Allosensitization, Antibody-mediated Rejection, Kidney Transplant Rejection
Conditions
Keywords
Allosensitization, Kidney Transplantation
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.
Interventions
DRUGDaratumumab 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
DRUGDaratumumab 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
Sponsors
Janssen, LP
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| Intra-patient variation of cPRA (calculated panel reactive antibodies) after daratumumab treatment | Baseline (Day 0) and at one month, three months and 12 months after daratumumab treatment. | PRA will be calculated on serum, analyzed with Luminex single antigen assays |
| 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 | At baseline (Day 0), three months, six months and 12 months after daratumumab treatment | ABO antibody titration will be performed by flow cytometry |
| Patient survival within one year after inclusion | Baseline (Day 0) and at six months after daratumumab treatment | — |
| 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 | — |
| Incidence of invasive infections | 6 months and on year after inclusion | — |
| 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. | — |
Countries
France
Outcome results
None listed