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

A Prospective, Randomized, Multicenter, Two-Parallel Arm Study Evaluating the Overall Efficacy and Safety of Desensitization Therapy on Selected Patients Awaiting Heart Transplantation

The primary objective is to evaluate the efficacy of desensitization therapy, which includes VELCADE® (bortezomib) and plasmapheresis, on select sensitized patients 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.