Belatacept Post Depletional Repopulation to Facilitate Tolerance

NCT00565773 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: IRB00005064Grant # FD-R-003539BMS IM103-036
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

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.

Conditions

Organ Transplantation

Outcome Measures

Primary Outcomes (1)

• Number of Patients Successfully Withdrawn From Oral Immunosuppression

  The primary endpoint is the number of patients successfully withdrawn from oral immunosuppression (sirolimus) for one year after their last dose of sirolimus.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 Outcomes (6)

• Number of Participants Experiencing Costimulation Blockade-resistant Rejection (CoBRR)

  Year 1, Year 3, Year 5

• Number of Participants Experiencing Chronic Allograft Nephropathy (CAN)

  Year 1, Year 3, Year 5

• Number of Participants With BK Viremia

  Up to Year 5

• Number of Participants Developing Donor-specific Alloantibody (DSA)

  Up to Year 5

• Number of Participants With Surviving Grafts

  Year 1, Year 3, Year 5

Study Arms (1)

Immunosuppressive medications

EXPERIMENTAL

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; Drug: Sirolimus; Drug: Alemtuzumab

Interventions

Belatacept DRUG

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.

Also known as: LEA29Y, Nulojix

Immunosuppressive medications

Sirolimus DRUG

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.

Also known as: Rapamycin

Immunosuppressive medications

Alemtuzumab DRUG

All participants will receive a single dose of 30 mgs of alemtuzumab on the day of transplantation.

Also known as: Campath, Lemtrada

Immunosuppressive medications

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Allan D Kirk, MD, PhD: lead
• Bristol-Myers Squibb: collaborator
• Duke University: collaborator

Study Sites (2)

Emory University Hospital

Atlanta, Georgia, 30322, United States

Location

The Emory Clinic

Atlanta, Georgia, 30322, United States

Location

Related Publications (5)

• 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.

  PMID: 31596034 BACKGROUND

• 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.

  PMID: 29136317 RESULT

• 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.

  PMID: 26436448 RESULT

• 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.

  PMID: 24684552 RESULT

• 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.

  PMID: 33942491 DERIVED

MeSH Terms

Interventions

Abatacept; Sirolimus; Alemtuzumab

Intervention Hierarchy (Ancestors)

Immunoconjugates; Antibodies; Immunoglobulins; Serum Globulins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Globulins; Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunoproteins

Results Point of Contact

• Title: Allan D. Kirk, MD, PhD
• Organization: Duke University

allan.kirk@duke.edu

919-681-1400

Study Officials

• Antonio Guasch, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 28, 2007
• First Posted: November 30, 2007
• Study Start: December 1, 2007
• Primary Completion: July 1, 2017
• Study Completion: July 1, 2017
• Last Updated: February 11, 2020
• Results First Posted: January 30, 2020

Record last verified: 2020-01

Locations

US (2)