Carfilzomib and Belatacept for Desensitization

NCT05017545 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: DAIT ITN089STITN089STNIAID CRMS ID#: 38685
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Highly Sensitized Prospective Kidney Transplant Recipients

Keywords

calculated panel reactive antibodies (cPRA); desensitization therapy; human leukocyte antigen (HLA) desensitization

Outcome Measures

Primary Outcomes (4)

• Proportion of subjects who do not meet a stopping rule for safety and remain free of all of the following through 26 weeks (Cohort 1) after starting treatment 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 26 post treatment initiation or until receiving a transplant, whichever occurs earlier: 1. Grade 3 or higher infusion reaction, 2. Grade 3 or higher infections, and 3. 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 26 weeks post treatment initiation

• Proportion of subjects who do not meet a stopping rule for safety and remain free of all of the following through Week 24 (Cohort 2) 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 24 post treatment initiation or until receiving a transplant, whichever occurs earlier: 1. Grade 3 or higher infusion reaction, 2. Grade 3 or higher infections, and 3. 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 24 weeks post treatment initiation

• Proportion of subjects who achieve any one of the following compared to Baseline - Cohort 1

  Proportion of subjects who achieve any one of the following compared to Baseline (Visit 0): 1. Elimination of one human leukocyte antigen (HLA) antibody at Week 20 (which is Study Week 24) post treatment initiation, 2. 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 3. 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

• 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

  Proportion of subjects who meet any one of the following compared to Baseline (Visit 0): 1. Elimination of one human leukocyte antigen (HLA) antibody at Week 24 (which is Study Week 28) post treatment initiation, 2. 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Week 24 (which is Study Week 28) after starting treatment, and/or 3. Kidney transplant with a previously incompatible donor within 52 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 24 post treatment initiation

Secondary Outcomes (18)

• Proportion of subjects transplanted with a DSA-negative donor to whom DSA was previously positive, within 52 weeks after starting treatment

  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

  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

  Within 52 weeks post-transplant

• Proportion of subjects with invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 24 weeks after starting treatment

  Within 24 weeks post treatment initiation

• Proportion of subjects with invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 52 weeks after starting treatment

  Within 52 weeks post treatment initiation

Study Arms (2)

Cohort 1

EXPERIMENTAL

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; Biological: belatacept; Procedure: Bone marrow aspiration

Cohort 2

EXPERIMENTAL

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 28 (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; Biological: belatacept; Procedure: Bone marrow aspiration

Interventions

belatacept BIOLOGICAL

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.

Also known as: Nulojix®

Cohort 1; Cohort 2

Bone marrow aspiration PROCEDURE

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.

Cohort 1; Cohort 2

carfilzomib BIOLOGICAL

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.

Also known as: Kyprolis®

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 6 months prior to screening)
• Negative Hepatitis C antibody test at screening or as documented in medical record, up to 6 months prior to screening.

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• Bristol-Myers Squibb: collaborator
• PPD Development, LP: collaborator
• Rho Federal Systems Division, Inc.: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (1)

Duke Transplant Center, Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Related Links

• Immune Tolerance Network
• National Institute of Allergy and Infectious Diseases
• Division of Allergy, Immunology, and Transplantation

MeSH Terms

Interventions

carfilzomib; Abatacept

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins

Study Officials

• Stuart J. Knechtle, MD

  Duke Department of Surgery, Duke University School of Medicine

  STUDY CHAIR

• Annette M. Jackson, PhD

  Duke Department of Surgery, Duke University School of Medicine

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 17, 2021
• First Posted: August 24, 2021
• Study Start: December 28, 2021
• Primary Completion (Estimated): February 28, 2027
• Study Completion (Estimated): February 28, 2028
• Last Updated: April 8, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Time Frame: On average, within 24 months after database lock for the trial.
• Access Criteria: Open access.

Locations

US (1)