Ixazomib for Desensitization

This is a pilot exploratory, proof of concept, open-label, single-center phase II
investigator initiated clinical trial entitled IXAzomib for DESensitization (IXADES). The
purpose of the study is (1) to examine the safety and efficacy of ixazomib for
desensitization of highly sensitized kidney transplant candidates and (2) to conduct
mechanistic studies to address the role of HLA and non-HLA antibodies, T and B cell
phenotypes, and BAFF/APRIL in immune monitoring of sensitized kidney transplant candidates
(Figure 1).

Specific Aim 1. To determine the safety and efficacy of ixazomib as a desensitization
strategy. There is currently no effective desensitization strategy for highly sensitized
patients defined as calculated Panel of Reactive Antibodies (cPRA) ≥ 80%. For this study, 10
highly sensitized kidney transplant candidates on the waitlist for more than 24 months will
receive ixazomib 3 mg (and dexamethasone 20 mg) on days 1, 8, and 15 of a 28 cycle for 12
months. The primary objective is to evaluate the safety (distal neuropathy, thrombocytopenia,
and gastrointestinal symptoms) and efficacy (decline in cPRA > 20%) of ixazomib. The
secondary efficacy endpoint is transplantation rate within 12 months of therapy.

Specific Aim 2. Identify immune indices which predict the course of disease and/or response
to treatment in highly sensitized patients. Mechanistic studies will use bone marrow and
blood obtained from subjects in Aim 1 to determine the effect of treatment on immune
regulation and reconstitution after therapy. Since the bone marrow microenvironment produces
BAFF/APRIL and supports plasma cell maturation,the effect of therapy on the generation of
BAFF/APRIL will be determined by bone marrow mesenchymal stem cells and the survival of bone
marrow-derived plasma cells after desensitization. Specifically it's proposed to:

- Identify if bone marrow plasma cells, IgG subsets, and levels including free light
chains, and circulating BAFF/APRIL predict outcomes.

- Determine if treatment is effective in downregulating circulating BAFF/APRIL and
anti-HLA, endothelin-1 type A receptor (ETAR), angiotensin type 1 receptor (AT1R), and
complement fixing C1q antibodies.

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

1. Male or female patients 18-70 years of age.

2. Able to provide informed consent.

3. Female patients who are postmenopausal for at least 1 year before the screening visit,
or are surgically sterile, or If they are of childbearing potential, agree to practice
2 effective methods of contraception, at the same time, from the time of signing the
informed consent form through 30 days after the last dose of study drug, OR agree to
practice true abstinence when this is in line with the preferred and usual lifestyle
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
post-ovulation methods] and withdrawal are not acceptable methods of contraception.)

4. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
to one of the following: Agree to practice effective barrier contraception during the
entire study treatment period and through 30 days after the last dose of study drug,
or Agree to practice true abstinence when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
contraception.)

5. Patients must be highly sensitized with a cPRA ≥ 80%

6. Be active on the waitlist for kidney transplantation > 24 months to confirm their
inability to receive a deceased donor transplant because of their sensitization
status.

7. Patients must meet the following clinical laboratory criteria:

- Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet count ≥ 75,000/mm3.
Platelet transfusions to help patients meet eligibility criteria are not allowed
within 3 days before study enrollment.

- Hemoglobin higher than 6 g/dL

- Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN).

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

1. Female patients who are lactating or have a positive serum pregnancy test during the
screening period

2. Major surgery requiring hospitalization within 6 months before enrollment

3. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment

4. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months

5. Systemic treatment, within 14 days before the first dose of ixazomib, with strong
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital), or use of St. John's wort

6. Any serious medical or psychiatric illness that could, in the investigator's opinion,
potentially interfere with the completion of treatment according to this protocol

7. Inability to take oral medication

8. Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection

9. Grade 2 or greater peripheral neuropathy according to NCI Common Terminology Criteria
for Adverse Events (CTCAE)

10. Participation in other interventional clinical trials, including those with other
investigational agents not included in this trial, within 6 months of the start of
this trial and throughout the duration of this trial

11. Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not

12. Active or treated infection for HIV, HCV or HBV

13. History of Liver cirrhosis, biopsy confirmed

14. Elevated transaminases (greater than 3 times the upper limit of normal)

15. Known hypersensitivity to ixazomib

16. Active substance abuse by self-report or medical record