Multi-Drug Desensitization Protocol for Heart Transplant Candidates
Condition: Heart Transplantation
Intervention: Bortezomib, Thymoglobulin, Rituximab, Gamimune N, (IVIG), Plasmapheresis
Intervention MeSH terms: Rituximab; Bortezomib; Thymoglobulin; Antilymphocyte Serum; Immunoglobulins, Intravenous
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Maximum age: 67 Years
Healthy volunteers: No
Keywords: alloantibody; immunologic; memory; heart; transplant; desensitization

Summary:

      Background: Patients may develop antibodies (human leukocyte antigen [HLA] alloantibodies) to
      other human tissues via pregnancy, transfusions or previous transplantation, which limits the
      ability to find an acceptable donor heart for transplantation. Such patients are at high risk
      for antibody mediated rejection, graft failure, and acute rejection (i.e. death). For
      successful transplantation, patients must receive organs from donors who lack the HLA
      antigens that correspond to their alloantibody specificities. No successful desensitization
      strategy currently exists.

      Purpose: To determine if desensitization by deletion of immunologic memory with a multi-drug
      approach including anti-T and B cell therapies and anti-plasma cell therapy can effectively
      eliminate or significantly reduce alloantibody levels and permit highly sensitized patients
      to obtain a heart transplant. This therapy is anticipated to remove immunologic memory and
      will require re-immunization.
    

Eligibility criteria:

        Inclusion Criteria:

          -  1. Voluntary signed 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             not part of normal medical care, with the understanding that consent may be withdrawn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.

             2.Female subject is either post-menopausal or surgically sterilized, or willing to use
             two acceptable methods of birth control for the duration of the study and for up to 2
             months after the last dose of study medication.

             3.Male subject agrees to use an acceptable method for contraception for the duration
             of the study.

             4.Patient is greater than or equal to 18 years of age but less than 70 years old
             (inclusive).

             5.Patients with a Calculated Panel Reactive Antibody (CPRA) of ≥ 50% by Luminex Single
             Antigen Flow Bead (SAFB) testing (LABScreen®, Canoga Park, CA), where a Mean
             Fluorescence Intensity (MFI) of 1000 is the positive threshold.

             6.Patient is considered compliant and intends to be available for follow-up study
             period of 1 year.

             7.Patient must have no known hypersensitivity to treatment with bortezomib, boron, or
             mannitol.

             8.Patient must have no hypersensitivity to rituximab. 9.Patient must have no history
             of allergy or anaphylaxis to rabbit proteins or to any product excipients, or have
             active acute or chronic infections which contraindicate additional immunosuppression.

             10.Patient must have no history of an anaphylactic or severe systemic response to
             Immune Globulin (Human). Individuals with selective IgA deficiencies who have antibody
             against IgA (anti-IgA antibody) should not receive IVIG since these patients may
             experience severe reactions to the IgA which may be present.

             11.Patients without an AICD implanted will need to consent to wear a Zoll LifeVest
             Wearable Defibrillator.

        Exclusion Criteria:

          1. Women who are pregnant, breastfeeding, or have a positive pregnancy test on
             enrollment. If the patient becomes pregnant during the study, she must be removed from
             the study before receiving any additional study drug.

          2. History of hepatitis C virus (HCV) positivity (by polymerase chain reaction, PCR)

          3. Patients who are human immunodeficiency virus (HIV)-positive, or hepatitis B surface
             antigen (HBsAg)-positive.

          4. Patient is deemed likely to have a second solid organ transplant or cell transplant
             (e.g. kidney or islet cell) in next 3 years.

          5. Patient at risk for tuberculosis (TB):

               1. Current clinical, radiographic, or laboratory evidence of active or latent TB as
                  determined by local standard of care

               2. History of active TB:

               3. Within the last 2 years, even if treated

               4. Greater than 2 years ago, unless there is documentation of adequate treatment
                  according to locally accepted clinical practice

               5. Patient at risk of reactivation of TB precludes administration of conventional
                  immunosuppression (as determined by investigator and based upon appropriate
                  evaluation)

          6. Patient with active peptic ulcer disease (PUD), chronic diarrhea, or gastrointestinal
             malabsorption

          7. Patient with a history of hypercoaguable state

          8. Patient with hemoglobin < 7 g/dL, white blood cell (WBC) count < 2000/mm3 (3 x 109/L)
             or platelet count < 30,000 /mm3 prior to transplant

          9. Receipt of a live vaccine within 4 weeks prior to study entry

         10. Patient treated with immunosuppressive therapy (e.g. methotrexate, abatacept, etc) for
             indications such as autoimmune disease, or patient with comorbidity to a degree that
             treatment with such agents is likely during the trial in the opinion of the
             investigator

         11. Patients with current or recent severe systemic infections within 2 weeks of
             medication start

         12. Evidence of severe liver disease with abnormal liver profile (aspartate
             aminotransferase [AST], alanine aminotransferase [ALT] or total bilirubin > 1.5 times
             upper limit of normal (ULN) at screening.)

         13. Patient has ≥ Grade 2 peripheral neuropathy within 14 days of medication start

         14. History of malignancy within the past 5 years that is not considered to be cured, with
             the exception of localized basal cell carcinoma of the skin (excised ≥ 2 years prior
             to study initiation)

         15. Prisoner or patient compulsorily detained (involuntarily incarcerated) for treatment
             of either a psychiatric or physical (e.g. infectious disease) illness

         16. Patient with a history of substance abuse (drugs or alcohol) within the past 6 months,
             or psychotic disorders that are not compatible with adequate study follow-up

         17. Patient with a history of amiodarone exposure within three months.

         18. Patient with a previous heart or other transplant