Conditions: Kidney Diseases End Stage Renal Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

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.

Arms:
arm 1: The study population will include all highly sensitized kidney transplant candidates on the waitlist for more than 24 months at University of Wisconsin.

Interventions: intervention 1: Ixazomib Oral Capsule
Intervention descriptions: intervention 1: 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.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
Ixazomib for Desensitization (IXADES) 
NCT03213158 
PI: Arjang Djamali, MD   
6-3-2019 
 


 
1
CLINICAL STUDY PROTOCOL 
Protocol Number: IISR-2014-100831 
 
Ixazomib for Desensitization (IXADES) 
 
 
Indication: 
 
 
 
Sensitization in Kidney Transplant Candidates 
Phase:  
 
 
 
II 
 
Protocol Version 
 
 
3 June 2019 
 
Investigator and Study Center: 
 
Principal Investigator:  
Arjang Djamali, MD 
Professor 
Department of Medicine-Nephrology 
5142 MFCB  
1685 Highland Avenue 
Madison, WI 53705  
Phone Number: (608) 262-7330  
Email: axd@medicine.wisc.edu 
 
UW IRB #: 
 
 
2017-0429 
 
Sub-Investigator(s): 
 
Brenda Muth, NP 
Robert Redfield, MD 
 
 
 
 
 
Brad Astor, PhD 
 
 
 
 
 
Peiman Hematti, MD 
 
 
 
 
 
 
Collaborators:  
 
 
Marilia Cascalho, PhD 
Jeffrey L. Platt, MD 
 
 
 
 
 
University of Michigan 
 
 
 
 
 
Department of Surgery 
Biomedical Sciences Research Bldg. 
109 Zina Pitcher Place 
2922D Taubman Center SPC 5331 
Ann Arbor, MI 48109-2200 
 
Outside Laboratory Services:  
Terasaki Foundation Laboratory 
 
 
 
 
 
Matthew J. Everly, PharmD 
11570 W Olympic Blvd. 
 
Los Angeles, CA 90064 
 
 
Local Laboratory Services:   
UW Health-University of Wisconsin Hospital and Clinics 
 
 
 
 
 
Clinical Laboratories 
600 Highland Ave., Room B4/251 
 
Madison, WI 53792 
 
 
 


 
2
ICTR Data Monitoring Committee Contact: 
 
 
 
 
 
Amy Siedschlag, MS 
2112 Health Sciences Learning Center 
 
 
 
 
 
School of Medicine and Public Health 
 
 
 
 
 
Madison, WI 53706 
 
 
 
 
 
Email: asiedschlag@wisc.edu 
 
ICTR Study Monitoring Service Contact:  
 
 
 
 
 
2112C Health Sciences Learning Center 
 
 
 
 
 
School of Medicine and Public Health 
 
 
 
 
 
Madison, Wi 53706 
 
 
 
 
 
Ph: 608-262-7505 
 
 
Funding Agency: This is an investigator-initiated study, funded by Millennium Pharmaceuticals, 
Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.  The principal 
investigator Arjang Djamali, (who may also be referred to as the sponsor-investigator), is 
conducting the study and acting as the sponsor.  Therefore, the legal/ethical obligations of the 
principal investigator include both those of a sponsor and those of an investigator. 


 
3
PROTOCOL SUMMARY 
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 currenty 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, we will determine the effect of therapy on the 
generation of BAFF/APRIL by bone marrow mesenchymal stem cells and the survival of bone 
marrow-derived plasma cells after desensitization.  We specifically propose 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. 
 
Figure 1.  Protocol Summary 
 
 


 
4
Study Title:  IXAzomib for DESensitization (IXADES) 
Phase:  II 
Number of Patients:  10 
Study Objectives  
The primary objective is to evaluate the efficacy of ixazomib in desensitizing highly sensitized 
kidney transplant recipient, defined as a decline in calculated PRA (cPRA) > 20%, or 
successful transplantation within 12 months.   
The secondary objective is to determine the toxicity and tolerability of ixazomib with particular 
focus on distal neuropathy, thrombocytopenia, and gastrointestinal symptoms. 
Overview of Study Design:   
We will examine the safety and efficacy of ixazomib for desensitization of highly sensitized 
kidney transplant candidates and conduct mechanistic studies to address the role of IgG 
subclasses, IgG complement binding capacity, non-HLA antibodies, T and B cell phenotypes, 
and BAFF/APRIL in immune monitoring and regulation.   
 
• 
Primary efficacy and safety endpoint:  
o Efficacy endpoint: A decline in cPRA > 20%.   
o Safety endpoint: infections, malignancies, hematological complications including 
leucopenia, anemia, and thrombocytopenia, cardiovascular complications and 
events, distal neuropathy, gastrointestinal symptoms, and immunosuppression-
related adverse effects 
 
• 
Secondary efficacy endpoint: Successful transplantation within 12 months  
• 
Tertiary/Exploratory Endpoints/Correlataive studies: Defining a marker of disease activity 
in sensitized patients will have a significant impact on the future of desensitization 
protocols.  Although DSA, cPRA, CDC and T cell and B cell flow crossmatch have been 
used to characterize the severity of sensitization, these assays are labor intensive and 
expensive.  The proposed plasma BAFF/APRIL ELISA assays can be performed in 2-3 
hours (1). We will determine whether these cytokines can reflect the immune response 
and predict response to desensitization and ultimately transplant outcome. In addition, 
we propose studies to address the effect of ixazomib on (a) bone marrow derived 
BAFF/APRIL generated by bone marrow-mesenchymal stem cells, knowing that these 
stromal cells play a key role during the maturation activation of plasma cells, (b) bone 
marrow-derived antibody secreting cells (plasma cells) (2) and (c) plasma IgG 
subclasses, anti-HLA, ETAR, AT1R, and C1q antibody response to treatment (3, 4). 


 
5
Study Population:   
Patients will be recruited from our center. All patients must be  (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 90 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 90 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 (a) 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 
21 days before study enrollment (b) Total bilirubin ≤ 1.5 × the upper limit of the normal range 
(ULN) (c) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × 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 (10) Participation in other desensitization 
therapies or investigational drug 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 (17) Electrocardiography evidence of acute ischemia or 
active conduction system abnormalities 
Duration of Study:  Patients will be on study for one year, plus 1 month. For those transplanted, 
data on rejection, graft and patient survival will be collected for 6 months. 


 
6
STUDY OVERVIEW DIAGRAM (optional) 
 
Table 1-1  IXADES Treatment Protocol 
 
 
 
 
 
Figure 1. Study Overview Diagram 
 
 


 
7
SCHEDULE OF EVENTS 
Table 2-1 (a)-Schedule of events (first six cycles) 
Procedures Performed 
Screening (</= 
30 days)  
Cycle 1 (< /= 3 months 
after screening) 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
Treatment Days (+6, -3) 
 
1 
8 
15 
29 
36 
43 
57 
64 
71 
85 
92 
99 
113 
120 
127 
141 
148 
155 
Ixazomib and 
Dexamethasone  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Physical Exam 
X 
X* 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Vital Signs 
(T, P, R, BP) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
AE Assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiodiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Drug Accountability 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Test (where 
appropriate) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
LFTs 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
cPRA 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
BAFF/APRIL 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
DSA Antibodies 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Bone Marrow Aspiration  
 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Physical examination to be completed at visit 1, if not completed during screening visit. 
1 Bone Marrow Aspiration must be done before drug administration and at one of the following endpoints: one month (+6,- 3 days) after the end of the 12 month study, cPRA 
decline > 20%, time of transplant, or time of subject withdrawal from the study.   


 
8
Table 2-1 (b)-Schedule of events (last six cycles) 
Procedures Performed 
Cycle 7 
Cycle 8 
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Final visit 
1M after 
last dose 
ETV or 
Unscheduled 
Visit 
Treatment Days 
169 
176 
183 
197 
204 
211 
225 
232 
239 
253 
260 
267 
281 
288 
295 
309 
316 
323 
373 
 
Ixazomib and 
dexamethasone 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Vital Signs  
(T, P, R, BP) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
AE Assessment 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Electrocardiogram  
(ECG)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Medication History 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Drug Accountability 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Pregnancy Test (where 
appropriate) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
LFTs 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
cPRA 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
BAFF/APRIL 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
DSA Antibodies 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Bone Marrow 
Aspiration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
X1 


 
9
TABLE OF CONTENTS 
PROTOCOL SUMMARY...................................................................................................... 3 
STUDY OVERVIEW DIAGRAM (optional) ........................................................................ 6 
SCHEDULE OF EVENTS .................................................................................................... 7 
LIST OF TABLES AND FIGURES (OPTIONAL)............................................................ 11 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ......................................... 12 
1. BACKGROUND AND STUDY RATIONALE .............................................................. 13 
1.1 Scientific Background .............................................................................................. 13 
1.1.1 Disease Under Treatment ................................................................................ 13 
1.1.2 Ixazomib (MLN9708) ........................................................................................ 14 
1.2 Preclinical Experience ............................................................................................. 14 
1.3 Clinical Experience ................................................................................................... 15 
1.4 Pharmacokinetics and Drug Metabolism .............................................................. 16 
1.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib ................... 18 
1.6 Relapsed and/or Refractory Multiple Myeloma .................................................... 24 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) ..................................................... 25 
1.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib ...... 25 
1.9 Study Rationale......................................................................................................... 25 
1.10 Potential Risks and Benefits ................................................................................. 28 
2. STUDY OBJECTIVES ................................................................................................... 29 
2.1 Primary Objectives ................................................................................................... 29 
2.2 Secondary Objectives .............................................................................................. 29 
3. STUDY ENDPOINTS ..................................................................................................... 30 
3.1 Primary Endpoints (safety and efficacy) ............................................................... 30 
3.2 Secondary Endpoints (efficacy endpoint) ............................................................. 30 
3.3 Tertiary/Exploratory Endpoints ............................................................................... 30 
4. STUDY DESIGN ............................................................................................................. 31 
4.1 Overview of Study Design ....................................................................................... 31 
4.2 Number of Patients ................................................................................................... 34 
4.3 Duration of Study ...................................................................................................... 34 
5. STUDY POPULATION ................................................................................................... 34 
5.1 Inclusion Criteria ....................................................................................................... 34 
5.2 Exclusion Criteria ...................................................................................................... 35 
6. STUDY DRUG ................................................................................................................. 36 
6.1 Description of Investigational Agents .................................................................... 36 
6.2 Study Drug Administration ...................................................................................... 36 
6.3 Dose-Modification Guidelines ................................................................................. 38 
6.3.1 Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated 
Toxicity .......................................................................................................... 38 
6.3.2 Recommended Dose Modifications for dexamethasone Treatment 
Associated Toxicity ..................................................................................... 40 
6.4 Excluded Concomitant Medications and Procedures ......................................... 41 
6.5 Permitted Concomitant Medications and Procedures ........................................ 41 
6.6 Precautions and Restrictions .................................................................................. 41 


 
10
6.7 Preparation, Reconstitution, and Dispensing ....................................................... 42 
6.8 Packaging and Labeling .......................................................................................... 42 
6.9 Storage, Handling, and Accountability .................................................................. 43 
6.10 Study Drug Compliance ........................................................................................ 43 
6.11 Treatment Assignment (if applicable) ................................................................. 44 
6.12 Termination of Treatment and/or Study Participation ....................................... 44 
7. STATISTICAL AND QUANTITATIVE ANALYSES .................................................... 45 
7.1 Statistical Methods ................................................................................................... 45 
7.1.1 Determination of Sample Size ......................................................................... 45 
7.1.2 Randomization and Stratification .................................................................... 46 
7.1.3 Populations for Analysis ................................................................................... 46 
7.1.4 Procedures for Handling Missing, Unused, and Spurious Data ................ 46 
7.1.5 Demographic and Baseline Characteristics .................................................. 46 
7.1.6 Efficacy Analysis ................................................................................................ 46 
7.1.7 Pharmacokinetics/Pharmacodynamics/Biomarkers (if applicable) ............ 47 
7.1.8 Safety Analysis .................................................................................................. 47 
7.1.9 Interim Analysis ................................................................................................. 47 
7.1.10 Study Stopping Rules ..................................................................................... 47 
8. ADVERSE EVENTS ....................................................................................................... 48 
8.1 Definitions .................................................................................................................. 48 
8.1.1 Adverse Event Definition .................................................................................. 48 
8.1.2 Serious Adverse Event Definition ................................................................... 48 
8.2 Procedures for Reporting Serious Adverse Events ............................................ 49 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events51 
9. SAFETY MONITORING ................................................................................................ 51 
9.1 Safety Monitoring ...................................................................................................... 51 
9.2 IND Monitoring Plan ................................................................................................. 52 
9.3 ICTR STUDY MONITORING SERVICE (SMS) ................................................... 53 
9.4 DATA MANAGEMENT SYSTEM ................................................................... 54 
9.4.1 Data Collection Tools .............................................................................. 54 
9.4.2 Data management Tool .................................................................................... 54 
10. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GMP ........................ 55 
10.1 Statement of Compliance ...................................................................................... 55 
10.2 Informed Consent ................................................................................................... 55 
10.3 Privacy and Confidentiality ................................................................................... 55 
11. ADMINISTRATIVE REQUIREMENTS ...................................................................... 55 
11.1 Product Complaints ................................................................................................ 55 
12. APPENDICES ............................................................................................................... 57 
12.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
.............................................................................................................................. 57 
13. REFERENCES.............................................................................................................. 58 
 


 
11
LIST OF TABLES and FIGURES (optional) 
 
Figure 1   
Protocol Summary 
Figure 2 
Sample Size analysis 
Table 1-1   
IXADES Treatment Protocol 
Table 2-1  
(a)-Schedule of events (first six cycles) 
Table 2-1  
(b)-Schedule of events (last six cycles) 
Table 3-1    
Clinical Studies of Oral Ixazomib 
Table 3-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Single-Agent Studies 
Table 3-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies 
Table 4-1  
Ixazomib Dose Adjustments 
Table 4-2    
Ixazomib Dose Adjustments for Hematologic Toxicities 
Table 4-3    
Ixazomib Treatment Modification (Delays, Reductions, and Discontinuations) Due 
to Adverse Events (Non-Hematologic Toxicities) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
12
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
AE:  
Adverse Event 
AL:  
Amyloid Light Chain 
AMR:  Antibody Mediated Rejection 
APRIL: A Proliferation-Inducing Ligand 
AUC:  Area under the Curve 
BAFF:  B cell activating factor  
C4d:  component of complement  
CBC:  Complete Blood Count 
CNI:  Calcineurin Inhibitor 
cPRA:  calculated Panel Reactive Antibody  
CSA:  Cylosporine A 
CYP:  Cytochrome P 
DLT:  Dose-Limiting Toxicity 
DMC:  Data Monitoring Committee 
DSA:  Donor Specific Antibodies 
ESRD: End-stage renal disease 
FDA:  Food and Drug Administration 
GI:  
gastrointestinal  
H&P:  History and Physical 
HLA:  Histocompatibility antigens 
ICTR:  Institute for Clinical and Translational Research 
IgG:  
Immunoglobulin G  
IV:  
Intravenous 
IXADES: IXAzomib for DESensitization  
LFTs:  Liver Function Tests 
MTD:  Maximum Tolerated Dose 
NDMM: Newly Diagnosed Multiple Myeloma 
PK:  
Pharmacokinetics 
PO:  
Oral (by mouth) 
RP2D:  Recommended Phase 2 Dose 
RRMM: Relapse/Refractory Multiple Myeloma 
SMS:  Study Monitoring Service 
TEAE:  Treatment-Emergent Adverse Event 
TLR:  Toll-like Receptors  
ULN:  Upper Limit of Normal 
 


 
13
1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Scientific Background 
1.1.1    
Disease Under Treatment 
The disease under treatment is sensitization in kidney transplant candidates. One of the major 
challenges in the current era of organ transplantation is to find suitable organs for highly sensitized 
patients 
defined 
as 
a 
cPRA 
> 
80%. 
 
The 
cPRA 
may 
be 
calculated 
at 
https://optn.transplant.hrsa.gov/resources/allocation-calculators/cpra-calculator/. These patients 
have developed antibodies against major histocompatibility (HLA) antigens due to previous 
transplantation, blood transfusion, or pregnancy.  Despite some success, current desensitization 
protocols are limited because of their complexity and lack of effective agents against plasma cells, 
which actually produce anti-HLA antibodies. As a result, many patients die on dialysis prior to 
receiving a transplant (5, 6). 
The two approaches for helping highly sensitized patients are: 1) To increase the chance of finding 
a crossmatch negative donor, or 2) To remove the pre-existing antibodies using desensitization 
protocols (7-11).  Emerging evidence suggests that strategies to improve transplant rates in highly 
sensitized patients enhance survival rates and the quality of life, while reducing costs compared 
to chronic dialysis (12, 13). Current desensitization protocols combine Rituximab (anti-CD20 
monoclonal antibody) to deplete B cells, and plasmapheresis plus intravenous immunoglobulins 
(IVIG) to block or remove preformed DSA (7-11). Since no agent previously used in 
transplantation has the adequate ability to inhibit mature plasma cells, there has been no effective 
way of reducing or preventing antibody production besides targeting B cells. Therefore, despite 
some success, contemporary desensitization protocols are limited by their inability to desensitize 
30 to 90% of patients (5, 8, 14).  For example, using a preconditioning regimen similar to the one 
used at our institution combining plasmapheresis, IVIG and Rituximab, the Mayo Clinic Transplant 
Program was unable to desensitize 15/29 patients who had an CDC crossmatch titer ≥ 1:8 (8).  
Similarly, Marfo et al demonstrated that pretransplant desensitization with high dose IVIG and 
rituximab was not successful in sensitized kidney transplant candidates with cPRA levels higher 
than 90% (5).  It is for this reason that we propose a pilot desensitization study targeting the cells 
responsible for generating alloantibodies using ixazomib (Ninlaro®), a second generation 
proteasome inhibitor, recently approved therapy for multiple myeloma. 
 
There is conflicting data regarding the effectiveness of bortezomib, a first generation proteasome 
inhibitor, in desensitization for kidney transplant candidates (15, 16).  The Cincinnati group 
reported a positive experience (26.3% responders) while the Mayo group did not show a favorable 
safety and efficacy profile.    However, none of this studies addressed the effect of bortezomib on 
target bone marrow plasma cells.  In addition, clinical and preclinical studies suggest that 
ixazomib has a superior safety and efficacy profile than bortezomib (17, 18).  Ixazomib has a 
shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, 
and antitumor activity compared with bortezomib. This is important as there is a correlation 
between greater pharmacodynamic responses and improved antitumor activity (18).  In a double-
blind, placebo-controlled, phase 3 trial of 722 patients with relapsed, refractory (including to 
bortezomib), or relapsed and refractory multiple myeloma, the addition of ixazomib to a regimen 
of lenalidomide and dexamethasone was associated with significantly longer progression-free 
survival; the additional toxic effects with this all-oral regimen were limited (17).  Lastly, The use of 
this oral drug is also significantly more convenient for patients on chronic dialysis who need 
dialysis therapy three times per week.   
 


 
14
Our long-term goal is to improve the quality-of-life and survival of kidney transplant recipients.  
Our specific hypothesis for this proposal is that ixazomib can significantly reduce DSA production 
and allow for kidney transplantation in highly sensitized patients.  Ixazomib is a second 
generation proteasome inhibitor, recently approved by the FDA for the treatment of multiple 
myeloma.  We further hypothesize that specific molecular and cellular indices can be predictive 
of treatment response and toxicity.  These hypotheses are based on preliminary findings 
demonstrating that: (a) The first-generation proteasome inhibitor, bortezomib (Velcade®), is an 
effective option for the treatment and prevention of antibody mediated rejection (AMR) in clinical 
settings; (b) Ixazomib prevents acute AMR in a robust preclinical model of kidney transplantation 
by downregulating B cell activation, antigen presentation, T cell and B cell signaling, and 
microcirculation inflammation; (c) IgG subclasses, IgG complement binding capacity, and serum 
B cell activating factor (BAFF) and  APRIL  (a  proliferation-inducing ligand) are associated with 
AMR and graft loss in kidney transplantation.   
 
Based on these observations and the critical need to define effective desensitization strategies, 
we propose a pilot exploratory, proof of concept, open-label, single-center phase II clinical trial 
entitled IXAzomib for DESensitization (IXADES).  We will examine the safety and efficacy of 
ixazomib for desensitization of highly sensitized kidney transplant candidates and conduct 
mechanistic studies to address the role of IgG subclasses, IgG complement binding capacity, 
non-HLA antibodies, T and B cell phenotypes, and BAFF/APRIL in immune monitoring and 
regulation.   
1.1.2 Ixazomib (MLN9708)  
1.2    Preclinical Experience 
There is a need for new immunosuppression strategies to minimize calcineurin inhibitor (CNI) 
toxicity while effectively preventing antibody-mediated rejection (AMR). We have been the first 
group to examine the impact of ixazomib on AMR in kidney transplantation.  We tested the efficacy 
of an investigational proteasome inhibitor, ixazomib, alone and in a CNI minimization strategy in 
a rat kidney transplant model of transfusion-elicited acute AMR. Nonsensitized (naïve) and 
sensitized allograft recipients were randomized into 4 treatment groups (8 groups total, n = 3 to 6 
in each group) and treated for 1 week. Groups included: no treatment, full dose cyclosporine 
(CsA, 10 mg/kg per day), ixazomib (0.25 mg/kg on days -5, -2 and +2) alone, and half dose CsA 
(5 mg/kg per day) + ixazomib (19). 
 
Compared to untreated animals, ixazomib alone or in combination with ½ dose CsA reduced 
donor-specific antibody, intragraft transcripts for chemokines CCL-21 and CXCL-13, and CD19 
expression in both sensitized and naïve transplants. Compared to full dose CsA, the CNI 
minimization strategy with ixazomib inhibited AMR and allograft injury as evidenced by reduced 
C4d staining in peritubular capillaries, microcirculation inflammation, splenic plasma cells, 
circulating B cell activating factor, and intragraft transcripts for major histocompatibility complex 
class II, Toll-like receptors (TLR-1, TLR-10, and TLR-12) and CCL-21 and CXCL-13 in sensitized 
animals, indicating downregulation of B cell activation, antigen presentation and T-cell and B-cell 
signaling. 
 
These studies suggest that CNI minimization strategies including ixazomib are effective to prevent 
AMR including in sensitized kidney allograft recipients. Clinical studies are needed to determine 
the role of novel proteasome inhibitors for the prevention and treatment of AMR. 


 
15
1.3    Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and relapsed or 
refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. Ongoing studies 
continue to investigate both single-agent ixazomib and ixazomib in combination with standard 
treatments. Based on encouraging preliminary data observed in patients with MM requiring 
systemic treatment, 2 phase 3 trials in newly diagnosed MM (NDMM) (C16014) and RRMM 
(C16010) patient populations are currently evaluating ixazomib in combination with Revlimid and 
Dexamethasone (RevDex) versus placebo/RevDex. Both trials are combining ixazomib at a 
weekly dose of 4.0 mg on Days 1, 8, and 15 in a 28-day cycle to a standard dose of lenalidomide 
with a weekly dexamethasone dose of 40 mg. In addition, clinical pharmacology studies have 
evaluated drug-drug interactions with ketoconazole, clarithromycin, and rifampin, as well as the 
effect of food, renal impairment, and hepatic impairment on the PK of ixazomib. Studies evaluating 
the safety and pharmacokinetics (PK) of ixazomib alone (in Japanese patients) and in 
combination with lenalidomide and dexamethasone in Asian adult patients (including Japanese 
patients) with a diagnosis of RRMM are ongoing. 
 
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and 
are similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, 
dose modification or discontinuation. 
 
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events includes 
rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous conditions; 
and exfoliative conditions. The dose escalation phases of most trials reported in the IB have now 
completed enrollment, and gastrointestinal (GI) symptoms were the common dose-limiting 
toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per protocol. In the 
expansion cohorts or phase 2 cohorts (as per each study), the incidence and severity of GI 
symptoms was mitigated by the use of the lower maximum tolerated dose (MTD)/recommended 
phase 2 dose (RP2D) (as per each study) and standard clinical usage of anti-emetics and/or 
antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics has not been 
required as with other agents but (as outlined in Section 6.7) has been used according to standard 
practice and are effective. 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with the 
PO formulation pooled from single-agent studies (n = 201) irrespective of causality to ixazomib, 
include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), vomiting (38%), 
decreased appetite (32%), fever (21%), and anemia (21%). The most frequent (at least 20%) 
TEAEs reported with the PO formulation pooled from combination trials (irrespective of the 
combination) (n = 173), irrespective of causality to ixazomib, include diarrhea (47%), fatigue 
(44%), nausea (38%), peripheral edema (35%), constipation (33%), insomnia (29%), 
thrombocytopenia (28%), anemia (26%), vomiting (26%), neutropenia (25%), back pain (24%), 
pyrexia (23%), peripheral edema (21%, each), fever (20%), cough (20%), hypokalemia (20%), 


 
16
neutropenia (20%), and upper respiratory tract infection (20%). Overall rash of all grades is 
reported in approximately 50% of patients and is more common when ixazomib is given in 
combination with lenalidomide where rash is an overlapping toxicity. 
 
Additional detailed information regarding the clinical experience of ixazomib may be found in the 
IB, including information on the IV formulation.   
1.4   Pharmacokinetics and Drug Metabolism 
After oral dosing, absorption of ixazomib is rapid with a median first time to maximum observed 
plasma concentration (Tmax) of approximately 1 hour postdose. The plasma exposure (AUC) of 
ixazomib increases in a dose-proportional manner over a dose range of 0.2 to 10.6 mg based on 
population PK analysis. The absolute oral bioavailability (F) of ixazomib is estimated to be 58% 
based on population PK analysis.  A high-fat meal reduced ixazomib Cmax by 69% and AUC0-216 
by 28%.  This indicates that a high-fat meal decreases both the rate and extent of absorption of 
ixazomib. Therefore, ixazomib should be dosed at least 2 hours after food or 1 hour before food. 
 
The steady-state volume of distribution of ixazomib is large and is estimated to be 543 L based 
on a population PK model. Based on in vitro plasma protein binding measurements on samples 
from clinical studies (Studies C16015 and C16018), ixazomib is highly bound to plasma proteins 
(99%). Ixazomib concentrations are higher in whole blood than in plasma, indicating extensive 
partitioning of ixazomib into red blood cells, which are known to contain high concentrations of 
the 20S proteasome. 
 
Metabolism appears to be the major route of elimination for ixazomib. In vitro studies indicate that 
ixazomib is metabolized by multiple cytochrome P450 (CYP) and non-CYP proteins. At 
concentrations exceeding those observed clinically (10 µM), ixazomib was metabolized by 
multiple CYP isoforms with estimated relative contributions of 3A4 (42.3%), 1A2 (26.1%), 2B6 
(16.0%), 2C8 (6.0%), 2D6 (4.8%), 2C19 (4.8%), and 2C9 (<1%). At 0.1 and 0.5 µM substrate 
concentrations, which are closer to clinical concentrations of ixazomib following oral 
administration of 4 mg ixazomib, non-CYP mediated clearance was observed and seemed to play 
a major role in ixazomib clearance in vitro.  These data indicate that at clinically relevant 
concentrations of ixazomib, non-CYP proteins contribute to the clearance of ixazomib and no 
specific CYP isozyme predominantly contributes to the clearance of ixazomib. Therefore, at 
clinically relevant concentrations of ixazomib, minimal CYP-mediated DDIs with a selective CYP 
inhibitor would be expected. 
 
