Conditions: Multiple Myeloma
Keywords: Relapsed Refractory Proteasome Inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of Ixazomib on inducing osteoblast activation as measured by bone markers and imaging in patients with relapsed/refractory myeloma.

Detailed description:
This is a phase II study designed to examine the bone anabolic effect of the next generation proteasome inhibitor, ixazomib, in relapsed/refractory myeloma patients. Treatment consists of Ixazomib 4 mg on days 1, 8, 15, 22 of a 28 day cycle, for a maximum of 6 cycles. Determination of relapsed/refractory disease as an entry criterion may be based on patient data obtained during or following the patient's most recent prior antineoplastic therapy. Treatment periods will be defined as 28-day cycles. Patients will be seen at regular intervals while they are participating in the study.

Arms:
arm 1: Ixazomib 4.0 mg given on days 1, 8 15, 22 of a 28 day cycle maximum of 6 cycles.

Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_001.pdf: 
Page 1 of 50 
 
CLINICAL STUDY PROTOCOL  
X16013  
UARK 2014-14:  A Phase II Prospective Evaluation of Bone Remodeling During Ixazomib Treatment in 
Relapsed/Refractory Multiple Myeloma Patients 
 
Principal Investigator 
Maurizio Zangari, MD 
University of Arkansas for Medical Sciences 
The Myeloma Institute 
4301 West Markham, Slot 816 
Little Rock, AR 72205 
 
Sub-Investigators 
Gareth Morgan, MD, PhD 
Faith Davies, MD, PhD 
Frits van Rhee, MD, PhD 
Christoph Heuck, MD 
Carolina Schinke, MD 
Sharmilan Thanendrarajan, MD 
University of Arkansas for Medical Sciences 
The Myeloma Institute  
4301 West Markham, Slot 816 
Little Rock, AR 72205 
 
 
Indication: 
Relapsed and/or Refractory Multiple Myeloma 
 
Phase: 
2 
 
 
Version: 
v5, May 15, 2017. 
 
 
 
 
 
IND Sponsor 
University of Arkansas for Medical Sciences 
 
Supplemental Funding:   
Millennium: The Takeda Oncology Company 
 
This is an investigator-initiated study.  The principal investigator is Maurizio Zangari, M.D.  The University of Arkansas for 
Medical Sciences (UAMS) is the IND sponsor.  The legal and ethical obligations of the principal investigator and the study 
sponsor are the joint obligations of Maurizio Zangari, M.D., and UAMS. 
 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 2 of 50 
 
PROTOCOL SUMMARY 
Study Title:  Phase II prospective evaluation of bone remodeling during Ixazomib treatment 
in relapsed/refractory MM patients. 
Phase:  2 
Number of Patients:  20 
Study Objectives  
Primary 
 
To evaluate the effect of ixazomib on inducing osteoblast activation as 
measured by bone markers and imaging in patients with relapsed/refractory 
myeloma 
Secondary 
 
To evaluate the association between osteoblastic activation and myeloma 
response to ixazomib  
 
To identify predictive factors for ixazomib-associated osteoblastic activation 
Overview of Study Design:   
Multiple myeloma (MM) is a clonal disease of plasma cells that is characterized by the 
accumulation of plasma cells in the bone marrow (and other organs) and sometimes results 
in bone marrow failure, bone destruction, hypercalcemia, and renal failure.  It constitutes 
approximately 1% of all reported neoplasms and approximately 13% of hematologic 
cancers worldwide.  Bone disease is extremely common at myeloma diagnosis.   It is 
present in the majority of patients and is associated with bone pain, fractures, spinal cord 
compression, and hypercalcemia.  Bone disease in myeloma results from the activation of 
osteoclast and suppression of osteoblast activity in the myelomatous bone marrow.   As 
treatment and survival of myeloma patients improve, new therapies to reduce complications 
are important and vitally needed.  The proteasome inhibitor, Bortezomib (VELCADE) has 
been shown to produce an anabolic bone effect (increase ALP, bone ALP, osteocalcin) in 
relapsed/refractory patients.  This study will examine the bone anabolic effect in patients 
with relapsed/refractory myeloma with the next generation proteasome inhibitor, ixazomib, 
treatment (4mg day 1, 8, 15, 22 Q 28 days cycle x 6 cycles). 
Study Population:  Adult patients with confirmed diagnosis of relapsed/refractory multiple 
myeloma. 
Duration of Study:  2 years 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 3 of 50 
 
TABLE OF CONTENTS 
PROTOCOL SUMMARY ................................................................................................. 2 
TABLE OF CONTENTS ................................................................................................... 3 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................. 5 
1. 
BACKGROUND AND RATIONALE .......................................................................... 9 
1.1. 
Scientific Background ......................................................................................... 9 
1.1.1. 
Multiple Myeloma ......................................................................................... 9 
1.1.2. 
Bone Disease in Multiple Myeloma ............................................................... 9 
1.1.3. 
Bortezomib and MM Bone Disease .............................................................. 9 
1.1.4. 
Ixazomib (MLN9708) .................................................................................. 11 
1.2. 
Study Rationale ................................................................................................ 18 
1.3. 
Potential Risks and Benefits ............................................................................. 19 
2. 
STUDY OBJECTIVES ............................................................................................ 20 
2.1. 
Primary Objectives ........................................................................................... 20 
2.2. 
Secondary Objectives ...................................................................................... 20 
3. 
STUDY ENDPOINTS ............................................................................................. 20 
3.1. 
Primary Endpoint .............................................................................................. 20 
3.2. 
Secondary Endpoint ......................................................................................... 20 
4. 
STUDY DESIGN .................................................................................................... 21 
4.1. 
Overview of Study Design ................................................................................ 21 
4.2. 
Number of Patients .......................................................................................... 21 
4.3. 
Duration of Study ............................................................................................. 21 
5. 
STUDY POPULATION ........................................................................................... 21 
5.1. 
Inclusion Criteria .............................................................................................. 21 
5.2. 
Exclusion Criteria ............................................................................................. 22 
6. 
TREATMENT PLAN ............................................................................................... 24 
6.1. 
Physical assessments ...................................................................................... 24 
6.2. 
Laboratory tests ............................................................................................... 24 
6.3. 
Bone Marrow Tests .......................................................................................... 24 
6.4. 
Radio-Imaging .................................................................................................. 25 
7. 
SCHEDULE OF EVALUATIONS ............................................................................ 25 
8. 
STUDY DRUG ....................................................................................................... 26 
8.1. 
Description of Investigational Agent ................................................................. 26 
8.2. 
Study Drug Administration ................................................................................ 26 
8.2.1. 
Ixazomib Administration ............................................................................. 26 
8.2.2. 
Ixazomib Destruction .................................................................................. 26 
 
Dose-Modification Guidelines ..................................................................... 27 
8.2.3. 
27 
8.2.4. 
Precautions and Restrictions ...................................................................... 31 
8.2.5. 
Management of Clinical Events .................................................................. 32 
8.2.6. 
Preparation, Reconstitution, and Dispensing .............................................. 34 
9. 
STATISTICAL AND QUANTITATIVE ANALYSES ................................................. 35 
9.1. 
Statistical methods ........................................................................................... 35 
10. 
ADVERSE EVENTS............................................................................................... 36 
10.1. 
Definitions ........................................................................................................ 36 
10.2. 
Monitoring, Recording and Reporting of AEs .................................................... 37 
10.3. 
Expedited Reporting of SAEs ........................................................................... 38 
10.4. 
Other Required Reporting ................................................................................ 38 
10.5. 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events . 39 
11. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................. 40 
11.1. 
Informed Consent ............................................................................................. 40 
11.2. 
Institutional Review .......................................................................................... 40 


PI:  Maurizio Zangari, MD 
 
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v5, May 15, 2017 
 
 
 
 
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11.3. 
Subject Confidentiality ...................................................................................... 41 
11.4. 
Investigator Responsibilities ............................................................................. 41 
11.5. 
Protocol Amendments ...................................................................................... 41 
11.6. 
Suspension of Study ........................................................................................ 41 
11.7. 
Protocol Deviations .......................................................................................... 41 
REFERENCES .............................................................................................................. 41 
APPENDICES ............................................................................................................... 45 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 5 of 50 
 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
Abbreviation 
Term 
5-HT3 
5-hydroxytryptamine 3 serotonin receptor 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
aPTT 
activated partial thromboplastin time 
Ara-C 
Cytarabine 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration versus time curve 
AUC24 hr 
area under the plasma concentration versus time curve from zero to 24 
hours 
AUCinf 
area under the plasma concentration versus time curve from zero to 
infinity 
AUCτ 
area under the plasma concentration versus time curve from zero to next 
dose 
BCRP 
breast cancer resistance protein 
hCG 
beta-human chorionic gonadotropin 
BID 
bis in die; twice a day 
BM 
bone marrow 
BSA 
body surface area 
BUN 
blood urea nitrogen 
BZD 
Benzodiazepines 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CL 
clearance, IV dosing 
CLP 
plasma clearance 
CLTotal 
total clearance 
Cmax 
single-dose maximum (peak) concentration   
CNS 
central nervous system 
CO2 
carbon dioxide 


PI:  Maurizio Zangari, MD 
 
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v5, May 15, 2017 
 
 
 
 
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Abbreviation 
Term 
CR 
complete remission  
CRM 
continual reassessment method 
CRP 
C-reactive protein 
CSF-1R 
colony-stimulating factor 1 receptor 
CT 
computed tomography 
Ctrough 
single-dose end of dosing interval (trough) concentration 
CV 
cardiovascular  
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DME 
drug metabolizing enzymes 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GM-CSF 
granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HNSTD 
highest nonseverely toxic dose 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 7 of 50 
 
Abbreviation 
Term 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IMWG 
International Myeloma Working Group 
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
KPS 
Karnofsky Performance Status 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MedDRA 
Medical Dictionary for Regulatory Activities 
Millennium 
Millennium Pharmaceuticals, Inc., and its affiliates 
MRI 
magnetic resonance imaging 
MRU 
medical resource utilization 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
PD 
progressive disease (disease progression) 
Progressive disease 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial response  
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 
QID 
quater in die; 4 times a day 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 8 of 50 
 
Abbreviation 
Term 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
RBC 
red blood cell 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
SmPC 
Summary of Product Characteristics 
t1/2 
terminal disposition half-life 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WHO 
World Health Organization 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 9 of 50 
 
1. BACKGROUND AND RATIONALE 
1.1. Scientific Background 
1.1.1. Multiple Myeloma 
Multiple myeloma (MM) is a clonal disease of plasma cells that is characterized by the 
accumulation of plasma cells in the bone marrow (and other organs) and sometimes results in 
bone marrow failure, bone destruction, hypercalcemia, and renal failure.  It constitutes 
approximately 1% of all reported neoplasms and approximately 13% of hematologic cancers 
worldwide.(1)   In the Americas, Canada, and Western European countries, approximately 5 
to 7 new cases of MM are diagnosed per 100,000 people each year(1, 2, 3).  Although less 
common in Asian countries, MM is a growing health problem with an incidence that is 
approaching western countries and a larger population base.(4, 5)   In the United States, 
approximately 20,000 cases of MM are diagnosed each year and 10,650 deaths per year are 
due to the disease (approximately 2% of all cancer deaths). 
 
MM is sensitive to many cytotoxic drugs including alkylating agents, anthracyclines, and 
corticosteroids for both initial treatment and relapsed disease.  Over the past decade, 
significant achievements have been made in expanding treatment options for MM with novel 
therapies such as thalidomide, Bortezomib (VELCADE), and lenalidomide.  These regimens 
have extended progression-free survival (PFS) and/or time-to-progression (TTP)(6, 7, 8, 9, 
10).  The introduction of novel therapies and the increased use of high-dose therapy 
significantly improved overall survival in patients with newly diagnosed myeloma who were 
eligible for autologous stem cell transplant (ASCT) (11, 12).  
 
Despite the increase in the number of therapeutic options, the disease remains incurable and 
there is a need for new and better agents.  Patients who relapse after their initial therapy 
demonstrate variable response to subsequent treatments with decreasing likelihood and 
duration of response (DOR).  Patients ultimately become refractory to approved therapies and 
have no alternative treatment options.  In an effort to further target the proteasome with 
improved activity in MM and other cancers, Millennium has developed ixazomib, a small 
molecule 20S proteasome inhibitor. 
 
1.1.2. Bone Disease in Multiple Myeloma 
Bone disease is extremely common at myeloma diagnosis (13).   It is present in the majority of 
patients and is associated with bone pain, fractures, spinal cord compression, and 
hypercalcemia (14, 15).  The pathogenesis of lytic bone disease in myeloma is complex and is 
associated with increased osteoclast activity through multiple interactions between myeloma 
cells and the bone marrow microenvironment, impairing osteoblast function which results in 
decreasing bone formation (13-15).   
 
1.1.3. Bortezomib and MM Bone Disease 
The proteasome inhibitor Bortezomib (VELCADE) has been shown through numerous clinical 
and preclinical studies to have an impact on bone health, density, and on the biomarkers related 
to osteoblast and osteoclast activity.  Evidence indicates that Bortezomib demonstrates a bone 
anabolic effect as shown in Table 1 (16).   
 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 10 of 50 
 
Table 1. Effects of bortezomib on bone health in myeloma: clinical data 
Reference 
Intervention 
Clinical endpoints 
Delforge et al. 
(analysis of 
VISTA study) 
VMP: n = 344; MP: n = 338 
 
Use of bisphosphonates: VMP = 73% of patients; MP = 82% 
Progression due to worsening bone disease: VMP = 3% of patients; 
MP = 11% 
Skeletal AEs (inc. pathologic fracture, spinal-cord compression, new 
osteolysis, vertebroplasty): VMP = 4% of patients; MP = 5% 
Lee et al.  
Bortezomib,n = 2 
 
After 
three 
cycles 
of 
bortezomib 
treatment 99mTc-methyl-
diphosphonate bone scans: increased uptake by osteoblasts was 
associated with re-building activity 
Terpos et al.  
Lenalidomide + 
dexamethasone ± 
bortezomib:n = 99 
 
No skeletal-related events were observed in the bortezomib arm; two 
patients treated with lenalidomide/dexamethasone who had not 
responded to therapy developed a vertebral pathological fracture 
Zangari et al.  
Bortezomib:n = 16 
 
A significant increase in bone volume/total volume from baseline 
(assessed via histomorphometric microCT) was observed in six of 
seven patients (P < 0.02) 
– 
In the responding patient, bone volume/total volume increased from 
12% at baseline to 90% after 12 doses 
Change in median PTH in patients responding to bortezomib 
treatment was significant at days 11, 21 and 33 (all P = 0.04); mean 
PTH over dosing interval: 85.6 (SD: 16.9) 
 
No significant change was recorded in non-responders; mean PTH: 
54.4 (SD: 7.1) 
Berno et al.  
Bortezomib:n = 16 
 
Change in lumbar bone mineral density T-score of 0.36 (−0.76 at 
baseline) and at femoral neck bone density T-score of 0.25 (−1.31 at 
baseline), compared with baseline 
Terpos et al.  
Bortezomib + 
dexamethasone 
+zoledronic acid: n = 27 
 
Significant (P < 0.001) increase in bone mineral density from 
baseline (mean [SD] T score: −2.59 ± 1.32) was reported after 
8 weeks’ therapy (−2.31 ± 1.30) in the lumbar spine (L1–L4, antero-
posterior view), as assessed via dual energy X-ray absorptiometry; 
this was not echoed in the femoral neck 
 
Four patients showed at least a 10% increase in L1–L4 bone mineral 
density (median: 16%), all of whom responded to therapy (3 = PR, 
1 = CR) 
Terpos et al.  
Post ASCTVDT:n = 42 
(block 1n = 32; block 
2n = 16) 
 
Only one skeletal-related AE was observed 
Ozaki et al.  
Bortezomib + 
dexamethasone:n = 14 
 
In two patients, a “dramatic improvement” in osteolytic lesions was 
observed (as assessed via multidetector CT scans) 
AE, adverse event; ASCT, autologous stem-cell transplant; CR, complete response; CT, computed tomography; MP, 
melphalan–prednisone; PR, partial response; PTH, parathyroid hormone; VDT, bortezomib–dexamethasone–thalidomide; 
VISTA, Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone; VMP, 
bortezomib–melphalan–prednisone. 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 11 of 50 
 
Multiple studies of bortezomib in both treated and untreated myeloma patients have shown a 
positive effect of bortezomib on bone health, including fewer bone disease-related MM 
progression events, increases in bone volume, and improvements in osteolytic lesions. Alkaline 
phosphatase (total and bone isoenzyme), a marker of bone formation, is increased during 
bortezomib treatment; the degree of increase may be associated with treatment response. 
Bortezomib is also related to a reduction in Dickkopf-1, an inhibitor of osteoblast function. 
Increases of other bone-formation markers and decreases of bone-resorption markers, have 
also been seen. These clinical effects are supported by preclinical data suggesting bortezomib 
is associated with an increase in bone formation and osteoblast numbers/activity, arising from 
direct effects of bortezomib and proteasome inhibition. Thus, evidence indicates that bortezomib 
exerts a positive effect on bone metabolism in MM and has a bone anabolic effect (16). 
 
1.1.4. Ixazomib (MLN9708) 
1.1.4.1. 
Preclinical Experience 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety 
Management Attachment (SMA). 
1.1.4.2. 
Clinical Experience 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have 
included patients with advanced solid tumors, lymphoma, relapsed/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, ongoing clinical pharmacology 
studies include evaluation of drug-drug interactions with ketoconazole and rifampin, 
effect of food, and oral bioavailability. Studies evaluating the safety and pharmacokinetic 
(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 
NDMM 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 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 12 of 50 
 
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%), 
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 Investigator’s Brochure, including information on the IV formulation.   
 
1.1.4.3. 
Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that ixazomib citrate (measured as 
the biologically active boronic acid form of ixazomib [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral ixazomib is 
rapidly absorbed with a median time to first maximum plasma concentration (Tmax) of 
approximately 0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 
to 7 days(14).  Results of a population PK analysis (N = 137) show that there is no 
relationship between body surface area (BSA) or body weight and clearance (CL).  Also, 
based on stochastic simulations for fixed dose, exposures are independent of the 
individual patient’s BSA (15).  Based on these data, a recommendation was made for 
fixed dosing in clinical trials. An absolute bioavailability of 67% was determined for 
ixazomib using the population PK analysis. Please refer to the current ixazomib IB and 
Safety Management Attachment (SMA) for information on the PK for IV doses of 
ixazomib. 
 
Metabolism appears to be the major route of elimination for ixazomib, and urinary 
excretion of the parent drug is negligible (< 5% of dose). In vitro studies indicate that 
ixazomib is metabolized by multiple cytochrome P450s (CYPs) and non-CYP 
enzymes/proteins. The rank order of relative biotransformation activity of the 5 major 
human CYP isozymes was 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 
2C19 (< 1%). Ixazomib is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4 nor a 
time-dependent inhibitor of CYP3A4/5. The potential for ixazomib treatment to produce 
drug-drug interactions (DDIs) via CYP inhibition is inferred to be low. However, there 
may be a potential for DDIs with a concomitant strong CYP3A4 or CYP1A2 inhibitor or 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
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v5, May 15, 2017 
 
 
 
 
Page 13 of 50 
 
inducer because of the potential for first-pass metabolism when ixazomib is administered 
via the PO route and because of the moderate contribution of CYP3A4- and CYP1A2-
mediated metabolism of ixazomib in human liver microsomes. Ixazomib may be a weak 
substrate of P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and 
multidrug resistance associated protein (MRP2) efflux pump transporters. Ixazomib is 
not an inhibitor of Pgp, BCRP, and MRP2. The potential for DDIs with substrates or 
inhibitors of Pgp, BCRP, and MRP2 is, therefore, inferred to be low. Clinical Study 
C16009 (Arm 1) with ketoconazole, a strong CYP3A4 inhibitor, showed a 2-fold increase 
in area under the plasma concentration versus time curve (AUC) in the presence of 
ketoconazole. This resulted in the continued exclusion of strong CYP3A4 inhibitors in 
ongoing/planned clinical studies. 
 
Further details on these studies are provided in the IB. 
 
1.1.4.4. 
Clinical Trial Experience Using Oral Ixazomib 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple 
myeloma, AL amyloidosis, non-hematologic 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 2. 
Table 2    
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 
3.0-3.7-mg fixed dosea W 
MTD:  3.0 mg 
Closed to enrollment 


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Table 2    
Clinical Studies of Oral Ixazomib 
 
Trial/Population 
Description 
Doses Investigated 
C16009 
Solid tumors, Lymphomas 
N = 54 
PO, W, single agent 
5.5-mg 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 
C16013 
RRMM 
N = 9 
PO, W, with LenDex 
4.0 mg W 
C16014 
Symptomatic 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 
Symptomatic 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 malignancies 
with varying degrees of liver 
dysf 
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 
 
1.1.4.5. 
Overview of the Oral Formulation of Ixazomib 
The emerging safety profile indicates that oral 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. 
 
 


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Table 3:  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) 
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 Infection 
31 (15) 


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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 1-3).  In 
combination trials, related is defined as related to any study drug in the combination 
regimen. 
 
Table 4    
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) 
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) 


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Table 4    
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 (%) 
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) 
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) (17), non-Hodgkin’s 
disease, Hodgkin’s disease (18), relapsed and/or refractory multiple myeloma 
[RRMM](19) relapsed or refractory systemic light chain amyloidosis [RRAL]; (20), and 
newly diagnosed multiple myeloma [NDMM]; (21-24) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of ixazomib. 
1.1.4.6. 
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. (25)  
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 
(26, 27).  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. 


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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.  
1.1.4.7. 
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 with 
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.  
1.1.4.8. 
Clinical Trial Experience Using IV 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). 
1.1.4.9. 
Preclinical Activity of Oral Ixazomib in Myeloma Bone Disease 
Ixazomib has demonstrated both preclinical and clinical activity.  Gomez et al 
investigated its bone anabolic and antiresporptive effects in myeloma and in comparison 
with Bortezomib (VELCADE) in preclinical models.  Clinically achievable concentrations 
of Ixazomib markedly inhibited osteoclast formation and resorption in ex vivo 
experiments, as well as promoted osteoblast differentiation and function (even in 
osteoprogenitor cells from MM patients with osteolytic lesions).   In a mouse model, 
Ixazomib was found to be at least as effective as intraperitoneally administered 
Bortezomib in the control of myeloma growth and in the prevention of bone loss (28).   
1.2. Study Rationale 
Bortezomib has been shown to produce on anabolic bone effect in relapsed/refractory MM patients . 
The next generation proteasome inhibitor, Ixazomib, has been evaluated in a pre-clinical setting and 
has demonstrated to be as equally effective to Bortezomib in both controlling tumor burden and 
providing a significant benefit in associated bone disease (as sustained by both bone anabolic and 
anticatabolic activities (28).  
Consequently, it is conceivable that this agent may achieve bone beneficial effects in addition to its 
anti-myeloma activity in multiple myeloma patients.    Therefore, this study is designed to  focus on the 
bone anabolic effect of Ixazomib (MLN 9708) on MM patients, with the  primary objective of determining 
the effect of a short course of ixazomib (6 cycles) on changes in bone on formation markers (BALP, 


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osteocalcin) and bone densitometry (Dexascan) indicies.  The dose of ixazomib will be given as 4mg 
weekly in a 28 day cycle for a maximum of 6 cycles.   
1.3. Potential Risks and Benefits 
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management Attachment 
(SMA). 
Risks of study drug: 
Blood and lymphatic system disorders: Lymphopenia. Reductions in blood counts may predispose 
patients to an increased susceptibility to infection (see Infections and infestations below). A rare risk is 
thrombotic thrombocytopenic purpura, a rare blood disorder where blood clots form in small blood 
vessels throughout the body, characterized by thrombocytopenia, petechiae, fever, and possibly more 
serious signs and symptoms. Reticulocytopenia was described in animals and may be associated with 
anemia. These potential risks should be managed according to standard medical practice.  
Gastrointestinal disorders: Intestinal obstruction including ileus and intussusception (described in 
animal studies), abdominal pain. 
General disorders and administration site conditions: Chills, influenza like illness.  
Infections and infestations: Pneumonia. Lymphopenia may be associated with increased risk of 
infection, including re-activation of herpes zoster. Antiviral therapy may be initiated as clinically 
indicated. 
Investigations: Blood creatinine increased (see Renal and urinary disorders below). 
Metabolism and nutrition disorders: Dehydration, electrolyte imbalance. 
Musculoskeletal and connective tissue disorders: Back pain, myalgia, arthralgia, bone pain, pain in 
extremity. 
Nervous system disorders: Headache, syncope. In addition, autonomic and motor neuropathy may 
be observed, as both have been reported for VELCADE, another proteasome inhibitor. Posterior 
reversible encephalopathy syndrome (PRES) has been reported with ixazomib. PRES has also been 
reported for VELCADE (refer to VELCADE for Injection Package Insert) and Kyprolis.(10) Transverse 
myelitis has also been reported with ixazomib. It is not known if ixazomib causes transverse myelitis; 
however, because it happened to a patient receiving ixazomib , the possibility that ixazomib may have 
contributed to transverse myelitis cannot be excluded.  
Renal and urinary disorders: Renal impairment, renal failures, and renal failure acute have been 
reported in association with dehydration due to nausea, vomiting, anorexia, and/or diarrhea, the use of 
nonsteroidal anti-inflammatory drugs (NSAIDs), and/or disease progression. In one situation, this has 
been severe, requiring temporary dialysis. 
Respiratory, thoracic and mediastinal disorders: Dyspnoea, cough, upper respiratory tract infection, 
pneumonitis. 
Skin and subcutaneous tissue disorders: A rare risk is Stevens-Johnson syndrome, a severe, life-
threatening or deadly rash with skin peeling and mouth sores, which should be managed 
symptomatically according to standard medical practice. Stevens-Johnson syndrome has also been 
reported for VELCADE (refer to VELCADE for Injection Package Insert(10)). It is also reported as risk 
with lenalidomide, an agent used in the treatment of hematologic malignancies including in combination 
with proteasome inhibitors. For more information about this risk with lenalidomide, refer to the Revlimid 
(lenalidomide) Package Insert.(11) 
Vascular disorders: Hypotension, orthostatic hypotension. 
Other: Acute phase response that may result in fever and metabolic changes (observed only in 


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nonclinical studies). Infrequent incidences of tumor lysis syndrome have also been reported. 
Potential Benefits: 
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 early signs of anti-
tumor activity as evidenced by at least 50% reduction in disease burden in some patients, including 
patients that have been heavily pretreated as well as those with newly diagnosed MM, and prolongs 
stabilization of the underlying disease in other patients across all ongoing trials.  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). 
2. STUDY OBJECTIVES 
2.1. Primary Objectives 
To evaluate the effect of Ixazomib (MLN 9708) on inducing osteoblast activation as measured by 
change in serum osteocalcin from baseline to end of study in patients with relapsed/refractory multiple 
myeloma. 
2.2. Secondary Objectives 
To evaluate the effect of ixazomib on osteoblast activation as measured by change in radiological 
studies and bone marrow parameters from baseline to end of study. 
 
To evaluate change from baseline in osteocalcin and other serum bone markers throughout ixazomib 
treatment. 
 
To evaluate the association between osteoblastic activation and myeloma response to Ixazomib.  
 
To identify predictive factors for Ixazomib-associated osteoblastic activation. 
3. STUDY ENDPOINTS 
3.1. Primary Endpoint  
The primary endpoint of this study is change in serum osteocalcin from baseline to study exit.  
3.2. Secondary Endpoint 
The secondary endpoints of this study include change in serum osteocalcin and other serum bone 
markers (BALP, NTX, Vitamin D25) at each study visit, including the exit visit; change in bone marrow 
parameters (immunohistochemistry, cytogenetics, and flow cytometry) and Dexascan T scores 
from baseline to end of study; and association between bone marker and radiological changes and anti-
myeloma activity in response to Ixazomib therapy. 
 
 


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4. STUDY DESIGN  
4.1. Overview of Study Design 
This is a phase 2 study designed to examine the bone anabolic effect of the next generation 
proteasome inhibitor, ixazomib, in relapsed/refractory myeloma patients.   Treatment consists of 
ixazomib 4 mg on days 1, 8, 15, 22 of a 28-day cycle, for a maximum of 6 cycles). 
General eligibility criteria may be assessed prior to the formal Screening period if it is part of standard 
clinical practice.  However, per the Schedule of Events, formal screening will occur during the 
Screening period, which may last for up to 35 days prior to initiating study treatment. Determination of 
relapsed/refractory disease as an entry criterion may be based on patient data obtained during or 
following the patient’s most recent prior antineoplastic therapy.   
Study drug (ixazomib 4.0 mg) will be given on Days 1, 8, 15, 22 of a 28- day cycle for a maximum of 6 
cycles.  Dose modifications may be made based on toxicities during treatment.  Patients will be 
discontinued from the study for progressive disease or unacceptable toxicity.   
Treatment periods will be defined as 28-day cycles.  Patients will be seen once per treatment cycle 
(Day 1) during their participation in the active treatment of the study.  More frequent follow-up would be 
only as clinically indicated at the discretion of the treating physician. 
Patients will be assessed for disease response and progression.  Response will be assessed according 
to the International Myeloma Working Group (IMWG) criteria (see APPENDIX  A) for all patients every 
4 weeks for a maximum of 6 cycles (unless disease progression or unacceptable toxicity).   
ECOG performance score (APPENDIX B), adverse events (AEs), laboratory values, and vital sign 
measurements will be collected and assessed throughout the study.  Toxicity will be evaluated 
according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.03, effective date 14 June 2010. 
Patients will attend an End of Treatment (EOT) visit after completion of their 6 cycles (or at study 
discontinuation due to progressive disease, unacceptable toxicity, or other reason) and will continue to 
be followed for survival.   
4.2. Number of Patients 
20 patients, male or female, 18 years of age or older, will be enrolled in this study.   
4.3. Duration of Study 
The duration of this study will be approximately 26 months, including 20 months for enrollment of 
subjects and approximately 6 months of treatment from the last patient enrolled. 
 
Patients may remain on treatment for a maximum of 6 cycles, unless the occurrence of progressive 
disease or unacceptable toxicity (or other reason).    Patients will continue to be followed for 
survival.   
5. STUDY POPULATION 
5.1. Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
Male or female patients 18 years or older.  
 
 
Voluntary written consent must be given before performance of any study related procedure not 
part of standard medical care, with the understanding that consent may be withdrawn by the 
patient at any time without prejudice to future medical care. 


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 
 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, AND 
 Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of 
the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) 
 
Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the 
following: 
 Agree to practice effective barrier contraception during the entire study treatment period and 
through 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.) 
 
Patients must have a diagnosis of relapsed/refractory multiple myeloma and must have received 
at least one line of prior therapy. 
 
 
Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance 
status 0, 1, or 2. 
  
 
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. 
 Total bilirubin  1.5  the upper limit of the normal range (ULN). 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  3  ULN. 
 Calculated creatinine clearance  30 mL/min. 
5.2. Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
Patients that have not been previously treated with a multi-drug regimen including a proteasome 
inhibitor, immunomodulatory drug, and corticosteroid. 
 
Female patients who are lactating or have a positive serum pregnancy test during the screening 
period.  
 


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 
Failure to have fully recovered (ie,  Grade 1 toxicity) from the reversible effects of prior 
chemotherapy. 
 
 
Major surgery within 14 days before enrollment. 
 
 
Radiotherapy within 14 days before enrollment. If the involved field is small (in the opinion of the 
enrolling investigator), 7 days will be considered a sufficient interval between treatment and 
administration of the ixazomib. 
 
 
Patients who have non-myeloma related bone disease that will interfere with the interpretation 
of the bone-related blood and radiology assessments, including Paget’s disease, Rickets, 
Osteomalacia, and any other metastatic bone cancer. 
 
 
History of myeloma-related central nervous system involvement. 
 
 
Infection requiring systemic antibiotic therapy or other serious infection within 14 days before 
study enrollment. 
 
 
Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, 
uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or 
myocardial infarction within the past 6 months. 
 
 
Systemic treatment, within 14 days before the first dose of ixazomib, with strong inhibitors of 
CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, 
telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong 
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or 
use of Ginkgo biloba or St. John’s wort. 
 
 
Ongoing or active systemic infection, known active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive. 
 
 
Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol. 
 
 
Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
 
 
Known GI disease or history of GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib including difficulty swallowing. 
 
 
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 non-melanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection. 
 
 
Patient has  Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination 
during the screening period. 
 
 
Participation in other clinical trials, including those with other investigational agents not included 
in this trial, within 21 days of the start of this trial and throughout the duration of this trial.  
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 24 of 50 
 
 
Patients who have taken bisphosphonate or RANK Ligand Inhibitor within 3 weeks from 
screening. 
 
6. TREATMENT PLAN  
All baseline assessments, labs, and bone marrow biopsies are to be completed within 35 days of 
enrollment.  Radiological studies are to be completed within 60 days prior to enrollment.   
Study drug (ixazomib 4.0 mg) will be given on Days 1, 8, 15, 22 of a 28- day cycle for a maximum of 6 
cycles. 
 
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 non-hematologic toxicities should, at the investigator’s discretion, generally be 
recovered to patient’s baseline condition or Grade 1 or lower. 
Dose modifications may be made based on toxicities during treatment described in detail in section 8.2.3.  
Treatment periods will be defined as 28-day cycles.  Patients will be seen in clinic once per treatment 
cycle (Day 1) during their participation in the active treatment of the study.  More frequent follow-up would 
be only as clinically indicated at the discretion of the treating physician. 
Patients will be assessed for disease response and progression.  Response will be assessed according to 
the IMWG criteria (see APPENDIX  A) for all patients every 4 weeks for a maximum of 6 cycles (unless 
disease progression or unacceptable toxicity).   
Patients will attend an End of Treatment (EOT) visit after completion of their 6 cycles (or at study 
discontinuation due to progressive disease, unacceptable toxicity, or other reason) and will continue to be 
followed for survival.  Follow-up for survival after end of treatment will be limited to contact via telephone 
approximately annually to verify the patient’s disposition.  Verification of the patient’s disposition may be 
performed by medical record review if the patient was seen in clinic at UAMS within 3 months of the 
scheduled follow-up interval. 
6.1. Physical assessments 
Physical Assessments include History and Physical (H&P), which includes a detailed medical and 
treatment history, vital signs, weight, height, and BSA, and performance evaluation (ECOG) as seen in 
Appendix B. H&P and performance evaluation will be performed at all visits. Toxicities will be evaluated 
according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0, effective date 14 June 2010 starting with cycle 1.    
6.2. Laboratory tests 
Laboratory tests (CBC with differential, BMP, LFTs, Uric Acid, Albumin, CRP, Pregnancy Test 
(WOCBP)), bone marker  tests (BALP, Osteocalcin, NTX, Vitamin D 25), and myeloma  lab tests 
(Serum Protein Electrophoresis, Serum Quantitative Immunoglobulins, Serum Free Light Chains, 
Serum IFE and/or Urine Beta-2-Microglobulin) will be performed at baseline, on day 1 of cycles 2-6, 
and at end of study. BNP and TSH will be performed at baseline and end of study only.  
6.3. Bone Marrow Tests 
Bone marrow aspirate and biopsies will be performed at baseline and at the end of study for 
immunohistochemistry, cytogenetics, and flow cytometry.   


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 25 of 50 
 
Bone marrow aspirates and biopsies for gene expression profiling (GEP) are optional and will be 
performed in subjects providing informed consent.  Based on the requirement of obtaining at least 3 
million plasma cells, approximately 50 ccs of bone marrow aspirate will be collected in a EDTA syringe 
and sent to the Myeloma Institute Research lab for gene array studies.  If there are insufficient plasma 
cells in the sample to perform gene array, an additional bone marrow pull and bone marrow biopsy may 
be requested.  The sample should be clearly labeled “for separation for GEP for UARK 2014-14”. 
6.4. Radio-Imaging 
The bone densitometry scan (Dexascan) and skeletal survey will be performed at baseline and at end 
of study. 
7. SCHEDULE OF EVALUATIONS 
All baseline assessments, labs, and bone marrow biopsies are to be completed within 35 days of enrollment.  Radiological 
studies are to be completed within 60 days prior to enrollment.   
 
