFI) of the immunodominant Human Leukocyte Antigen (HLA) antibody, Class I and Class II - only collected for Cohort 1
timeFrame: Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation
measure: 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 (Cohort 1)
timeFrame: Baseline (Visit 0), Weeks 16, 20, and 52 post treatment initiation
measure: 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 (Cohort 2)
timeFrame: Baseline (Visit 0), Weeks 16, 24, and 52 post treatment initiation
Other outcomes:
Locations:
city: Durham
country: United States
facility: Duke Transplant Center, Duke University Medical Center
state: North Carolina
Study officials:
affiliation: Duke Department of Surgery, Duke University School of Medicine
name: Stuart J. Knechtle, MD
role: STUDY_CHAIR
affiliation: Duke Department of Surgery, Duke University School of Medicine
name: Annette M. Jackson, PhD
role: STUDY_CHAIR
References: