End Stage Renal Disease, Kidney Diseases
Conditions
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.
Interventions
DRUGIxazomib 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.
Sponsors
Millennium Pharmaceuticals, Inc.
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Efficacy of Ixazomib: Percentage of Participants With > 20 Percent Decline in Calculated Panel Reactive Antibody (cPRA) | up to 12 months |
| Efficacy of Ixazomib: Percentage of Participants Received Successful Kidney Transplantation Within 12 Months | up to 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Ixazomib as Assesses by Percentage of Participants With Hematological Complications Within 12 Months | up to 12 months | Hematological complications include leucopenia, anemia, and thrombocytopenia |
| Safety of Ixazomib as Assesses by Percentage of Participants With Malignancies Within 12 Months | up to 12 months | — |
| Safety of Ixazomib as Assesses by Percentage of Participants Caught Infection Within 12 Months | up to 12 months | — |
| Safety of Ixazomib as Assesses by Percentage of Participants With Thrombocytopenia Within 12 Months | up to 12 months | — |
| Safety of Ixazomib: as Assesses by Percentage of Participants With Distal Neuropathy Within 12 Months | up to 12 months | — |
| Safety of Ixazomib as Assesses by Percentage of Participants With Gastrointestinal Symptoms Within 12 Months | up to 12 months | — |
| Safety of Ixazomib as Assesses by Percentage of Participants With Cardiovascular Complications Within 12 Months | up to 12 months | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating BAFF Levels as Assessed by BAFF ELISA Assay | Baseline, 3 months | B cell activating factor belonging to the TNF family (BAFF) are members of the TNF ligand superfamily. Plasma BAFF ELISA assays can be performed in 2-3 hours. It can be used as a marker of disease activity in sensitized patients. |
| Change in Circulating APRIL Levels as Assessed by APRIL ELISA Assay | Baseline, 3 months | B cell activating factor belonging to a proliferation-inducing ligand (APRIL) are members of the TNF ligand superfamily. Plasma APRIL ELISA assay can be performed in 2-3 hours. It can be used as a marker of disease activity in sensitized patients. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Highly Sensitized Kidney Transplant Candidates |
|---|---|
| Age, Continuous | 40.8 years |
| Age, Customized 20-29 years | 2 Participants |
| Age, Customized 30-39 years | 4 Participants |
| Age, Customized 40-49 years | 2 Participants |
| Age, Customized 50-59 years | 1 Participants |
| Age, Customized 60-69 years | 1 Participants |
| Cause of ESRD Alport's Syndrome | 1 Participants |
| Cause of ESRD Congenital | 3 Participants |
| Cause of ESRD Diabetes Mellitus (DM) | 2 Participants |
| Cause of ESRD Focal segmental glomerulosclerosis (FSGS) | 1 Participants |
| Cause of ESRD Glomerulonephritis (GN) | 1 Participants |
| Cause of ESRD Polycystic Kidney Disease (PKD) | 1 Participants |
| Cause of ESRD Systemic Lupus Erythematosus (SLE) | 1 Participants |
| cPRA 81-85% | 1 Participants |
| cPRA 86-90% | 2 Participants |
| cPRA 91-95% | 0 Participants |
| cPRA 96-100% | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Interval of Previous Treatment | 11.1 years |
| Previous Treatment 2 previous kidney transplants | 2 Participants |
| Previous Treatment Previous kidney and pancreas transplant | 1 Participants |
| Previous Treatment Previous kidney transplant | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 7 / 10 |
| serious Total, serious adverse events | 6 / 10 |
Outcome results
Primary
Efficacy of Ixazomib: Percentage of Participants Received Successful Kidney Transplantation Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Efficacy of Ixazomib: Percentage of Participants Received Successful Kidney Transplantation Within 12 Months | 2 Participants |
Primary
Efficacy of Ixazomib: Percentage of Participants With > 20 Percent Decline in Calculated Panel Reactive Antibody (cPRA)
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Efficacy of Ixazomib: Percentage of Participants With > 20 Percent Decline in Calculated Panel Reactive Antibody (cPRA) | 0 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants Caught Infection Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants Caught Infection Within 12 Months | 5 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants With Cardiovascular Complications Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants With Cardiovascular Complications Within 12 Months | 2 Participants |
Secondary
Safety of Ixazomib: as Assesses by Percentage of Participants With Distal Neuropathy Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib: as Assesses by Percentage of Participants With Distal Neuropathy Within 12 Months | 1 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants With Gastrointestinal Symptoms Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants With Gastrointestinal Symptoms Within 12 Months | 5 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants With Hematological Complications Within 12 Months
Hematological complications include leucopenia, anemia, and thrombocytopenia
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants With Hematological Complications Within 12 Months | 2 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants With Malignancies Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants With Malignancies Within 12 Months | 0 Participants |
Secondary
Safety of Ixazomib as Assesses by Percentage of Participants With Thrombocytopenia Within 12 Months
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Safety of Ixazomib as Assesses by Percentage of Participants With Thrombocytopenia Within 12 Months | 0 Participants |
Other Pre-specified
Change in Circulating APRIL Levels as Assessed by APRIL ELISA Assay
B cell activating factor belonging to a proliferation-inducing ligand (APRIL) are members of the TNF ligand superfamily. Plasma APRIL ELISA assay can be performed in 2-3 hours. It can be used as a marker of disease activity in sensitized patients.
Time frame: Baseline, 3 months
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Change in Circulating APRIL Levels as Assessed by APRIL ELISA Assay | Baseline | 163 pg/ml |
| Highly Sensitized Kidney Transplant Candidates | Change in Circulating APRIL Levels as Assessed by APRIL ELISA Assay | 3 months | 172 pg/ml |
Other Pre-specified
Change in Circulating BAFF Levels as Assessed by BAFF ELISA Assay
B cell activating factor belonging to the TNF family (BAFF) are members of the TNF ligand superfamily. Plasma BAFF ELISA assays can be performed in 2-3 hours. It can be used as a marker of disease activity in sensitized patients.
Time frame: Baseline, 3 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Highly Sensitized Kidney Transplant Candidates | Change in Circulating BAFF Levels as Assessed by BAFF ELISA Assay | Baseline | 126 pg/ml |
| Highly Sensitized Kidney Transplant Candidates | Change in Circulating BAFF Levels as Assessed by BAFF ELISA Assay | 3 months | 160 pg/ml |