Ixazomib is neither a time-dependent inhibitor nor a reversible inhibitor of CYPs 1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, or 3A4/5.  Ixazomib did not induce CYPs 1A2, 2B6, and 3A4/5 activity or 
corresponding immunoreactive protein levels. Thus, the potential for ixazomib to produce DDIs 
via CYP isozyme induction or inhibition is low. 
 
Ixazomib is not a substrate of BCRP, MRP2 and OATPs. Ixazomib is not an inhibitor of Pgp-, 
BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1 and MATE2K. Ixazomib- is 
unlikely to cause or be susceptible to clinical DDIs with substrates or inhibitors of clinically relevant 
drug transporters. 
 
The geometric mean terminal halflife- (t1/2) of ixazomib is 9.5 days based on population PK 
analysis. For both IV and oral dosing, there is an approximately average 3fold accumulation 
(based on AUC) following the Day 11 dose for the -twiceweekly- schedule and a 2fold 
accumulation (based on AUC) following the Day 15 dose for the -onceweekly- schedule. 


 
17
Mean plasma clearance (CL) of ixazomib is 1.86 L/hr based on the results of a population PK 
analysis. Taken together with the blood-to-plasma AUC ratio of approximately 10, it can be 
inferred that ixazomib is a low clearance drug. Using the absolute oral bioavailability (F) estimate 
of 58% (also from a population PK model), this translates to an apparent oral plasma clearance 
(CL/F) of 3.21 L/hr. The geometric mean renal clearance for ixazomib is 0.119 L/hr, which is 3.7% 
of CL/F and 6.4% of CL estimated in a population PK analysis. Therefore, renal clearance does 
not meaningfully contribute to ixazomib clearance in humans. Approximately 62% of the 
administered radioactivity in the ADME study (Study C16016) was recovered in the urine and 
22% of the total radioactivity was recovered in the feces after oral administration. Only 3.2% of 
the administered ixazomib dose was recovered in the urine as unchanged ixazomib up to 
168 hours after oral dosing, suggesting that most of the total radioactivity in urine was attributable 
to metabolites.  
 
The PK of ixazomib was similar with and without co-administration of clarithromycin, a strong 
CYP3A inhibitor, and hence no dose adjustment is necessary when ixazomib is administered with 
strong CYP3A inhibitors. Consistently, in a population PK analysis, coadministration of strong 
CYP1A2 inhibitors did not affect ixazomib clearance. Therefore, no dose adjustment is required 
for patients receiving strong inhibitors of CYP1A2.  Based on information from the clinical rifampin 
DDI study, ixazomib -Cmax and AUC0-last were reduced in the presence of rifampin by 
approximately 54% and 74%, respectively. Therefore, the co-administration of strong CYP3A 
inducers with ixazomib is not recommended.  
 
Mild or moderate renal impairment (CrCL ≥ 30 mL/min) did not alter the PK of ixazomib based on 
the results from a population PK analysis. As a result, no dose adjustment is required for patients 
with mild or moderate renal impairment.  In a dedicated renal impairment study (C16015), 
unbound AUC0-last was 38% higher in patients with severe renal impairment or ESRD patients 
requiring dialysis as compared to patients with normal renal function.  Accordingly, a reduced 
starting dose of ixazomib is appropriate in patients with severe renal impairment or ESRD 
requiring dialysis.  Pre- and post-dialyzer concentrations of ixazomib measured during the 
hemodialysis session were similar, suggesting that ixazomib is not readily dialyzable, consistent 
with its high plasma protein binding (99%). 
 
The PK of ixazomib is similar in patients with normal hepatic function and in patients with mild 
hepatic impairment, as defined by the National Cancer Institute Organ Dysfunction Working 
Group (total bilirubin <1.5 times the upper limit of normal [ULN]), based on the results from a 
population PK analysis. Consequently, no dose adjustment is required for patients with mild 
hepatic impairment. In a dedicated PK study in patients with moderate (total bilirubin >1.5 to 
3 times the ULN) or severe (total bilirubin >3 times the ULN) hepatic impairment (Study C16018), 
unbound dose-normalized AUC0-last was 27% higher in patients with moderate or severe hepatic 
impairment as compared to patients with normal hepatic function. Therefore, a reduced starting 
dose of ixazomib is appropriate in patients with moderate or severe hepatic impairment.  
 
There was no statistically significant effect of age (23-91 years), sex, body surface area 
(1.2-2.7 m2), or race on the clearance of ixazomib based on the results from a population PK 
analysis. 
Further details on these studies are provided in the IB. 


 
18
1.5    Clinical Trial Experience Using the Oral Formulation of Ixazomib 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma,  AL 
amyloidosis, nonhematologic cancers, and lymphoma) have been treated in studies evaluating 
the oral ixazomib formulation.  These patients have been treated with different  doses of ixazomib 
either as a single-agent treatment (in 201 patients) or in combination with currently clinically 
available treatments (in 306 patients).  Information regarding the ongoing studies, patient 
populations, and doses investigated is included in Table 3-1. 


 
19
Table 3-1-1    Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 60 
PO, TW, single agent 
0.24-2.23 mg/m2 TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
Closed to enrollment 
C16004 
RRMM 
N = 60 
PO, W, single agent 
0.24-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
Closed to enrollment 
C16005 
NDMM 
N = 65 
PO, W, combination with LenDex 
28-day cycle 
1.68-3.95 mg/m2 W 
MTD:  2.97 mg/m2 
DLT:  nausea, vomiting, diarrhea, syncope 
RP2Da:  4.0 mg fixed (switched to fixed 
dosing in phase 2, equivalent  to 2.23mg/m2) 
Closed to enrollment 
C16006 
NDMM 
N = 20 
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone 
Arm Aa:  3-3.7-mg fixed dose TW 
DLT:  rash, thrombocytopenia, subileus 
Arm Ba:  3-5.5-mg fixed dose, W 
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder 
MTD = 3.0 mg 
C16007 
RRAL 
N = 27 
PO, W, single agent 
4-5.5-mg fixed dosea W 
DLT:  thrombocytopenia, diarrhea, dyspnea, 
acute rise in creatinine, cardiac arrest  
MTD:  4.0  mg W 
 
C16008 
NDMM 
N = 64 
PO, TW, combination with LenDex 
21-day cycle 
3.0-3.7mg fixed -dosea W 
MTD:  3.0 mg 
Closed to enrollment 
C16009 
Solid 
tumors, 
Lymphomas 
N = 54 
PO, W, single agent 
5.5mg fixed -dosea W 
C16010 
RRMM 
N = 200 
PO, W, with LenDex versus 
placebo-LenDex 
4.0 mg W 
C16011 
RRAL 
N = 4 
PO, W, with Dex versus 
physician’s choice of a Dex-based 
regimen 
4.0 mg W 


 
20
Table 3-1-1    Clinical Studies of Oral Ixazomib 
Trial/ 
Population 
Description 
Doses Investigated 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 
C16014 
Symptomati
c MM 
N=701 
PO, combination with LenDex 
ixazomib 4.0 mg or matching placebo on 
Days 1, 8, and 15, plus Len 25 mg on Days 
1-21 (10 mg if low creatinine clearance, with 
escalation to 15 mg if tolerated) and Dex 
40 mg (or 20 mg if >75 years old) on Days 1, 
8, 15, and 22 
C16015 
Symptomati
c MM with 
normal renal 
function or 
severe renal 
impairment 
N=28 
PO, combination with Dex 
Part A: ixazomib  3.0 mg on Day 1 
Part B: ixazomib  4.0 mg on Days 1, 8, and 
15, plus Dex 40 mg (or 20 mg if >75 years 
old) on Days 1, 8, 15 and 22 of a 28-day 
cycle 
 
C16017 
RR follicular 
lymphoma 
N=58 
PO, W 
4.0, 5.3, and 7.0 mg, W 
Treatment at RP2D once determined. 
 
C16018 
Advanced 
solid tumors 
or 
hematologic 
malignancie
s with 
varying 
degrees of 
liver 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg 
(normal hepatic function) 
 
TB-
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations:  RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = body surface 
area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = orally; RR= 
relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light chain amyloidosis RRMM = relapsed and/or 
refractory multiple myeloma; TBD = to be determined; TW = twice weekly; W = weekly; RP2D= recommended phase 2 
dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included.   
a Approximate BSA and fixed dosing equivalence:  3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ equivalent to 
2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 


 
21
Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that ixazomib is generally well tolerated.  The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are similar 
to what has been previously reported with VELCADE though the severity of some, for example 
peripheral neuropathy, is less.  While some of these potential toxicities may be severe, they can 
be managed by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.   
 
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent oral 
ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 
March 2013. These patients have been treated with different doses of ixazomib as they are all 
phase 1 trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled safety 
population from single-agent oral ixazomib Studies (C16003, C16004, C16007, and C16009) is 
shown in Table 3-2. 
Table 3-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
Subjects with at Least One Adverse 
Event 
197 (98) 
Gastrointestinal disorders 
160 (80) 
Nausea 
106 (53) 
Diarrhoea 
88 (44) 
Vomiting 
77 (38) 
Constipation 
46 (23) 
Abdominal pain 
33 (16) 
General disorders and administration 
site conditions 
151 (75) 
Fatigue 
103 (51) 
Pyrexia 
51 (25) 
Oedema peripheral 
27 (13) 
Asthenia 
31 (15) 
Nervous system disorders 
92 (46) 
Headache 
29 (14) 
Dizziness 
26 (13) 
Neuropathy peripheral 
21 (10) 
Metabolism and nutrition disorders 
107 (53) 
Decreased appetite 
64 (32) 
Dehydration 
37 (18) 
Blood and lymphatic system disorders 
98 (49) 
Thrombocytopenia 
68 (34) 


 
22
Table 3-2    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
Primary System Organ Class 
     Preferred Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
Anaemia 
42 (21) 
Neutropenia 
29 (14) 
Lymphopenia 
20 (10) 
Skin and subcutaneous tissue 
disorders 
90 (45) 
Rash maculara 
23 (11) 
Musculoskeletal and connective tissue 
disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal 
disorders 
78 (39) 
Cough 
28 (14) 
Dyspnoea 
30 (15) 
Infections and infestations 
89 (44) 
Upper respiratory tract infection 
31 (15) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated subjects as the 
denominator. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash. 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma to 
investigate oral ixazomib in combination with standard combination regimens.  The most frequent 
(at least 10%) AEs occurring in the pooled safety population from Studies C16005, C16006, 
C16008, and C16013 are shown for all grades (Table 3).  Note that in combination trials, related 
is defined as related to any study drug in the combination regimen. 
 
Table 3-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse 
Event 
163 (94) 
Gastrointestinal disorders 
139 (80) 
Nausea 
65 (38) 


 
23
Table 3-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Diarrhoea 
81 (47) 
Vomiting 
51 (29) 
Constipation 
57 (33) 
General disorders and administration 
site conditions 
132 (76) 
Fatigue 
76 (44) 
Pyrexia 
39 (23) 
Oedema peripheral 
61 (35) 
Asthenia 
20 (12) 
Nervous system disorders 
115 (66) 
Headache 
28 (16) 
Dizziness 
34 (20) 
Neuropathy peripheral 
45 (26) 
Metabolism and nutrition disorders 
91 (53) 
Decreased appetite 
25 (14) 
Hypokalaemia 
34 (20) 
Blood and lymphatic system disorders 
88 (51) 
Thrombocytopenia 
49 (28) 
Anaemia 
45 (26) 
Neutropenia 
43 (25) 
Lymphopenia 
20 (12) 
Skin and subcutaneous tissue 
disorders 
102 (59) 
Rash maculopapulara 
29 (17) 
Rash maculara 
22 (13) 
Musculoskeletal and connective tissue 
disorders 
99 (57) 
Back pain 
42 (24) 
Pain in extremity 
31 (18) 
Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
Cough 
36 (21) 
Dyspnoea 
26 (15) 
Infections and infestations 
92 (53) 
Upper respiratory tract infection 
35 (20) 


 
24
Table 3-3    
Most Common (At Least 10% of Total) Treatment-Emergent Adverse Events in 
Oral Combination Studies 
Primary System Organ Class 
     Preferred Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Psychiatric disorders 
73 (42) 
Insomnia 
50 (29) 
Source:  Ixazomib Investigator’s Brochure Edition 7 
Abbreviations:  MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence:  A subject counts once for each preferred term.  Percentages use the number of treated subjects as the 
denominator.  
Data from ongoing blinded pivotal trials (C16010) are not included. 
a Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash.  
 
The clinical experience with ixazomib also shows early signs of antitumor activity as evidenced 
by at least a 50% reduction in disease burden in some patients and prolonged disease 
stabilization in others across all ongoing trials. The antitumor activity has been seen with single-
agent ixazomib, when combined with established therapies, and across the malignancies studied 
(advanced solid tumors (20), non-Hodgkin’s disease, Hodgkin’s disease (21), relapsed and/or 
refractory multiple myeloma (22, 23), relapsed or refractory systemic light chain amyloidosis (24), 
and newly diagnosed multiple myeloma (25-27) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the emerging 
data supports the ongoing development of ixazomib. 
 
1.6    Relapsed and/or Refractory Multiple Myeloma 
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and 
C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules commonly 
used with the first-in-class proteasome inhibitor, VELCADE. 
 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a twice-
weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with RRMM (28, 29).  
Study C16004 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a weekly 
schedule on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM (30-32) Both 
studies have now completed enrollment.  The DLTs in Study C16003 were rash macular and 
thrombocytopenia and the DLTs in C16004 were nausea, diarrhea, vomiting, and erythema 
multiforme. 
 
