Ixazomib for Desensitization
Condition: Kidney Diseases; End Stage Renal Disease
MeSH terms: Kidney Diseases; Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this research study is to find out how well ixazomib (the study drug) works to
      desensitize highly sensitized kidney transplant recipients.
    

Detailed description: 
      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.

      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.
    

Intervention name(s): Ixazomib Oral Capsule
Intervention type(s): Drug
Intervention description(s): 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. Patients will take ixazomib and dexamethasone for twelve (12) 28-day cycles.
Intervention MeSH terms: Ixazomib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment