A Study to Evaluate the Safety and Efficacy of Dual Costimulation Blockade With VIB4920 and Belatacept for Prophylaxis of Allograft Rejection in Adults Receiving a Kidney Transplant

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and tolerability of dual costimulation blockade with VIB4920 in combination of belatacept in adult male or female recipients of a renal allograft from a deceased, living unrelated or human leukocyte antigen (HLA) non-identical living related donor.

Official Title
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A Phase 2a Single-arm, Prospective, Open-label Pilot Study to Evaluate the Safety and Efficacy of Dual Costimulation Blockade With VIB4920 and Belatacept for Prophylaxis of Allograft Rejection in Adults Receiving a Kidney Transplant

Conditions
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Allografts, Rejection; Transplant, Kidney, Transplant Rejection, Kidney Transplantation

Intervention / Treatment
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* Drug: Belatacept
* Drug: VIB4920
* Drug: Thymoglobulin
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipients of a first renal transplant from standard criteria deceased, living unrelated or HLA non-identical living related donor. Recipients who are at low immunologic risk: No donor specific antibodies (DSA), and Negative cross-match testing. Recipients with up to date vaccination as per local immunization schedules. Male and female participants who agree to follow protocol defined contraceptive methods. Exclusion Criteria: Participants receiving an allograft from an ABO-incompatible donor. Participants treated with systemic immunosuppressive drug therapy for more than a total of 2 weeks within 24 weeks prior to informed consent form signature. Participants who have undergone lymphodepleting therapy. Participants with medical history of confirmed venous thromboembolism, arterial thrombosis, coagulopathy or known platelet disorders. Participants with risk factors for venous thromboembolism or arterial thrombosis, prothrombotic status. Participants requiring treatment with antithrombotic drugs (clopidogrel, prasugrel, warfarin, others). Participants requiring long-term systemic anticoagulation after transplantation, which would interfere with obtaining biopsies. Participants with any contraindication to kidney biopsy. Cytomegalovirus (CMV)-seronegative recipients of a CMV-seropositive donor kidney, or unknown CMV serostatus. Epstein-Barr virus (EBV)-seronegative or with unknown EBV serostatus. Receipt of live (attenuated) vaccine within the 4 weeks before screening. Participants with high potential of graft loss due to recurrence of underlying kidney disease. Prior solid organ transplant or potential to require a concurrent organ or cell transplant. Previous treatment with belatacept and cluster of differentiation 40 (CD40) or anti-CD40L agents. Use of B cell depleting therapy, non-depleting B cell directed therapy e.g., belimumab or abatacept within 1 year prior to enrolment. At screening blood tests any of the following: Aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) > 2.5 × ULN Alkaline phosphatase (ALP) > 2.5 × ULN Total bilirubin (TBL) > 2 × ULN Hemoglobin < 75 g/L Neutrophils < 1.5 × 10^9/L Platelets < 100 × 10^9/L Participants with severe systemic infections, current or within the 2 weeks prior to transplant surgery. Positive test for chronic hepatitis B infection at screening or within the last 12 months. Positive test for hepatitis C virus antibody at screening or within the last 12 months. Positive test for human immunodeficiency viruses antibody at screening or within the last 12 months. History of or active tuberculosis (TB), or a positive QuantiFERON®-TB Gold test at screening, unless previously treated for latent tuberculosis. History of cancer, except as follows: In situ carcinoma of the cervix treated with apparent success with curative therapy > 12 months prior to screening; or Cutaneous basal cell or squamous cell carcinoma treated with apparent success with curative therapy. Lactating or pregnant females.

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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belatacept+VIB4920<br>Participants will be admitted to the transplant center for the administration of VIB4920 and belatacept (with Thymoglobulin and corticosteroids) and will be discharged on Day 3/4 at the discretion of the investigator. Participants will return to the study center to receive study drugs (VIB4920 and /or belatacept) weekly for 2 visits, then every 2 weeks for 5 visits, and then monthly for 9 visits for safety monitoring. | Drug: Belatacept<br>* Protocol versions 1 through 4: Belatacept 10 mg/kg by intravenous (IV) infusion on post-op Day 1, repeated on post-op Day 3 or 4 (timing is at investigator's discretion), and at the end of Weeks 2, 4, 8 and 12; then 5 mg/kg IV every 4 weeks from Week 16 to Week 48.<br>Drug: VIB4920<br>* Protocol versions 1 and 2: VIB4920 1500 mg by IV infusion on post-op Days 1 and 14, and at the end of Weeks 4, 6, 8 and 10; then 1500 mg every 4 weeks from Week 12 to Week 48. Protocol versions 3 and 4: VIB4920 1500 mg by IV infusion on post-op Days 1, repeated on post-op Day 3 or 4 (timing is at investigator's discretion), Week 2, and at the end of Weeks 4, 6, 8, and 10; then 1500 mg every 4 weeks from Week 12 to Week 48.<br>Drug: Thymoglobulin<br>* Protocol versions 1 and 2: Thymoglobulin 3.0 mg/kg by intravenous (IV) infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0) (1 dose). Protocol versions 3 and 4: Thymoglobulin 1.5 mg/kg by intravenous infusion prior to reperfusion of the allograft on the day of transplantation surgery (Day 0), prior to VIB4920+belatacept infusion on post-op Day 1, on post-op Day 2, and prior to VIB4920+belatacept infusion on post-op Day 3 or 4.<br>Drug: Methylprednisolone<br>* Protocol versions 1 and 2: Methylprednisolone by IV infusion (500, 250, 125 and 60 mg on Days 0, 1, 2 and 3, respectively) followed by oral administration of prednisone 30 mg per day on Days 4, 5, and 6. Protocol versions 3 and 4: Methylprednisolone by IV infusion (500, 250, 125 and 60 mg on Days 0, 1, 2 and 3, respectively) followed by oral administration of prednisone 30 mg per day on Days 4, 5, 6 and 7. Participants may be tapered to at least 20 mg per day on Day 8, to at least 10 mg per day on Day 15, and to at least 5 mg per day on Day 22. Discontinuation of prednisone following the post-op Day 28 visit.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Week 24 | Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) of Grade 1A or Higher, Graft Loss or Death at Weeks 12 and 48 | Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. | Weeks 12 and 48 | 
| Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR), Graft Loss, Death or Loss to Follow-up (LTFU) | Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. | Week 12, 24, 48 | 
| Percentage of Participants With Antibody-Mediated Rejection | The diagnosis of antibody-mediated rejection was based on Banff criteria 2017 - a set of standardized guidelines used by pathologists and clinicians to diagnose and classify rejection based on specific features observed in biopsy samples from the transplanted organ, such as the presence of certain types of immune cells, inflammation, and injury patterns. | Week 12, 24, 48 | 
| Percentage of Participants With Treated Biopsy-proven Acute Rejection (tBPAR) | Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. | Week 12, 24, 48 | 
| Percentage of Participants With Biopsy Proven Acute Rejection (BPAR) | Histological grading of acute allograft rejection from biopsy specimens was based on Banff criteria 2017. Grade IA: Moderate tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade IB: Severe tubulitis and at least moderate total cortical inflammation and at least moderate scarred cortical inflammation and other known causes ruled out. Grade II. Arterial intimal fibrosis with mononuclear cell inflammation, formation of neointima. | Week 12, 24, 48 | 
| Percentage of Participants With Treated Acute Rejections | Acute rejections, per clinical judgement of the investigator followed by confirmatory biopsy, were treated with bolus methylprednisolone (other corticosteroids were acceptable at an equivalent dose) according to local practice. | Week 12, 24, 48 | 
| Percentage of Participants With De Novo Donor-specific Antibodies (dnDSA) | Serum samples were collected for de novo donor-specific antibodies (dnDSA) using solid phase (bead-based) assays. | Week 12, 24, 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal allograft dysfunction, Cell-mediated rejection, Antibody mediated rejection, Immunosuppression, Acute rejection, VIB4920, MEDI4920, Belatacept, Thymoglobulin, Methylprednisolone, Corticosteroids