In the dose escalation component of both studies, patients had multiple myeloma that had 
relapsed following at least 2 lines of therapy that must have included bortezomib, thalidomide (or 
lenalidomide), and corticosteroids.  In both studies, when the MTD was established, cohorts of 
patients representing the heterogeneous patient population currently seen in clinical practice were 
to be enrolled into 1 of 4 expansion cohorts, including a relapsed and refractory cohort, a 
carfilzomib cohort, a proteasome inhibitor-naïve cohort, and a VELCADE-relapsed cohort.  Final 
study results are currently being analyzed, but preliminary data suggest that ixazomib has anti-
tumor activity in heavily pretreated MM patients, with durable responses/disease control, and is 
generally well tolerated. Please refer to the ixazomib IB and SMA for further information.  


 
25
1.7    Newly Diagnosed Multiple Myeloma (NDMM) 
Multiple research paths are being explored in patients with NDMM with a focus on evaluating 
ixazomib in combination with agents commonly used across treatment settings.  The development 
of ixazomib in combination with lenalidomide and dexamethasone (LenDex) in patients with 
NDMM who are transplant eligible or ineligible involves 2 studies (C16005 and C16008) with 
similar study designs except for a few key differences, namely the schedules of ixazomib and 
dexamethasone.  Ixazomib is also being evaluated in combination with melphalan and prednisone 
(MP) for patients who are not transplant eligible due to age or coexisting morbidity (in Study 
C16006).  
All 3 studies are phase 1/2, with phase 1 focusing on safety and phase 2 on efficacy (and further 
characterization of safety).  Please refer to the ixazomib IB and SMA for further information.  
1.8      Clinical Trial Experience Using the Intravenous Formulation of Ixazomib 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid tumors 
and advanced lymphoma (Studies C16001 and C16002, respectively). 
1.9 
Study Rationale 
One of the major challenges in the current era of organ transplantation is to find suitable organs 
for highly sensitized patients. These patients have developed antibodies against major 
histocompatibility (HLA) antigens due to previous transplantation, blood transfusion, or 
pregnancy.  Despite some success, current desensitization protocols are limited because of their 
complexity and inability to reduce donor specific antibodies (DSA) in 30-90% of patients, and the 
absence of effective agents against plasma cells, which actually produce the HLA alloantibodies. 
As a result, many patients die on dialysis prior to receiving a transplant.  
 
Our long-term goal is to improve the quality-of-life and survival of kidney transplant recipients.  
Our specific hypothesis for this proposal is that ixazomib (Ninlaro®) can significantly reduce DSA 
production and allow for kidney transplantation in highly sensitized patients.  Ixazomib is a 
second generation proteasome inhibitor, recently approved by the FDA for the treatment of 
multiple myeloma.  We further hypothesize that specific molecular and cellular indices can be 
predictive of treatment response and toxicity.  These hypotheses are based on preliminary 
findings demonstrating that: (a) The first-generation proteasome inhibitor, bortezomib (Velcade®), 
is an effective option for the treatment and prevention of antibody mediated rejection (AMR) in 
clinical settings; (b) Ixazomib prevents acute AMR in a robust preclinical model of kidney 
transplantation by downregulating B cell activation, antigen presentation, T cell and B cell 
signaling, and microcirculation inflammation; (c) IgG subclasses, IgG complement binding 
capacity, and serum B cell activating factor (BAFF) and  APRIL  (a  proliferation-inducing ligand) 
are associated with AMR and graft loss in kidney transplantation.   
 
Based on these observations and the critical need to define effective desensitization strategies, 
we propose a pilot exploratory, proof of concept, open-label, single-center phase II clinical trial 
entitled IXAzomib for DESensitization (IXADES).  We will examine the safety and efficacy of 
ixazomib for desensitization of highly sensitized kidney transplant candidates and conduct 
mechanistic studies to address the role of IgG subclasses, IgG complement binding capacity, 
non-HLA antibodies, T and B cell phenotypes, and BAFF/APRIL in immune monitoring and 
regulation.   
 
 


 
26
Sensitization in kidney transplant candidates.  Alloantibodies (anti-HLA antibodies) arise 
through previous transplants, blood transfusions, and pregnancy.  Currently, 39% of patients on 
the active kidney transplant waitlist are sensitized, evidenced by a Panel Reactive Antibody (PRA) 
≥ 1% (33).  Of these, nearly 15,000 are highly sensitized, which means that they have a PRA ≥ 
80% (33).  Transplant rates vary by PRA, ranging from 143.0 per 100 active waitlist years for 
candidates with a PRA of less than 1% to only 6.9 for those with a PRA of 98% or higher (33).  
Median waiting time for kidney transplantation in highly sensitized patients approaches 12 years, 
which is more than 3 times than for non-sensitized patients (33).  As a result, a significant number 
of highly sensitized patients die before receiving a transplant, outlining the critical importance of 
desensitization strategies.  
 
Desensitization protocols. The two approaches for helping highly sensitized patients are: 1) To 
increase the chance of finding a crossmatch negative donor, or 2) To remove the pre-existing 
antibodies using desensitization protocols (7-11).  Emerging evidence suggests that strategies to 
improve transplant rates in highly sensitized patients enhance survival rates and the quality of 
life, while reducing costs compared to chronic dialysis (12, 13). Current desensitization protocols 
combine Rituximab (anti-CD20 monoclonal antibody) to deplete B cells, and plasmapheresis plus 
intravenous immunoglobulins (IVIG) to block or remove preformed DSA (7-11). Since no agent 
previously used in transplantation has the adequate ability to inhibit mature plasma cells, there 
has been no effective way of reducing or preventing antibody production besides targeting B cells. 
Therefore, despite some success, contemporary desensitization protocols are limited by their 
inability to desensitize 30 to 90% of patients (5, 8, 14).  For example, using a preconditioning 
regimen similar to the one used at our institution combining plasmapheresis, IVIG and Rituximab, 
the Mayo Clinic Transplant Program was unable to desensitize 15/29 patients who had an CDC 
crossmatch titer ≥ 1:8 (8).  Similarly, Marfo et al demonstrated that pretransplant desensitization 
with high dose IVIG and rituximab was not successful in sensitized kidney transplant candidates 
with cPRA levels higher than 90% (5).  It is for this reason that we propose a pilot desensitization 
study targeting the cells responsible for generating alloantibodies using ixazomib, a recently 
approved therapy for multiple myeloma. 
 
Ixazomib (Ninlaro®, Takeda-Millennium Pharmaceuticals, Inc).  In kidney transplantation, the 
first generation proteasome inhibitor bortezomib (Velcade®) has been utilized as part of 
desensitization (16) and AMR treatment strategies (14, 34-37).  Ixazomib is a second generation 
oral proteasome inhibitor, recently approved for the treatment of multiple myeloma (38-43). 
Ixazomib is administered as a citrate ester, ixazomib citrate, that rapidly hydrolyzes under 
physiological conditions to its biologically active form, ixazomib The active form potently, 
reversibly and selectively inhibits the proteasome (39-41). It is more effective than earlier 
generation proteasome inhibitors in targeting plasma cells with improved side effect profile (38, 
44-49).  Having a more potent, less toxic proteasome inhibitor that does not need to be delivered 
intravenously and can be used in patients with reduced kidney function will be clinically 
advantageous (46).  Despite the absence of data on the use of ixazomib in clinical transplantation 
(only FDA approved in November 2015), we have been the only group to demonstrate that the 
drug is safe and effective for the treatment of antibody mediated rejection (AMR) in a robust 
preclinical model (19).  More specifically, it is unknown whether ixazomib depletes plasma cells, 
prevents their generation or both. For example, the effects of treatment on differentiated bone 
marrow-derived CD138+ plasma cells in clinical transplantation are unknown.  These antibody 
producing cells thrive in a microenvironment rich in BAFF and APRIL generated by stromal 
mesenchymal stem cells (MSCs).  We propose to test the safety and efficacy of this drug in a 
phase II trial for desensitization. 
 
BAFF/APRIL and Desensitization. BAFF and APRIL are homologues and members of the tumor 


 
27
necrosis factor superfamily (50). They are produced by neutrophils, macrophages, dendritic cells 
and stromal mesenchymal stem cells in the bone marrow (1, 50, 51).  Both cytokines are potent 
activators and survival factors for B cells and plasma cells.  Through their receptors BAFF-R 
(BAFF receptor), TACI (transmembrane activator and calcium modulator and cyclophilin ligand 
interactor) and BCMA (B cell maturation protein), BAFF/APRIL activate the prosurvival NF-
kappaB and MEK signaling pathways (1, 50, 51).  In animal models, excess BAFF leads to the 
development of autoimmune disorders including lupus nephritis, while APRIL deficient mice lack 
proper activation and maturation of plasmablasts (50, 51).  High levels of BAFF/APRIL are 
detected in the serum of patients with autoimmune disease, which in some studies correlate with 
disease activity (50, 51).  BAFF and APRIL inhibitors such as Belimumab (Lymphostat-B) and 
TACI-Fc fusion protein (Atacicept) have been recently used in phase II and III clinical trials of 
lupus and rheumatoid arthritis (50, 51).  Consistent with these data, serum BAFF levels are 
increased in kidney transplant recipients undergoing AMR, where this cytokine may play an 
important role in the immune response to the allograft (1, 52). We hypothesize that in highly 
sensitized patients, BAFF/APRIL generated by bone marrow-derived mesenchymal stem cells 
(BM-MSCs) play a key role in the survival and maturation of donorspecific- plasma cells and that 
serum BAFF/APRIL levels have an important clinical value in predicting and monitoring treatment 
response.  
 
Immunoglobulins and Desensitization.  Terasaki et al. identified HLA antibodies in the serum 
of patients after transplantation nearly 45 years ago (53). Preexisting (54-56) and de novo 
circulating antibodies (dnDSA) (57, 58) have been shown to compromise renal allograft survival. 
These antibodies may be directed against HLA or non-HLA molecules on endothelial cells 
including angiotensin II type 1 receptor (AT1R), or endothelin type A receptor (ETAR) (59-61).  It 
is important to note that currently available HLA antibody tests are qualitative and have not been 
cleared by the FDA for quantitative measurements (62).  In addition, the critical issue for patient 
care is discerning which of the detected antibodies are pathogenic as many patients with donor 
specific antibodies prior and after transplantation have stable allograft function and experience no 
rejection. 
 
For example, patients with dnDSA at the time of biopsy have worse graft survival than those with 
preexisting DSA, indicating a more pathogenic role for dnDSA (63).  Similarly, it has been 
proposed that the assessment of the complement-binding capacity of donor-specific anti-HLA 
antibodies by the C1q assay may be useful in identifying patients at high risk for kidney-allograft 
loss (64).  However, we have recently conducted studies demonstrating that the C1q binding 
activity by DSA largely reflects differences in antibody strength, questioning the biologic 
significance of this test (65).  It has also been proposed that among IgG subclasses, IgG3 may 
have a more pathogenic role in AMR (66, 67) but the role of immunoglobulin subclasses in 
desensitization and kidney transplantation remains unknown. To address these questions, we 
propose to identify risk stratification strategies and to determine the pathogenic role and specificity 
of anti-HLA, non-HLA-DSA and complement fixing antibodies in desensitization. 
 
Future Biomedical Research.  Subjects will be asked in the consent form if they agree to allow 
a portion of their bone marrow aspiration sample to be used for a future research project that will 
involve groiwing the mesenchymal stromal cells in Dr. Djamali’s laboratory.  If subjects do not 
achieve desensitization during their participation in this research study, they may be offered 
injection with their mesenchymal stromal cells, in an effort to achieve desensitization in a future 
research study. 


 
28
1.10 Potential Risks and Benefits 
Please refer to the current ixazomib IB and SMA for a complete list of the risks of ixazomib.  The 
clinical benefit of ixazomib continues to be studied in a comprehensive and global development 
plan that involves studies sponsored by Millennium.  Ixazomib appears to show a significant 
impact on the production of allo antibodies in preclinical studies of AMR.  The preliminary findings 
are favorable when considering historical and currently available therapies for the patient 
populations evaluated.  Though additional data are needed to characterize the clinical benefit of 
this drug, the emerging data supports expanded development of ixazomib for the treatment of 
patients with advanced malignancy.   
This study will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines. 
 
Compliance with eligibility criteria:  The PI will sign-off on the eligibility checklist for each subject 
prior to study drug dispensation. 
 
The risks to subjects in this trial will be minimized by compliance with eligibility criteria, clinical 
monitoring, adherence to protocol contraception requirements and investigator guidance 
regarding specific safety areas.   
 
The specific safety areas that will be closely monitored in this subject population are; 
 
Ixazomib:  thrombocytopenia, diarrhea, fatigue, nausea, vomiting, rash, risk of reactivation of 
herpes infection, neutropenia, fluid deficit, hypotension, posterior reversible encephalopathy 
syndrome (PRES), and transverse myelitis.   
 
Bone Marrow Aspiration Risks:  This procedure may be very painful; however, the pain only lasts 
for about 15 to 30 seconds. The hip area may be sore for a day or two. It is possible, but not likely 
that the subject could get an infection or have a large amount of bleeding. In very rare cases, 
people might have an allergic reaction to the local anesthesia. The allergic reaction could include 
rash/hives, flushing of the face, itching, wheezing and tightness in the throat. 
 
For subjects that are on warfarin, INR levels will be checked prior to the BMA, and pressure will 
be applied for 
• 
10 minutes after the procedure if INR 1.5-2 
• 
15 minutes after the procedure if INR 2-2.5 
• 
20 minutes after the procedure if INR > 2.5 
Warfarin dosing will not be adjusted.  Blood Draw Risks:  The risks of taking blood include 
pain, a bruise at the point where the blood is taken, redness and swelling of the vein 
and infection, and a rare risk of fainting. 
 
Overall, the balance of benefit and risk supports the proposed clinical study to evaluate the 
potential of ixazomib to significantly reduce DSA production and allow for kidney transplantation 
in highly sensitized patients. 


 
29
Subject Remuneration 
Subjects will receive $100 after Visit 1 and will receive $20 per visit for visits 2 - 13.  Payment will 
be made by check approximately 6 weeks after each study visit. 
2.    
STUDY OBJECTIVES 
2.1    Primary Objectives 
Specific Aim 1. To determine the safety and efficacy of ixazomib as a desensitization 
strategy.  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. 
2.2    Secondary Objectives 
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, we will determine the effect of therapy on the 
generation of BAFF/APRIL by bone marrow mesenchymal stem cells and the survival of bone 
marrow-derived plasma cells after desensitization.  We specifically propose to: 
• 
Identify if bone marrow plasma cells, IgG subsets, 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. 
• 
Identify immunological indices which predict treatment toxicity and responders vs. non-
responders.  
 
In summary, sensitization is a significant clinical and immunological problem in kidney 
transplantation. In a unique effort involving the University of Wisconsin’s Divisions of Nephrology, 
Transplantation, and Hematology-Oncology (clinical core), The University of Michigan (Plasma 
cell core), and The Terasaki Foundation Laboratory (DSA core), coordinated by the UW Office of 
Clinical Trials, an experienced clinical research organization, we propose the planning of a pilot 
phase II safety and efficacy trial of ixazomib for desensitization of highly sensitized kidney 
transplant candidates.  We further outline mechanistic studies to determine the pathogenesis of 
alloantibody generation and define novel biomarkers and surrogate endpoints for a future Clinical 
Trial Implementation grant (NIAID PAR-13-149).  The results are expected to have a positive 
impact as proposed studies are crucial steps towards developing improved therapies and 
monitoring options to reduce the long-term impact of sensitization. 
 


 
30
3. STUDY ENDPOINTS 
3.1    Primary Endpoints (safety and efficacy)  
Primary efficacy and safety endpoint:  
• 
Efficacy endpoint: A decline in cPRA > 20%.   
• 
Safety endpoint: infections, malignancies, hematological complications including 
leucopenia, anemia, and thrombocytopenia, cardiovascular complications and events, 
distal neuropathy, gastrointestinal symptoms, and immunosuppression-related adverse 
effects. 
3.2    Secondary Endpoints (efficacy endpoint) 
Secondary efficacy endpoint: Successful transplantation in 12 months  
3.3   Tertiary/Exploratory Endpoints  
Correlataive studies: Defining a marker of disease activity in sensitized patients will have a 
significant impact on the future of desensitization protocols.  Although DSA, cPRA, CDC and T 
cell and B cell flow crossmatch have been used to characterize the severity of sensitization, these 
assays are labor intensive and expensive.  The proposed plasma BAFF/APRIL ELISA assays can 
be performed in 2-3 hours (1). We will determine whether these cytokines can reflect the immune 
response and predict response to desensitization and ultimately transplant outcome. In addition, 
we propose studies to address the effect of ixazomib on (a) bone marrow derived BAFF/APRIL 
generated by bone marrow-mesenchymal stem cells, knowing that these stromal cells play a key 
role during the maturation activation of plasma cells, (b) bone marrow-derived antibody secreting 
cells (plasma cells) (2) and (c) plasma IgG subclasses, anti-HLA, ETAR, AT1R, and C1q antibody 
response to treatment (3, 4). 
 
BAFF/APRIL studies (Djamali lab and Platt lab): 
• 
These studies will be performed at time zero, prior to initiation of therapy, then every three 
months for 12 months. 
• 
To define the range of BAFF/APRIL in sensitized patients, we will determine baseline 
levels and end of study levels in the sera and marrow obtained from peripheral blood and 
bone marrows of all 10 patients prior to treatment initiation.  Higher BAFF/APRIL levels 
may be an indication of higher sensitization status.  
• 
To determine whether serum BAFF/APRIL levels predict the level of sensitization, we will 
assess the correlation between BAFF/APRIL and other markers of sensitization in all 10 
patients prior to treatment initiation.  Using appropriate parametric and nonparametric 
statistical analyses we will determine whether BAFF or APRIL can independently predict 
cPRA, DSA and B cell flow crossmatch channel shift in case of transplantation to 
demonstrate the clinical value of these tests in defining sensitization intensity. 
• 
To determine whether serum BAFF/APRIL levels predict treatment response, we will first 
determine if baseline serum BAFF/APRIL levels were higher in patients who failed to reach 
the primary or secondary endpoints.  Next we will examine the correlation between 
BAFF/APRIL levels and outcomes using Pearson correlation coefficient analyses.  Last, 
the effect of serum BAFF/APRIL on endpoints will be measured using Kaplan-Meier and 
Cox proportional-hazards models. 
• 
To determine whether ixazomib therapy inhibits BAFF/APRIL generation by stromal BM-
MSCs, we will determine if ixazomib inhibits BAFF/APRIL generation by BM-MSCs in vivo 


 
31
and in vitro by (a) determining the difference in the production of BAFF/APRIL by BM-
MSCs at enrollment and after study completion and (b) by measuring the direct effects of 
ixazomib on BAFF/APRIL generation in MSC cultures from pretreatment samples.  
Antibody Secreting Studies (Platt lab): 
• 
These studies will be performed at time zero prior to initiation of therapy, and at 12 months 
unless patients receive a kidney transplant.  10-60 mL of marrow will be collected from the 
iliac crest either in the transplant clinic or in the operating room right before the kidney 
transplant procedure.   
• 
To determine the effect of treatment on bone marrow derived CD138+ plasma cells, we 
will (a) determine the difference in the percentage of bone marrow plasma cells at 
enrollment and after study completion (kidney transplantation or failure of desensitization) 
and (b) measure antibody secretion against the tetanus antigen and the three HLA 
peptides the patient is most sensitized against (c) conduct similar analyses to 
BAFF/APRIL studies described above in order to determine the level of sensitization and 
prediction to treatment response.  These studies will be performed in collaboration with 
the laboratories of Dr. Platt and Cascalho laboratory as described previously (2, 37).   
Antibody assays (Terasaki Research Foundation Laboratory) 
• 
These studies will be performed at time zero, prior to initiation of therapy, then every three 
months for 12 months. 
• 
As mentioned earlier, the critical issue for patient care is discerning which of the detected 
antibodies are pathogenic.  In addition, the role of immunoglobulin subclasses in 
desensitization and kidney transplantation remains unknown.  To address these 
questions, we propose to identify risk stratification strategies and to determine the 
pathogenic role and specificity of IgG subclasses, anti-HLA, non-HLA-DSA and 
complement fixing antibodies in desensitization. 
4. STUDY DESIGN  
4.1    Overview of Study Design 
Recruitment 
 
Two avenues of recruitment will be followed. 
• 
The first option is when the physician of a patient who has a cPRA < 80% and has been 
on the kidney transplant list for over 24 months, believes the patient is an eligible candidate 
for this study, the patient's physician or other clinical personnel involved in the care of the 
patient will describe the study to the patient. If the individual is interested, has provided 
permission for their name and contact information to be shared with the study team, and 
agrees to be contacted by the study team, the study team may contact the individual either 
in person (at this visit) or via telephone or e-mail (after this visit). If study personnel are 
available to meet with the potential subject in clinic, the study personnel will explain the 
study thoroughly and ask the potential subject if they are interested in hearing more 
information.  If so, the study personnel will continue and review the consent form, 
answering questions and concerns. If the patient is comfortable with the study, they can 
sign the consent form at that time or they may take the consent form home for further 
review and finalize consent at a later date.  If the study team is not available to meet with 
the potential subject in the clinic, the study team will follow-up by telephone.  If the study 
discussion occurs via phone, the informed consent document and authorization form will 
be mailed to the potential subject for review.   
• 
The second option for potential subject identification is to pre-screen highly sensitized 
patients (cPRA ≥ 80%) on the kidney transplant waitlist (> 24 months) in the Transplant 


 
32
Database.  If a potential subject is identified, the subject will be sent a letter of introduction 
that includes information about the study and informs them that they will receive a phone 
call from a member of the study team to discuss the details of the study, and provides 
contact information to opt out of receiving the phone call.  
 
Use of E-mail:  E-mail will be used as a means of communicating with subjects two different 
ways; 
1.  E-mail may be used to schedule the initial study visit.  After the subject has had the study 
introduced to them through a physician or other clinical personnel involved in their clinical care, 
the study team will e-mail them using the template provided in the recruitment section. 
2.  E-mail may be used throughout the course of the study for the purpose of scheduling study 
visits and notifying subjects of other study-related information.   
 
Study Procedures 
 
Screening Visit 
 
The screening visit procedures will occur within a 30-day window prior to the Visit 1, Cycle 1 
window (3-month window after screening).  The following procedures will occur at the screening 
visit; 
 
• 
Physical exam 
• 
Medical history (including most recent cPRA results prior to enrollment) 
• 
Vital Signs (Temperature, pulse, respirations, and blood pressure) 
• 
Medication History 
• 
Pregnancy Test (Serum HCG) for females of child-bearing potential 
• 
CBC 
• 
LFTs 
Re-screening 
Subjects who fail screening may be considered for re-screening if, in the opinion of the 
principal investigator, their clinical status has changed such that they may now be eligible 
for study participation per all eligibility criteria.  At the discretion of the principal 
investigator, selected tests, such as lab tests, will not be repeated if previous screening 
results remain valid per the protocol-defined window for that test. 
 
Visits: Patients will only receive one month’s supply of ixazomib and dexamethasone and will 
return monthly for resupply.  At each visit, they will be assessed for AEs by the study team.  They 
will be examined by the principal investigator 5 times  (please see tables 2-1 a-b and Figure 1, 
below): Days 1, 85, 169, 253, and 373 +6, - 3). 
• 
Day 1: Prior to treatment initiation.  H&P, Labs, Bone Marrow Aspirate 
• 
Day 85 + 6, - 3: Prior to treatment dose.  H&P, Labs 
• 
Day 169 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 253 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 373 + 6, - 3 One month after treatment completion, H&P, Labs, Bone Marrow Aspirate 
• 
Study drug will be dispensed at each month’s in-person visit, prior the initiation of the next 
cycle, and after reviewing the AEs and monthly labs. 


 
33
• 
Liver Function tests will be conducted twice a month (+ 6 /- 3 days) for the first 3 months, 
then monthly thereafter. The complete blood count (CBC) will be checked monthly.  cPRA, 
BAFF/APRIL, DSA and antibodies will be checked every three months (5 times total).  
Bone marrow aspirates will be collected at the beginning and at one of the following 
endpoints: one month (+6, - 3 days) after the end of the 12 month study, cPRA decline > 
20%, time of transplant, or time of subject withdrawal from the study.  ECG and 
echocardiograms will be done at the baseline, 6 months, and end of the study visits. 
• 
During the first three months of study participation, the bi-weekly Liver Function Tests may 
be done at the subject’s local lab.  The local lab will process the sample and send the 
result to the study team. 
• 
Additional visits may be required if the subject has to hold treatment and needs to return 
to the clinic for blood draws to confirm eligibility to continue.  Please see Table 4-3, Dose 
Adjustments for Hematologic Toxicities for dose adjustment plan. 
• 
Data on acute rejection, graft and patient survival will be collected for six months after 
surgery for those subjects who receive a successful kidney transplant. 
Unscheduled Visits:  Subjects may have unscheduled visits due to dose adjustments based on 
lab results, an acute illness of undetermined cause, for other reasons, or at the discretion of the 
Investigator.  Unscheduled visits may include any of the following procedures; 
• 
Adverse Event Assessment 
• 
Medication History 
• 
Drug Accountability 
• 
Physical Exam 
• 
Vital Signs (Temperature, Pulse, Respirations, Blood Pressure) 
• 
Lab work (CBC, LFTs, cPRA, BAFF/APRIL, DSA Antibodies) 
• 
Bone Marrow Aspiration 
 
Early Termination Visit:  All subjects who end study participation prior to the end of the 
scheduled treatment will undergo an early termination visit within one week from study 
discontinuation.  The early termination visit will consist of the following procedures; 
 
• 
Adverse Event Assessment 
• 
Medication History 
• 
Drug Accountability 
• 
Physical Exam 
• 
Vital Signs (Temperature, Pulse, Respirations, Blood Pressure) 
• 
Lab work (CBC, LFTs, cPRA, BAFF/APRIL, DSA Antibodies) 
• 
Bone Marrow Aspiration (bone marrow aspiration will be done within 48 hours of 
transplant) 
 
 


 
34
Figure 1. Study Overview Diagram 
 
 
 
4.2    Number of Patients 
A total of 10 patients will be enrolled in this pilot clinical trial.  We currently have more than 40 
patients that qualify for the study based on the inclusion criteria described below.  A patient will 
be considered enrolled after the first day of ixazomib treatment.   
4.3    Duration of Study 
Participants will be followed for the entire length of treatment, plus one month.  All subjects, 
including those that receive a a kidney transplant and those that do not, will continue to be 
monitored for one month following the last dose of study drug to monitor for and address potential 
adverse events from treatment (Final visit on day 373 + 6, - 3).  Thereafter, dialysis nephrologists 
will routinely follow the patients.  For those tansplanted, data on acute rejection, graft and patient 
survival will be collected for 6 months after surgery. 
5.    
STUDY POPULATION 
The study population will include all highly sensitized kidney transplant candidates on the waitlist 
for more than 24 months at UW. A preliminary query of the Transplant Database indicates more 
than 40 candidates who are eligible for this study. This study will enroll 10 subjects.  
 
