Belatacept Post Depletional Repopulation to Facilitate Tolerance

Study Overview
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Brief Summary
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Acute rejection is a common problem after a kidney transplant. Rejection can occur when the kidney recipient's immune system tries to attack (or reject) the new kidney. Rejection typically most often develops in the first few months after a transplant. This single center study will seek to determine if a new combination of anti-rejection medications, including the recently FDA approved drug called Belatacept, is better than the current standard anti-rejection drug regimen at preventing rejection. Also to be determined will be whether the new combination of drugs will allow participants to wean off their oral anti-rejection medications over time. This study will test the safety and effectiveness of a new investigational drug combination using alemtuzumab, belatacept, and sirolimus when given with or without donor bone marrow. This combination of medicines has not been tested before in humans. Alemtuzumab (Campath) is approved for use in some types of white blood cell cancers, but is considered investigational in transplant patients. Belatacept is now FDA approved and is being studied in transplant patients. Sirolimus (Rapamune) is approved for use in transplant patients, but its use with belatacept and alemtuzumab is investigational. In the initial 20 subjects enrolled in the study, half tested whether an infusion of bone marrow from the kidney donor would improve the effect of these drugs. This bone marrow infusion was also considered investigational. Enrollment of 20 additional subjects began in January, 2013. The donor bone marrow infusion has been eliminated. Enrollment was open to primary living and deceased donor kidney recipients. Enrollment was closed as of 8/12/2014.

Detailed Description
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This study will be a single-center, open-label,proof of concept study in non-human leukocyte antigen (HLA)-identical living and deceased donor renal transplants. The initial 20 subjects were randomized to either receive/not to receive a single donor bone marrow infusion in addition to the investigational combination of alemtuzumab, belatacept, and sirolimus. Since the bone marrow infusion has been eliminated in the second group of 20 subjects, no randomization was required. All recipients in the second group of 20 subjects will receive the same investigational combination of alemtuzumab, belatacept, and sirolimus. At the time of transplant, participants will receive a 3-hour IV infusion of 30 mg. of alemtuzumab. Participants will receive a combination of sirolimus and belatacept for at least one year. At that time, eligible participants will consent to and begin oral immunosuppressive withdrawal or continue therapy through study close. Sirolimus will first be weaned by halving the dose and/or increasing the dosing interval over at least a 2-6 month period. After sirolimus is discontinued, participants will remain on monthly IV belatacept monotherapy indefinitely. Follow-up will continue for at least five years. If subjects are successfully weaned from oral immunosuppression during their participation in this trial, no other alternative therapy will be warranted. Since belatacept is now FDA approved, subjects will be eligible to continue this therapy after their study participation has ended.

Official Title
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Use of Belatacept During Post Depletional Repopulation to Facilitate Tolerance in Renal Allograft Recipients

Conditions
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Organ Transplantation

