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

Inclusion Criteria:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
• Female subject is either postmenopausal for at least 1 year before the screening visit, is 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 have high DSA levels (defined as MFI levels >2000 by solid phase and single antigen bead LABscreen assays) at any of the early post-transplant protocol time points (4, 12, 24 months after transplant) and who do not have TG on protocol biopsy at the same time point. To verify the DSA level, the subject must have a DSA with MFI>2000 on 2 sequential measurements within 1 month of each other.

Exclusion Criteria:

• Patient has a platelet count of < 30 x 109/L within 14 days before enrollment.
• Patient has an absolute neutrophil count of < 1.0 x 109/L within 14 days before enrollment.
• Patient has > 1.5 x ULN Total Bilirubin
• Patient has > or equal Grade 2 peripheral neuropathy
• Patient had any history of myocardial infarction prior to enrollment or has New York Heart Association (NYHA) Class I to IV heart failure (see Appendix 8.4), 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. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for postmenopausal or surgically sterilized women.
• Female patients who are lactating or have a positive serum pregnancy test during the screening period, or a positive urine pregnancy test on Day 1 before first dose of study drug, if applicable.
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• 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.
• 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.
• Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.
• Renal transplant patients who already have TG on their protocol biopsy.
• Active infection.
• Inability to perform follow-up or to undergo protocol biopsy.
• Diabetic neuropathy
• Other current or past history of neuropathy
• Patient who is CMV or EBV negative
• Patients with BK viremia (peripheral blood viral load of 5000 to 5,000,000 copies/mL)