Treating antibody-mediated kidney transplant rejection with carfilzomib and belatacept

Targeting the B Cell Response to Treat Antibody-Mediated Rejection With Carfilzomib and Belatacept (CarBel)

We will test whether adding carfilzomib and belatacept to steroids and standard immunosuppression can safely reduce antibody-mediated injury in kidney transplant recipients with donor-specific antibodies.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Drugs / interventions: Eculizumab, alemtuzumab, prednisone
• Locations: 10 sites (Birmingham, Alabama and 9 other locations)
• Trial ID: NCT06918990 on ClinicalTrials.gov

What this trial studies

This is a prospective, multicenter, open-label Phase 1 study in which 25 kidney transplant recipients with donor-specific antibody (DSA)-associated graft injury will receive a steroid pulse/taper plus carfilzomib and belatacept alongside maintenance tacrolimus, mycophenolate, and prednisone. Participants will be followed for 12 months after starting investigational therapy with protocol kidney biopsies at 3 and 12 months to document tissue changes. The study will also track immune cell responses, blood and urine biomarkers, and biopsy-based pathomic features related to antibody-mediated injury. Safety and early signs of efficacy will guide interpretation for larger future trials.

Who should consider this trial

Good fit: Ideal candidates are kidney transplant recipients with DSA-associated antibody-mediated injury, adequate kidney function (eGFR ≥30 mL/min/1.73 m²), prior EBV exposure, acceptable cardiac function (LVEF ≥40%), and who meet the protocol biopsy and timing criteria.

Not a fit: Patients with advanced graft failure or very low eGFR, EBV-seronegative status, severe uncontrolled comorbidity (including significant heart or pulmonary hypertension), or rejection types outside the protocol-defined criteria are unlikely to benefit from this regimen.

Why it matters

Potential benefit: If successful, the regimen could reduce antibody-mediated damage and help preserve kidney graft function in patients with DSA-associated rejection.

How similar studies have performed: Prior work with proteasome inhibitors (like bortezomib) and with belatacept has shown mixed but sometimes promising signals in antibody-mediated rejection, while combining carfilzomib and belatacept in this setting is relatively novel and not yet proven.

Eligibility criteria

Inclusion Criteria:

1. Able to understand and agree to participate in the study.
2. Have received a kidney transplant from a living or deceased donor (including re-transplants).
3. Men and women must agree to use birth control during the study and for 3 months after the last dose of study drugs, or be surgically sterile or post-menopausal.
4. Heart function must be good enough (LVEF of at least 40%) without severe heart issues or high blood pressure in the lungs.
5. Must have been previously exposed to the Epstein-Barr Virus (EBV).
6. Diagnosed with specific types of kidney transplant rejection based on criteria, with certain conditions on timing and treatment history.
7. Kidney function must be at a certain level (eGFR of at least 30 ml/min/1.73 m²).
8. Specific scores related to kidney biopsy results must be within certain limits.
9. Patient is ≥6-months post-transplant or is \<6 months post-transplant but has documentation that they have been offered and/or received the local standard of care treatment prior to enrollment.
10. Must have a measurable level of specific antibodies against the donor kidney (HLA DSA) with a certain intensity.
11. Up-to-date vaccinations according to guidelines for transplant patients.
12. Must have a negative tuberculosis (TB) test and chest x-ray before enrollment, no symptoms or known contact with TB, and not have recently traveled to or lived in areas with high TB rates. If previously infected with TB, must have completed treatment and have a recent negative chest x-ray.
13. If previously infected with COVID-19, must be fully recovered for at least 21 days before joining the study. No COVID-19 test required for those without symptoms.

Exclusion Criteria:

1. Unable or unwilling to give consent or follow study rules.
2. Kidney transplant with incompatible blood types.
3. Very high levels of protein in urine, indicating severe kidney issues.
4. Previously had a non-kidney organ or bone marrow transplant.
5. Any other medical issues that might increase risk, make following the study rules hard, or affect study results, as judged by the study doctor.
6. Heart attack within the last year, uncontrolled chest pain, or signs of a recent heart problem on an ECG.
7. Severe heart failure (Class 3 or higher).
8. Irregular heartbeats that can't be controlled with medication.
9. Participants who are actively receiving any of the therapies listed below, or who have previously received these therapies without meeting the required washout period prior to the qualifying biopsy and donor-specific antibody (DSA) assessment:

   * ≥4 weeks since last dose: IVIG (intravenous immunoglobulin), therapeutic plasma exchange (TPE)
   * ≥6 weeks since last dose: Proteasome inhibitors
   * ≥3 months since last dose: Eculizumab; lymphocyte-depleting agents (e.g., rabbit anti-thymocyte globulin, alemtuzumab); anti-CD20 agents
   * ≥6 months since last dose: Anti-CD38 agents; anti-IL-6 agents
10. Used any experimental drug not specified within the last 4 weeks or longer if the drug stays in the body longer.
11. Serious medical or mental health issues that could interfere with the study.
12. Cancer diagnosis or treatment within the past 2 years, except for certain skin cancers or cancers with a high cure rate.
13. Known allergy to Captisol® (used in the study drug).
14. Very low blood counts (hemoglobin, neutrophils, or platelets).
15. Positive for HIV, Hepatitis B, or Hepatitis C, unless Hepatitis C was successfully treated.
16. Severe infections needing treatment in the last 4 weeks.
17. Specific kidney infection (BK nephropathy) or high levels of BK virus.
18. Certain kidney biopsy results indicating other types of rejection or kidney diseases.
19. Treated for a specific viral infection (CMV) in the last 90 days or resistant to certain CMV treatments.
20. Received a live vaccine in the last 4 weeks.
21. Severe liver disease or abnormal liver tests.
22. Pregnant or breastfeeding women. Women who can become pregnant must have a negative pregnancy test or proof they are not pregnant.
23. Any other significant medical condition that could interfere with the study according to the doctor.
24. Received certain antibody treatments in the last 3 months.
25. Kidney rejection within 6 months post-transplant without standard care.
26. Confirmed severe protein levels in urine.
27. Underwent certain treatments from the time of entry DSA result and biopsy screening.
28. History of multiple unprovoked blood clots.
29. Diagnosed with Atypical Hemolytic Uremic Syndrome (aHUS).

Where this trial is running

Birmingham, Alabama and 9 other locations

• University of Alabama Medical Center — Birmingham, Alabama, United States (Not_yet_recruiting)
• Mayo Clinic Arizona — Phoenix, Arizona, United States (Not_yet_recruiting)
• UCLA Medical Center (Site #: 71123) — Los Angeles, California, United States (Not_yet_recruiting)
• Northwestern University, Feinberg School of Medicine — Chicago, Illinois, United States (Not_yet_recruiting)
• Washington University — St Louis, Missouri, United States (Not_yet_recruiting)
• NYU Langone Health — New York, New York, United States (Recruiting)
• Duke University — Durham, North Carolina, United States (Not_yet_recruiting)
• University of Cincinnati — Cincinnati, Ohio, United States (Not_yet_recruiting)
• Cleveland Clinic — Cleveland, Ohio, United States (Not_yet_recruiting)
• University of Wisconsin - Madison — Madison, Wisconsin, United States (Not_yet_recruiting)

Study contacts

• Principal investigator: Stuart J Knechtle, M.D. — Duke University Medical Center: Transplantation
• Study coordinator: Yvonne Morrison, MS

Conditions Kidney Transplant Rejection; Carfilzomib; Kidney transplant; Belatacept