Treg Modulation With CD28 and IL-6 Receptor Antagonists

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of using lulizumab pegol with tocilizumab, belatacept, and everolimus in kidney transplant recipients.

Detailed Description
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This research study is for adults who are planning to have a kidney transplant from a living donor. In Brief: Those who have a transplant take immunosuppressive therapy to prevent the body from rejecting the transplanted organ. Rejection occurs when the body's defense system (immune cells) recognizes the transplant as a foreign object. These immune cells and the substances they produce can damage the transplanted kidney. It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible. Most transplant doctors in the United States give a combination of two or three drugs to prevent rejection. People with a transplant must take these drugs every day. Although kidney transplant recipients usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and avoid the side effects that the current drugs can cause. This study will test a new combination of four drugs to evaluate whether this combination is safe for kidney transplant recipients: lulizumab pegol (BMS-931699) tocilizumab belatacept and everolimus. Belatacept and everolimus are already approved for use as anti-rejection drugs in kidney transplant recipients. Lulizumab pegol and tocilizumab act on specific molecules (specifically CD28 and interleukin 6, respectively) on immune cells: these actions are different from how the older rejection drugs work. Summary: This is a prospective multicenter open-label clinical trial of 10 living donor kidney transplant recipients. Safety of lulizumab pegol (BMS-931699) in the context of a novel immunosuppressive regimen (anti-thymocyte globulin (rabbit) (ATG), steroids,) Nulojix® (belatacept), Actemra® (tocilizumab), and Zortress®(everolimus)) will be assessed. Study participation involves a minimum of one year of follow-up post-transplant. *** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Clinical Trials in Organ Transplantation (CTOT) do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Official Title
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Regulatory T Cell Modulation in Kidney Transplantation With Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 (CTOT-24)

Conditions
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Living-Donor Kidney Transplant, Kidney Transplant Recipients

Intervention / Treatment
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* Biological: lulizumab pegol
* Biological: antithymocyte globulin (rabbit)
* Drug: methylprednisolone
* Biological: tocilizumab
* Drug: Prednisone
* Drug: everolimus
* Biological: belatacept
* Drug: mycophenolate mofetil
* Drug: mycophenolic acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals who meet all the following criteria are eligible for enrollment as study participants: Able to understand and provide informed consent Agreement to use highly effective (<1% failure rate) methods of contraception: Women of Childbearing Potential (WOCBP)- Progestogen only hormonal contraception associated with inhibition of ovulation, Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen + progesterone, vagina ring, injectables, implants and intrauterine devices (IUDs), Non-hormonal IUDs, Bilateral tubal occlusion, Vasectomized partner, Intrauterine hormone-releasing system (IUS), or Complete abstinence. Note: Female participants of childbearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 12 months while on study drug regimen. Male Participants- --Must use a latex or other synthetic condom during any sexual activity with WOCBP until one month after the last dose of lulizumab (e.g., up to 3.5 months in duration). Recipient of primary, nonhuman leukocyte antigen identical living donor kidney transplant No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator Epstein-Barr virus (EBV) positive serology Cytomegalovirus (CMV) positive serology, unless donor-recipient pair are both CMV negative Negative testing for latent Tuberculosis (TB) infection within 3 months prior to transplant Testing should be conducted using either a purified protein derivative (PPD) or an interferon-gamma release assay blood test for TB (i.e. QuantiFERON®-TB Gold in-Tube test or T-SPOT® TB test) Subjects with a positive test for latent TB infection must complete appropriate therapy for Latent tuberculosis infection (LTBI). ---A subject is considered eligible only if they have a negative test for LTBI within 3 months prior to transplant or, they have appropriately completed LTBI therapy prior to transplant. Note: Latent TB infection treatment regimens should be among those endorsed by the CDC (Division of TB Elimination, 2016). In the absence of contraindication, vaccinations must be up to date for hepatitis B, influenza, pneumococcal, varicella and herpes zoster, and measles, mumps, and rubella (MMR) Hepatitis C Virus (HCV) antibody positive subjects with negative HCV by PCR testing are eligible if they: have spontaneously cleared infection, or are in sustained virologic remission for at least 12 weeks after treatment for HCV. Negative SARS-CoV-2 PCR test result performed within 2 weeks of transplant (SARS-CoV-2 is the virus that causes COVID-19) Exclusion Criteria: Individuals who meet any of these criteria are not eligible for enrollment as study participants- Prisoners or subjects who are compulsorily detained Inability or unwillingness of a participant to give written informed consent or comply with study protocol Candidate for a multiple solid organ or tissue transplants Prior history of organ or cellular transplantation Known to have idiopathic focal segmental glomerulosclerosis (FSGS) as the underlying cause of kidney failure (ESRD) Requirement for uninterrupted anticoagulation therapy, including Plavix. Known hypersensitivity to mechanistic target of rapamycin (mTOR) inhibitors or contraindication to everolimus (including history of wound healing complications) History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies Hypersensitivity to rabbit proteins or rabbit anti-thymocyte Globulin (ATG) Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol (BMS-931699) The human immunodeficiency virus (HIV) infected subjects, including those who are well controlled on antiretrovirals Positive hepatitis B surface antigen (HBSAg), or hepatitis B core antibody (HBcAB) serology Hepatitis C virus antibody positive (HCV Ab+) subjects who have failed to demonstrate sustained viral remission for more than 12 weeks after anti-viral treatment Subjects with a previous history of active Tuberculosis (TB) Known active current viral, fungal, mycobacterial or other infections (including, but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster) Donor or recipient residing in areas where the annual incidence ≥ 21 cases per 100,000) for coccidioidomycosis according to current CDC map: (https://www.cdc.gov/fungal/diseases/coccidioidomycosis/causes.html) Donors or recipients residing in low risk zones (annual <21 cases per 100,000) will not require additional screening History of malignancy except treated basal cell cancer of the skin History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy) History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation Receipt of a live vaccine within 30 days prior to transplantation. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may: pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study Severe hyperlipidemia (defined by total cholesterol >350 mg/dL, LDL >190 mg/dL, or triglycerides >500 mg/dL) Transaminase levels elevated more than 1.5 times the upper limit of normal (ULN) within 7 days prior to enrollment The absolute neutrophil count (ANC) < 2,000 per mm^3 within 7 days prior to enrollment Platelet count less than 100,000 per mm^3 within 7 days prior to enrollment More than 50% CD8+/ CD28- T-cells in peripheral blood A calculated panel reactive antibody (cPRA) ≥20%, as determined by each participating site's laboratory Positive pregnancy test in women of child bearing potential, currently breastfeeding, or planning to become pregnant during the timeframe of the study or follow-up period Participation in any other studies with investigational drugs or regimens in the preceding year A history of a positive SARS-CoV-2 PCR test result (SARS-CoV-2 is the virus that causes COVID-19)

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 |
| --- | --- |
| Experimental: lulizumab pegol + novel ISR<br>lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus) | Biological: lulizumab pegol<br>* 25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11)<br>* Other names: BMS-931699;Biological: antithymocyte globulin (rabbit)<br>* 1.5 mg/kg intravenously (IV) on Day 0 (day of transplantation) and the day following (Day 1)<br>* Other names: Thymoglobulin®;Drug: methylprednisolone<br>* 500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2<br>* Other names: Solu-Medrol ®;Biological: tocilizumab<br>* 8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24)<br>* Other names: Actemra®;Drug: Prednisone<br>* Beginning on Day 3 post transplantation, taken orally: 60 mg daily Days 4 through 10: 30 mg daily Days 11 through 17: 20 mg daily Days 18 through 24: 10 mg daily After Day 24: continued taper of dose to final maintenance dose of 5 mg, per protocol<br>* Other names: Rayos®;Drug: everolimus<br>* Initial dose of 0.75 mg taken orally twice daily on Day 14 days after transplantation. Dose will be titrated to target trough levels 3-8 ng/mL.<br>* Other names: Zortress®;Biological: belatacept<br>* 5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52)<br>* Other names: Nulojix®;Drug: mycophenolate mofetil<br>* An option for participants who do not tolerate everolimus: to be switched to either mycophenolate mofetil 1000 mg administered orally twice daily or mycophenolic acid<br>* Other names: CellCept®;Drug: mycophenolic acid<br>* An option for participants who do not tolerate everolimus: to be switched to either mycophenolic acid 720 mg taken orally twice daily or mycophenolate mofetil<br>* Other names: Myfortic®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria | Definitions: Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection. Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury. Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms. | 6 months post transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria | Definitions: Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection. Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury. Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms. | 12 months post transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult living-donor kidney transplant recipients, novel immunosuppressive (IS) therapy regimen, lulizumab pegol (BMS-931699), CD28 and IL-6 biologic blockade, CD28 and IL-6 receptor antagonists, T regulatory cells (Treg) modulation