Safety and Efficacy of Desensitization Therapy in Sensitized Participants Awaiting Heart Transplantation

Bortezomib works by decreasing plasma cells in the blood. Plasma cells produce antibodies.
Plasmapheresis is a procedure that removes antibodies from the blood. Plasma cells and
antibodies produced by plasma cells can be involved in organ rejection after
transplantation.

This trial will evaluate if decreasing plasma cells and antibodies with bortezomib and
plasmapheresis can reduce complications while participants are waiting for their heart
transplant. The evaluation of efficacy is defined by a lower complication rate while on the
heart transplant waitlist.

Inclusion Criteria:

- Subject must be able to understand and provide informed consent;

- Candidate (as recipient) for a primary heart transplant (single organ transplant);

- Calculated panel reactive antibody (cPRA) of greater than 30% with a threshold using
mean fluorescent intensity (MFI) of 3,000 or standard fluorescence intensity (SFI) of
60,000;

- Status 1 (1A or 1B) enrollment and randomization to occur within 2 weeks after status
1 listing;

- 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;

- Negative test for HIV (human immunodeficiency virus), HBsAg (hepatitis B surface
antigen), HBcAb (hepatitis B core antibody), and HCV (hepatitis C virus) antibodies
within 6 months prior to study entry.

Exclusion Criteria:

- Recipient of multiple solid organ or tissue transplants;

- Prior history of organ transplantation;

- Women of childbearing potential with a positive serum β-human chorionic gonadotropin
(β-hCG) pregnancy test.Pregnancy testing is not required for postmenopausal or
surgically sterilized women;

- Currently breast-feeding a child or plans to become pregnant during the timeframe of
the study follow-up period;

- Subject has a hypersensitivity to VELCADE® (bortezomib), boron, or mannitol;

- Active systemic infection at time of enrollment;

- Any history of serologic positivity to HIV, HBsAg, HBcAb and HCV Ab;

- History of malignancy except when noted by an oncology specialist that tumor
recurrence is low based on tumor type, response to therapy and negative metastatic
work-up;

- 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;

- Subjects with a platelet count of less than 75,000 within 7 days prior to enrollment;

- Subjects with an absolute neutrophil count (ANC) of less than 1,500 within 7 days
prior to enrollment;

- Subjects with >1.5 x ULN (upper limit of normal) total bilirubin;

- Subjects with any grade or history of neuropathy;

- Any condition that, in the opinion of the investigator, would interfere with the
subject's ability to comply with study requirements;

- Participation in another interventional clinical trial or requiring treatment using
un-marketed investigational drug(s) within 14 days of start of this trial and
throughout the duration of this trial.