The Safety/Efficacy Of Daratumumab With Belatacept In Highly HLA-Sensitized Patients Awaiting Kidney Transplantation

Study Overview
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Brief Summary
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While the number of kidney transplants is increasing worldwide every year, there is a clear imbalance between the high number of patients in the waiting list and those receiving a transplant and importantly, among waitlist patients there is a progressively higher number of highly sensitised patients that have very low or even no chance to receive a compatible organ. These patients remain for very long periods of time on dialysis therapy, having lower quality of life, lower life expectancy and produce higher health-related costs. Unfortunately, current desensitization therapies have shown very poor success and patients usually lose these grafts very fast if transplanted across a positive cross-match. Therefore, there is an urgent need for novel desensitization strategies capable of overcoming this immunological barrier and allow an increasing number of patients to receive a HLA-compatible kidney allograft.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 or TGI ≥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.

Detailed Description
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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 or TGI ≥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.

Official Title
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Non-Randomized, Single-Center Pilot Trial Assessing The Safety/Efficacy Of Targeting Peripheral And Central Humoral Alloimmune Memory With Daratumumab And With Belatacept In Highly HLA-Sensitized Patients Awaiting Kidney Transplantation

Conditions
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Sensitisation, Highly Sensitised Dialysis Patients

Intervention / Treatment
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* Combination Product: Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females age 18-70 years 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: Inability or unwillingness of a participant to give written informed consent or comply with study protocol 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients with cPRA ≥99%<br>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. | Combination Product: Each patient will undergo in the first step of the study belatacept treatment and in the second apheresis and daratumumab<br>* 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<br>* Other names: combination trial designed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of severe or medically significant Adverse and Serious Adverse Events | Proportion of severe or medically significant Adverse and Serious Adverse Events, defined by: Any grade 3 or higher infection (according to the CTCAE definition, i.e. IV antibiotic, antifungal, or antiviral intervention indicated; or invasive intervention indicated) during the interventional study period (6 months). Success will be defined by a proportion of toxicity below 17% (≤2/12). | end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the efficacy of dual targeting with anti-CD38 mAb daratumumab (Darzalex®) and co-stimulation blockade with belatacept (Nulojix®) in HLA-sensitized patients | Proportion of patients in whom ≥10 HLA antibodies (class I and/or class II) are eliminated (undetectable or <2000 MFI) OR cPRA(or TGI) decrease to <99% at the end of step I and at the end of step II. Success will be defined by an efficacy of 66% (≥8/12) | end of study | 
| Evaluate the impact of belatacept on anti-HLA antibody reduction using single antigen beads (SAB) in terms of MFI and specificities | Total number and mean number of HLA antibodies at the end of Step I (belatacept) as compared to baseline | Week 9 | 
| Evaluate the impact of belatacept on circulating Tfh cells compared to baseline belatacept therapy and at the end of this therapy (Step I). | Change in number and percentages of subtypes of circulating Peripheral T helper cells (TPH) including Tfh cells at the end of belatacept therapy | week 9 compared to baseline | 
| Evaluate the impact of belatacept on circulating HLA-specific mBC and their capacity to produce anti-HLA antibodies as well as numbers function of HLA-specific LLPC in bone marrow compared to baseline therapy and at the end of this therapy (Step I) | Proportion of patients with a reduction of circulating HLA-specific memory B cells (both class I and class II) | Week 9 | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on anti-HLA antibody reduction using single antigen beads (SAB) in terms of MFI and specificities | Change in number and mean number of HLA antibodies at the end of Step II (belatacept followed by daratumumab) | week 24 compared to baseline | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on circulating Tfh cells compared to baseline and the end of this dual therapy and at the time of a kidney transplantation, if any (Step II). | Change in number and percentages of subtypes of circulating Tfh cells at the end of dual therapy and at the time of an kidney transplantation as compared to baseline | week 24 compared to baseline | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on circulating HLA-specific mBc and their capacity to produce anti-HLA antibodies as well as numbers and function of LLPC in bone marrow compared to baseline and the end of this | Proportion of patients with a reduction of circulating HLA-specific memory B cells (both class I and class II) | week 24 | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on immunodominant HLA antibody (class I and Class II) at the end Step II as compared to baseline and as compared to the end of Step I | Mean reduction in MFI of the immunodominant HLA antibody, class I and Class II at the end Step II | week 24 | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on HLA-specific Antibody secreting cells (ASC) frequencies in bone marrow aspirates at the end of Step II as compared to baseline | Proportion of patients with a reduction of HLA-specific ASC frequencies in bone marrow aspirates | week 24 | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0' | End of study | 
| Evaluate the impact of the dual combination of belatacept and daratumumab on patients transplanted with a compatible donor | Proportion of patients transplanted with a compatible donor | week 18, week 24 | 
| In case of kidney transplantation, investigate the germinal center activation of iliac lymph nodes obtained at the time of kidney transplantation | At the time of kidney transplantation investigate the germinal center activation of iliac lymph nodes obtained during surgery | day of transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Highly sensitized kidney transplant, Desensitization, BELATACEPT, Daratumumab