Impact of Proteasome Inhibition on Anti-Donor HLA Antibody Production After Kidney Transplantation

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Mayo Clinic
Sponsor:
Collaborator:
Millennium Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Mark Stegall, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01349595
First received: May 5, 2011
Last updated: April 16, 2014
Last verified: April 2014
  Purpose

The purpose of this study is to see if treating patients who have high levels of donor specific alloantibodies post-transplant with bortezomib might prevent the development of transplant glomerulopathy and preserve allograft function.


Condition Intervention Phase
Disorder of Transplanted Kidney
Donor Specific Alloantibodies
Drug: Bortezomib
Other: Standard posttransplant treatment
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Impact of Proteasome Inhibition on Anti-Donor HLA Antibody Production After Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • The incidence of a combined endpoint of death-censored graft loss or greater than 50% reduction in estimated glomerular filtration (eGFR) in study subjects. [ Time Frame: 60 months after enrollment in the study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Reduction in donor-specific PCs in the marrow using AlloELISpot assay in bortezomib-treated patients (paired t test). [ Time Frame: 2 months after the last dose of study drug ] [ Designated as safety issue: No ]
    This might be after 2 or 4 cycles depending on the results of the interim assessment between cycles 2 and 3.

  • Reduction in serum anti-donor HLA antibody from baseline to follow-up time points of 60 months post -treatment initiation. [ Time Frame: 60 months post-treatment ] [ Designated as safety issue: No ]
  • Graft survival [ Time Frame: 60 months post -treatment initiation ] [ Designated as safety issue: No ]
  • Incidence of severe transplant glomerulopathy (Banff score cg3) [ Time Frame: 60 months after treatment initiation ] [ Designated as safety issue: No ]
  • Stabilization of glomerulopathy or lack of progression of cg score by Banff scoring system [ Time Frame: 60 months post -treatment initiation ] [ Designated as safety issue: No ]
  • Proportion of patients that achieve a complete DSA response within 2 months of treatment completion [ Time Frame: within 2 months of treatment completion ] [ Designated as safety issue: No ]
  • Proportion of patients that achieve a partial DSA response within 2 months of treatment completion [ Time Frame: within 2 months of treatment completion ] [ Designated as safety issue: No ]
  • Proportion of patients in DSA remission at 24 and 36, and 60 months post-treatment initiation [ Time Frame: 24 and 36, and 60 months post-treatment initiation ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: December 2011
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomib dosing Drug: Bortezomib
Patients randomized to bortezomib treatment will receive 2, 4-dose cycles of drug followed by a 2 month "hiatus". At the end of this time, subjects will be re-evaluated for the appropriateness of receiving a 3rd and 4th cycle of bortezomib. Bortezomib will be given subcutaneously. If unable to give subcutaneously, bortezomib will be given as a single IV push over a time of 3 to 5 seconds. Patients will receive up to 4, four-dose cycles of 1.3 mg/m(2) (based on body surface area).
Active Comparator: Standard Posttransplant Treatment Other: Standard posttransplant treatment
Mayo Clinic protocolized post kidney transplant follow-up.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Female subject is either postmenopausal for at least 1 year before the screening visit, surgically sterilized, or if they are of childbearing potential agree to practice 2 effective methods of contraception from the time of signing the informed consent form through 30 days after the last dose of bortezomib, or agree to completely abstain from heterosexual intercourse.
  • Male subjects, even if surgically sterilized (i.e. status postvasectomy), must agree to 1 of the following: practice effective barrier contraception during the entire study treatment period and through a minimum of 30 days after the last dose of study drug or completely abstain from heterosexual intercourse.
  • Kidney transplant recipients (living and deceased donors) who received a transplant in the last 3 years and have high DSA levels (defined as MFI levels >2000 by solid phase and single antigen bead LABscreen assays).

Exclusion Criteria:

  • Patients who are recipients of ABO incompatible kidney transplants.
  • Patient with an eGFR ≤30 m/min at time of study entry.
  • Patient with biopsy proven transplant glomerulopathy (Banff 2007 - cg score ≥2) within 2 months prior to randomization.
  • Patients with biopsy-proven acute rejection at the time of randomization defined as Acute Cellular Rejection Patients with documented biopsy proven recurrence of disease or de novo glomerular disease post-transplant prior to enrollment.
  • Patient has a platelet count of <30 x 10(9)/L within 14 days before enrollment.
  • Patient has an absolute neutrophil count of <1.0 x 10(9)/L within 14 days before enrollment.
  • Patient has a history of post-transplant neutropenia on mycophenolate based immunosuppressive therapy.
  • Evidence of severe liver disease with abnormal liver profile (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >3 times upper limit of normal [ULN]) at screening.
  • Patient has >1.5 x ULN Total Bilirubin.
  • Patient had any history of myocardial infarction in the past 3 years prior to enrollment or has New York Heart Association (NYHA) Class II to IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
  • Patient has hypersensitivity to bortezomib, boron, or mannitol.
  • Female subject is pregnant or lactating.
  • Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
  • CMV sero-negative recipients who received a transplant from a CMV-sero-positive donor.(CMV- recipients of CMV- donor kidneys are acceptable)
  • EBV sero-negative recipients.
  • History of CMV + or EBV + viremia since transplantation.
  • History of HCV positivity (by PCR).
  • History of Post-transplant lymphoproliferative disease.
  • History of polyoma virus nephropathy or BK virus viremia (peripheral blood viral load of 5000 to 5,000,000 copies/mL).
  • Patients who are HIV-positive or HBsAg-positive.
  • Recipients of a kidney from a donor who tests positive for HIV, HBsAg or anti-HCV.
  • Patients with current or recent severe systemic (pathogen detected in blood or CSF fluid) infections within the 4 weeks prior to randomization.
  • Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
  • Patient is currently receiving everolimus, sirolimus, or azathioprine as one of the immunosuppressive agents and intends to remain on this regimen.
  • Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial.
  • Inability to perform followup or to undergo protocol biopsy.
  • Active diabetic neuropathy at the time of treatment initiation.
  • Patient has ≥Grade 2 peripheral neuropathy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01349595

Contacts
Contact: Nong Yowe Braaten, LPN 507-538-9617 braaten.nong@mayo.edu

Locations
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Nong Yowe Braaten, LPN    507-538-9617    braaten.nong@mayo.edu   
Principal Investigator: Mark Stegall, MD         
Sponsors and Collaborators
Mark Stegall
Millennium Pharmaceuticals, Inc.
Investigators
Principal Investigator: Mark Stegall, MD Mayo Clinic
  More Information

No publications provided

Responsible Party: Mark Stegall, Sponsor-Investigator, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01349595     History of Changes
Other Study ID Numbers: 10-001487
Study First Received: May 5, 2011
Last Updated: April 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Bortezomib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 23, 2014