Intervention / Treatment
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* Drug: Belatacept
* Drug: Sirolimus
* Drug: Alemtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipients age 18 or older of an HLA-non-identical, living or deceased donor kidney transplant. A willing renal donor who consents for subsequent donation of donor blood for testing throughout the follow-up period and for use of his/her kidney in this experimental study. Exclusion Criteria: Immunosuppressive drug therapy within 1 year prior to enrollment. Active malignancy or history of malignancy within 5 years of enrollment. Any history of blood malignancy or lymphoma. Any known immunodeficiency syndrome, including HIV infection. Absence of Epstein-Barr virus (EBV) or cytomegalovirus (CMV) specific antibodies in cases with evidence of EBV and/or CMV infection. Women of child-bearing potential unwilling or unable to use an acceptable method of birth control. Women who are pregnant or breastfeeding at the time of enrollment or study drug administration. Donor age <18 years. Subjects with protocol-specific etiologies of underlying renal disease. Subjects with a positive T-cell lymphocytic crossmatch or historical evidence of donor specific alloantibody by solid phase or flow-based detection methods. Prior solid organ transplant or potential to require a concurrent organ or cell transplant. Positive Hepatitis B or C antibodies and polymerase chain reaction (PCR) positive for the same. Active tuberculosis (TB) requiring treatment within the previous 3 years. Known positive purified protein derivative (PPD) unless chest x-ray is negative or treatment for latent TB has been completed. Active infection or other contraindications. History of drug or alcohol abuse within the past 5 years. Psychotic disorders which would interfere with adequate study follow-up. Active peptic ulcer disease, chronic diarrhea, or gastric malabsorption. All women 40 years or older with first degree family history of breast cancer will be required to have a screening mammogram within 6 months of study enrollment. Subjects with suspicion of breast malignancy which cannot be ruled out will be excluded. Belatacept use within 30 days prior to the day 1 visit. Prisoners or individuals who are involuntarily incarcerated.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppressive medications<br>Renal transplant recipients will be given an experimental combination of immunosuppressive drugs. Participants will receive a single dose of alemtuzumab on the day of transplantation and will receive belatacept and sirolimus for 1 year. At the time of transplant, all patients will receive a single dose of 500 mg of methylprednisolone IV over 30 minutes, followed within 1 hour by an IV infusion of 30 mg of alemtuzumab over 3 hours. | Drug: Belatacept<br>* Belatacept will be given within 24 hours of transplantation via a peripheral intravenous catheter at a dose of 10mg/kg (actual body weight) infused over 30 mins. The dose will be repeated on study days 4 (post op day 3) and 8 (post op day 7), then every 2 weeks for 5 additional doses. Thereafter, belatacept will be given once every 4 weeks (+/- 3 days) at 10mg/kg through 6 months then at 5mg/kg indefinitely.<br>* Other names: Nulojix;Drug: Sirolimus<br>* Sirolimus will be started on postoperative day 1 at a dose of 2 mg per day orally. Doses will be adjusted to maintain 24-hour trough levels of 8-10ng/ml until the drug is weaned. Toxicity attributable to sirolimus (e.g., mouth ulcers, arthralgias) will prompt dose reduction to address clinical concerns in this regard. If sirolimus trough levels need to be reduced below 4ng/ml to control drug side effects, the patient will be considered intolerant to the drug and will be changed to other medications.<br>* Other names: Rapamycin;Drug: Alemtuzumab<br>* All participants will receive a single dose of 30 mgs of alemtuzumab on the day of transplantation.<br>* Other names: Lemtrada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Successfully Withdrawn From Oral Immunosuppression | The primary endpoint is the number of patients successfully withdrawn from oral immunosuppression (sirolimus) for one year after their last dose of sirolimus. After taking sirolimus for one year, participants meeting certain pre-specified criteria were offered the opportunity to wean from sirolimus and continue with belatacept monotherapy. To be eligible for weaning of sirolimus, participants were required to have a kidney biopsy negative for all signs of rejection, including borderline findings. | Year 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Costimulation Blockade-resistant Rejection (CoBRR) | Assessment of the proposed therapies to prevent biopsy proven acute rejection, also known as CoBRR, was determined by the number of participants experiencing CoBRR at 1, 3 and 5 years post-transplant. | Year 1, Year 3, Year 5 | 
| Number of Participants Experiencing Chronic Allograft Nephropathy (CAN) | Assessment of biopsy proven chronic allograft nephropathy at 1, 3 and 5 years post-transplant is presented as the number of participants experiencing CAN. | Year 1, Year 3, Year 5 | 
| Number of Participants With BK Viremia | The number of participants experiencing BK viremia, an opportunistic infection, during the study is presented here. | Up to Year 5 | 
| Number of Participants Developing Donor-specific Alloantibody (DSA) | Long term assessment of donor-specific immune responsiveness after prolonged therapy with belatacept (with or without sirolimus), and during and following drug withdrawal as determined by in vitro alloresponsiveness in carboxyfluorescein succinimidyl ester (CFSE) mixed lymphocyte reactivity and intracellular cytokine staining (ICCS). | Up to Year 5 | 
| Number of Participants With Surviving Grafts | The number of participants whose grafts survived without graft failure at each follow up time point is presented here. | Year 1, Year 3, Year 5 | 
| Estimated Glomerular Filtration Rate (eGFR) | Graft function was assessed throughout the study by the estimated glomerular filtration rate. The eGFR indicates the percentage of kidney function that a person has based on creatinine, age, body size, and gender. An eGFR of below 60 indicates chronic kidney disease. A higher eGFR means that there is greater kidney function. | Year 1, Year 3, Year 5 |