Clinical trial NCT05145296: The Safety/Efficacy Of Daratumumab With Belatacept In Highly HLA-Sensitized Patients Awaiting Kidney Transplantation
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Sensitisation
Highly Sensitised Dialysis Patients
Keywords: Highly sensitized kidney transplant
Desensitization
BELATACEPT
Daratumumab
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2021-12-06
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of severe or medically significant Adverse and Serious Adverse Events
timeFrame: end of study
Secondary outcomes:
measure: Assess the efficacy of dual targeting with anti-CD38 mAb daratumumab (Darzalex®) and co-stimulation blockade with belatacept (Nulojix®) in HLA-sensitized patients
timeFrame: end of study
measure: Evaluate the impact of belatacept on anti-HLA antibody reduction using single antigen beads (SAB) in terms of MFI and specificities
timeFrame: Week 9
measure: Evaluate the impact of belatacept on circulating Tfh cells compared to baseline belatacept therapy and at the end of this therapy (Step I).
timeFrame: week 9 compared to baseline
measure: 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)
timeFrame: Week 9
measure: 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
timeFrame: week 24 compared to baseline
measure: 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).
timeFrame: week 24 compared to baseline
measure: 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
timeFrame: week 24
measure: 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
timeFrame: week 24
measure: 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
timeFrame: week 24
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: End of study
measure: Evaluate the impact of the dual combination of belatacept and daratumumab on patients transplanted with a compatible donor
timeFrame: week 18, week 24
measure: In case of kidney transplantation, investigate the germinal center activation of iliac lymph nodes obtained at the time of kidney transplantation
timeFrame: day of transplantation
Other outcomes:
Locations:
city: La Tronche
country: France
facility: Chu Grenoble
Study officials:
affiliation: University Hospital, Grenoble
name: Paolo Malvezzi, MD
role: PRINCIPAL_INVESTIGATOR
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