Desensitization in Kidney Allograft Using Daratumumab

Study Overview
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Brief Summary
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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.

Official Title
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Desensitization in Kidney Allograft Recipients Before Transplantation Using Daratumumab

Conditions
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Allosensitization, Kidney Transplant Rejection, Antibody-mediated Rejection

Intervention / Treatment
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* Drug: Daratumumab dose escalation
* Drug: Daratumumab full dose


Participation Criteria
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Eligibility Criteria
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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 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: 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/security 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation and full dose<br>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<br>* - 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<br>Drug: Daratumumab full dose<br>* - 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allosensitization, Kidney Transplantation