The Safety/Efficacy Of Daratumumab With Belatacept In Highly HLA-Sensitized Patients Awaiting Kidney Transplantation
NCT ID: NCT05145296
Last Updated: 2025-12-10
Study Results
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Basic Information
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TERMINATED
PHASE2
5 participants
INTERVENTIONAL
2022-01-19
2025-10-10
Brief Summary
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Detailed Description
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Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Patients with cPRA ≥99%
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.
Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab
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
Interventions
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Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
* Hypersensitivity to any active substance or component of the investigational medicinal products
* Any contra-indication to premedication drugs (paracetamol, dexchlorpheniramine, cetirizine, dexamethasone, montelukast) or post-medication drugs (corticosteroids, bronchodilators, valaciclovir)
* Immunization with live vaccine within 2 months of study entry
* Dry body weight ≥75kg.
* Pregnancy or lactation
* Females with childbearing status, defined as a premenopausal female capable of becoming pregnant, and not using an effective form of birth control. Effective birth control methods include oral, implant or patch hormone contraception; intrauterine device; abstinence and outercourse; tubal ligation; vasectomy.
* Participant involved in another interventional clinical study
* Person deprived of liberty by judicial order
* Person under guardianship or curatorship
18 Years
70 Years
ALL
No
Sponsors
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Bristol-Myers Squibb
INDUSTRY
University Hospital, Grenoble
OTHER
Responsible Party
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Principal Investigators
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Paolo Malvezzi, MD
Role: PRINCIPAL_INVESTIGATOR
University Hospital, Grenoble
Locations
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Chu Grenoble
La Tronche, , France
Countries
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References
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Wiebe C, Tambur A, Nickerson PW. A call to action-The transplant recipient's expectation of precision in transplant medicine. Am J Transplant. 2018 Dec;18(12):2845-2846. doi: 10.1111/ajt.15027. Epub 2018 Aug 13. No abstract available.
Kiernan JJ, Ellison CA, Tinckam KJ. Measuring alloantibodies: a matter of quantity and quality. Curr Opin Organ Transplant. 2019 Feb;24(1):20-30. doi: 10.1097/MOT.0000000000000593.
Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M. Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant. 2014 Feb;14(2):255-71. doi: 10.1111/ajt.12589. Epub 2014 Jan 8.
Formica RN Jr, Kulkarni S. Being Thoughtful about Desensitization. Clin J Am Soc Nephrol. 2017 Nov 7;12(11):1878-1880. doi: 10.2215/CJN.09000817. Epub 2017 Oct 3. No abstract available.
Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant. 2015 May;15(5):1293-302. doi: 10.1111/ajt.13168. Epub 2015 Mar 2.
Loupy A, Lefaucheur C. Antibody-Mediated Rejection of Solid-Organ Allografts. N Engl J Med. 2018 Sep 20;379(12):1150-1160. doi: 10.1056/NEJMra1802677. No abstract available.
Pruthi R, Hilton R, Pankhurst L, Mamode N, Hudson A, Roderick P, Ravanan R. UK Renal Registry 16th annual report: chapter 4 demography of patients waitlisted for renal transplantation in the UK: national and centre-specific analyses. Nephron Clin Pract. 2013;125(1-4):81-98. doi: 10.1159/000360023. Epub 2014 Feb 14.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, Moal MC, Mondragon-Ramirez GA, Kothari J, Polinsky MS, Meier-Kriesche HU, Munier S, Larsen CP. Belatacept and Long-Term Outcomes in Kidney Transplantation. N Engl J Med. 2016 Jan 28;374(4):333-43. doi: 10.1056/NEJMoa1506027.
Bray RA, Gebel HM, Townsend R, Roberts ME, Polinsky M, Yang L, Meier-Kriesche HU, Larsen CP. Posttransplant reduction in preexisting donor-specific antibody levels after belatacept- versus cyclosporine-based immunosuppression: Post hoc analyses of BENEFIT and BENEFIT-EXT. Am J Transplant. 2018 Jul;18(7):1774-1782. doi: 10.1111/ajt.14738. Epub 2018 Apr 17.
Kwun J, Burghuber C, Manook M, Ezekian B, Park J, Yoon J, Yi JS, Iwakoshi N, Gibby A, Hong JJ, Farris AB, Kirk AD, Knechtle SJ. Successful desensitization with proteasome inhibition and costimulation blockade in sensitized nonhuman primates. Blood Adv. 2017 Oct 26;1(24):2115-2119. doi: 10.1182/bloodadvances.2017010991. eCollection 2017 Nov 14.
Alishetti S, Farr M, Jennings D, Serban G, Uriel N, Sayer G, Vasilescu R, Restaino S, Chong AS, Habal MV. Desensitizing highly sensitized heart transplant candidates with the combination of belatacept and proteasome inhibition. Am J Transplant. 2020 Dec;20(12):3620-3630. doi: 10.1111/ajt.16113. Epub 2020 Jul 7.
Jain D, Rajab A, Young JS, Yin D, Nadasdy T, Chong AS, Pelletier RP. Reversing donor-specific antibody responses and antibody-mediated rejection with bortezomib and belatacept in mice and kidney transplant recipients. Am J Transplant. 2020 Oct;20(10):2675-2685. doi: 10.1111/ajt.15881. Epub 2020 Apr 28.
Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, Blanco L, Lasa M, Maiso P, Rodriguez I, Garate S, Jelinek T, Segura V, Moreno C, Merino J, Rodriguez-Otero P, Panizo C, Prosper F, San-Miguel JF, Paiva B. The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma. Clin Cancer Res. 2019 May 15;25(10):3176-3187. doi: 10.1158/1078-0432.CCR-18-1597. Epub 2019 Jan 28.
Kwun J, Matignon M, Manook M, Guendouz S, Audard V, Kheav D, Poullot E, Gautreau C, Ezekian B, Bodez D, Damy T, Faivre L, Menouche D, Yoon J, Park J, Belhadj K, Chen D, Bilewski AM, Yi JS, Collins B, Stegall M, Farris AB, Knechtle S, Grimbert P. Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use. J Am Soc Nephrol. 2019 Jul;30(7):1206-1219. doi: 10.1681/ASN.2018121254. Epub 2019 Jun 21.
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Related Links
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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
Other Identifiers
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38RC21.171
Identifier Type: -
Identifier Source: org_study_id
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