Screening/Baseline 
 
Cycles 1-6 
End of 
Treatment 
PHYSICAL ASSESSMENTS 
H&P1 
X 
X 
X 
Performance Evaluation  (ECOG) 
X 
X 
X 
Toxicity Evaluation 
--- 
X 
X 
LABORATORY 
CBC with differential 
X 
X 
X 
Basic Metabolic Panel (BMP), Liver 
Function Tests (LFTs), Uric Acid,  
Albumin, and CRP 2 
X 
X 
X 
BNP 3 
X 
--- 
X 
Pregnancy Test4 (WOCBPonly) 
X 
X 
X 
TSH 
X 
--- 
X 
BALP, Osteocalcin, NTX 
X 
X 
X 
Vitamin D 25 
X 
X 
X 
Serum Protein Electrophoresis 
X 
X 
X 
Serum Quantitative Immunoglobulins 
X 
X 
X 
24 hour urine for total protein, & 
electrophoresis and calcium 
X 
X 
X 
Serum IFE and/or Urine 
Beta-2-Microglobulin6 
X 
X 
X 
Serum Free Light Chains 
X 
X 
X 
BONE MARROW 
Bone Marrow Aspirate & Biopsy and 
Gene Expression Profiling5 
X 
--- 
X 
RADIO-IMAGING 
Bone Densitometry (Dexascan) 
X 
--- 
X 
Skeletal Survey 
X 
--- 
X 
BANKING FOR FUTURE RESEARCH 
Blood and/or bone marrow7 
X 
 
1 History and Physical (H&P) includes a detailed medical and treatment history, vital signs, weight, height, and BSA. 
2 BMP includes Na, K, Cl, CO2, BUN, Creatinine, Ca, glucose; LFTs include bilirubin total and direct, SGOT, SGPT, Alkaline phosphatase, 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 26 of 50 
 
albumin, total protein, and LDH  
3 BNP = B-type natriuretic peptide 
4 Required while receiving study drug for WOCBP (women of childbearing potential) only 
5 BM Aspirate & Biopsy for immunohistochemistry, cytogenetics, and flow cytometry. GEP optional. 
6 Upon disappearance of the Urine M and as clinically indicated. 
7 Optional blood and/or bone marrow specimens may be collected and stored for future research at any time that sample collection is already 
required for other tests  
8. STUDY DRUG  
8.1. Description of Investigational Agent 
The ixazomib drug product is provided in strengths of 4.0, 3.0, and 2.3 mg capsules as the active 
boronic acid. The different dose strengths are differentiated by both capsule size and color as 
described below: 
Dose 
Strength 
Capsule Size 
Capsule Color 
4.0 mg 
Size 4 
Ivory 
3.0 mg 
Size 3 
Light gray 
2.3 mg 
Size 2 
Light pink 
For additional details, please see the ixazomib IB. 
8.2.  Study Drug Administration 
8.2.1. Ixazomib Administration 
All protocol-specific criteria for administration of study drug must be met and documented before 
drug administration.  Study drug will be administered or dispensed only to eligible patients under 
the supervision of the investigator or identified sub-investigator(s).  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 on 8.2.3 for dose modifications). 
Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 4.0, 3.0, and 2.3 mg ixazomib.  
The prescribed administration of ixazomib doses in this study is 4.0mg ixazomib weekly 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.  Study drug should be taken on an empty stomach (no food or 
drink) at least 1 hour before or 2 hours after a meal.  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.   
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. 
8.2.2. Ixazomib Destruction 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 27 of 50 
 
Investigational ixazomib (expired or end of study) should be destroyed on site according to the 
UAMS Research Pharmacy standard operating procedure.  Be sure to document removal and 
destruction on drug accountability logs. 
8.2.3. Dose-Modification Guidelines 
8.2.3.1. 
Criteria for Beginning/Delaying Treatment Cycles & Dose Modifications for 
Treatment Assoc.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 non-hematologic toxicities should, at the physician’s discretion, generally be 
recovered to patient’s baseline condition or Grade 1 or lower  
 
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 is discontinued is 3 weeks.  
 
8.2.3.2. 
Ixazomib Dose Adjustment Schedule 
Dose Level 
Dose 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 
 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 28 of 50 
 
8.2.3.3. 
Ixazomib Dose Adjustments for Hematological Toxicities 
Ixazomib Dose Adjustments for Hematologic Toxicities 
Criteria 
Action 
Within-Cycle Dose Modifications 
 
 
If platelet count  30  109/L or ANC ≤ 0.50  
109/L on a ixazomib dosing day (other than Day 
1) 
 
Ixazomib dose should be withheld.   
 
Complete blood count (CBC) with differential should be 
repeated at least every other day until the ANC and/or 
platelet counts have exceeded the prespecified values ( 
section 8.3.1 above on at least 2 occasions.   
 
Upon recovery, ixazomib may be reinitiated with 1 dose 
level reduction.  
Dose Modifications for Subsequent Treatment Cycles 
 
 
Delay of > 2 weeks in the start of a subsequent 
cycle due to lack of toxicity recovery as defined 
in Section 8.3.1   
 
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 
8.3.1 
 
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. 
Dose Modifications for Subsequent Treatment Cycles 
 
 
All hematologic toxicities 
 
For hematologic toxicity that occurs during a cycle 
but recover in time for the start of the next cycle,: 
o 
 If dose was reduced within the cycle, 
start the next cycle at that same dose. 
o 
If due to toxicity timing, ie, after Day 22 
dosing thus a dose reduction was not 
required at that point in the cycle, reduce 
ixazomib by 1 dose level at the start of 
the next cycle. 
o 
Do not reduce the dose both within a 
cycle and at the start of the next cycle for 
the same most severe toxicity. 
 
 
 
 
 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 29 of 50 
 
 
8.2.3.4. 
Ixazomib Dose Adjustments for Non-Hematological Toxicities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Once ixazomib is reduced for any toxicity, the dose may not be re-escalated. 
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] 
 
 
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 8.2.5 
The investigator and project clinician 
may discuss considerations for dose 
modifications and symptom 
management. 
 
Grade 3 nonhematologic toxicity 
judged to be related to study drug 
 
 Hold study drug until 
resolution to Grade < 1 or 
baseline 
 
Symptomatic recommendations 
noted in Section 8.2.5 
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 
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  


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 30 of 50 
 
8.2.3.5. 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study.  A DDI with a strong inhibitor would increase MLN2238 
exposure. 
 
Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
 
Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, 
voriconazole, ketoconazole, nefazodone, and posaconazole 
 
Systemic treatment with any of the following metabolizing enzyme inducers should be 
avoided unless there is no appropriate alternative medication for the patient to use.  A 
DDI with a strong inducer would decrease MLN2238 exposure. 
 
Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, 
phenytoin, and phenobarbital 
 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 
 
Additional treatment or procedures  prohibited during the study: 
 
Adjuvant hormone therapy for breast or prostate cancer. 
 
Bisphosphonates: Concomitant treatment with bisphosphonates will not be 
permitted. 
 
Any antineoplastic treatment with activity against MM except for drugs in this 
treatment regimen. 
 
Radiation therapy (the requirement for local radiation therapy generally indicates 
disease progression). 
 
Platelet transfusions to help patients meet eligibility criteria are not allowed within 
3 days before study drug dosing. 
8.2.3.6. 
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. 
IVF 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 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 31 of 50 
 
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 (except 
as noted in 8.2.4) and according to institutional guidelines. 
 
Antiviral therapy such as acyclovir may be administered if medically 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. 
8.2.4. Precautions and Restrictions  
Fluid deficits should be corrected before and throughout treatment. 
Nonsteroidal anti-inflammatory drugs (NSAIDs) induced prevalence of nephrotoxicity is 
relatively low; however, given the wide use of these agents many persons are at risk, including 
for example, patients with cardio-renal disease, dehydration, and the aging kidney. NSAIDs 
should be avoided with impaired renal function given reported NSAID-induced renal failure in 
patients with decreased renal function.  
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 criteria:  
 
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, at the same time, from the time of signing the informed consent form 
through 90 days after the last dose of study drug, AND 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 32 of 50 
 
 
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.) 
8.2.5. Management of Clinical Events  
Adverse drug reactions such as thrombocytopenia, diarrhea, fatigue, nausea, vomiting, and 
rash have been associated with ixazomib treatment. Management guidelines regarding these 
events are outlined below. Further details of management of ixazomib AEs are described in 
Section 6 of the ixazomib IB. 
Transverse Myelitis 
Transverse myelitis has also been reported with ixazomib. It is not known if ixazomib causes 
transverse myelitis; however, because it happened to a patient receiving ixazomib, the 
possibility that ixazomib may have contributed to transverse myelitis cannot be excluded. 
Prophylaxis Against Risk of Infection 
If lymphopenia is noted, patients may be at an increased risk of infection.  In particular, 
lymphopenia can be associated with reactivation of herpes zoster and herpes simplex viruses.  
Antiviral therapy such as acyclovir or valacyclovir may be initiated as clinically indicated.  Other 
antivirals are also acceptable. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered.  Dexamethasone 
should not be administered as an anti-emetic.  Fluid deficits should be corrected before initiation 
of study drug and during treatment. 
Diarrhea 
Diarrhea should be managed according to clinical practice, including the administration of 
antidiarrheals once infectious causes are excluded.  Fluid intake should be maintained to avoid 
dehydration.  Fluid deficits should be corrected before initiation of treatment and during 
treatment. Prophylactic antidiarrheals are not generally recommended. 
Erythematous Rash With or Without Pruritus 
As with bortezomib, rash with or without pruritus has been reported with ixazomib, primarily at 
the higher doses tested and when given with agents where rash is an overlapping toxicity.  The 
rash may range from limited erythematous areas, macular and/or small papular bumps that may 
or may not be pruritic over a few areas of the body, to a more generalized eruption that is 
predominately on the trunk or extremities.  Rash has been most commonly characterized as 
maculopapular or macular.  To date, when it does occur, rash is most commonly reported within 
the first 3 cycles of therapy.  The rash is often transient, self-limiting, and is typically Grade 1 to 
2 in severity.  


