Daratumumab and Belatacept for Desensitization

NCT04827979 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: DAIT ITN090STUM1AI109565NIAID CRMS ID#: 38686
• Study Type: interventional
• Target: 19
• 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 on waitlist. The purpose of this study is to find out whether two drugs, daratumumab (Darzalex®), 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 (3)

• Proportion of subjects who have not met a subject stopping rule and remain free of all of the safety events listed in the outcome description, through 26 weeks 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 26 weeks after starting treatment or until receiving a transplant, whichever occurs earlier: 1. Grade 3 or higher infusion reaction 2. Grade 3 or higher infections 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).

  Baseline up to 26 weeks post treatment initiation

• Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to Week 26 - Cohort 1

  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 Visit 12 (16 weeks ±7 days after starting treatment); 2. 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Visit 12 (16 weeks ±7 days after starting treatment); and/or 3. Kidney transplant with a previously incompatible donor within 26 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) up to 26 weeks post treatment initiation

• Proportion of subjects who meet any one of the pre-specified events detailed in the outcome description: from Baseline up to Week 26 - 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 Visit 14 (26 weeks ±7 days after starting treatment); 2. 50% or greater reduction in the mean fluorescence intensity (MFI) of at least three HLA antibodies at Visit 14 (26 weeks ±7 days 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) up to 52 weeks post treatment initiation

Secondary Outcomes (11)

• Proportion of subjects transplanted with a previously incompatible donor within 52 weeks after starting treatment - Cohort 1

  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

• Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 16 weeks after starting treatment

  Within 16 weeks post treatment initiation

• Incidence of invasive fungal infections, mycobacterial infections or Pneumocystis jirovecii infection within 26 weeks after starting treatment

  Within 26 weeks post treatment initiation

Study Arms (2)

Cohort 1 (N=5 Subjects)

EXPERIMENTAL

Multiple intravenous infusions of daratumumab and belatacept over 10 weeks: * Daratumumab will be administered intravenously at a dose of 8 mg/kg weekly for 4 weeks, then every other week for 4 weeks (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, and 14). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit, and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%.

Biological: daratumumab; Biological: belatacept; Procedure: Bone marrow aspiration

Cohort 2 (N=10 Subjects)

EXPERIMENTAL

The enrollment of ten additional subjects is dependent on the results in Cohort 1. Multiple intravenous infusions of daratumumab and belatacept over 14 weeks:° * Daratumumab will be administered intravenously at a dose of 8 mg/kg for the first dose, then 16 mg/kg for subsequent given weekly for 3 weeks, then every 2 weeks for 2 doses (week 9 and week 11). The dose administered will be calculated based on the actual body weight of the subject at each visit. * Belatacept will be administered intravenously at a dose of 10 mg/kg every 2 weeks starting at week 8 (dosed at weeks 8, 10, 12, 14, 16 and 18). The total infusion dose of belatacept will be based on the actual body weight of the subject at the baseline visit and will not be modified during the course of therapy, unless there is a change in body weight of greater than 10%. * Was modified based on the safety and efficacy analysis of Cohort 1.

Biological: daratumumab; Biological: belatacept; Procedure: Bone marrow aspiration

Interventions

daratumumab BIOLOGICAL

Daratumumab is a CD38 (Cluster of Differentiation 38)-directed cytolytic monoclonal antibody indicated for the treatment of multiple myeloma. In this study, daratumumab will be used in highly sensitized subjects without myeloma who are awaiting a kidney transplant. Definition of highly sensitized: Potential kidney transplant recipients with either: * calculated panel reactive antibodies (cPRA) ≥99.9% awaiting deceased donor transplant, or * cPRA \>98% (with \>5 years of waiting time) awaiting living donor transplant

Also known as: Darzalex®, immunoglobulin G1 kappa human monoclonal antibody, IgG1k human mAb

Cohort 1 (N=5 Subjects); Cohort 2 (N=10 Subjects)

belatacept BIOLOGICAL

Belatacept, a monoclonal antibody, is indicated for the prophylaxis of organ rejection in adult patients receiving a kidney transplant. In this study, belatacept will be used in subjects who have not received a kidney transplant.

Also known as: Nulojix®

Cohort 1 (N=5 Subjects); Cohort 2 (N=10 Subjects)

Bone marrow aspiration PROCEDURE

Subjects will undergo a bone marrow aspiration prior to starting the study regimen and at 12 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 (N=5 Subjects); Cohort 2 (N=10 Subjects)

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 listed with current calculated panel reactive antibodies (cPRA) ≥99.9% or \>98% (with \>5 years of waiting time) awaiting deceased donor transplant
• Note: Those with cPRA \>98% with human leukocyte antigen (HLA)-incompatible approved living donor who have not received a transplant after 1 year in a paired kidney exchange program are also eligible
• 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 TB infection (LTBI) therapy.
• Testing should be conducted using either a PPD or interferon-gamma release assay (i.e., QuantiFERON-TB, T-SPOT.TB)
• 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 for LTBI must complete appropriate therapy for LTBI ---LTBI treatment regimens should be among those endorsed by the Centers for
• Disease Control and Prevention (CDC), Division of TB Elimination, 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 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 HCV RNA are eligible.

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 or non-tuberculous mycobacterial infection
• Hepatitis B surface antigen or core antibody positive
• Serious uncontrolled concomitant major organ disease excluding kidney failure
• Previous non-kidney solid organ or bone marrow transplant
• Any infection requiring hospitalization and intravenous (IV) antibiotics within 4 weeks of screening or by mouth (PO) antibiotics within 2 weeks
• Primary or secondary immunodeficiency
• History of active tuberculosis (TB), even if treated
• History of positive result for 2019-novel Coronavirus (2019-nCoV) by real-time reverse transcriptase (RT-PCR)
• Malignancy within the last 5 years except treated basal and squamous cell cancer of the skin or treated in situ cervical cancer
• History of plasma cell dyscrasia
• Alcohol, drug, or chemical abuse within 1 year
• Difficult peripheral venous access
• Need for uninterrupted anticoagulation

Sponsors & Collaborators

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

Study Sites (1)

University of California at San Francisco Medical Center

San Francisco, California, 94143, United States

Location

Related Links

• Division of Allergy, Immunology, and Transplantation (DAIT)
• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

MeSH Terms

Interventions

daratumumab; Abatacept

Intervention Hierarchy (Ancestors)

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

Study Officials

• Flavio G. Vincenti

  UCSF Kidney Transplant Research

  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: March 30, 2021
• First Posted: April 1, 2021
• Study Start: November 1, 2021
• Primary Completion (Estimated): March 31, 2027
• Study Completion (Estimated): April 30, 2028
• Last Updated: January 20, 2026

Record last verified: 2026-01

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)