Disorder of Transplanted Kidney
Conditions
Brief 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.
Interventions
DRUGBortezomib
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).
Sponsors
Millennium Pharmaceuticals, Inc.
Mark Stegall
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The Incidence of a Combined Endpoint of Death-censored Graft Loss or Greater Than 50% Reduction in Estimated Glomerular Filtration (eGFR) in Study Subjects. | 60 months after enrollment in the study |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Mayo Clinic transplant program in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib Bortezomib is a type of targeted chemotherapy
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 (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). | 2 |
| Standard Post-transplant Treatment Mayo Clinic standard post kidney transplant follow-up. | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of funding | 2 | 2 |
Baseline characteristics
| Characteristic | Bortezomib | Standard Post-transplant Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
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
Population: Results data for zero participants were analyzed; long-term follow-up evaluation of participants was not possible due to discontinuation of funding.