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 33 of 50 
 
Symptomatic measures such as antihistamines or corticosteroids (oral or topical) have been 
successfully used to manage rash and have been used prophylactically in subsequent cycles.  
The use of a topical, IV, or oral steroid (eg, prednisone ≤ 10 mg per day or equivalent) is 
permitted.  Management of a Grade 3 rash may require intravenous antihistamines or 
corticosteroids.  Administration of ixazomib (and/or other causative agent if given in 
combination) should be modified per protocol and re-initiated at a reduced level from where rash 
was noted (also, per protocol).   
In line with clinical practice, dermatology consult and biopsy of Grade 3 or higher rash or any 
SAE involving rash is recommended.  Prophylactic measures should also be considered if a 
patient has previously developed a rash (eg, using a thick, alcohol-free emollient cream on dry 
areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a 
severe and potentially life-threatening rash with skin peeling and mouth sores, which should be 
managed symptomatically according to standard medical practice.  Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator. 
Thrombocytopenia 
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. Ixazomib 
administration should be modified as noted as per dose modification recommendations in the 
protocol when thrombocytopenia occurs. Therapy can be reinitiated at a reduced level upon 
recovery of platelet counts. A rare risk is thrombotic thrombocytopenic purpura (TTP), a rare 
blood disorder where blood clots form in small blood vessels throughout the body characterized 
by thrombocytopenia, petechiae, fever, or possibly more serious signs and symptoms. TTP 
should be managed symptomatically according to standard medical practice. 
Neutropenia 
Neutropenia has been reported with ixazomib.  Blood counts should be monitored regularly as 
outlined in the protocol with additional testing obtained according to standard clinical practice.  
Neutropenia may be severe but has been manageable with G-CSF according to standard 
clinical practice.  Neutropenic nadirs commonly recover without intervention by the beginning of 
the next scheduled cycle or with a short delay in treatment.  ixazomib administration should be 
modified when neutropenia occurs, as noted in the dose modification recommendations table.  
Therapy can be reinitiated at a reduced level upon recovery of absolute neutrophil counts. 
Fluid Deficits 
Dehydration should be avoided because ixazomib may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported with ixazomib.  Fluid deficits should be 
corrected before initiation of study drug and during treatment and as needed during therapy.  
Until further information is available, intake of NSAIDs while on this protocol should be avoided. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with ixazomib. Blood 
pressure should be closely monitored while the patient is on study treatment and fluid deficit 
should be corrected as needed, especially in the setting of concomitant symptoms such as 
nausea, vomiting, diarrhea, or anorexia. Patients taking medications and/or diuretics to manage 
their blood pressure (for either hypo- or hypertension) should be managed according to 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 34 of 50 
 
standard clinical practice, including considerations for dose adjustments of their concomitant 
medications during the course of the trial.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
ixazomib.  While this case ultimately resolved, PRES has also been reported rarely with other 
proteasome inhibitors, VELCADE and Kyprolis.  PRES is characterized by headache, seizures 
and visual loss, as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ 
damage. 
8.2.6. Preparation, Reconstitution, and Dispensing 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules. 
Packaging and Labeling 
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be 
handled as open-label material bearing a label with the following statement:  “Caution: New 
Drug – Limited by Federal Law to Investigational Use.”   
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.  
Storage, Handling, and Accountability 
Study drug will be stored in the UAMS Research Pharmacy under the supervision of the 
research pharmacist who will be responsible for maintaining the supply according to the 
manufacturer’s specifications, dispensing the drug for administration, and maintaining all 
accountability records. 
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. 
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. 
Because ixazomib is an investigational agent, it should be handled with due care. Patients 
should be instructed not to chew, break, or open capsules. In case of contact with broken 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
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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. 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified sub-investigator(s).  The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
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: 
 Adverse event 
 Protocol violation 
 Lost to follow-up 
 Progressive disease  
 Study terminated  
At the time of withdrawal, all study procedures outlined for the End of Treatment visit should be 
completed (unless already completed and withdrawal is only from long-term follow-up for 
survival). The primary reason for patient’s withdrawal from the study should be documented. 
9. STATISTICAL AND QUANTITATIVE ANALYSES 
9.1. Statistical methods 
This is a single-arm, phase 2 study to evaluate bone remodeling during ixazomib treatment in 
relapsed/refractory MM patients. The primary objective is to evaluate the effect of ixazomib on inducing 
osteoblast activation as measured by change in osteocalcin from baseline to end of study. Ixazomib will 
be administered orally at the dosage of 4.0 mg weekly in a 28-day cycle for 6 cycles.   
The study parameters of interest are described in Section 3. A similar study outlined in Zangari (16) by 
Terpos (30) evaluated bone markers after treatment with bortezomib in relapsed myeloma and found 
marked improvement. Terpos (30) reported the median and range osteocalcin level for myeloma 
patients at baseline and after 8 cycles of treatment with bortezomib.  Based on an observed median 
osteocalcin level (and estimated standard deviation) of 7.46 ng/ml (sd = 12.65) in baseline myeloma 
patients compared to 19 ng/ml (sd = 18.6) after treatment with bortezomib, differences in pre- and post- 


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ixazomib continuous study parameters will be evaluated using a nonparametric Wilcoxon sign-rank test 
for paired data. The correlation between the pre and post treatment groups is assumed to be 0.5.  
Using the asymptotic relative efficiency method to define power of a nonparametric test relative to a 
one sample t test, and a significance level of 0.05, the design gives a power of 88% for 20 patients. If 
normality assumptions are met, then the paired t-test will be used.  Difference in binary study 
parameters will be evaluated using McNemar’s test for correlated proportions.  Correlation between 
bone marker parameters will be evaluated using the Spearman correlation coefficient.  One-sided p-
values <0.05 will be regarded as statistically significant.   
The association between osteoblastic activation and myeloma response to ixazomib and to identify 
predictive factors for ixazomib-associated osteoblastic activation will be explored using differential 
expression analysis. All subjects meeting the eligibility criteria who have signed a consent form and 
have begun treatment will be evaluable for response, toxicities, and safety. Baseline and end of study 
descriptive statistics will be collected and analyzed per the statistical plan.  
10. ADVERSE EVENTS 
10.1. 
Definitions 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence in a patient or subject who has signed 
informed consent to participate in a study but before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation. 
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. 
With the exception of grade 3-4 laboratory abnormalities, 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.   
Serious Adverse Event Definition 
 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
 
Results in death.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. 
 
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.  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 


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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, 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. 
Related 
An event is “related” if more likely than not it was caused by the study drug 
Unexpected 
An event is “unexpected” when its specificity, nature, severity or incidence is not accurately reflected in 
the consent form, protocol, or IB previously reviewed and approved by the IRB.  Examples include 
lower rate of response to treatment or a side effect that is more severe than initially expected. 
Study Period 
The study period is defined as the period of time from start of study drug through the End of Treatment 
visit.  Events occurring after enrollment but prior to the study period will be considered pretreatment 
events (see above). 
10.2. 
Monitoring, Recording and Reporting of AEs 
Maurizo Zangari, M.D., is the principal investigator of this study; The University of Arkansas for Medical 
Sciences (UAMS) is the study sponsor.  UAMS is responsible for reporting serious adverse events 
(SAEs) to any regulatory agency; the principal investigator is responsible for reporting to the IRB and 
other entities (see Section 10.4). 
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.  All AEs occurring during the study period must be recorded.  The clinical course 
of each event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  SAEs that are still ongoing at the end of the study 
period must be followed up for up to 30 days to determine the final outcome.  Any SAE that occurs after 
the study period and is considered to be possibly related to the study treatment or study participation 
should be recorded and reported immediately to the Sponsor (UAMS).   
All subjects will be monitored for AE’s during the study.  Assessments may include monitoring the 
patient’s clinical symptoms; laboratory, pathological, radiological, or surgical findings; physical 
examination; or other appropriate tests and procedures. 
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 


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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). 
AE’s are to be reported in a routine fashion at scheduled times during the trial, such as with the annual 
continuing review to the IRB.  Certain AEs must be reported in an expedited manner to allow for more 
timely monitoring of subject safety and care.  The preporting of these events depends on the 
characteristics of the event: 
 
Seriousness (grading of event) 
 
Relatedness to study therapy 
 
Expectedness 
Steps to Determine if the event requires expedited Reporting: 
 
Identify the type of event and grade the event using NCI CTCAE version 4.0 
 
Determine whether the adverse event is related to the investigational drug.  Attribution 
categories are as follows: 
o Unrelated 
o Unlikely 
o Possible 
o Probable 
o Definite 
 
Determine the expectedness of the event.  Expected events are those previously identified 
resulting from administration of the agent.  See definition for “unexpected” above. 
10.3. 
Expedited Reporting of SAEs 
Only adverse events meeting the UPIRTSO (Unanticipated Problem Involving Risks to Subjects or 
Others) will need to be reported to the UAMS IRB within the required 10 day period of being notified of 
the event. UPIRTSO requires that an unanticipated problem meet the following qualifications: a) 
unanticipated or unexpected; b) related to the research; and c) involves new or increased risk to the 
subject(s).  All other adverse events should be recorded and reported to the UAMS IRB at continuing 
review. 
The Sponsor (UAMS) will be promptly notified of all SAEs that are related to the study and 
unanticipated/unexpected. These SAEs will be reported to the Sponsor using the FDA Medwatch 
3500A.  UAMS will report events to FDA in accordance with 21CFR312.  
All other SAEs will be reported to the Sponsor and FDA in the Annual Progress Report. 
Deaths that are related to research will be reported to the Sponsor immediately upon Investigator 
notification.  A death due to a terminal condition of the research participant would be considered 
anticipated and not related to the research and therefore not immediately reportable under this policy.  
The sponsor will report deaths to FDA in accordance with 21CFR312.   
10.4. 
Other Required Reporting 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from the date 
the participant signs Informed Consent through 30 days after administration of the last dost of ixazomib. 
Any SAE that occurs at any time after completion of ixazomib treatment or after the study period that 
the principal-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, for a 
minimum of three years 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). 


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Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must also be 
reported to Millennium Pharmacovigilance: 
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days of the 
investigator’s observation or awareness of the event 
All other serious (non-fatal/non-life threatening) events within 4 calendar days of the investigator’s 
observation or awareness of the event 
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance.   
The investigator must fax 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): Principal- 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): Principal- 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.   
Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI CTCAE 
version 4.0, as a guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
Relationship to the 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)? 
The 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 
SAE and Pregnancy Reporting Contact Information 
 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
 
Suggested Reporting Form:   
 
SAE Report Form (if 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 and/or Principal Investigator 
 
 


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10.5. 
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 of the subject’s last dose of study drug she must inform the investigator immediately and 
permanently discontinue study drug.  The investigator must immediately fax a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see above).  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 investigator must also immediately fax a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance or designee (see above).  Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
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 MedComm Solutions 
(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. 
For Product Complaints, 
call 1-877-TAKEDA (1-877-825-3327) 
Email: medicalinformation@tpna.com 
Fax: 1-800-247-8860 
Hours: Mon-Fri, 8am-6pm EST 
 
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. 
 
12. ETHICAL AND REGULATORY CONSIDERATIONS 
12.1. 
Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal Register 
Vol 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research Risks Reports: 
Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They must be followed to 
comply with FDA regulations for the conduct and monitoring of clinical investigations. 
12.2. 
Institutional Review 
This study must be approved by the UAMS Institutional Review Board, as defined by Federal 
Regulatory Guidelines (Ref Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the Office 
for Protection from Research Risks Reports: Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
The Investigator will be responsible for preparing documents for submission to the relevant IRB/EC and 
obtaining written approval for this study.  The approval will be obtained prior to the initiation of the 
study.   
 
Any modifications/amendments to the protocol after receipt of IRB/EC approval must be submitted by 
the Investigator to the IRB/EC for approval and to the sponsor. The Investigator is also responsible for 
notifying the IRB/EC and sponsor of any serious deviations from the protocol, or anything that may 


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involve added risk to study subjects.  
12.3. 
Subject Confidentiality 
The Myeloma Institute affirms the subject’s right to protection against invasion of privacy. In compliance 
with United States Federal regulations, representatives of the FDA, NCI and other regulatory authorities 
may review medical records and copy relevant research records in accordance with local laws. 
 
Should direct access to medical records require a waiver or authorization separate from the subject’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
12.4. 
Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice and the Code of 
Federal Regulations. 
 
The Investigator will permit IRB/EC review and regulatory inspection(s) (e.g. FDA, EMEA, TPP), 
providing direct access to the facilities where the study took place, source documents and all other 
study documents. 
 
The Investigator or a designated member of the Investigator’s staff must be available at some time 
during auditing visits to review data and resolve any queries and to allow direct access to the subject’s 
records (e.g. medical records, office charts, hospital charts, and study related charts) for source data 
verification. All study documents must be made available to the auditing representative so that the 
accuracy and completeness of study documents may be confirmed.  
12.5. 
Protocol Amendments 
If modification of the protocol is necessary, the modification must be confirmed in writing, and the 
Sponsor will inform the FDA in accordance with 21CFR 312; the Investigator will inform the IRB.  
Amendments that are administrative in nature do not require IRB approval but will be submitted to the 
IRB for information.   
12.6. 
Suspension of Study 
If conditions arise requiring further clarification before the decision to proceed with or terminate the 
study can be reached, the study will be suspended until the situation has been resolved. 
12.7. 
Protocol Deviations 
When an emergency occurs that requires a deviation from the protocol for a study subject, a deviation 
will be made only for that subject. The Principal Investigator or other physician in attendance in such an 
emergency will, if circumstances and time permit, contact the IRB immediately by telephone. If time 
does not allow for this, the Investigator will notify of the IRB of the deviation as soon as possible in 
writing. 
 
Such contacts will be made as soon as possible to determine whether or not the subject (for whom the 
deviation from protocol was effected) is to continue in the study.  The subjects’ medical and/or research 
record will completely describe the deviation from the protocol and state the reasons for such deviation.   
 
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13. P.I. Croucher, J.F. Apperley. Bone disease in multiple myeloma Br J Haematol, 103 (1998), pp. 902–
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15. G.D. Roodman Pathogenesis of myeloma bone disease Leukemia, 23 (2009), pp. 435  
 
16. Zangari M, Evangelos T, Zhan, F, Tricot, G.  Impact of bortezomib on bone health in myeloma:  A 
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Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
 
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melphalan and prednisone in patients with previously untreated multiple myeloma: a phase 1 study in 
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Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): 
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30. Terpos E, Heath D, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptor activator of 
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APPENDICES 
 
APPENDIX A 
Response Criteria and Survival Outcome Definitions 
 
Timing of Response Evaluation 
 
Response will be evaluated according to the Schedule of Evaluations listed above (Section 6.0)  
 
Definition of Measurable Disease 
 
a. Measurable protein criteria of the serum are defined as serum M-protein of IgG, IgA, IgD, IgE Isotype ≥ 1.0 gm/dl 
(10.0 g/L).   Measurable protein criteria of the urine are defined as urine M-protein (Bence-Jones Protein) > 200 
mg/24 hours. 
 
b. Participants with IgM peaks must have either  20% bone marrow plasmacytosis or >3 lytic lesions on skeletal 
survey. 
 
c. Non-Secretory Disease:  Participants without quantifiable M-proteins but with 20% bone marrow plasmacytosis 
will be assessed using plasma cell percentages.  These participants will be evaluated for CR, no CR, and 
progression/relapse using the criteria above. 
Response Criteria: 
 
Multiple Myeloma:  For the purpose of establishing one set of criteria for both Phase II and Phase III multiple myeloma 
studies, the following definitions will be used.  These definitions are based on the International Uniform Response Criteria 
for Multiple Myeloma. 
 
a. Measurable Disease:  Measurable, quantifiable protein criteria must be present.  Acceptable protein criteria are:  
 
 
Serum M protein ≥ 1 g/dL (≥ 10 g/L), quantified by using densitometry on serum protein electrophoresis 
(SPEP).  
 
AND / OR 
 
 
Urine M protein [Bence-Jones Protein] ≥ 200 mg/24 hrs (> 0.2 g/24 hrs), quantified by 24-hour urine 
protein electrophoresis (UPEP).  
 
OR 
 
 
Patients who have both serum M protein levels < 1 g/dL AND urine M protein levels < 200 mg/24 hrs at 
baseline may be followed by serum free light chain (FLC) assay if involved free light chain level ≥ 10 
mg/dL (≥ 100mg/L). 
 
Oligosecretory and Non-secretory Disease:  Patients that do not meet the criteria for measurable disease 
above may only be assessed for the following objective statuses: Stringent Complete Response, Stable, and 
Progression. 
 
 
b. Objective Status: 
 
Stringent Complete Response (sCR):   
 
 
Meets all of the criteria for Complete Response (CR) and   
 
normal serum free light chain ratio and 
absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence  
Complete Response (CR): 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 46 of 50 
 
 
Disappearance of all evidence of serum and urine M proteins on immunofixation electrophoresis studies 
and 
 
≤ 5% plasma cells in bone marrow and 
 
disappearance of any soft tissue plasmacytomas 
 
 
Very Good Partial Response (VGPR): 
 
 
Meets all of the criteria for Partial Response (PR) and 
 
Serum and urine M proteins detectable by immunofixation but not on electrophoresis or  
 
≥ 90% reduction in serum M protein and urine M protein < 100 mg/24 hrs. 
 
Partial Response (PR): 
 
 
If the patient had soft tissue plasmacytomas present at baseline and they were assessed at this disease 
assessment: ≥ 50% reduction in size of soft tissue plasmacytomas (see Appendix A; Notes h.)and 
 
If the patient had ≥ 30% plasma cells in bone marrow at baseline and a bone marrow biopsy was done: ≥ 
50% reduction in plasma cells and 
 
≥ 50% reduction in serum M protein and reduction in urine M protein ≥ 90% or to < 200 mg/24hr or 
 
If patient had serum M protein < 1 g/dL, urine M protein < 200 mg/24 hrs, and an involved serum free light 
chain level ≥ 10 mg/dL at baseline: ≥ 50% decrease in the difference between involved and uninvolved 
serum free light chain levels 
 
Stable Disease (STA): 
 
 
Patient does not meet criteria for Stringent Complete Response, Complete Response, Very Good Partial 
Response, Partial Response, or Progression. 
 
Progression (PROG):  Any one or more of the following: 
 
 
Serum M protein increase ≥ 25% from baseline (or an increase of ≥ 1 g/dL if serum M protein was ≥ 5 
g/dL at baseline), with an absolute increase of ≥ 0.5 g/dL or 
 
Urine M protein increase ≥ 25% from baseline, with an absolute increase of ≥ 200 mg/24 hrs or 
 
If patient had serum M protein < 1 g/dL, urine M protein < 200 mg/24 hrs, and an involved serum free light 
chain level ≥ 10 mg/dL at baseline: ≥ 25% increase in the difference between involved and uninvolved 
serum free light chain level, with an absolute increase of ≥ 10 mg/dL or 
 
Bone marrow plasma cell percentage increase ≥ 25% from baseline, with the absolute plasma cell % ≥ 
10% or 
 
New bone lesions or soft tissue plasmacytomas, or definite increase in size of existing bone lesions or 
soft tissue plasmacytomas (see Appendix A: Notes h.) or 
 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) that can be 
attributed solely to multiple myeloma 
 
NOTE: If a disease assessment indicates that a patient is experiencing a Stringent Complete 
Response, Complete Response, Very Good Partial Response, Partial Response, or Progression, this 
should be confirmed by a second disease assessment and this should be done prior to the institution 
of any new therapy.  The second disease assessment may be done at any time. 
 
