Using carfilzomib and belatacept to help highly sensitized kidney transplant candidates

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

This study is testing if the combination of two drugs, carfilzomib and belatacept, can help people with end-stage kidney disease who have a high chance of not finding a matching donor, making it easier for them to get a kidney transplant.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Locations: 1 site (Durham, North Carolina)
• Trial ID: NCT05017545 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the effectiveness of two drugs, carfilzomib and belatacept, in reducing sensitization in highly sensitized kidney transplant candidates. Participants will include individuals with end-stage renal disease on dialysis who have a very high calculated panel reactive antibody (cPRA) score, indicating a low chance of finding a compatible donor. The study will enroll 15 participants across two cohorts and assess the safety and efficacy of the treatment over a period of up to 76 weeks. The goal is to facilitate quicker access to kidney transplants for these patients by lowering their immune system's sensitization to potential donors.

Who should consider this trial

Good fit: Ideal candidates for this study are adults aged 18 to 65 with end-stage renal disease on dialysis and a cPRA score of 98% or higher.

Not a fit: Patients who are not highly sensitized or those who do not meet the specific cPRA criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could significantly increase the chances of kidney transplant for highly sensitized patients, reducing their wait time and improving their quality of life.

How similar studies have performed: While the approach of using these specific drugs for desensitization is novel, similar desensitization therapies have shown promise in other studies.

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.

Where this trial is running

Durham, North Carolina

• Duke Transplant Center, Duke University Medical Center — Durham, North Carolina, United States (Recruiting)

Conditions Highly Sensitized Prospective Kidney Transplant Recipients; calculated panel reactive antibodies; desensitization therapy; human leukocyte antigen desensitization