Clinical trial NCT04204980: Desensitization in Kidney Allograft Using Daratumumab
Official title: Desensitization in Kidney Allograft Recipients Before Transplantation Using Daratumumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Allosensitization
Kidney Transplant Rejection
Antibody-mediated Rejection
Keywords: Allosensitization
Kidney Transplantation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Janssen, LP
First posted: 2019-12-19
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: * 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 daratumumabProvide
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Serious adverse events (SAEs) and adverse event (AEs) related and unrelated to the treatment during the dose-escalation step
timeFrame: up to 21 months
measure: Intra-patient variation of cPRA after daratumumab treatment
timeFrame: Baseline (Day 0) and at six months after daratumumab treatment
Secondary outcomes:
measure: Patient survival within one year after inclusion
timeFrame: Baseline (Day 0) and at six months after daratumumab treatment
measure: Intra-patient variation of sum of mean fluorescence intensity (MFI) of anti-HLA antibodies
timeFrame: 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.
measure: Intra-patient variation of cPRA (calculated panel reactive antibodies) after daratumumab treatment
timeFrame: Baseline (Day 0) and at one month, three months and 12 months after daratumumab treatment.
measure: Percentage of patients engrafted
timeFrame: At six months and 12 months after inclusion
measure: Variation of immunoglobulin's blood titers
timeFrame: At baseline (Day 0), three months, six months and 12 months after daratumumab treatment
measure: Intra-patient variation of ABO antibody titers
timeFrame: At baseline (Day 0), three months, six months and 12 months after daratumumab treatment
measure: Incidence of invasive infections
timeFrame: 6 months and on year after inclusion
measure: Incidence of opportunistic infections
timeFrame: 6 months and one year after inclusion
measure: Absolute number of Blood plasma cell
timeFrame: At baseline (Day 0), one month, three months , six months and 12 months after daratumumab treatment
measure: Percentage of Blood plasma cell
timeFrame: At baseline (Day 0), one month, three months , six months and 12 months after daratumumab treatment
Other outcomes:
Locations:
city: Créteil
country: France
facility: Henri Mondor
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Marie Matignon, MD
role: STUDY_CHAIR
References: