Impact of Proteasome Inhibition on Anti-Donor HLA Antibody Production After Kidney Transplantation
Condition: Disorder of Transplanted Kidney
Intervention: Bortezomib
Intervention description: 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 (under the skin). If unable to give subcutaneously, bortezomib will be given as a single IV (injection into vein) 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).
Intervention MeSH terms: Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility 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 Donor Specific Antibody (DSA) levels (defined as Mean
             Fluorescent Intensity levels >2000 by solid phase and single antigen bead LABscreen
             assays).

        Exclusion Criteria:

          -  Patients who are recipients of ABO (blood type) incompatible kidney transplants.

          -  Patient with an Glomerular Filtration Rate (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.

          -  Cytomegalovirus (CMV) sero-negative recipients who received a transplant from a
             CMV-sero-positive donor.(CMV- recipients of CMV- donor kidneys are acceptable)

          -  Epstein Barr Virus (EBV) sero-negative recipients.

          -  History of CMV + or EBV + viremia since transplantation.

          -  History of SPELL OUT 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
             Cerebrospinal 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.