5.1    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 


 
35
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 × the upper limit of the normal range (ULN). 
• 
Alanine 
aminotransferase 
(ALT) 
and 
aspartate 
aminotransferase 
(AST) ≤ 3 × ULN. 
5.2    Exclusion Criteria 
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 desensitization therapies or investigational drug 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  


 
36
(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 
(17) Electrocardiography evidence of acute ischemia or active conduction system abnormalities 
6.    
STUDY DRUG 
6.1  Description of Investigational Agents 
Ixazomib Capsules.  Provided by Millennium-Takeda.  The ixazomib drug product is provided in 
strengths of 3.0-, and 2.3-mg and 0.5-, and capsules as the active boronic acid. The different 
dose strengths are differentiated by both capsule size and color as described below: For this 
study, we will initiate therapy with the 3 mg capsules according to the package insert information 
for patients with end-stage renal disease.  For additional details, please see the ixazomib IB.   
 
Dose Strength 
Capsule Size 
Capsule Color 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
0.5 mg 
Size 3 
Dark green 
 
Dexamethasone tablets,  Dexamethasone Tablets USP are available for oral administration 
containing either 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 4 mg or 6 mg of dexamethasone USP.  
For this study, we will use the 20 mg dose (5 tablets of 4 mg each).  For additional information 
please refer to the attached IB for dexamethasone. 
 
6.2    Study Drug Administration 
• 
Ixazomib and dexamethasone will be taken based on the information in the package 
insert.   
• 
The starting dose of ixazomib will be 3 mg taken orally on days 1, 8, and 15 of a 28-day 
cycle.  The dose of dexamethasone will be 20 mg taken orally on the same days as 
ixazomib.   
• 
Patients will take ixazomib and dexamethasone for twelve (12) 28-day cycles.  
• 
Ixazomib should be taken once a week on the same day and at approximately the same 
time for the first three weeks of a four week cycle.  Ixazomib should be taken at least one 
hour before or at least two hours after food. The whole capsule should be swallowed with 
water. The capsule should not be crushed, chewed or opened.  If an ixazomib dose is 
delayed or missed, the dose should be taken only if the next scheduled dose is ≥ 72 hours 
away. A missed dose should not be taken within 72 hours of the next scheduled dose.  A 
double dose should not be taken to make up for the missed dose.  If vomiting occurs after 
taking a dose, the patient should not repeat the dose. The patient should resume dosing 
at the time of the next scheduled dose.   
• 
Ixazomib and dexamethasone should not be taken at the same time, because 
dexamethasone should be taken with food and ixazomib should not be taken with food. 
• 
Ixazomib and dexamethasone will be dispensed monthly by the PRC  
• 
Diaries/logs will be used by patients to track their doses. 
 
Treatment Plan and Laboratory Assessment. Participants will undergo a 12-month treatment 


 
37
regimen of ixazomib-dexamethasone on days 1, 8, and 15 of a 28-day cycle, for 12 cycles (Table 
1-1 below).  The dose of ixazomib (3 mg) is based on packet information for patients with reduced 
kidney function and will be taken at least one hour before or at least two hours after food.  The 
dose of dexamethasone is 50% lower than the dose recommended in the package insert to reduce 
the possibility of metabolic complications in ESRD.  
 
Table 1-1  IXADES Treatment Protocol for desensitization 
 
 
 
 
Duration of Treatment and Follow-up. All participants, those that receive a kidney transplant 
during the defined period and those that do not will be followed for the entire length of treatment, 
plus one month following the last dose of the study drug. All subjects will be asked to return for a 
final study visit approximately one month following the last dose of study drug. During this final 
study visit, subjects will undergo physical examination, bone marrow aspirate collection, CBC, 
LFT check, ECG and echocardiogram. 
 
Bone Marrow Aspirate Collection Procedure:  Subjects will be given the option of having the 
bone marrow aspirate performed under conscious sedation or local anesthetic only.  The bone 
marrow aspirate will be collected in a transplant clinic room.  If the bone marrow aspiration is done 
under conscious sedation, subjects will be given instructions to fast for six hours before the 
procedure (medications are allowed) and not to drive themselves home or operate dangerous 
equipment after the procedure.   
 
Measurement of effect.  We will determine the effect of ixazomib by measuring cPRA, whether 
patients receive a kidney transplant while participating in the study, antibody strength by MFI, and 
the toxicity (measured by the incidence of adverse events)of the treatment quarterly up to the end 
of the study. 
Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration.  Study drug will be dispensed only to eligible patients by a member of the 
study team.  Patients should be monitored for toxicity, as necessary, and doses of ixazomib 
should be modified as needed to accommodate patient tolerance to treatment; this may include 
symptomatic treatment, dose interruptions, and adjustments of ixazomib dose (see Section 6.3). 
 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules 0.5, 2.3, and 3.0 mg ixazomib. The prescribed administration of ixazomib 
doses in this study is 9 mg ixazomib in a 28 day cycle. Patients should be instructed to swallow 
ixazomib capsules whole, with water, and not to break, chew, or open the capsules.  Ixazomib 
should be taken on an empty stomach (no food or drink) at least 1 hour before or at least 2 hours 
after food.  Each capsule should be swallowed separately with a sip of water.  A total of 
approximately 8 ounces (240 mL) of water should be taken with the capsules.   


 
38
 
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 
72 hours or more away.  A double dose should not be taken to make up for a missed dose.  If the 
patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
Ixazomib Destruction 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
institution’s standard operating procedure.  We will document removal and destruction on drug 
accountability logs. 
Dexamethasone: 20 mg of dexamethasone (5 tablets of 4 mg each) will be taken with food on 
days 1, 8, and 15 of a 28 day cycle (same days as ixazomib). 
 
6.3    Dose-Modification Guidelines  
The ixazomib dose reduction steps are 3 mg -> 2.3 mg -> 1.5 mg (Table 4-1), and the dose 
modification guidelines are provided in the IB and Table 4-2 and 4-3 below. 
 
Treatment monitoring and dose modifying strategies. Liver Function Tests will be conducted 
twice a month for the first 3 months, then monthly thereafter. The Complete Blood Count (CBC) 
will be checked monthly.  They will undergo clinical evaluation at baseline and every three months 
until the end of the study.  Ixazomib dose modifying strategies will be implemented as outlined in 
the IB. 
 
6.3.1 
Recommended Ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 
Treatment with ixazomib will use a cycle length of 28 days. For a new cycle of treatment to begin, 
the patient must meet the following criteria: 
 
• 
ANC must be ≥ 1,000/mm3. 
• 
Platelet count must be ≥ 75,000/mm3. 
• 
All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ Grade 1 or 
to the patient’s baseline condition 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of treatment, dosing 
should be delayed for 1 week. At the end of that time, the patient should be re-evaluated to 
determine whether the criteria have been met. If the patient continues to fail to meet the above-
cited criteria, delay therapy and continue to re evaluate. The maximum delay before treatment 
should be discontinued will be 3 weeks or at the discretion of the Principal Investigator. 
 
For dosing recommendations upon recovery, refer to Table 642 and Table 4-3. 
 
Table 4-1 Ixazomib Dose Adjustments 
Dose Level 
Dose (mg) 
Starting Dose 
3.0 mg 


 
39
First Level Dose 
Reduction 
2.3 mg 
Second Level Dose 
Reduction 
1.5 mg 
Third Level Dose 
Reduction 
Discontinue 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
 
Dosage adjustments for hematologic toxicity are outlined in Table 4-2. 
Table 4-2    Ixazomib Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Dose Modifications for Treatment Cycles 
 
• 
Delay of > 2 weeks in the start of a 
subsequent cycle due to lack of toxicity 
recovery as defined in Section 6.3.1 
• 
ANC < 1.0 × 109/L, platelet count < 75 × 
109/L, or other nonhematologic toxicities > 
Grade 1 or not to the patient’s baseline 
condition 
• 
Hold ixazomib until resolution as per criteria 
Section 6.3.1. 
• 
Upon recovery, reduce ixazomib 1 dose 
level. 
• 
The maximum delay before treatment should 
be discontinued will be 3 weeks or at the 
discretion of the PI. 
 
 
Treatment modifications due to ixazomib-related AEs are outlined in Table 4-3. 
Table 4-3    Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic 
Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
Peripheral Neuropathy: 
Grade 1 peripheral neuropathy 
 
• No action 
 
Grade 1 signs and symptoms:  
asymptomatic; without pain or 
loss of function; clinical or 
diagnostic observations only 
[14] 
 
 
New or worsening Grade 1 
peripheral neuropathy with pain 
or Grade 2 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
Grade 2 signs and symptoms:  
Moderate symptoms; limiting 
instrumental activities of daily 
living (ADL) [14] 
 
 


 
40
Table 4-3    Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Adverse Events (Non-Hematologic 
Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further Considerations 
New or worsening Grade 2 
peripheral neuropathy with pain 
or Grade 3 
• Hold study drug until 
resolution to Grade ≤ 1 or 
baseline 
• Reduce study drug to next 
lower dose upon recovery 
 
Grade 3 signs and symptoms:  
severe symptoms; limiting self-
care ADL; assistive device 
indicated [14] 
New or worsening Grade 4 
peripheral neuropathy 
• Discontinue study drug 
 
 
 
Grade 2 Rash 
• 
Symptomatic 
recommendations as per 
section 6.7 
The investigator and project 
clinician may discuss 
considerations for dose 
modifications and symptom 
management. 
 
Grade 3 nonhematologic 
toxicity including hepatic and 
cardiac judged to be related to 
study drug 
 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Symptomatic recommendations 
noted in Section 6.7 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 
• Reduce study drug 1 to next 
lower dose upon return to 
< Grade 1 or baseline 
 
Subsequent recurrence 
Grade 3 that does not 
recover to < Grade 1 or 
baseline within 4 weeks 
• Hold study drug until 
resolution to Grade < 1 or 
baseline 
• Reduce study drug to next 
lower dose  
Monitor closely, take 
appropriate medical 
precautions, and provide 
appropriate symptomatic care 
 
Grade 4 nonhematologic 
toxicities including hepatic and 
cardiac judged to be related to 
study drug 
 
• Consider permanently 
discontinuing study drug 
 
Exceptions are cases in which 
the investigator determines the 
patient is obtaining a clinical 
benefit  
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
 
6.3.2 
Recommended Dose Modifications for dexamethasone Treatment Associated 
Toxicity 
 
The primary complications of dexamethasone requiring a dose reduction or discontinuation of 
therapy will be severe allergic reaction, psychosis, self-reported or diagnosed infection or 


 
41
hyperglycemia requiring hospitalization.  In case of severe allergic reaction or psychosis we will 
discontinue dexamethasone therapy.  Otherwise, dexamethasone will be reduced or discontinued 
in accordance with clinical guidelines.Re-escalation is allowable. 
 
 
6.4 Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study. 
Systemic treatment with any of the following metabolizing enzyme inducers should be avoided, 
unless there is no appropriate alternative medication for the patient’s use (Rationale:  If there 
were to be a drug-drug interaction with an inducer, ixazomib exposure would be decreased): 
• 
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital 
The following medicinal products and procedures are prohibited during the study. 
• 
Excluded dietary supplements include St. John’s wort  
• 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days 
prior to study drug dosing for any dosing day 
6.5    Permitted Concomitant Medications and Procedures  
The following medications and procedures are permitted during the study: 
• 
Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
• 
Loperamide or other antidiarrheal should be used for symptomatic diarrhea at discretion 
of the investigator. The dose and regimen will be according to institutional guidelines. 
Intravenous fluids should be given to prevent volume depletion. 
• 
Growth factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage-colony stimulating factor [GM-CSF], recombinant erythropoietin) are 
permitted. Their use should follow published guidelines and/or institutional practice;  
however, alternative usage may be reviewed with the Millennium Clinical or Medical 
Representative . Erythropoietin will be allowed in this study. Their use should follow 
published guidelines and/or institutional practice. 
• 
Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines as long as “3 days prior to study drug dosing for any 
dosing day” – per excluded procedures in seciton 6.4 above. 
• 
Antiviral therapy such as acyclovir may be administered if medically appropriate. 
• 
Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
• 
Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of the 
investigator. 
• 
Supportive measures consistent with optimal patient care may be given throughout the 
study. 
6.6    Precautions and Restrictions  
Fluid deficit  Fluid deficit should be corrected as per standard of care before initiation of treatment 
and during treatment. 


 
42
 
Pregnancy 
It is not known what effects ixazomib has on human pregnancy or development of the embryo or 
fetus.  Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following:  
• 
Postmenopausal for at least 1 year before the screening visit, or 
• 
Surgically sterile, or 
• 
If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form through 90 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, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following: 
• 
Practice effective barrier contraception during the entire study treatment period and 
through 90 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, 
postovulation methods for the female partner] and withdrawal are not acceptable methods 
of contraception.) 
6.7  Preparation, Reconstitution, and Dispensing 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules. 
 
Dexamethasone is a corticosteroid drug and will be provided by the study sponsor through the 
UW-Pharmaceutical Research Center (PRC). 
 
Subjects will be dispensed one cycle of ixazomib and dexamethasone at each visit. 
 
Ixazomib:  Subjects will be dispensed a wallet/carton of 3 capsules in each wallet/carton. 
 
Dexamethasone: Subjects will be dispensed 15 4mg tablets in an amber bottle per cycle. 
6.8  Packaging and Labeling 
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be labeled 
and handled as open-label material, and packaging labels will fulfill all requirements specified by 
governing regulations.   
 
The capsules are individually packaged using cold-form foil-foil blisters that are in a child-resistant 
carton.  There are 3 capsules in each wallet/carton.  
Dexamethasone 4mg tablets will be provided by the UW-PRC.  For each 20 mg dose, 5 tablets 
will be prepared in a small package.  Three packages of 20 mg total dexamethasone tablets will 


 
43
be used for each cycle.  The PRC will provide treatment for one cycle at a time.  The package will 
be provided to subjects at each study visit. 
6.9  Storage, Handling, and Accountability 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided 
until use or until drug is dispensed. The container should be stored at the investigative site 
refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before the retest expiry date 
provided by Millennium. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life. 
 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for take-
home dosing should remain in the blister packaging and refrigerated as noted above until the 
point of use. The investigative site is responsible for providing the medication to the patient in the 
correct daily dose configurations. Comprehensive instructions should be provided to the patient 
in order to ensure compliance with dosing procedures. Patients who are receiving take-home 
medication should be given only 1 cycle of medication at a time. Patients should be instructed to 
store the medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each cycle. Patients 
should be instructed to return their empty blister packs to the investigative site, rather than 
discarding them. Reconciliation will occur accordingly when the patient returns for their next cycle 
of take-home medication. Any extreme in temperature should be reported as an excursion and 
should be dealt with on a case-by-case basis. 
 
Ixazomib will be handled with due care. Patients should be instructed not to chew, break, or open 
capsules. In case of contact with broken capsules, raising dust should be avoided during the 
clean-up operation. The product may be harmful by inhalation, ingestion, or skin absorption. 
Gloves and protective clothing should be worn during cleanup and return of broken capsules and 
powder to minimize skin contact. 
 
The area should be ventilated and the site washed with soap and water after material pick-up is 
complete. The material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations. 
 
In case of contact with the powder (eg, from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified. Patients are to be instructed on proper storage, 
accountability, and administration of ixazomib, including that ixazomib is to be taken as intact 
capsules. 
 
Dexamethasone 4mg tablets will be provided by the UW-PRC.  For each 20 mg dose, 5 tablets 
will be prepared in a small package.  Three packages of 20 mg total dexamethasone tablets will 
be used for each cycle.  The PRC will provide treatment for one cycle at a time.  The package will 
be provided to subjects at each study visit. 
6.10      Study Drug Compliance 
Study drug will be administered or dispensed only to eligible patients by the investigator, identified 
sub-investigator(s), or study coordinators.  The appropriate study personnel will maintain records 
of study drug receipt and dispensing. The study personnel will monitor the following compliance 


 
44
criteria quarterly for subjects to remain in the study (i.e. subjects <75% study drug compliance will 
be re-educated). If they fall below 75% study drug compliance again, they will be withdrawn. 
6.11   
Treatment Assignment (if applicable) 
N/A 
6.12   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• 
If study drug is discontinued due to AE  
• 
Protocol violation 
• 
Lost to follow-up 
• 
Study terminated  
• 
Non-compliance as defined above in section 6.10 
 
Patients who are withdrawn from the study will not be replaced. The primary reason for patient’s 
withdrawal from the study should be recorded in the source documents and CRF.  Subjects will 
complete an early termination visit. 
 
6.14   Specimen Handling and Confidentiality 
 
Samples that will be sent to the Terasaki Research Foundation Laboratory and University of 
Michigan will be labeled with the study ID number, date of service and subject age.  Researchers 
at outside institutions will not have access to the key that links the code to identifiable information.  
Any leftover samples that are not used for the analysis will be destroyed after the study is over.  
The Terasaki Research Foundation Lab will perform analysis of HLA-DSA, IgG subclasses, ETA-
R and AT1-R antibodies in 10 subjects at 5 time points (50 samples total). 
 
6.15   Bone Marrow Studies  
 
Mechanistic studies on B cells and plasma cells (University of Michigan) and mesenchymal 
stromal cells (UW) witll be conducted to better understand the effect of treatment on 
desensitization.  Dr. Cascalho and Dr. Platt at UM will participate in the research by processing 
bone marrow studies (ASCs, BAFF/APRIL).  All subjects will be enrolled in the IXADES study at 
the University of Wisconsin-Madison.  University of Michigan will not be involved with subject 
recruitment or subject interaction.  The samples that will be sent to the University of Michigan will 
be labeled with a study ID number and will contain; date of service, and subject age.  Dr. Cascalho 
and Dr. Platt will process the samples in the lab and perform mechanistic studies to achieve the 
aims of the research.  Dr. Cascalho and Dr. Platt will analyze the bone marrow samples, provide 
the results to the study team at UW, and assist with writing the manuscript.  Dr. Cascalho and Dr. 
Platt will not have access to the key to the code.  The UW study team will communicate with the 
study team at the University of Michigan once per month through phone calls or e-mails. 
 
A portion of marrow aspirates will be saved at UW for future research studies related to 
sensitization or transplantation.  In addition, the samples may be used in a future therapeutic 
study to reinject mesenchymal stromal cells in subjects who did not achieve desensitization 


 
45
through the current study.  Samples will be banked at UW for an indefinite period of time.  Subjects 
may withdraw their permission at any time.   
7.    
STATISTICAL AND QUANTITATIVE ANALYSES 
7.1    Statistical Methods 
More than 50% of patients with CDC T cell crossmatch titers ≥ 1:8 and/or cPRA > 80% fail to 
respond to desensitization (5, 8).  In this pilot exploratory, proof of concept, open-label, single-
center phase II clinical trial, we hypothesize that our study will have a higher rate of 
transplantation.  Dr. Brad Astor, PhD, epidemiologist and biostatistician in the division of 
nephrology, will perform the statistical analyses.  Primary efficacy (decline in cPRA > 20%) and 
safety (discontinuation of therapy due to adverse events) endpoint will be analyzed using the 
exact binomial test.  The secondary endpoint (time to transplantation) will be assessed using 
Kaplan-Meier analyses and log rank tests.  Baseline characteristics will be compared between 
participants with and without the primary end point using the 2-sample t test for continuous 
variables and the Fisher's exact test for categorical variables. Relationships between serum 
BAFF/APRIL, antibodies, and baseline cPRA will be assessed using the Pearson correlation 
coefficient. The influence of serum BAFF/APRIL, antibodies, and bone marrow plasma cells on 
end points of interest will be investigated using Kaplan-Meier curves and Cox proportional-
hazards models. 
7.1.1     
Determination of Sample Size 
The primary outcome will be considered as a dichotomous outcome (decline in cPRA of >20% or 
not).  We will test the hypothesis that the success rate (i.e., the % that have a decline in 
cPRA>20%) is 0% using the exact binomial test (Figure 2a) (5).  The figure shows the lower and 
upper 95% confidence limits resulting from any observed success rate. For example, if we 
observe success in 3/10 (30%), the resulting 95% confidence interval (CI) is (6.7%, 65.2%). Any 
observed success demonstrates that the success rate of the proposed treatment is >0.  Figure 
2b represents the power curve, that is, the probability of observing any success, given different 
values of true success rate. For example, we would have  > 80% chance of observing at least 
one success if the true success rate is > 0.2. 
         
 
 


 
46
 Figure 2a.  Sample Size Analysis  
 
    Figure 2b.  Power curve 
 
  
 
 
7.1.2 
Randomization and Stratification   
N/A 
 
7.1.3 
Populations for Analysis 
All patients enrolled will be included in the safety analysis. 
 
7.1.4    
Procedures for Handling Missing, Unused, and Spurious Data 
All available data will be included in the data listings and tabulations. Where appropriate, 
imputations of values for missing data will be performed using last observation carried forward 
and specified in the Statistical Analysis Plan. All data recorded on the CRF will be included in the 
data listings that will accompany the clinical study report. 
 
7.1.5    
Demographic and Baseline Characteristics 
Demographic and baseline characteristics in all enrolled patients will be reported in a table format.  
These will include age, gender, race, ethnicity, cause of ESRD, history of sensitization 
(transfusion, previous transplantation, pregnancy), type of renal replacement therapy, baseline 
cPRA, CBC, LFTs, and medications. 
 
7.1.6    
Efficacy Analysis 
Primary outcome will be a decline in cPRA > 20%.  Secondary outcome will be kidney 
transplantation within 12 months of therapy. These outcomes will be assessed using paired t-
Test, Kaplan-Meier methods and log rank tests, where appropriate.  In addition, we will analyze 
the change in HLA antibody strength by comparing the MFI values pre and post therapy. 
 
0%
20%
40%
60%
80%
100%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
95% Confidence Limits
Observed Success Rate
95% Confidence Limits, by Observed 
Success Rate


 
47
7.1.7    
Pharmacokinetics/Pharmacodynamics/Biomarkers (if applicable) 
N/A 
 
7.1.8    
Safety Analysis 
Together with the UW ICTR Data Monitoring Committee (DMC) we will develop a detailed a data 
and safety monitoring plan (DSMP) which will ensure ongoing safety of participating patients 
commensurate with the level of risk and complexity of the protocol treatment to minimize risks, 
integrity of trial data and scientific validity of the trial. The development of the DSMP will be guided 
by the NIH Policy for Data and Safety Monitoring and by the FDA Guidance on the Establishment 
and Operation of Clinical Trial Data Monitoring Committees.  The plan will make certain that 
review of the conduct of research is rigorous, independent and objective, interim safety and 
efficacy data is collected and presented and progress towards achieving study goals is made.  It 
will cover policies and procedures for reporting adverse events to the DSMB, IRB, and the FDA. 
 
The safety analysis will focus on infections, malignancies, hematological complications including 
leucopenia, anemia, and thrombocytopenia, cardiovascular complications and events, distal 
neuropathy, gastrointestinal symptoms, and immunosuppression-related adverse effects.  
Patients will have a physical exam 5 times (beginning and end of the study, and quarterly during 
the study) following enrollment: Days 1, 85, 169, 253, and 373 (+ 6, - 3 for all visits except for visit 
1). 
• 
Day 1: Prior to treatment initiation.  H&P, Labs, Bone Marrow Aspirate 
• 
Day 85 + 6, - 3: Prior to treatment dose.  H&P, Labs 
• 
Day 169 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 253 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 373 + 6, - 3 After treatment completion, H&P, Labs, Bone Marrow Aspirate 
• 
At each of these visits, the patients will undergo a medical history and physical exam, 
reviewing the adverse event data, vital signs, monthly labs, changes in patients’ health 
status and medications. 
• 
Study drug will be dispensed at each month’s in-person visit, prior the initiation of the next 
cycle, and after reviewing the AEs and monthly labs. 
Liver Function Tests (LFTs) will be conducted twice a month for the first 3 months, then 
monthly thereafter. The Complete Blood Count (CBC) will be checked monthly. 
7.1.9    
Interim Analysis 
We will utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study and is 
described further in section 9.1 Source documents may be reviewed to allow the DMC to 
independently judge whether the overall integrity and conduct of the protocol remain acceptable 
based on data provided and reported by the Principal Investigator.  The DMC will make 
recommendations to the Principal investigator that could include actions of continuation, 
modification, suspension or termination.  
 
7.1.10 Study Stopping Rules 
 
Subject Stopping Rules 


 
48
 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care.  The investigator also has the right to withdraw 
patients from the study for any of the following reasons: 
• 
If study drug is discontinued due to AE 
If a subject is withdrawn due to an adverse event, the dose adjustment, modification and 
withdrawal procedures related to adverse events described in section 6.3 of the clinical 
protocol will be followed.  
• 
Protocol violation 
• 
Lost to follow-up 
• 
Study terminated  
• 
Non-compliance 
 
Study Stopping Rules 
 
Serious Adverse Events (SAEs) as described below, will be reviewed to determine if additional 
risk could be posed to the subject in question or others participating in the study. If it is determined 
that a serious adverse event, new information, or an unanticipated event could pose a potential 
risk to subjects,the DMC and/or the investigator may decide to stop the study. 
 
8.    
ADVERSE EVENTS   
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and rash 
have been associated with ixazomib treatment. 
8.1    Definitions 
8.1.1       Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject administered 
a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not it is related to the medicinal product.  
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.  AEs will be assessed at study visits and during 
the final follow-up study visit.  In addition, data on rejection, graft, and patient survival will be 
collected for 6 months following kidney transplantation. 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.  These AEs will be entered 
into the OnCore system. 
8.1.2    
Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• 
Results in death. 


 
49
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event.  It does not refer to an event which hypothetically might have caused death if it 
were more severe). 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations). 
• 
Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions). 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event (Tables 4-2 and 4-3).  This refers to an AE that may not 
result in death, be immediately life threatening, or require hospitalization, but may be 
considered serious when, based on appropriate medical judgment, may jeopardize the 
patient, require medical or surgical intervention to prevent 1 of the outcomes listed above, 
or involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, grade 4 neuropathy, cardiac, or hepatic 
toxicity, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (eg, prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent.   
 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the event 
itself, however, may be of relatively minor medical significance (such as a Grade 3 headache).  
This is NOT the same as serious, which is based on patient/event outcome or action criteria 
described above, and is usually associated with events that pose a threat to a patient’s life or 
ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
8.2    Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic procedures. 
When possible, signs and symptoms indicating a common underlying pathology should be noted 
as one comprehensive event.  For serious AEs, the investigator must determine both the intensity 
of the event and the relationship of the event to study drug administration.  
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from the 
first dose of study drug through 30 days after administration of the last dose of ixazomib. Any SAE 
that occurs at any time after completion of ixazomib treatment or after the designated follow-up 
period that the sponsor-investigator and/or sub-investigator considers to be related to any study 
drug must be reported to Millennium Pharmacovigilance (or designee). In addition, new primary 
malignancies that occur during the follow-up periods must be reported, regardless of 
causality to study regimen, up to one month after the last dose of the investigational 
product, starting from the first dose of study drug. All new cases of primary malignancy must 
be reported to Millennium Pharmacovigilance (or designee).    
 


 
50
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated 
in an unexpected manner during the trial (e.g., surgery was performed earlier or later than 
planned).  All SAEs should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the principal investigator Dr. Arjang Djamali, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency and to the sponsor- investigator’s EC or IRB.    
 
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported in English to Millennium Pharmacovigilance (or designee): 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event 
 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance.   
The sponsor-investigator must fax or email the SAE Form per the timelines above.  A sample of 
an SAE Form will be provided.   
The SAE report must include at minimum: 
• 
Event term(s) 
• 
Serious criteria 
• 
Intensity 
of 
the 
event(s): 
Sponsor-investigator’s 
or 
sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, 
whenever 
possible.  
The 
criteria 
are 
available 
online 
at 
http://ctep.cancer.gov/reporting/ctc.html. 
• 
Causality 
of 
the 
event(s): 
Sponsor-investigator’s 
or 
sub-investigator’s 
determination of the relationship of the event(s) to study drug administration.  
Follow-up information on the SAE may be requested by Millennium.   
 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that 
the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator so 
that the sponsor-investigator can meet his/her foregoing reporting obligations to the required 
regulatory agencies and to Millennium Pharmacovigilance, unless otherwise agreed between the 
sponsor-investigator and sub-investigator(s).   
 
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the AE 
is associated with the study drug(s)? 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s), as soon as 
possible but no later than 4 calendar days of such communication. 
SAE and Pregnancy Reporting Contact Information 
 
US & Canada 


 
51
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
Rest of World 
Fax #: 1 202 315 3560 
E-mail: TakedaOncoCases@cognizant.com 
Suggested Reporting Form:   
• 
SAE Report Form (provided by Millennium) 
• 
US FDA MedWatch 3500A:   
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
8.3    Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study or 
within 90 days after the last dose, she must inform the investigator immediately and permanently 
discontinue study drug.  The sponsor-investigator must immediately fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  The 
pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
• 
Pregnancy Report Form (provided by Millennium)   
9.    
SAFETY MONITORING  
9.1 Safety Monitoring  
The investigator is responsible for monitoring the safety of subjects who have enrolled in the 
study.   For this study,  adverse events will be solicited from subjects to identify an occurrence or 
worsening of an unintended sign or symptom, related to the  ingestion of the study drug.  The 
study team will ask subjects prior to each cycle if they experienced any new medical related signs 
or symptoms since taking the study drug. Subjects will be asked about any adverse events they 
may have experienced again monthly, prior to each cycle, and at the five study visits.  Only the 
adverse events considered related (possibly, probably or definitely) to the ingestion of the study 
drug will be entered into and managed in the ICTR OnCore system quarterly.   
 
At each visit, subjects will be assessed for AEs by the study team.  They will be examined by the 
principal investigator 5 times  (please see tables 2-1 a-b and Figure 1, below): Days 1, 85, 169, 
253, and 373 + 6, - 3). 
• 
Day 1: Prior to treatment initiation.  H&P, Labs, Bone Marrow Aspirate 
• 
Day 85 + 6, - 3: Prior to treatment dose.  H&P, Labs 
• 
Day 169 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 253 + 6, - 3 Prior to treatment dose.  H&P, Labs 
• 
Day 373 + 6, - 3 After treatment completion, H&P, Labs, Bone Marrow Aspirate 
• 
Study drug will be dispensed at each month’s in-person visit, prior the initiation of the next 
cycle, and after reviewing the AEs and monthly labs. 


 
52
• 
Patients will undergo monthly CBC and bi-weekly liver function tests (LFTs) for the first 
three months.  After the first 3 months, CBCs and LFTs will be done monthly.  cPRA, 
BAFF/APRIL, DSA and antibodies will be checked every three months (5 times total).  
Bone marrow aspirates will be collected at the beginning and at one of the following time 
points: one month (+ 6, - 3 days) after the end of the 12 month study, cPRA<80%, time of 
transplant, or time of subject withdrawal from the study. 
• 
Additional visits may be required if the subject has to hold treatment and needs to return 
to the clinic for blood draws to confirm eligibility to continue.  Please see Table 4-3, Dose 
Adjustments for Hematologic Toxicities for dose adjustment plan. 
 
Based on the subject population, it is anticipated that the laboratory results that will be abstracted 
from the EMR for study purposes will be abnormal. The PI will not make clinically significant/non-
clinically significant determinations of these results, as this subject population is expected to be 
abnormal and clinically significant hence their current clinical treatment. All reportable events 
related to the study protocol and its associated procedures will be reported to the IRB.  It is the 
responsibility of the Investigator to promptly notify the Institutional Review Board of all 
unanticipated problems involving risk to human research subjects.  Reportable events, such as 
protocol noncompliance, serious adverse events, new information, and unanticipated problems 
will be reported to the IRB and DMC in accordance with the UW IRB guidelines.   
 
We will utilize the UW ICTR Data Monitoring Committee (DMC) to oversee the study. The UW 
ICTR DMC is comprised of experienced members (core plus ad hoc) with expertise required to 
oversee this study. In providing oversight for the conduct of this study, the ICTR DMC will meet 
annually during the five year time period in which subjects will have any study procedures. At 
these annual meetings, the DMC members will review protocol-specific reports created by 
statisticians using data pulled from the ICTR OnCore clinical research management system. 
These standard reports will include an overview of study objectives, a review of actual and 
projected accrual rates, an evaluation of patient demographics, a summary of the number and 
seriousness of adverse events, and an analysis of the primary and secondary outcomes.  The 
safety data that will be reviewed includes the number and seriousness of infections, malignancies, 
hematological 
complications 
including 
leucopenia, 
anemia, 
and 
thrombocytopenia, 
cardiovascular complications and events, distal neuropathy, gastrointestinal symptoms, and 
immunosuppression-related adverse effects.  Additional specific safety areas that will be closely 
monitored are listed in Section 1.10.   
 
Source documents may be reviewed to allow the DMC to independently judge whether the overall 
integrity and conduct of the protocol remain acceptable based on data provided and reported by 
the Principal Investigator.  The DMC will make recommendations to the Principal investigator that 
could include actions of continuation, suspension, modification or termination. 
 
The boundary for excess harm will equal observed harm which, in the judgment of the DMC, is 
excessive.  We will report all AEs and SAEs  into OnCore for review by the DMC and the IRB 
oversight committee UW Madison Health Sciences IRB (HS-IRB) in accordance with the HS-IRB 
reporting guidelines. 
9.2 IND Monitoring Plan 
The principal investigator will follow the FDA regulations in 21 CFR 312 applicable to sponsor 
responsibilities, particularly Subpart D.  This includes: 


 
53
• 
Filing protocol amendments when required by 21 CFR 312.30; 
• 
Notifying the FDA and participating investigators of adverse events as required in 21 CFR 
312.32; 
• 
Filing annual reports with the FDA as required by 21 CFR 312.33; 
• 
Record keeping requirements of 21 CFR 312.57; and 
• 
Promptly reporting as required in 21 CFR 312.56(b) to the FDA and all participating 
investigators of significant new adverse effects or risks with respect to the study drug. 
The Investigator will permit trial-related monitoring, audits, IRB review and regulatory 
inspection(s) by providing direct access to source data and study documents.  
9.3 ICTR STUDY MONITORING SERVICE (SMS) 
While many institutions involved in clinical research conduct various types of quality assurance 
reviews and audits, University of Wisconsin Institute for Clinical and Translational Research 
(ICTR) is one of a few institutions to offer independent Study Monitoring Services, a robust 
academic equivalent to the industry Contract Research Organization (CRO) standards for 
ongoing study monitoring.  
 
The sponsor-investigator has contracted with ICTR Study Monitoring Service (SMS) for the 
proposed study to provide ongoing monitoring services to conduct and follow-up of monitoring 
visits throughout the life cycle of the study. Refer to the Study Monitoring Plan.  
 
For this study, UW ICTR SMS personnel will conduct a Site Initiation Visit (SIV) and ongoing 
Interim Monitoring Visits (IMVs), either on-site, remotely, centrally or a combination thereof, 
throughout the duration of the study. During IMVs, the monitors will review study materials, 
including but not limited to: regulatory files, consent forms, case report forms, and drug 
accountability logs.  UW ICTR SMS will review FDA communications to ensure compliance with 
applicable FDA IND regulations, guidelines, and institutional policies.  UW ICTR SMS personnel 
will conduct a Close-Out Visit (COV) upon completion of the study at the study site.  
 
Monitoring will consist of all (100%) of the study-related records representing 50-75% of those 
enrolled at a minimum. SMS personnel could increase the percentage of study or subject records 
to be reviewed if warranted by the ongoing monitoring findings, resulting in a partial or full review 
of up to 100% of the study-related subject records.  Based on the plan to review approximately 
50-75% of the subject records, it is anticipated that the following monitoring visit schedule will 
implemented; 1 SIV, 1 IMV following the enrollment of the first subject(s), followed by 
approximately 8-9 IMVs through the end of the study, planned on an approximate quarterly basis.  
The frequency of the IMVs could increase based on subject enrollment and preivous monitoring 
visit findings, but will not decrease. 
 
The SMS will review the accuracy and completeness of completed consent and HIPAA 
documents for each enrolled subject.  For approximately 50-75% of enrolled subjects, the SMS 
will evaluate the completeness and accuracy of the data collected and conduct a comparison with 
the electronic data captured, resulting in electronic queries with resolution or validation. In 
addition, the SMS staff will verify adherence to protocol eligibility criteria, verify documentation for 
the accountability and administration of the study product, verify documentation of study 
procedures, and verify that FDA required SAE reports were appropriately submitted.  
 
The study monitor(s) will work closely with the ICTR DMC statistician and the study statistician to 
conduct periodic central data reviews, with follow-up conducted by the study monitors for any data 
discrepancies identified. 


 
54
 
 
9.4  DATA MANAGEMENT SYSTEM 
9.4.1  Data Collection Tools 
The critical data collected to address the study objectives will be electronically captured and 
managed in the clinical trials management software, OnCore, managed by the Institute for 
Clinical and Translational Research (ICTR). The study specific data collection tools will be 
developed and maintained with the assistance of the ICTR OnCore data management team, in 
consultation with the ICTR Study Monitoring Service and the ICTR Data Monitoring Committee 
to ensure the collection and recording all subject considered critical to answer the study 
objectives. It is the Investigator’s responsibility to ensure that these are properly, legibly and 
fully completed and signed where appropriate. The data collection forms are used to record 
study data and are an integral part of the study and subsequent reports.  
9.4.2  Data management Tool 
The critical data collected to address the study objectives will be electronically captured and 
managed in the clinical trials management software, OnCore, managed by the Institute for 
Clinical and Translational Research (ICTR). The ICTR OnCore data management team will 
work with the investigator and study team to develop the data collection tools, both in paper and 
electronic format, to collect the relevant, applicable study data. The ICTR OnCore data 
management team will also work with the study team to identify and implement quality 
assurance features at the time of data entry (i.e. use of minimum/maximum limits, constraints 
and branching logic to require or skip data based on preceding data entered). These features 
will reduce the amount of data entry error at the time of entry.  
OnCore is a sophisticated, web-based study and data management system that: a) ensures 
secure, easy data entry at multiple sites; b) integrates multiple data sources; c) provides 
controlled, secure access to sensitive data using role-based access control; d) provides 
workflow automation; and e) allows export and reporting of data for Data and Safety Monitoring 
Boards and biostatisticians.  
In addition to being a secure web-based system with restricted access, the ICTR OnCore 
system provides an audit trail from the moment the data is first entered, revised and locked. The 
ICTR OnCore system also provides the functionality to the SMS staff to electronically query 
data, the study team to electronically respond, resulting in a final state of validation prior to the 
locking of study data. The various states (i.e. Started, Completed, Queried, Ameneded, 
Validated) are built in the system to allow easy navigation as well as an assessment of the state 
of the data at any given moment.  


 
55
10. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GMP  
10.1 Statement of Compliance 
This trial will be conducted in compliance with the protocol, current Good Clinical Practices (GCP), 
adopting the principles of the Declaration of Helsinki, and all applicable regulatory requirements. 
 
Prior to study initiation, the protocol and the informed consent documents will be reviewed and 
approved by an appropriate ethics review committee or Institutional Review Board (IRB). Any 
amendments to the protocol or consent materials must also be approved before they are 
implemented. 
 
10.2 Informed Consent 
The informed consent form is a means of providing information regarding the trial to a prospective 
participant and allows for an informed decision about participation in the study. All participants in 
the IXADES study must read, sign and date a consent form prior to participation in the study, 
taking study drug and/or undergoing any study-specific procedures.  
 
The informed consent form must be updated or revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new information 
becomes available that may affect a patients’ participation in the trial. 
 
A copy of the informed consent will be given to a prospective participant for review. The Study 
Investigator or a designee of the Investigator will review the consent and answer any questions 
that the potential participant may have. The participant will be informed that their participation is 
voluntary and they may withdraw from the study at any time, for any reason. 
10.3 Privacy and Confidentiality  
Subject privacy and confidentiality will be respected throughout the study.  Each study participant 
will be assigned a sequential subject identification number specific to the given study (i.e., IXA001 
– IXA-010).  These numbers rather than names will be used to collect, store and report participant 
information.  Contact with subjects will be conducted in private exam or procedure rooms to 
ensure subjects' privacy. No information other than information needed specifically for the study 
will be collected. 
 
The ICTR data management team will work with investigators to collect only relevant, applicable 
study data, which will be entered in a secure web-based system with restricted access. 
 
11. ADMINISTRATIVE REQUIREMENTS  
11.1    
Product Complaints   
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact Millennium (see below) 
and report the event.  Whenever possible, the associated product should be maintained in 
accordance with the label instructions pending further guidance from a Millennium Quality 
representative. 


 
56
For Product Complaints, 
• 
Phone: 1-844-ONC-TKDA (1-844-662-8532) 
• 
E-mail: GlobalOncologyMedinfo@takeda.com 
• 
FAX: 1-800-881-6092 
• 
Hours: Mon-Fri, 9 a.m. – 7 p.m. ET 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to Millennium Pharmacovigilance 
 


 
57
12. APPENDICES 
12.1    
Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance 
without restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable 
to carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol 1982; 5 (6):649-55.  
 
 
 
 
 


 
58
 
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