Desensitization in Kidney Allograft Using Daratumumab (DARDAR)

Desensitization in Kidney Allograft Recipients Before Transplantation Using Daratumumab

Patients highly allosensitized against HLA antigen awaiting for a kidney transplant have less compatible transplants to them, increasing their waitlist time and mortality. Current desensitization strategies need to be improved with a high remaining acute rejection rate in this population and a substantial survival benefit which is not uniformly reported in the literature. The investigators propose to use daratumumab, a human IgG1 (Immunoglobulin Gamma-1) monoclonal antibody directed against the CD38 molecule (cluster of differentiation 38) witch induce response in refractory multiple myeloma by depleting plasma cells, as a new agent of desensitization. The study will address the hypothesis that daratumumab can lead to a significant decrease in calculated panel reactive antibodies by elimination of anti-HLA antibodies-producing plasma cells and facilitate the access to transplantation with a safety profile in highly sensitized patients registered in our kidney transplantation center.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant Rejection; Antibody-mediated Rejection; Allosensitization
• Intervention / Treatment: Drug: Daratumumab dose escalation; Drug: Daratumumab full dose

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Marie Matignon, MD; Phone Number: +33149814451; Email: marie.matignon@aphp.fr
• Study Contact Backup: Name: Nizar Joher, MD; Email: nizar.joher@aphp.fr

Study Locations

• France
  • Créteil, France, 94000
    • Henri Mondor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults ≥ 18 years awaiting a kidney allograft transplantation
• Registration on the French National kidney allograft waiting-list for at least three years
• cPRA ≥ 95% for at least three years
• COVID-19 vaccination using Pfizer BioNtech vaccine for: Patients who have never been infected with COVID-19, inclusion at least one month after the third dose OR Patients previously infected with COVID-19 proved with PCR or serology, inclusion at least one month after the second injection of Pfizer BioNtech vaccine.
• Effective contraception up to three months after the end of treatment
• Informed consent obtained in accordance with local regulations;
• Affiliation to a social security regime.

Exclusion Criteria:

• Refusal of COVID-19 vaccination using Pfizer BioNtech vaccine
• Hypersensitivity to daratumumab or to any of the excipients),
• Known allergy to methylprednisolone and its excipients or to diphenhydramine and its excipients or to acetaminophen and its excipients or to valacyclovir and its excipients.
• Severe hepatocellular insufficiency
• Psychotic state not yet controlled by treatment
• Patient refusal
• Pregnant or breastfeeding woman or ineffective contraception
• Active neoplasia
• Active infection
• Active HBV infection, including HBsAg positive at screening
• Participation in another interventional study involving human participants or being in the exclusion period at the end of a previous study involving human participants
• Persons deprived of their liberty by judicial or administrative decision,
• Persons under legal protection/safeguard of justice,
• Patients under duress psychiatric care,
• Persons admitted to a health or social institution
• Patient on AME (state medical aid)
• Contraindication to kidney transplantation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose escalation and full dose; Step I: dose-escalation 3 patients treated weekly during four weeks with 4 mg/kg of daratumumab, then 3 patients treated weekly during four weeks with 8 mg/kg of daratumumab, then 3 patients treated weekly four weeks with 16 mg/kg of daratumumab Step II: expansion cohort to 13 patients (with 10 new patients included and the last 3 patients from the step I) with eight weekly doses of 16 mg/kg daratumumab

Drug: Daratumumab dose escalation; - Step I: dose-escalation 3 patients treated weekly during four weeks with 4 mg/kg of daratumumab, then 3 patients treated weekly during four weeks with 8 mg/kg of daratumumab, then 3 patients treated weekly four weeks with 16 mg/kg of daratumumab; Drug: Daratumumab full dose; - Step II: expansion cohort to 13 patients (with 10 new patients included and the last 3 patients from the step I) with eight weekly doses of 16 mg/kg daratumumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Serious adverse events (SAEs) and adverse event (AEs) related and unrelated to the treatment during the dose-escalation step	up to 21 months
Intra-patient variation of cPRA after daratumumab treatment	Baseline (Day 0) and at six months after daratumumab treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient survival within one year after inclusion		Baseline (Day 0) and at six months after daratumumab treatment
Intra-patient variation of sum of mean fluorescence intensity (MFI) of anti-HLA antibodies		Baseline (Day 0) and at one month, three months, six months and 12 months after daratumumab treatment.Baseline (Day 0) and at one, three, six and 12 months after daratumumab treatment.
Intra-patient variation of cPRA (calculated panel reactive antibodies) after daratumumab treatment	PRA will be calculated on serum, analyzed with Luminex single antigen assays	Baseline (Day 0) and at one month, three months and 12 months after daratumumab treatment.
Percentage of patients engrafted		At six months and 12 months after inclusion
Variation of immunoglobulin's blood titers		At baseline (Day 0), three months, six months and 12 months after daratumumab treatment
Intra-patient variation of ABO antibody titers	ABO antibody titration will be performed by flow cytometry	At baseline (Day 0), three months, six months and 12 months after daratumumab treatment
Incidence of invasive infections		6 months and on year after inclusion
Incidence of opportunistic infections		6 months and one year after inclusion
Absolute number of Blood plasma cell		At baseline (Day 0), one month, three months , six months and 12 months after daratumumab treatment
Percentage of Blood plasma cell		At baseline (Day 0), one month, three months , six months and 12 months after daratumumab treatment

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Janssen, LP
• Investigators: Study Chair: Marie Matignon, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): February 18, 2020
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: December 9, 2019
• First Submitted That Met QC Criteria: December 18, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Actual): March 19, 2024
• Last Update Submitted That Met QC Criteria: March 18, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Kidney Transplantation; Allosensitization
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Daratumumab; Antibodies, Monoclonal
• Other Study ID Numbers: APHP190500

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: DATAS ARE OWN BY ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, PLEASE CONTACT SPONSOR FOR FURTHER INFORMATION

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No