The Safety/Efficacy Of Daratumumab With Belatacept In Highly HLA-Sensitized Patients Awaiting Kidney Transplantation

NCT05145296 | Terminated Phase 2 DMC

• 1 other identifier: 38RC21.171
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

While the number of kidney transplants is increasing worldwide every year, there is a clear imbalance between the high number of patients in the waiting list and those receiving a transplant and importantly, among waitlist patients there is a progressively higher number of highly sensitised patients that have very low or even no chance to receive a compatible organ. These patients remain for very long periods of time on dialysis therapy, having lower quality of life, lower life expectancy and produce higher health-related costs. Unfortunately, current desensitization therapies have shown very poor success and patients usually lose these grafts very fast if transplanted across a positive cross-match. Therefore, there is an urgent need for novel desensitization strategies capable of overcoming this immunological barrier and allow an increasing number of patients to receive a HLA-compatible kidney allograft.This is a non-randomized, single arm study, combination trial designed according to the Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee. The study will enroll 12 patients with cPRA or TGI ≥99% on the deceased donor kidney transplant waiting list, who have not received a compatible donor offer for \>3 year. According to inclusion and exclusion criteria patients will be screened to participate in the trial.

Conditions

Sensitisation; Highly Sensitised Dialysis Patients

Keywords

Highly sensitized kidney transplant; Desensitization; BELATACEPT; Daratumumab

Outcome Measures

Primary Outcomes (1)

• Proportion of severe or medically significant Adverse and Serious Adverse Events

  Proportion of severe or medically significant Adverse and Serious Adverse Events, defined by: Any grade 3 or higher infection (according to the CTCAE definition, i.e. IV antibiotic, antifungal, or antiviral intervention indicated; or invasive intervention indicated) during the interventional study period (6 months). Success will be defined by a proportion of toxicity below 17% (≤2/12).

  end of study

Secondary Outcomes (12)

• Assess the efficacy of dual targeting with anti-CD38 mAb daratumumab (Darzalex®) and co-stimulation blockade with belatacept (Nulojix®) in HLA-sensitized patients

  end of study

• Evaluate the impact of belatacept on anti-HLA antibody reduction using single antigen beads (SAB) in terms of MFI and specificities

  Week 9

• Evaluate the impact of belatacept on circulating Tfh cells compared to baseline belatacept therapy and at the end of this therapy (Step I).

  week 9 compared to baseline

• Evaluate the impact of belatacept on circulating HLA-specific mBC and their capacity to produce anti-HLA antibodies as well as numbers function of HLA-specific LLPC in bone marrow compared to baseline therapy and at the end of this therapy (Step I)

  Week 9

• Evaluate the impact of the dual combination of belatacept and daratumumab on anti-HLA antibody reduction using single antigen beads (SAB) in terms of MFI and specificities

  week 24 compared to baseline

Study Arms (1)

Patients with cPRA ≥99%

OTHER

This is a non-randomized, single arm study, combination trial designed according to the Recommendations of the Clinical Trial Design Task Force of the NCI Investigational Drug Steering Committee. The study will enroll 12 patients with cPRA ≥99% on the deceased donor kidney transplant waiting list, who have not received a compatible donor offer for \>3 year. According to inclusion and exclusion criteria patients will be screened to participate in the trial.

Combination Product: Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab

Interventions

Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab COMBINATION_PRODUCT

Four consecutive cohorts each comprising 3 patients are planned. STEP I: Patients receive Belatacept 10mg/kg, administered on days 1, 5, end of week 2, 4 and 8 . Patients without a significant decrease in the global cPRA (cPRA or TGI ≥99%) or significant reduction of anti-HLA Ab MF will continue to the second step. STEP II: (15 weeks) One week after the last injection of belatacept, patients will undergo 4 sessions of apheresis (plasmapheresis (PF) or Immunoadsorption (IA)) which will be given every 48h. At week 11, patients will receive 4 doses of daratumumab (8mg/kg) every two weeks until week 17. Daratumumab will be alternated with 4 additional doses of belatacept 5 mg/kg FOLLOW-UP (24 weeks) All patients exiting the study, either having completed all treatment courses or exiting prematurely (transplanted or not), will be proposed monthly follow-up visits

Also known as: combination trial designed

Patients with cPRA ≥99%

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females age 18-70 years
• End Stage Renal Disease (ESRD) on dialysis
• Patient listed and active for a deceased donor kidney transplant and have not received compatible donor offer for ≥3 year.
• Calculated PRA ≥ 99%
• Positive CMV serology
• Positive EBV serology
• Current vaccination for more than one month for diphtheria, tetanus, poliomyelitis, influenza, pneumococcus, meningococcus, herpes zoster and SARS CoV-2.
• Patient affiliated to social security insurance or beneficiary of social security insurance

You may not qualify if:

• Inability or unwillingness of a participant to give written informed consent or comply with study protocol
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including HIV, hepatitis B, hepatitis C, zoster)
• Patient with positive hepatitis core antigen and/or positive hepatitis B surface antigen
• Serious uncontrolled concomitant major organ disease
• Any infection requiring hospitalization and intravenous antibiotics within 4 weeks of screening or Per os antibiotics within 2 weeks
• Primary or secondary immunodeficiency
• History of active tuberculosis (TB) (even if treated) or untreated latent TB
• Malignancy within the last 5 years except documented and treated basal and squamous cell cancer of the skin
• Alcohol, drug or chemical abuse within 1 year
• Difficult peripheral venous access
• Negative EBV serology
• Negative CMV serology
• Neutropenia (ANC \<1000/uL) or thrombocytopenia (platelet count \<100,000/uL) within 4 weeks prior to study entry
• Patient previously treated with investigational products (belatacept, daratumumab)
• Severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies

Sponsors & Collaborators

• University Hospital, Grenoble: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Chu Grenoble

La Tronche, 38700, France

Location

Related Publications (25)

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• Luque S, Lucia M, Crespo E, Jarque M, Grinyo JM, Bestard O. A multicolour HLA-specific B-cell FluoroSpot assay to functionally track circulating HLA-specific memory B cells. J Immunol Methods. 2018 Nov;462:23-33. doi: 10.1016/j.jim.2018.07.011. Epub 2018 Jul 31.

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• Lucia M, Luque S, Crespo E, Melilli E, Cruzado JM, Martorell J, Jarque M, Gil-Vernet S, Manonelles A, Grinyo JM, Bestard O. Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation. Kidney Int. 2015 Oct;88(4):874-87. doi: 10.1038/ki.2015.205. Epub 2015 Jul 15.

  PMID: 26176829 BACKGROUND

• Perry DK, Pollinger HS, Burns JM, Rea D, Ramos E, Platt JL, Gloor JM, Stegall MD. Two novel assays of alloantibody-secreting cells demonstrating resistance to desensitization with IVIG and rATG. Am J Transplant. 2008 Jan;8(1):133-43. doi: 10.1111/j.1600-6143.2007.02039.x.

  PMID: 18184311 BACKGROUND

• Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, Stegall MD. 32 Doses of Bortezomib for Desensitization Is Not Well Tolerated and Is Associated With Only Modest Reductions in Anti-HLA Antibody. Transplantation. 2017 Jun;101(6):1222-1227. doi: 10.1097/TP.0000000000001330.

  PMID: 27379560 BACKGROUND

• Kwun J, Burghuber C, Manook M, Iwakoshi N, Gibby A, Hong JJ, Knechtle S. Humoral Compensation after Bortezomib Treatment of Allosensitized Recipients. J Am Soc Nephrol. 2017 Jul;28(7):1991-1996. doi: 10.1681/ASN.2016070727. Epub 2017 Feb 23.

  PMID: 28232617 BACKGROUND

• Chen J, Yin H, Xu J, Wang Q, Edelblum KL, Sciammas R, Chong AS. Reversing endogenous alloreactive B cell GC responses with anti-CD154 or CTLA-4Ig. Am J Transplant. 2013 Sep;13(9):2280-92. doi: 10.1111/ajt.12350. Epub 2013 Jul 15.

  PMID: 23855587 BACKGROUND

• Yang J, Chen J, Young JS, Wang Q, Yin D, Sciammas R, Chong AS. Tracing Donor-MHC Class II Reactive B cells in Mouse Cardiac Transplantation: Delayed CTLA4-Ig Treatment Prevents Memory Alloreactive B-Cell Generation. Transplantation. 2016 Aug;100(8):1683-91. doi: 10.1097/TP.0000000000001253.

  PMID: 27362308 BACKGROUND

• Kim EJ, Kwun J, Gibby AC, Hong JJ, Farris AB 3rd, Iwakoshi NN, Villinger F, Kirk AD, Knechtle SJ. Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection. Am J Transplant. 2014 Jan;14(1):59-69. doi: 10.1111/ajt.12526.

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• Leibler C, Thiolat A, Henique C, Samson C, Pilon C, Tamagne M, Pirenne F, Vingert B, Cohen JL, Grimbert P. Control of Humoral Response in Renal Transplantation by Belatacept Depends on a Direct Effect on B Cells and Impaired T Follicular Helper-B Cell Crosstalk. J Am Soc Nephrol. 2018 Mar;29(3):1049-1062. doi: 10.1681/ASN.2017060679. Epub 2018 Jan 10.

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• Leibler C, Matignon M, Pilon C, Montespan F, Bigot J, Lang P, Carosella ED, Cohen J, Rouas-Freiss N, Grimbert P, Menier C. Kidney transplant recipients treated with belatacept exhibit increased naive and transitional B cells. Am J Transplant. 2014 May;14(5):1173-82. doi: 10.1111/ajt.12721. Epub 2014 Apr 14.

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Related Links

• EMA Summary of product characteristics - Nulojix.
• EMA Summary of product characteristics - Darzalex.
• 1\. Global Observatory on Donation and Transplantation. GODT at \<http://www.transplant-observatory.org/\>
• Global Observatory on Donation and Transplantation. GODT

MeSH Terms

Interventions

daratumumab

Study Officials

• Paolo Malvezzi, MD

  University Hospital, Grenoble

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2021
• First Posted: December 6, 2021
• Study Start: January 19, 2022
• Primary Completion: December 1, 2024
• Study Completion: October 10, 2025
• Last Updated: December 10, 2025

Record last verified: 2023-05

Locations

FR (1)