Notes: 
 
a. “M protein” may also be known by the following synonyms: M-spike, monoclonal protein, myeloma protein, monoclonal 
paraprotein, M-component. 
 
b. Urine M protein measurement is estimated using 24-hour urine protein electrophoresis (UPEP) only.  Random or 24 hour 
urine tests measuring kappa and lambda light chain levels are not reliable and are not recommended. 
 
c. Patients with ‘measurable disease’ in both the serum and urine (serum M protein ≥ 1g/dL and urine M protein ≥ 200 
mg/24h) at baseline need to be followed by both SPEP and UPEP for response assessment. 
 
d. Except for assessment of Complete Response, patients with ‘measurable disease’ restricted to the serum (serum M 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 47 of 50 
 
protein ≥ 1 g/dL and urine M protein < 200 mg/24h) at baseline may be followed by SPEP only.  Likewise, except for 
assessment of Complete Response, patients with ‘measurable disease’ restricted to the urine (serum M protein < 1 g/dL 
and urine M protein ≥ 200 mg/24h) at baseline may be followed by UPEP only. 
 
e. Patients with serum M protein ≥ 1 g/dL and/or urine M protein ≥ 200 mg/24h at baseline will be assessed for response 
based on SPEP and/or UPEP results only.  Except for assessment of Stringent Complete Response, serum free light 
chain (FLC) assay response requirements are only applicable to patients who had serum M protein < 1 g/dL, urine M 
protein < 200 mg/24 hrs, and an involved serum free light chain level ≥ 10 mg/dL at baseline.  A normal serum free light 
chain ratio is required for all patients for a Stringent Complete Response. 
 
f. 
To qualify for a Complete Response, both serum and urine immunofixation must be carried out and must be negative, 
regardless of the size of the baseline M protein in the serum or urine. 
 
g. Skeletal survey is not required for assessment of response unless clinically indicated, but is recommended once a year in 
clinical practice.  Stringent Complete Response, Complete Response, Very Good Partial Response, Partial Response, 
and Stable Disease all require no known evidence of progressive or new bone lesions if radiographic studies were 
performed, but radiographic studies are not required to satisfy these response requirements. 
 
 
 
h. The size of the soft tissue plasmacytomas is defined as the sum of the products of the cross-diameters of each 
plasmacytoma.  The size of the bone lesions will be determined in a similar manner.  A definite increase in the size is 
defined as a ≥ 50% increase (and at least 1 cm2) of this sum. 
 
Best Response: This is calculated from a sequence of Objective Status evaluations 
 
Stringent Complete Response (sCR): An objective status of Stringent Complete Response on at least two sequential 
disease assessments.  Only one bone marrow biopsy, done during one of these two disease assessments, is required to 
confirm the response. 
 
Complete Response (CR): An objective status of Complete Response on at least two sequential disease assessments.  
Only one bone marrow biopsy, done during one of these two disease assessments, is required to confirm the response.  
  
Very Good Partial Response (VGPR): An objective status of Very Good Partial Response on at least two sequential 
disease assessments.  
Partial Response (PR):  An objective status of Partial Response on at least two sequential disease assessments. 
 
Unconfirmed sCR (UsCR): One objective status of Stringent Complete Response (based on evidence from serum and 
urine studies and, if drawn, bone marrow biopsy) but the confirmation studies are either not done, or when done, do not 
meet the requirements necessary to confirm response.  This must be documented before progression and at least three 
weeks after registration. 
 
Unconfirmed CR (UCR): One objective status of Complete Response (based on evidence from serum and urine studies 
and, if drawn, bone marrow biopsy) but the confirmation studies are either not done, or when done, do not meet the 
requirements necessary to confirm response.  This must be documented before progression and at least three weeks 
after registration. 
 
Unconfirmed VGPR (UVGPR): One objective status of Very Good Partial Response, but the confirmation studies are 
either not done, or when done, do not meet the requirements necessary to confirm response.  This must be documented 
before progression and at least three weeks after registration. 
 
Unconfirmed PR (UPR): One objective status of Partial Response, but the confirmation studies are either not done, or 
when done, do not meet the requirements necessary to confirm response.  This must be documented before progression 
and at least three weeks after registration. 
 
Stable / No Response (STA): At least one objective status of Stable at least three weeks after registration, but not 
qualifying as any of the above.  If radiographic studies were performed there should be no known progressive or new 
bone lesions. 
 
Increasing Disease (lNC): First objective status recorded (other than Unknowns or those before three weeks) of 
Progression, provided this occurs within eight weeks of registration. 
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 48 of 50 
 
Inadequate Assessment. Response Unknown (NASS): Progression greater than eight weeks after registration and either 
all objective statuses prior to registration are unknown or the only known objective statuses occurred less than three 
weeks after registration. 
 
Relapse:  In patients with a confirmed response as described above, relapse is defined as the first occurrence of any of 
the following, reconfirmed by repeat analysis of serum and/or 24-hour urine M protein, done more than 2 weeks apart: 
 
 
 
a. 
Myeloma protein increase by more than 100% from the lowest level recorded on study, or a rise of 2.0 g/dl 
(this increase must be to a level > 1.0 g/dL if it is to constitute the sole manifestation of relapse). 
b. 
Myeloma protein increase above the response criteria for PR (see criteria for Partial Remission). 
c. 
Reappearance of M-protein in blood or urine not related to immune recovery or recent infection.  
d. 
Increase in the size and number of lytic bone lesions recognized on radiographs.  New skeletal or MRI 
lesions, preferentially confirmed by fine needle aspirate. 
e. 
Myeloma related cytogenetic abnormalities. 
f. 
BM plasmacytosis > 10% or > 5% light chain restricted, non-diploid, plasma cells on cIg/DNA. 
g. 
Hypercalcemia, not explained by any other cause. 
 
 
Survival Outcomes 
 
Overall Survival:  measured as the time from initial registration to death from any cause. 
 
Event-Free Survival:  measured as the time from initial registration to progression/relapse of disease or death from any 
cause 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 49 of 50 
 
APPENDIX B 
    
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.  
 


PI:  Maurizio Zangari, MD 
 
UARK 2014-14 
Clinical Study Protocol X16013  
 
v5, May 15, 2017 
 
 
 
 
Page 50 of 50 
 
 APPENDIX C  
Diagnostic and Staging Criteria 
 
Diagnostic Criteria 
 
Revised IMWG Diagnostic Criteria for Multiple Myeloma (Rajkumar, et al, 2014) 
Clonal bone marrow plasma cells ≥ 10% or biopsy-proven bony or extramedullary plasmacytomaa 
And any one or more of the following myeloma defining events: 
 
Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative 
disorder, specifically: 
o 
Hypercalcemia:  serum calcium >0.25 mmol/L (>1 mg/dL) higher than the ULN or 
>2.75 mmol/L (>11 mg/dL) 
o 
Renal insufficiency:  CrCl <40 mL per minb or SCr >177 µmol/L (>2 mg/dL) 
o 
Anemia:  Hb >20 g/L below the LLN, or Hb <100 g/L 
o 
Bone lesions:  one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc 
 
Any one or more of the following biomarkers of malignancy: 
o 
Clonal bone marrow plasma cell percentagea ≥60% 
o 
Involved:uninvolved serum FLC ratiod ≥100 
o 
>1 focal lesions on MRI studiese 
CrCl, Creatinine clearance; CT, computed tomography; FLC, free light chain; Hb, hemoglobin; Ig, immunoglobulin; 
IMWG, International Myeloma Working Group; LLN, lower limit of normal; M protein, monoclonal protein; MRI, 
magnetic resonance imaging; PET-CT, Positron emission tomography-computed tomography; ULN, upper limit of 
normal; SCr, serum creatinine 
aClonality should be established by showing κ/λ –light-chain restriction on flow cytometry, immunohistochemistry, 
or immunofluorescence.  Bone marrow plasma cell percentage should preferably be estimated from a core biopsy 
specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used. 
bMeasured or estimated by validated equations. 
cIf bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from 
solitary plasmacytoma with minimal marrow involvement. 
dThese values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK).  The involved 
free light chain must be ≥100 mg/L. 
eEach focal lesion must be 5 mm or more in size. 
 
 
Staging Criteria 
 
International Staging system [ISS] 
 
New International Staging System (Greipp, et al, JCO 2005) 
Stage 
Criteria 
Median 
Survival 
(months) 
I 
Serum 2-microglobulin < 
3.5mg/L 
Serum Albumin > 3.5 g/dL 
 
62 
II 
Not stage I or III 
44 
 
III 
Serum 2-microglobulin > 5.5 
mg/L 
29 
 
*There are two categories for stage II: serum 2-microglobulin < 3.5 mg/L but serum 
albumin < 3.5 g/dL; or serum 2-microglobulin 3.5 to < 5.5 mg/L irrespective of the serum 
albumin level.