Clinical trial NCT00565773: Belatacept Post Depletional Repopulation to Facilitate Tolerance
Official title: Use of Belatacept During Post Depletional Repopulation to Facilitate Tolerance in Renal Allograft Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Organ Transplantation
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Duke University
First posted: 2007-11-30
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Patients Successfully Withdrawn From Oral Immunosuppression
timeFrame: Year 2
Secondary outcomes:
measure: Number of Participants Experiencing Costimulation Blockade-resistant Rejection (CoBRR)
timeFrame: Year 1, Year 3, Year 5
measure: Number of Participants Experiencing Chronic Allograft Nephropathy (CAN)
timeFrame: Year 1, Year 3, Year 5
measure: Number of Participants With BK Viremia
timeFrame: Up to Year 5
measure: Number of Participants Developing Donor-specific Alloantibody (DSA)
timeFrame: Up to Year 5
measure: Number of Participants With Surviving Grafts
timeFrame: Year 1, Year 3, Year 5
measure: Estimated Glomerular Filtration Rate (eGFR)
timeFrame: Year 1, Year 3, Year 5
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Atlanta
country: United States
facility: The Emory Clinic
state: Georgia
Study officials:
affiliation: Emory University
name: Antonio Guasch, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Xu H, Mehta AK, Gao Q, Lee HJ, Ghali A, Guasch A, Kirk AD. B cell reconstitution following alemtuzumab induction under a belatacept-based maintenance regimen. Am J Transplant. 2020 Mar;20(3):653-662. doi: 10.1111/ajt.15639. Epub 2019 Nov 13.
citation: Xu H, Bendersky VA, Brennan TV, Espinosa JR, Kirk AD. IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. Am J Transplant. 2018 Mar;18(3):720-730. doi: 10.1111/ajt.14589. Epub 2017 Dec 12.
citation: Xu H, Samy KP, Guasch A, Mead SI, Ghali A, Mehta A, Stempora L, Kirk AD. Postdepletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients. Am J Transplant. 2016 Feb;16(2):550-64. doi: 10.1111/ajt.13469. Epub 2015 Oct 5.
citation: Kirk AD, Guasch A, Xu H, Cheeseman J, Mead SI, Ghali A, Mehta AK, Wu D, Gebel H, Bray R, Horan J, Kean LS, Larsen CP, Pearson TC. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant. 2014 May;14(5):1142-51. doi: 10.1111/ajt.12712. Epub 2014 Mar 31.
citation: Xu H, Lee HJ, Schmitz R, Shaw BI, Li S, Kirk AD. Age-related effects on thymic output and homeostatic T cell expansion following depletional induction in renal transplant recipients. Am J Transplant. 2021 Sep;21(9):3163-3174. doi: 10.1111/ajt.16625. Epub 2021 May 20.