Ixazomib for Desensitization

NCT ID: NCT03213158

Last Updated: 2022-06-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-15
• Study Completion Date: 2021-04-16

Brief 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.

Conditions

Kidney Diseases; End Stage Renal Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Highly sensitized kidney transplant candidates

The study population will include all highly sensitized kidney transplant candidates on the waitlist for more than 24 months at University of Wisconsin.

Group Type: EXPERIMENTAL

Ixazomib Oral Capsule

Intervention Type: DRUG

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.

Interventions

Ixazomib Oral Capsule

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 Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female patients 18-70 years of age.
• Able to provide informed consent.
• 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.)
• 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.)
• Patients must be highly sensitized with a cPRA ≥ 80%
• 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.
• Patients must meet the following clinical laboratory criteria:

1. 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.

2. Hemoglobin higher than 6 g/dL

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

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

Exclusion Criteria

• Female patients who are lactating or have a positive serum pregnancy test during the screening period
• Major surgery requiring hospitalization within 6 months before enrollment
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment
• 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
• 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
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol
• Inability to take oral medication
• 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
• Grade 2 or greater peripheral neuropathy according to NCI Common Terminology Criteria for Adverse Events (CTCAE)
• 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
• Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not
• Active or treated infection for HIV, HCV or HBV
• History of Liver cirrhosis, biopsy confirmed
• Elevated transaminases (greater than 3 times the upper limit of normal)
• Known hypersensitivity to ixazomib
• Active substance abuse by self-report or medical record

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Arjang Djamali, MD, MS, FASN

Role: PRINCIPAL_INVESTIGATOR

University of Wisconsin, Madison

Locations

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, United States

Countries

United States

References

Wilson N, Reese S, Ptak L, Aziz F, Parajuli S, Jucaud V, Denham S, Mishra A, Cascalho M, Platt JL, Hematti P, Djamali A. Ixazomib for Desensitization (IXADES) in Highly Sensitized Kidney Transplant Candidates: A Phase II Clinical Trial. Kidney360. 2023 Jun 1;4(6):e796-e808. doi: 10.34067/KID.0000000000000113. Epub 2023 Mar 23.

Reference Type: DERIVED

PMID: 36951387 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

A534280

Identifier Type: OTHER

Identifier Source: secondary_id

SMPH\MEDICINE\NEPHROLOGY

Identifier Type: OTHER

Identifier Source: secondary_id

Protocol ver 3June 2019

Identifier Type: OTHER

Identifier Source: secondary_id

2017-0429

Identifier Type: -

Identifier Source: org_study_id