Clinical trial NCT02302846
Conditions: Leukemia
Keywords: Leukemia Acute myeloid leukemia AML High-risk myelodysplastic syndrome MDS Ixazomib MLN9708
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-03-20; Completion date: 2017-05-30
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if ixazomib can prevent AML or MDS from coming back in patients who are in remission. The safety of this drug will also be studied.

Detailed description:
Study Drug Administration:

Each study cycle is 28 days.

If you are found to be eligible to take part in this study, you will take ixazomib capsules on Days 1, 8 and 15 of each cycle. Ixazomib capsules should be swallowed whole, with water, on an empty stomach (take the dose at least 1 hour before or 2 hours after a meal).

If you miss a dose, take it as soon as you remember, as long as the next scheduled dose is more than 3 days away. If you vomit after taking a dose, do not make up the dose but continue with the next scheduled dose as planned.

You may receive the study drug for up to 12 cycles. If the doctor thinks it is in your best interest, you may be able to continue taking the study drug beyond Cycle 12.

Study Visits:

On Day 1 of each cycle (+/- 1 day):

* You will have a physical exam.
* Blood (about 2-3 teaspoons) will be drawn for routine tests.

On Days 8 and 15 of Cycle 1, blood (about 2-3 teaspoons) will be drawn for routine tests.

Every third cycle, you will have a bone marrow aspiration and/or biopsy to check the status of the disease.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the end-of-study visit.

End-of-Study Visit:

After your last dose of study drug, you will return to the clinic for an end-of-study visit.

* Blood (about 2-3 tablespoons) will be drawn for routine tests.
* You will have a bone marrow aspirate and/or biopsy to check the status of the disease.

This is an investigational study. Ixazomib is not FDA-approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drug is designed to work.

Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.

Arms: arm 1: Participants receive 4 mg oral dose of Ixazomib on Days 1, 8 and 15 of each 28-day cycle.
Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: 4 mg by mouth on Days 1, 8 and 15 of each 28-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
MDACC 2014-0379 
Phase II Study of ixazomib as maintenance therapy for patients with AML and 
high risk MDS in remission 
 
 
 
 
 
 
 
Indication: 
Maintenance therapy 
Phase: 
Phase II 
 
 
 
 
Protocol History 
Original 
20 February 2014 
 
Investigator and Study Center: 
PI: Courtney DiNardo, MD, 
MSCE 
Co-PI: Jorge Cortes, MD 
MD Anderson Cancer 
Center 1515 Holcombe 
Blvd 
Unit 0428 
713-794-1141 
 
 
 
 
 
 
 
 
This is an investigator-initiated study
.  Courtney DiNardo, MD is the principle 
investigator and MD Anderson (MDACC) the study sponsor. 
 
 
 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .............................................. 3 
1. BACKGROUND AND STUDY RATIONALE 
................................
................................... 8 
1.1 Scientific Background  ................................................................................................... 8 
1.1.1 Disease Under Treatment  
........................................................................................ 8 
1.1.2 Ixazomib  
................................
................................................................................. 9 
1.2 Preclinical Experience  
................................................................................................... 9 
1.3 Clinical Experience  
....................................................................................................... 9 
1.4 Pharmacokinetics and Drug Metabolism  
..................................................................... 10 
1.5 Clinical Trial Experience Using the Oral Formulation of ixazomib  ........................... 11 
1.6 Relapsed and/or Refractory Multiple Myeloma  
.......................................................... 18 
1.7 Newly Diagnosed Multiple Myeloma (NDMM)  
......................................................... 19 
1.8 Study Rationale  
........................................................................................................... 20 
1.9 Potential Risks and Benefits  
........................................................................................ 20 
2. STUDY OBJECTIVES 
................................................................................
2.1 Primary Objectives  ...................................................................................................... 21 
2.2 Secondary Objectives  
.................................................................................................. 21 
2.3 Tertiary/Exploratory Objectives (if applicable)  .......................................................... 21 
3. STUDY ENDPOINTS 
.................................................................................
3.1 Primary Endpoints  
................................
....................................................................... 21 
3.2 Secondary Endpoints  
................................................................................................... 21 
3.3 Tertiary/Exploratory Endpoints (if applicable)  
........................................................... 22 
4. STUDY DESIGN ..................................................................................
4.1 Overview of Study Design  
........................................................................................... 22 
4.2 Number of Patients  
................................
...................................................................... 23 
4.3 Duration of Study  ........................................................................................................ 23 
5. STUDY POPULATION 
...............................................................................
5.1 Inclusion Criteria  
................................
......................................................................... 23 
5.2 Exclusion Criteria  
................................
........................................................................ 25 
6. STUDY PROCEDURES 
...............................................................................
6.1 Study Drug Administration  
.......................................................................................... 32 
6.2 Dose-Modification Guidelines  
..................................................................................... 34 
6.2.1 Recommended ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated       
Toxicity 
.......................................................................................................... 34 
6.3 Excluded Concomitant Medications and Procedures  
.................................................. 38 
6.4 Permitted Concomitant Medications and Procedures  
.................................................. 39 
6.5 Precautions and Restrictions  
........................................................................................ 40 
6.6 Preparation, Reconstitution, and Dispensing  
............................................................... 44 
6.7 Packaging and Labeling  
............................................................................................... 44 
6.8 Storage, Handling, and Accountability  
........................................................................ 44 
6.9 Study Compliance  
....................................................................................................... 45 
6.10 Termination of Treatment and/or Study Participation  
............................................... 45 


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7. STATISTICAL AND QUANTITATIVE ANALYSES 
.................................................. 46 
7.1 Statistical Methods 
................................
....................................................................... 46 
7.1.1 Determination of Sample Size 
............................................................................... 46 
7.1.2 Populations for Analysis 
........................................................................................ 47 
7.1.3 Demographic and Baseline Characteristics 
........................................................... 47 
7.1.4 Efficacy Analysis 
.................................................................................................. 47 
7.1.5 Safety Analysis 
................................
...................................................................... 48 
8. ADVERSE EVENTS…………………………………………………………………….49 
8.1 Event Definition……………………………………………………………………….49 
8.2 Serious Adverse Event Definition………………………………………………… 
. 50 
8.3 Procedures for Reposrting Drug Exposure During Pregnancy and Birth Events …… 51 
8.4 SAE Reporting to Study Supporter (Millenium)……………………………………  52 
9. ADMINISTRATIVE  REQUIREMENTS 
....................................................................... 55 
9.1 Product Complaints 
.................................................................................................. 55 
10. REFERENCES 
............................................................................................................... 56 
11. APPENDICES 
................................................................................................................ 58 
11.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.......... 58 
 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific 
or protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable.  Abbreviations that are retained should not be changed. 
 
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 


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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 


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Abbreviation 
Term 
CO2 
carbon 
dioxide 
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 


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Abbreviation 
Term 
IB 
Investigator’s 
Brochure 
IC50 
concentration 
producing 
50% inhibition 
ICF 
informed consent form 
ICH 
International 
Conference 
on 
Harmonisation 
IEC 
independent 
ethics 
committee 
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 
Pharmacodynamics(s) 
Pgp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PR 
partial remission or partial response choose one 
PRO 
patient-reported 
outcome 
PSA 
prostate-specific 
antigen 
QD 
quaque die; each day; once daily 


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Abbreviation 
Term 
QID 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of 
electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable 
disease 
SmPC 
Summary 
of Product Characteristics 
t
1/2 
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 


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1. 
BACKGROUND AND STUDY RATIONALE 
 
1.1 Scientific Background 
 
1.1.1 Disease Under Treatment 
 
Effective therapies for relapsed AML and high-risk MDS represent an unmet clinical need. 
Standard intensive chemotherapy for AML consists of the nucleoside analogue cytarabine 
with or without an anthracycline as induction therapy, followed by consolidation therapy 
with repeated cycles of high-dose cytarabine and/or stem cell transplantation (SCT) once in 
a complete remission. With this therapy
, CR rates are approximately 60-80%, however 
long-term cure rates are approximately 40% or less in younger adults.(1, 2)  In older patients 
or those with poor-risk cytogenetics, CR rates are closer to 35-50% and cure rates with 
intensive front-line therapy are less than 10%, with a median survival of less than 9 
months.(3, 4) 
 
 
The median progression-free survival in adults with AML is less than 1 year and most 
patients with AML will still ultimately die of their disease.(5, 6)  In patients with relapsed or 
refractory disease after front-line therapy
, the prognosis is even more dismal, and there is a 
need to improve the results obtained with front-line therapy. Continued intensive 
chemotherapy may improve relapse free survival (RFS), but it is toxic and most patients are 
unable to receive continued intensive chemotherapy for an extended period of 
time.{Buchner, 1985 #6225}  Newer agents with novel mechanisms of action that 
demonstrate single-agent activity in leukemia may be able to circumvent resistance 
mechanisms and improve clinical outcomes by reducing the relapse rate once remission is 
attained. Considering the high remission rate with standard chemotherapy, a potential way 
to employ such agents is to administer them to patients who have achieved and sustained a 
CR after front-line therapy in an attempt to eradicate any detectable or undetectable minimal 
residual disease (MRD) and to therefore improve RFS and OS. 
 
 
Relative to normal hematopoietic cells, AML blasts and leukemic stem cells (LSCs) have 
higher levels of NFκB activity
, contributing to pro-survival signaling and chemoresistance. 
Modulating NFκB activity with ixazomib may therefore represent an important therapeutic 


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approach that can target LSCs and modulate chemoresistance. 
 
 
 
1.1.2 
Ixazomib 
 
1.2 Preclinical Experience 
 
Please refer to the current ixazomib Investigator’s Brochure (IB). 
 
 
1.3 Clinical Experience 
 
Ixazomib has been evaluated as an oral single agent in phase 1 studies that have included 
patients with advanced solid tumors, lymphoma, relapse/refractory MM (RRMM), and 
relapsed or refractory light-chain (AL) amyloidosis and demonstrated early signs of activity. 
Ongoing studies continue to investigate both single-agent ixazomib and ixazomib in 
combination with standard treatments. Based on encouraging preliminary data observed in 
patients with MM requiring systemic treatment, 2 phase 3 trials in newly diagnosed MM 
(NDMM) (C16014) and RRMM (C16010) patient populations are currently evaluating 
ixazomib in combination with Revlimid and Dexamethasone (RevDex) versus 
placebo/RevDex. Both trials are combining ixazomib at a weekly dose of 4.0 mg on Days 1, 
8, and 15 in a 28-day cycle to a standard dose of lenalidomide with a weekly dexamethasone 
dose of 40 mg. In addition, 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 


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commonly reported treatment-emergent event; however, there is some variety in its 
characterization and causality resulting in different preferred terms to describe it. A high- 
level term outline of rash events includes rashes, eruptions and exanthems NEC; pruritus 
NEC; erythemas; papulosquamous conditions; and exfoliative conditions. The dose 
escalation phases of most trials reported in the IB have now completed enrollment, and 
gastrointestinal (GI) symptoms were the common dose-limiting toxicities (DLTs) when the 
use of prophylactic anti-emetics was not permitted per protocol. In the expansion cohorts or 
phase 2 cohorts (as per each study), the incidence and severity of GI symptoms was 
mitigated by the use of the lower maximum tolerated dose (MTD)/recommended phase 2 
dose (RP2D) (as per each study) and standard clinical usage of anti-emetics and/or 
antidiarrheal medications as deemed appropriate. Prophylactic use of anti-emetics has not 
been required as with other agents but (as outlined in Section 6.7) has been used according 
to standard practice and are effective. 
 
 
The most frequent (at least 20%) treatment-emergent adverse events (TEAEs) reported with 
the PO formulation pooled from single-agent studies (n = 201) irrespective of causality to 
ixazomib, include nausea (53%), fatigue (51%), diarrhea (44%), thrombocytopenia (34%), 
vomiting (38%), decreased appetite (32%), fever (21%), and anemia (21%). The most 
frequent (at least 20%) TEAEs reported with the PO formulation pooled from combination 
trials (irrespective of the combination) (n = 173), irrespective of causality to ixazomib, 
include diarrhea (47%), fatigue (44%), nausea (38%), peripheral edema (35%), constipation 
(33%), insomnia (29%), thrombocytopenia (28%), anemia (26%), vomiting (26%), 
neutropenia (25%), back pain (24%), pyrexia (23%), peripheral edema (21%, each), fever 
(20%), cough (20%), hypokalemia (20%), neutropenia (20%), and upper respiratory tract 
infection (20%). Overall rash of all grades is reported in approximately 50% of patients and 
is more common when ixazomib is given in combination with lenalidomide where rash is an 
overlapping toxicity
. 
 
 
Additional detailed information regarding the clinical experience of ixazomib may be found 
in the IB, including information on the IV formulation. 
 
1.4 Pharmacokinetics and Drug Metabolism 
 
Clinical IV and PO 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 citrate is rapidly absorbed with a 


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median single-dose first time of occurrence of maximum (peak) concentration (Tmax) of 
approximately 0.5 to 2.0 hours and a terminal disposition half-life (t
1/2) after multiple dosing 
of approximately 5 to 7 days [1]. 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 [2]. 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 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. 
 
 
1.5 Clinical Trial Experience Using the Oral Formulation of ixazomib 
 
As of 27 March 2013, a total of 507 patients with differing malignancies (multiple myeloma, 
AL amyloidosis, nonhematologic cancers, and lymphoma) have been treated in studies 


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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 1-1. 


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


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Table 1-1  
Clinical Studies of Oral Ixazomib 
 
Trial/ 
Population 
 
Description 
 
Doses 
Investigated 
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 
dysfunction 
N=45 
Part A: PO, Day 1 of 15-day cycle 
Part B: PO, W 
1.5 mg (severe hepatic impairment), 2.3 mg 
(moderate hepatic impairment), or 4.0 mg (normal 
hepatic 
function) 
TB- 
MC010034 
RRMM 
N = 10 
PO, W 
4.0 mg, W 
Single agent: 4.0 mg 
Combination with Rd 
Abbreviations: RRAL = Relapsed and/or refractory Primary systemic light chain (AL) amyloidosis; BSA = 
body surface area; Dex=dexamethasone; DLT = dose-limiting toxicity; IV = intravenously; LenDex = 
lenalidomide plus dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple 
myeloma; PO = orally; RR= relapsed and/or refractory; RRAL= relapsed and/or refractory systemic light 
chain amyloidosis RRMM = relapsed and/or refractory multiple myeloma; TBD = to be determined; TW 
= twice weekly; W = weekly; RP2D= recommended phase 2 dose. 
Note that blinded data from pivotal Studies C16010 and C16011 are not included. 
a  Approximate BSA and fixed dosing equivalence: 3 mg~ equivalent to 1.68 mg/m2 BSA dosing; 4.0 mg ~ 
equivalent to 2.23 mg/m2 BSA dosing; and 5.5 mg~ equivalent to 2.97 mg/m2 BSA dosing. 
 
 
 
 
 
Overview of the Oral Formulation of ixazomib 


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


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Table 1-2  
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Single-Agent Studies 
 
 
 
 
Primary System Organ Class 
Preferred 
Term 
Oral Single Agent 
Total 
n = 201 
n (%) 
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 macular
a 
23 (11) 
Musculoskeletal 
and connective tissue 
disorders 
93 (46) 
Back pain 
24 (12) 
Arthralgia 
28 (14) 
Respiratory, thoracic and mediastinal 
disorders 
78 (39) 
Cough 
28 (14) 
Dyspnoea 
30 (15) 
Infections 
and infestations 
89 (44) 
Upper respiratory 
tract infection 
31 (15) 
Source: Ixazomib Investigator’s Brochure Edition 7 
Abbreviations: MedDRA = Medical Dictionary for Regulatory Activities, version 15.0. 
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated 
subjects as the denominator. 
a  Note that rash maculopapular and rash macular represent the 2 most common terms used to describe rash. 
 
 
 
As of 27 March 2013, there are 5 studies actively enrolling patients with multiple myeloma 
to investigate oral ixazomib in combination with standard combination regimens. 
The most frequent (at least 10%) AEs occurring in the pooled safety population from 
Studies C16005, C16006, C16008, and C16013 are shown for all grades (Table 1-3).  Note 
that in combination trials, related is defined as related to any study drug in the combination 
regimen. 


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Table 1-3 
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
 
 
 
Primary System Organ Class 
Preferred 
Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
Subjects with at Least One Adverse Event 
163 (94) 
Gastrointestinal 
disorders 
139 (80) 
Nausea 
65 (38) 
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 
maculopapular
a 
29 (17) 
Rash macular
a 
22 (13) 
Musculoskeletal 
and connective tissue 
disorders 
99 (57) 
Back pain 
42 (24) 
Pain in extremity 
31 (18) 
Arthralgia 
22 (13) 
Respiratory, thoracic and mediastinal 
disorders 
80 (46) 
Cough 
36 (21) 
Dyspnoea 
26 (15) 


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Table 1-3  
Most Common (At Least 10% of Total) Treatment-Emergent Adverse 
Events in Oral Combination Studies 
 
 
 
 
Primary System Organ Class 
Preferred 
Term 
Total Oral Combo Agent 
(5/6/8/13) 
n = 173 
n (%) 
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 [3], non-Hodgkin’s disease, Hodgkin’s disease 
[4], relapsed and/or refractory multiple myeloma [RRMM; 5; 6], relapsed or refractory 
systemic light chain amyloidosis [RRAL; 7], and newly diagnosed multiple myeloma 
[NDMM; 8; 9; 10]) to date. 
 
 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of ixazomib. 
 
 
1.6 Relapsed and/or Refractory Multiple Myeloma 
 
The early development of ixazomib in patients with RRMM involves 2 studies (C16003 and 
C16004) with similar objectives, but each investigated 1 of the 2 dosing schedules 
commonly used with the first-in-class proteasome inhibitor, VELCADE. 
 
Study C16003 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a 
twice-weekly schedule on Days 1, 4, 8, and 11 of a 21-day cycle in adult patients with 
RRMM.(11, 12) 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 


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RRMM.(13, 14, 15)  Both studies have now completed enrollment. The DLTs in Study 
C16003 were rash macular and thrombocytopenia and the DLTs in C16004 were nausea, 
diarrhea, vomiting, and erythema multiforme. 
 
In the dose escalation component of both studies, patients had multiple myeloma that had 
relapsed following at least 2 lines of therapy that must have included bortezomib, 
thalidomide (or lenalidomide), and corticosteroids.  In both studies, when the MTD was 
established, cohorts of patients representing the heterogeneous patient population currently 
seen in clinical practice were to be enrolled into 1 of 4 expansion cohorts, including a 
relapsed and refractory cohort, a carfilzomib cohort, a proteasome inhibitor-naïve cohort, 
and a VELCADE-relapsed cohort. 
 
Final study results are currently being analyzed, but preliminary data suggest that ixazomib 
has anti-tumor activity in heavily pretreated MM patients, with durable responses/disease 
control, and is generally well tolerated. Please refer to the ixazomib IB and SMA for further 
information. 
 
1.7 Newly Diagnosed Multiple Myeloma (NDMM) 
 
Multiple research paths are being explored in patients with NDMM with a focus on 
evaluating ixazomib in combination with agents commonly used across treatment settings. 
The development of ixazomib in combination with lenalidomide 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 I
B and SMA for further 
information. 
 
1.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib 
 
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 


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1.9 Study Rationale 
 
In adult AML and high-risk MDS patients that achieve remission, the median progression- 
free survival is less than 1 year, and most patients will still ultimately die of their disease. 
Additionally
, the median age of AML and MDS of 65 to 70 years of age prevents curative 
stem cell transplantation procedures in the majority of our patients. Thus additional 
therapies are warranted at the time of remission to prevent a very high risk of relapse. 
 
Relative to normal hematopoietic cells, AML blasts and leukemic stem cells (LSCs) have 
higher levels of NFkB activity
, which can contribute to pro-survival signaling and 
chemoresistance.  The novel, orally bioavailable, reversible and selective small molecule 
20S proteasome inhibitor ixazomib has been shown to induce apoptosis in cancer cells with 
downregulation of survival proteins including NFkB, phospho-Rb, and Bcl-2.  Thus, 
modulating NFkB activity with ixazomib may represent an important therapeutic approach 
that can target any residual LSCs at the time of remission. 
 
1.10 
Potential Risks and Benefits 
 
Please refer to the current ixazomib IB and SMA. 
 
 
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) 
guidelines. 


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2. 
STUDY OBJECTIVES 
 
2.1 Primary Objectives 
 
The primary objective of this study is to determine the efficacy of ixazomib in patients with 
acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in 
complete remission (CR) or complete remission with incomplete count recovery (CRi) 
assessed by improvement on relapse-free survival (RFS). 
 
2.2 Secondary Objectives 
 
The secondary objectives of the study are to determine the efficacy of ixazomib at 
eradicating MRD (minimal residual disease) as assessed by multiparameter flow cytometry, 
as well as to determine the safety of ixazomib in this patient population. 
 
2.3 Tertiary/Exploratory Objectives 
 
The exploratory objectives of this study are: 
 
 
1. To evaluate molecular or other genetic features of the patients hematologic 
malignancy that may be predictive of response 
2. Correlative laboratory studies of subjects including gene expression profiling and 
other biomarkers to determine the in vivo mechanism of action and biological effects 
 
 
3. 
STUDY ENDPOINTS 
 
3.1 Primary Endpoints 
 
The primary efficacy endpoint is relapse free survival (RFS), defined as the interval from the 
date of the achievement of CR/CRi to the date of first objective documentation of disease 
relapse or death from any cause. Subjects who are lost to follow-up without documented 
relapse, or are alive at last follow-up without documented relapse will be censored at the 
date of their last response assessment. 
 
 
3.2 Secondary Endpoints 
 
The secondary endpoint is to evaluate the efficacy of ixazomib at eradicating MRD as 
assessed by multiparameter flow cytometry in those patients who are MRD positive at the 
start of study. 
 
The safety endpoint will assess overall incidence and severity of all adverse events events 
using Common Toxicity Criteria v 4.0.  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) most current 


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version will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
 
3.3 Tertiary/Exploratory Endpoints 
 
The following exploratory endpoints and correlative laboratory studies will be examined to 
determine the in vivo mechanism of action and biological effects of treatment, as well as to 
detect whether certain molecular or other genetic patterns can predict response to ixazomib: 
 
- Correlation of initial cytogenetic and mutational status (of 28 genes known to be 
affected in myelodysplastic syndromes and acute leukemias) performed through the 
bone marrow and molecular diagnostics laboratory of MD Anderson. 
 
- Gene expression profiling and gene-specific DNA methylation may be performed. 
DNA methylation will be assessed using bisulfite PCR assays (i.e. COBRA or 
pyrosequencing analysis) and gene expression profiling by real-time PCR analysis. 
 
- Additional exploratory subgroup analyses will be performed where an adequate 
number of subjects are available in each subgroup to allow for meaningful 
interpretation of results and these include: age group, sex, race, response (CR vs CRi 
at start), prior history of MDS (yes/no), cytogenetic category, induction therapy and 
consolidation therapy received, ECOG performance score. 
 
 
4. 
STUDY DESIGN 
 
4.1 Overview of Study Design 
 
This is an open-label single arm Phase II study in subjects with AML or high-risk MDS in 
CR/CRi.  Patients will receive single 4mg oral dose of ixazomib on days 1, 8 and 15 of each 
28-day cycle. Treatment with ixazomib will be administered for 12 cycles for patients who 
remain in CR. 
 
 
For patients with MRD positive CR/CRi at study start, treatment with ixazomib may 
continue for a total of 12 cycles after achievement of MRD negativity is observed. 
 
 
Patients who are experiencing clinical benefit may be eligible to continue therapy after the 
allotted 12 cycles after discussion with the PI and the discussion documented in the patient’s 
medical record. 
 
 
Subjects will be assessed for outcome status (i.e. maintenance of CR/CRi) every 3 cycles or 
as clinically indicated.  Adverse events, compliance and concomitant medications will be 
assessed continually throughout the study; specific information will be requested at each 
study visit. 


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Study cycles will be administered every 28 days + 5 days or upon resolution of any 
clinically significant study drug related AE to grade 0-1, whichever occurs first. 
 
 
Administration of subsequent cycles should be administered when neutrophils recover to > 
0.5 x 10⁹/L and platelets to > 50 x 10⁹/L
, or to baseline levels prior to the start of the last 
cycle of therapy. 
 
 
Ixazomib will be self-administered primarily on an outpatient basis; but may be 
administered as an inpatient.  Patient compliance will be documented using the MD 
Anderson (MDACC) Research Medication Diary and will be assessed at each study visit. 
 
 
4.2 Number of Patients 
 
This study is planned for 40 patients.  All patients who receive at least one dose of the study 
drug will be included in the efficacy and safety analysis. Subjects who do not receive any 
dose of the study drug will be replaced. 
 
 
 
4.3 Duration of Study 
 
Treatment will continue until discontinuation due to relapse or disease progression, 
unacceptable toxicity
, or completion of therapy
.  Completion of therapy includes 12 cycles 
of ixazomib. Note that in patients with MRD positive disease at study start, treatment may 
continue for 12 cycles after achievement of MRD negativity is observed.  For patients 
experiencing clinical benefit, treatment may be continued beyond 12 cycles if in the best 
interest of the patient. 
 
 
 
 
5. 
STUDY POPULATION 
 
5.1 Inclusion Criteria 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
 
 
1. Male or female patients 18 years of age or older. 
 
 
2. 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. 
 
3. Female patients who: 


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 Are postmenopausal for at least 1 year before the screening visit, OR 
 
 
 Are surgically sterile, OR 
 
 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
form through 90 days after the last dose of study drug, OR 
 
 Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) 
 
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.) 
 
4. Patients must have a history of de novo or therapy-related AML (defined by WHO 
classification of > 20% bone marrow blasts) or high-risk MDS (defined by IPSS or 
IPSS-R) 
 
5. Patients must be in a documented CR/CRi from either their front-line or first salvage 
therapy as evidenced by < 5% bone marrow blasts and absence of extramedullary 
disease.  (For patients with prior MDS who then transformed to AML, therapy 
received for MDS is not considered prior therapy for AML) 
 
6. Patients should have received at least 2 cycles of induction therapy or 1 induction 
and 1 consolidation cycle, OR patient should be considered to have completed all 
planned chemotherapy, OR patient is considered to be unable, unfit or unwilling to 
receive additional chemotherapy. 
 
7. Eastern Cooperative Oncology Group (ECOG) performance 0, 1, or 2. 
 
8. Patients must meet the following clinical laboratory criteria: 


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 Absolute neutrophil count (ANC) 500/mm3 and platelet count 50,000/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/or 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: 
 
 
1. Female patients who are lactating or have a positive serum or urine pregnancy test 
during the screening period. 
 
2. Failure to have fully recovered (ie, Grade 1 toxicity) from the reversible effects of 
prior chemotherapy. 
 
3. Major surgery within 14 days before enrollment. 
 
 
4. Radiotherapy within 14 days before enrollment. If the involved field is small, 7 days 
will be considered a sufficient interval between treatment and administration of the 
ixazomib. 
 
5. Known central nervous system involvement. 
 
 
6. Infection requiring systemic antibiotic therapy or other serious infection within 
14 days before study enrollment. 
 
7. Evidence of current uncontrolled cardiovascular conditions, including sustained 
hypertension (SBP >150mmHg on two or more readings one week apart without 
normalization in between) , clinically significant uncontrolled cardiac arrhythmias, 
Class III-IV NYHA congestive heart failure, or unstable angina, or myocardial 
infarction within the past 6 months. 
 
8. Systemic treatment within 7 days, or the half life of the treatment, whichever is 
longer, before the first dose of ixazomib, with strong inhibitors of CYP1A2 


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(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. 
 
9. Ongoing or active systemic infection, history of hepatitis B or C virus infection, or 
known human immunodeficiency virus (HIV) positive. 
 
10. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
 
11. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent. 
 
12. Known GI disease or GI procedure that is expected to interfere with the oral 
absorption or tolerance of ixazomib including difficulty swallowing. As determined 
by investigator. 
 
13. Diagnosed or treated for another malignancy within 2 years before study enrollment 
or previously diagnosed with another malignancy and have any evidence of residual 
disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are 
not excluded if they have undergone complete resection. 
 
14. Patient has Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical 
examination during the screening period. 
 
15. Administration of other investigational agents for the treatment of AML/MDS within 
21days (or 5 times the terminal half life of the investigational treatment whichever is 
longer) of the start of this trial and throughout the duration of this trial. 
 
16. At the time of registration, stem cell transplantation is not planned within the next 3 
months. 
 
6. 
STUDY PROCEDURES 
 
6.1 Screening 
 
The following procedures are performed during screening. These procedures are to be 
performed within 4 weeks prior to study drug administration, except where otherwise 
indicated. 


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A signed and dated IEC/IRB approved informed consent form must be obtained before any 
study specific procedures are performed.  Procedures that are part of routine care are not 
considered study specific procedures. All subjects will be screened for eligibility before 
enrollment.  Once the subject has met all inclusion criteria, they may be enrolled onto the 
study. 
 
Table 6.1: Procedures during Screening 
 
 
Procedures 
Specifics 
Informed 
consent 
 
Full History and Physical Examination 
History – present illness, prior surgeries, other 
medical illnesses, review of systems, allergies, prior 
therapy for cancer and concurrent meds; 
 
Physical exam – record weight, and note 
abnormalities in any major organ system 
(including but not limited to neurologic, head 
and neck, lymph nodes, cardiovascular, 
pulmonary, 
abdomen, 
extremities) 
Concomitant 
Medications 
Documentation of last use of other investigational 
agents for treatment of AML/MDS including 
terminal half-life of the agent 
Vital signs (including temperature, pulse, and 
blood 
pressure) 
 
ECOG performance status 
 
Urine or serum pregnancy test (females of child- 
bearing potential only) 
Within 7 days prior to first dose 
Disease status (IPSS or R-IPSS classification for 
MDS and WHO disease classification for AML) 
 
Note: Bone marrow aspirate and/or biopsy within 
4 weeks prior to first dose of drug in all patients. 
Cytogenetics 
and 
immunohistochemistries 
performed as indicated. 
Staging with bone marrow aspiration and/or biopsy 
for disease assessment. 
Serum 
chemistries (repeat if screening chemistries 
completed greater than 72 hours prior to the first 
dose) 
Sodium, potassium, blood urea nitrogen, creatinine, 
glucose, AST and/or ALT, total bilirubin, alkaline 
phosphatase 
CBC with differential (repeat if screening test 
completed greater than 72 hours prior to the first 
dose) 
Differential may be omitted if WBC ≤0.5 x109/L 
 
6.2 
Study Drug Administration 
 
Study calendar 
 
PROCEDURES 
Pre-Study 
Screenº 
Cycle 1 
Day 1 
 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Day 1 of Cycle 
2 onwards 
(+/- 5 days) 
End of 
Treatment  
(+/- 5 days) 
Informed Consent 
X 
 
 
 
 
 
Med
ica
l H
istory  
X 
 
 
 
 
 
V
ita
l S
igns (
inc
lud
ing 
temperature, pu
lse and b
lood 
pressure) 
X 
X 
X 
X 
X 
X 


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Phys
ica
l Exam and 
Performance Status 
X 
X 
 
 
X 
X 
Concom
itant Med
icat
ions 
X 
X 
 
 
X 
X 
CBC w
ith d
ifferent
ia
l 
 
X* 
X 
X² 
X² 
X¹,² 
X 
B
lood Chem
istr
ies  
X* 
X 
X 
X 
X 
X 
Bone marrow asp
irat
ion and/or 
b
iopsy  
X 
 
 
 
X³ 
X 
IPSS score &/or WHO d
isease 
c
lass
if
icat
ion 
X 
 
 
 
 
 
Pregnancy Test (fema
les of 
ch
i
ld-bear
ing potent
ia
l on
ly) 
X† 
 
 
 
 
 
AE and SAE assessment 
X 
X 
X 
X 
X 
X 
ºScreen
ing must be performed w
ith
in 4 weeks pr
ior to study drug 
in
it
iat
ion / study start un
less otherw
ise 
ind
icated 
*CBC w
ith d
ifferent
ia
l and b
lood chem
istr
ies (sod
ium, potass
ium, BUN, creat
in
ine, g
lucose, AST and/or ALT, tota
l b
i
l
irub
in, 
a
lka
l
ine phosphate) must be performed w
ith
in 72 hours of Cyc
le 1 Day 1  
†W
ith
in 7 days of Day 1 
in fema
les of ch
i
ld-bear
ing potent
ia
l 
¹ANC must be > 500/mm³ and p
late
let count must be > 50,000/mm³, or have recovered to base
l
ine hemato
log
ic va
lues 
²If p
late
let count <25,000/mm³ or ANC < 500/mm³ on any 
ixazom
ib dos
ing day, CBC shou
ld be repeated tw
ice week
ly unt
i
l 
counts have exceeded the prespec
if
ied va
lues (as per Sect
ion 6.3.1)  
³Bone marrow asp
irat
ion and/or b
iopsy requ
ired for study entry, and every 3 cyc
les for pr
imary outcome un
less requ
ired more 
frequent
ly as c
l
in
ica
l
ly 
ind
icated.   
Ixazomib will be self-administered primarily on an outpatient basis; but may be 
administered as an inpatient.  3 doses of ixazomib corresponding to the three treatment days 
(days 1, 8 and 15) will be dispensed for the first cycle. For subsequent cycles, up to 1 month 
of therapy (3 doses) may be dispensed. 
 
 
On day 1 (+/- 5 days) of each cycle the following procedures will be performed and


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documented: physical exam including vital signs and performance status, evaluation of 
concomitant medications, laboratory analysis including CBC and serum chemistries, and 
assessment of any side effects. 
 
 
Subjects will be assessed for outcome status (i.e. maintenance of CR/CRi) every 3 cycles or 
as clinically indicated.  Adverse events, compliance and concomitant medications will be 
assessed continually throughout the study; specific information will be requested at each 
study visit. 
Patient compliance will be documented using the MD Anderson (MDACC) Research 
Medication Diary and will be assessed at each study visit. 
 
 
Destruction of unused study drug will be in accordance with the institution’s drug 
destruction policy. 
 
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 subinvestigator(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 6.3). 
 
Capsules of ixazomib will also be referred to as study drug. Study drug will be supplied by 
Millennium as capsules of 2.3, 3.0 and 4.0 mg ixazomib. 
 
The prescribed administration of ixazomib doses in this study is 4mg ixazomib on days 1, 8 
and 15 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. 


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Ixazomib Destruction 
 
Investigational ixazomib (expired or end of study) should be destroyed on site according to 
the institution’s standard operating procedure.  Be sure to document removal and destruction 
on drug accountability logs. 
 
 
 
 
6.3 Dose-Modification Guidelines 
 
 
 
6.3.1  Recommended ixazomib Criteria for Beginning or Delaying a Subsequent 
Treatment Cycle & Dose Modifications for Treatment Associated Toxicity 
 
Treatment with ixazomib will use a cycle length of 28 days. For a new cycle of treatment to 
begin, the patient must meet the following criteria: 
 
 
 ANC must be ≥ 500/mm3 and  platelet count must be ≥ 50,000/mm3, or have 
recovered to baseline hematologic values 
 All other nonhematologic toxicity (except for alopecia) must have resolved to ≤ 
Grade 1 or to the patient’s baseline condition 
 
 
If the patient fails to meet the above-cited criteria for initiation of the next cycle of 
treatment, dosing should be delayed for 1 week. At the end of that time, the patient should 
be re-evaluated to determine whether the criteria have been met. If the patient continues to 
fail to meet the above-cited criteria, delay therapy and continue to re evaluate. The 
maximum delay before treatment should be discontinued will be 4 weeks or at the discretion 
of the Principal Investigator. 
All decisions for dose adjustments will be made by the MD Anderson treating physician. 
For dosing recommendations upon recovery, refer to Table 6-2 and Table 6-3.  Dose 
adjustments different than those described below are acceptable after discussion with the PI
, 
and will require documentation of the rationale for such action. 


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Table 6-1 MLN908 Dose Adjustments 
 
 
Dose Level 
Dose (mg) 
Starting Dose 
4.0 mg 
-1 
3.0 mg 
-2 
2.3 mg 
-3 
Discontinue 


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Dosage adjustments for hematologic toxicity are outlined in Table 6-2. 
 
Table 6-2  ixazomib Dose Adjustments for Treatment Related Hematologic 
Toxicities 
 
Criteria 
Action 
Within-Cycle Dose Modifications 
 If platelet count 25 109/L or ANC ≤ 0.50  
109/L on a ixazomib dosing day (other than Day 
1) 
 
 
 
 
 
 
 
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 6.2ANC < 0.50 109/L, 
platelet count < 50 109/L, or other 
nonhematologic toxicities > Grade 1 or not to 
the patient’s baseline condition 
 
Dose Modifications for Subsequent Treatment Cycles 
 ixazomib dose should be withheld. 
 Complete blood count (CBC) with differential 
should be repeated twice weekly until the ANC 
and/or platelet counts have exceeded the 
prespecified values (see Section 6.3.1) on at least 
2 occasions. 
 Upon recovery, ixazomib may be reinitiated with 
1 dose level reduction. 
 
 
 Hold ixazomib until resolution as per criteria 
Section 6.3. 
 Upon recovery, reduce ixazomib 1 dose level. 
 The maximum delay before treatment should be 
discontinued will be 4 weeks or at the discretion 
of the PI. 
 All hematologic toxicities 
 For hematologic toxicity that occurs during a 
cycle but recovers 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 15 dosing thus a dose 
reduction was not required at that 
point in the cycle, reduce ixazomib 
by 1 dose level at the start of that 
cycle. 
o Do not reduce the dose both within 
a cycle and at the start of the cycle 
for the same most severe toxicity. 


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Treatment modifications due to ixazomib -related AEs are outlined in Table 6-3. 
 
 
Table 6-3 
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Treatment Related Adverse Events (Non- 
Hematologic 
Toxicities) 
Adverse Event (Severity) 
Action on Study Drug 
Further 
Considerations 
Peripheral 
Neuropathy: 
Grade 1 
 
 
 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 
 
 May 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 6.7 
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 6.7 
If not recovered to 
< Grade 1 or baseline 
within 4 weeks 
 Reduce study drug to next 
lower dose upon return to 
</= Grade 1 or baseline 
 


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Table 6-3  
Ixazomib Treatment Modification (Delays, Reductions, and 
Discontinuations) Due to Treatment Related Adverse Events (Non- 
Hematologic Toxicities) 
 
Adverse Event (Severity) 
Action on Study Drug 
Further 
Considerations 
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 
 
 
Once ixazomib is reduced for any toxicity
, the dose may not be re-escalated. 
 
 
6.4 Excluded Concomitant Medications and Procedures 
 
The following medications and procedures are prohibited during the study: 
 
 
Systemic treatment with any of the following metabolizing enzyme inhibitors is not 
permitted during this study.  (A drug-drug interaction [DDI] with a strong inhibitor would 
increase ixazomib exposure and could lead to a higher probability of an AE.):. 
 
 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’s use. A DDI 
with a strong inducer would decrease MLN2238 exposure. (Rationale: Unlike with 
inhibitors, if there were to be a DDI with an inducer, ixazomib exposure would be less; 
therefore, there would be a reduced chance of an AE. However, there may be less chance for 
an antitumor effect, but that is not an absolute reason to be taken off ixazomib): 
 
 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital 
 
The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 


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The following procedures are prohibited during the study: 
 
 
 Any antineoplastic treatment with activity against AML or MDS except for drugs in 
this treatment regimen. 
 
 Radiation therapy (note that, in general, the requirement for local radiation therapy 
indicates disease progression). 
 
 Platelet transfusions to help patients meet treatment criteria are not allowed within 3 
days prior to study drug administration on any dosing day. 
 
6.5 Permitted Concomitant Medications and Procedures 
 
The following medications and procedures are permitted during the study: 
 
 
 Antiemetics, including 5-HT3 serotonin receptor antagonists, may be used at the 
discretion of the investigator. 
 
 Loperamide or other antidiarrheal should be used for symptomatic diarrhea at 
discretion of the investigator. The dose and regimen will be according to institutional 
guidelines. 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 principal investigator . 
Erythropoietin will be allowed in this study. Their use should follow published 
guidelines and/or institutional practice. 
 
 Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
 
 Antiviral therapy such as acyclovir may be administered if medically appropriate. 
 
 
 Concomitant treatment with bisphosphonates will be permitted, as appropriate. 
 
 
 Patients who experience worsening neuropathy from baseline may be observed for 
recovery, and have dose reductions/delays as indicated in the protocol, and any 
supportive therapy or intervention may be initiated as appropriate at the discretion of 
the investigator. 


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 Supportive measures consistent with optimal patient care may be given throughout 
the study. 
 
6.6 Precautions and Restrictions 
 
 Fluid deficit should be corrected before initiation of treatment and during treatment. 
 
 
 Nonsteroidal anti-inflammatory drugs (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.) 
 
 Two forms of barrier contraception:   Females - Diaphragm plus spermicide Males- 
Condom plusspermicide 
 
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following: 


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 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.) 
 
 Two forms of barrier contraception: 1. Condom 2. Spermicide 
 
6.7 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. 
 
Prophylaxis Against Risk of Reactivation of Herpes Infection 
 
Patients may be at an increased risk of infection including reactivation of herpes zoster and 
herpes simplex viruses.  Antiviral therapy such as acyclovir, valacyclovir, or other antivirals 
may be initiated as clinically indicated.  Other antivirals are also acceptable. 
 
Nausea and/or Vomiting 
 
Standard anti-emetics including 5-hydroxytryptamine 3 serotonin receptor antagonists are 
recommended for emesis if it occurs once treatment is initiated; prophylactic anti-emetics 
may also be considered at the physician’s discretion. Dexamethasone should not be 
administered as an anti-emetic. Fluid deficit should be corrected before initiation of study 
drug and during treatment. 
 
Diarrhea 
 
Prophylactic antidiarrheals will not be used in this protocol. However, 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 deficit should be corrected before initiation of treatment and during treatment. 
 
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 


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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. 
 
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. Thrombocy
topenia 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 (see Table 6-2). 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 
 
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 


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been manageable.  Growth factor support is not required but may be considered according to 
standard clinical practice.  Ixazomib administration should be modified as noted as per dose 
modification recommendations in the protocol when neutropenia occurs (see Table 6-2). 
Therapy can be reinitiated at a reduced level upon recovery of ANCs. 
 
Fluid Deficit 
 
Dehydration should be avoided since ixazomib may cause vomiting, diarrhea, and 
dehydration.  Acute renal failure has been reported in patients treated with ixazomib, 
commonly in the setting of the previously noted gastrointestinal toxicities and dehydration. 
 
Fluid deficit should be corrected before initiation of study drug and as needed during 
treatment to avoid dehydration. 
 
Hypotension 
 
Symptomatic hypotension and orthostatic hypotension with or without syncope 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 standard clinical practice, including 
considerations for dose adjustments of their concomitant medications during the course of 
the trial. Fluid deficit should be corrected before initiation of study drug and as needed 
during treatment to avoid dehydration. 
 
Posterior Reversible Encephalopathy Syndrome 
 
One case of posterior reversible encephalopathy syndrome, which ultimately resolved, has 
been reported with ixazomib.  This condition is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure. Diagnosis may be confirmed by 
magnetic resonance imaging (MRI).  If the syndrome is diagnosed or suspected, symptom- 
directed treatment should be maintained until the condition is reversed by control of 
hypertension or other instigating factors. 


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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. 
 
6.8 Preparation, Reconstitution, and Dispensing 
 
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should 
be exercised when handling ixazomib capsules. 
 
6.9 Packaging and Labeling 
 
The study drug ixazomib capsules will be provided by Millennium. The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations. 
 
The capsules are individually packaged in cold form foil-foil blisters in a child-resistant 
carton.  There are 3 capsules in each wallet/carton. 
 
6.10 
Storage, Handling, and Accountability 
 
Upon receipt at the investigative site, ixazomib should remain in the blister and carton 
provided until use or until drug is dispensed. The container should be stored at the 
investigative site refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before 
the retest expiry date provided by Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. 
 
In countries where local regulations permit, ixazomib capsules dispensed to the patient for 
take-home dosing should remain in the blister packaging and refrigerated as noted above 
until the point of use. The investigative site is responsible for providing the medication to 
the patient in the correct daily dose configurations. Comprehensive instructions should be 
provided to the patient in order to ensure compliance with dosing procedures.  Patients who 
are receiving take-home medication should be given only 1 cycle of medication at a time. 
Patients should be instructed to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) 
for the duration of each cycle. Patients should be instructed to return their empty blister 
packs to the investigative site, rather than discarding them. Reconciliation will occur 
accordingly when the patient returns for their next cycle of take-home medication. Any 
extreme in temperature should be reported as an excursion and should be dealt with on a 
case-by-case basis. 


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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 
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. 
 
6.11 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. 
 
6.12 
Termination of Treatment and/or Study Participation 
 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care. The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
 
 Adverse event that in the opinion of the investigator makes continued administration 
of ixazomib undesirable or unsafe 
 
 Protocol violation that makes continued participation undesirable or unsafe 
 
 Lost to follow-up 
 
 Clinically significant progressive disease 
 
 Study terminated 
 
 Other 


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At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded 
in the source documents and CRF. 
 
6.13End of Study Visit: 
 
Subjects will undergo an end of study visit at the time of discontinuation of ixazomib. 
Whenever possible, a laboratory analysis including CBC and serum chemistries along with a 
bone marrow aspirate and/or biopsy will be performed at this visit. 
 
7. 
STATISTICAL AND QUANTITATIVE ANALYSES 
 
7.1 Statistical Methods 
 
This is a phase II study of ixazomib in AML/MDS patients who have achieved CR/CRi after 
front-line or first salvage therapy. Up to 40 patients will be enrolled in the study with an 
estimated accrual rate of one patient per month. The additional follow up will be 12 months 
after the last patient enrolls in the study
. The primary objective is to evaluate relapse-free 
survival (RFS). The study will monitor futility and toxicity
. 
 
 
7.1.1 Determination of Sample Size and Futility Monitoring 
 
Futility will be monitored for the study. We will monitor RFS using the methods of Thall et 
al. (2005), and we will stop enrolling patients to the study if we have reason to believe that 
the median RFS is less than that from the historical data, which is around 11 months.  The 
trial will be stopped if Pr( lamda(E)  > lamda(S) | data from the trial ) < 0.05, where 
lamda(S) is the median RFS for standard treatment in the historical data with an inverse 
gamma distribution IG(123, 1342), which corresponds to a mean of 11 months and a 
standard deviation of 1 month, the corresponding 95%CI of (9.2, 13.1) months. The prior 
for lamda(E) is assumed to be IG(3.21, 24.31),  corresponding to a mean of 11 months and a 
larger standard deviation of 10.   Futility monitoring will start once 10 patients have been 
enrolled. Assuming an accrual rate of 1 per month and an additional follow-up of 12 
months, the operating characteristics for the futility stopping rule under various true states 
are summarized in the following table 1, with results based on 5000 simulations. 
 
 
Table 1: Operating characteristics for futility monitoring 
 
Median OS (M) 
Prob(Stop Early) 
Mean No. of Patients 
(25%, 75%) 
17 
0.012 
39.6 (40, 40) 
14 
0.036 
39.1 (40, 40) 
11 
0.164 
36.8 (40, 40) 
8 
0.673 
28.2 (17, 40) 


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5 
1 
14.2 (10, 17) 
 
 
Multc Lean V2.1 and OneArmTTE Version 4.1.1 were used for the trial design. The 
Department of Biostatistics will provide and maintain a website (“Clinical Trial Conduct”: 
https://biostatistics.mdanderson.org/ClinicalTrialConduct/) for futility monitoring for each 
treatment arm on this study. The Clinical Trial Conduct website resides on a secure server, 
and access is gained through usernames and passwords provided to personnel responsible 
for enrolling patients and updating patient data.  The website is accessed through a browser 
using secure socket layer (SSL) technology. Personnel responsible for enrolling patients on 
trials, which includes the principal investigator(s), research nurse(s), and data coordinator(s), 
will be trained by members of the Department of Biostatistics in the use of the trial website; 
the importance of timely updating of follow-up times and recording of events will be 
emphasized in training. 
 
 
 
7.1.2 Populations for Analysis 
 
All analyses including the efficacy and safety analysis will include all patients who have 
received at least 1 dose of study drug. 
 
7.1.3 Demographic and Baseline Characteristics 
 
Demographic and baseline laboratory results will be summarized using descriptive statistics, 
including means with standard deviations, or medians with ranges, histograms and box-plot. 
Fisher’s exact test and Wilcoxon rank test will be used in the data analyses of categorical 
and continuous variables, respectively. Survival or times to failure and time to progression 
functions will be estimated using the Kaplan-Meier method. The two-sided log-rank test will 
be used to assess the differences of time to events between groups, and Cox proportional 
hazards model will also be fitted to evaluate the association between tiem-to-event outcomes 
with patient characteristics.. 
 
 
 
7.1.4 Efficacy Analysis 
 
It is expected that the median RFS time will be 11 months or higher under this study 
treatment. If the trial continues to maximum accrual of 40 patients and maintains sufficient 
follow-up to observe 25 events (relapse/death) with a median RFS of 11 months, then a 95% 
credible interval for median RFS would extend from 7.4 to 16.3 months.  The median RFS 
time will be estimated by Bayesian posterior estimates, along with the 95% credible 
intervals. 


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7.1.5 Safety Analysis 
 
Unacceptable toxicities will also be monitored closely using the method of Thall et al 
(1995). Denote the probability of unacceptable toxicity by TE, where toxicity is defined as 
any clinically significant treatment-related grade 3 or higher toxicities. We assume TE ~ 
beta (0.3, 0.7).  We will stop the study if at any time point Pr(TE > 0.30 | data)  >0.9. That is, 
we will stop the trial if, at any time during the study, we determine that there is more than 
90% chance that the unacceptable toxicity rate is more than 30%. The trial will be stopped 
if (the number of severe toxicity observed / among number of patients)≥4/5, 6/10, 8/15, 
9/20, 11/25, 13/30, 15/35. The toxicity stopping rules were created for examining data in 
patient cohorts of size 5.The operating characteristics are listed in table 2.   
 
Toxicity will be reported by type, frequency and severity
. Highest toxicity grades per patient 
per course will be tabulated for selected adverse events and laboratory measurements. 
 
 
Table 2: OCs for unacceptable toxicity monitoring 
 
 
True Prob(severe tox) Pr(stop) 
mean # Pts 
0.1 
0.0006 
39.98 
0.2 
0.021 
39.43 
0.3 
0.186 
35.76 
0.4 
0.583 
26.84 
0.5 
0.905 
17.30 
 
 
7.1.8. Study Endpoints 
 
 
 
Relapse-Free Survival (RFS): 
Is defined as the interval from the date of enrollment to the date of first objective 
documentation of disease relapse or death from any cause. Subjects who are lost to follow- 
up without documented relapse, or are alive at last follow-up without documented relapse 
will be censored at the date of their last response assessment. 
 
 
Overall Survival (OS): 
Time from date of treatment start until date of death due to any cause. 
 
 
Complete Remission (CR): 


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Peripheral counts: No circulating blasts, neutrophil count > 1 x 10⁹/L and platelet count > 100 
x 10⁹/L Bone marrow: < 5% blasts, no detectable auer rods, no extramedullary leukemia with 
normal maturation of all cell lines.  Persistent dysplasia will be noted. 
 
 
Complete remission with incomplete count recovery (CRi): 
  Defined as a morphologic complete remission but the ANC may be <1 x 10⁹/L or the platelet  
  count may be <100 x 10⁹/L. 
Time to discontinuation from treatment will be assessed as an estimate of treatment 
failure/tolerability and is defined as the interval from the date of enrollment to the date of 
discontinuation.  Subjects who are ongoing in treatment at the time of study closure will be 
censored at the date of last visit. 
 
 
 
8. 
SAFETY AND ADVERSE EVENTS 
 
8.1 Event Definitions 
 
Adverse event reporting will be as per the NCI criteria and the MDACC Leukemia Specific 
Adverse Event Recording and Reporting Guidelines and the study will be monitored for 
compliance by the IND office 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) most current version (version 4.0) will be utilized for 
adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html). 
 
Adverse drug reaction is a response to a drug which is noxious and unintended and which 
occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for 
the modification of physiologic function. 
 
 
All “suspected adverse reactions” (as defined in 21 CFR 312.32(a)) will be captured in the 
case report forms. For abnormal chemical values grade 3 or 4, the apogee will be reported 
per course in the CRF. 
 
 
Assessing causal connections between agents and disease is fundamental to the 
understanding of adverse drug reactions. In general, a drug may be considered a contributory 
cause of an adverse event if, had the drug not been administered, 1) the event would not 
have happened at all, 2) the event would have occurred later than it actually did, or 3) the 
event would have been less severe. 
 
 
The Investigator or physician designee is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for each event for all 
subjects enrolled on the trial.  Protocol specific data and adverse events will be entered into 
PDMS/CORe, the electronic case report form for this protocol. 


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8.2 Serious Adverse Event Definition 
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 
- Death 
- A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred.  It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
- Inpatient hospitalization or prolongation of existing hospitalization 
- A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
- A congenital anomaly/birth defect 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
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 (21 
CFR 312.32). 
 
 
Important medical events as defined above may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND office. 
 
 
All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy 
for Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported 
to the IND Office, regardless of attribution (within 5 working days of knowledge of the 
event). 
 
 
Only unexpected AEs will be recorded in the Case Report Form (CRF).  The Principal 
Investigator will sign and date the PDMS/CORe Case Report Form toxicity pages per each 
patient at the completion of each course.  Following signature, the Case Report Form will be 


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used as source documentation for the adverse events for attribution. 
 
 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office. 
 
 
 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB. 
 
 
Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or 
there has been acceptable resolution of the event. 
 
 
Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
 
The following SAEs are not subject to expedited reporting, but would still be included in the 
annual report via the SAE log. 
Disease progression leading to death, life-threating AE, hospitalization or 
prolongation of hospitalization, or disability 
Reporting to FDA: 
 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
 
 
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth 
Events 
 
 
 
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 3 months from the discontinuation of dosing, the investigator should report 
the information to the study supporter as if it is an SAE. The PI must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 


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designee (see Section 8.3). The expected date of delivery or expected date of the end of the 
pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data 
etc., should be included in this information.  The investigator will follow the medical status 
of the mother, as well as the fetus, as if the pregnancy is an SAE. 
 
 
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below. 
- "Spontaneous abortion" includes abortion and missed abortion. 
- Death of an infant within 28 days after birth should be reported as an SAE regardless 
of its relationship with the study drug. 
- Any infant death after 28 days that the Investigator suspects is related to the in utero 
exposure to the IP should also be reported to MPI/PPD Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved 
equivalent form. 
- In the case of a delivery of a living newborn, the "normality" of the infant is 
evaluated at the birth. 
- "Normality" of the miscarried fetus is evaluated by visual examination unless test 
results which indicate a congenital anomaly are obtained prior to miscarriage. 
 
 
8.4 SAE Reporting to Study Supporter (Millenium) 
 
 
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.  Any clinically relevant deterioration in laboratory assessments or other clinical 
finding is considered an AE. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  For serious AEs, the 
investigator must determine both the intensity of the event and the relationship of the event 
to study drug administration.  All SAEs, regardless of attribution, and adverse events related 
to study drug, will be entered in the CRF. 
 
 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) 
from the first dose of study drug through 30 days after administration of the last dost of 
ixazomib. Any SAE that occurs at any time after completion of ixazomib treatment or after 
the designated follow-up 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 seriousness or causality to study regimen, for a 


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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). 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
 
Since this is an investigator-initiated study
, the principal investigator Dr. Courtney DiNardo, 
is responsible for reporting serious adverse events (SAEs) to any regulatory agency and to 
the investigator’s EC or IRB. 
 
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance (or designee): 
Fatal and Life Threatening SAEs within 24 hours of the principle investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
principle investigator’s observation or awareness of the event 
 
 
See below for contact information for the reporting of SAEs to Millennium 
Pharmacovigilance. 
 
The PI must fax or email the SAE Form per the timelines above.  A sample of an SAE Form 
will be provided. 
 
The SAE report must include at minimum: 
 
 
 Event term(s) 
 
 Serious criteria 
 
 Intensity of the event(s): The PI 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): PI’s or sub-investigator’s determination of the 
relationship of the event(s) to study drug administration. 


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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 used at your institution, as a guideline, whenever possible. The criteria 
are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
In the event that this is a multisite study
, the PIis responsible to ensure that the SAE reports 
are sent to Millennium Pharmacovigilance (or designee) from all sites participating in the 
study. Sub-investigators must report all SAEs to the PI so that the PI can meet his/her 
foregoing reporting obligations to the required regulatory agencies and to Millennium 
Pharmacovigilance, unless otherwise agreed between the PI and sub-investigator(s). 
 
Relationship to all study drugs for each SAE will be determined by the investigator or sub- 
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
 
The PI 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 
 
• 
US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
• 
Any other form deemed appropriate by the PI 


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9. 
ADMINISTRATIVE REQUIREMENTS 
 
9.1 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 MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
 
 
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 (refer to 
Section 8.3). 


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10. REFERENCES 
 
1. 
Gupta, N., et al., Clinical Pharmacokinetics of Intravenous and Oral MLN9708, An 
Investigational Proteasome Inhibitor: An Analysis of Data From Four Phase 1 Monotherapy 
Studies. Blood (ASH Annual Meeting Abstracts), 2010. 116(21): p. abstr 1813. 
2. 
Gupta, N., M. Saleh, and K. Venkatakrishnan. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) 
Analysis of Pooled Data From 4 Phase-1 Studies in 53rd ASH Annual Meeting and 
Exposition. 2011. San Diego, CA. 
3. 
Chow, L.Q., et al. MLN9708, an investigational proteasome inhibitor, in patients with solid 
tumors; Updated phase 1 results in Head and Neck Symposium. 2012. Phoenix, AZ 
4. 
Assouline, S., et al. Once-weekly MLN9708, an investigational proteasome inhibitor, in 
patients with relapsed/refractory lymphoma: results of a phase 1 dose-escalation study in 
17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
5. 
Lonial, S., et al. Phase I study of twice-weekly dosing of the investigational oral proteasome 
inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM) 
in ASCO Annual Meeting. 2012. Chicago, Illinois. 
6. 
Kumar, S., et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in 
combination with lenalidomide and dexamethasone in patients (pts) with previously 
untreated multiple myeloma (MM): A phase I/II study in ASCO Annual Meeting. 2012. 
Chicago, Illinois. 
7. 
Merlini, G., et al. MLN9708, a Novel, Investigational Oral Proteasome Inhibitor, in Patients 
with Relapsed or Refractory Light-Chain Amyloidosis (AL): Results of a Phase 1 Study in 
54th ASH Annual Meeting and Exposition. 2012. Atlanta, Georgia. 
8. 
Kumar, S. et al. A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome 
Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with 
Previously Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 
2012. Atlanta, Georgia. 
9. 
Richardson, P.G., et al. MLN9708, an investigational proteasome inhibitor, in combination 
with lenalidomide and dexamethasone in previously untreated multiple myeloma patients 
(pts): 
Evaluation of weekly and twice-weekly dosing in 17
th EHA Annual Congress. 2012. 
Amsterdam, the Netherlands. 
10. 
San Miguel, J., et al. Oral MLN9708, an an investigational proteasome inhibitor, in 
combination with melphalan and prednisone in patients with previously untreated multiple 
myeloma: a phase 1 study in 17th EHA Annual Congress. 2012. Amsterdam, the Netherlands. 
11. 
Kumar S., et al. Weekly Dosing of the Investigational Oral Proteasome Inhibitor MLN9708 
in Patients with Relapsed and/or Refractory Multiple Myeloma: Results From a Phase 1 
Dose  Escalation Study in 53rd ASH Annual Meeting and Exposition. 2011. San Diego, CA 
12. 
Kumar S., et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in 
patients (pts) with relapsed/refractory multiple myeloma (MM): A phase I study in ASCO 
Annual Meeting. 2012. Chicago, Illinois. 
13. 
Sanchorawala V., et al. Poster Presentation: Phase 1 study of MLN9708, a novel, 
investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain 
amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 
2012. 
14. 
Common Terminology Criteria for Adverse Events (CTCAE). 2010. 
 
1. 
Lowenberg B, Downing JR, Burnett A. Acute myeloid leukemia. The New England 
journal of medicine. 1999 Sep 30;341(14):1051-62. PubMed PMID: 10502596. 


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2. 
Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. 
Blood. 2005 Aug 15;106(4):1154-63. PubMed PMID: 15870183. 
 
3. 
Kantarjian H, O
'Brien S, Cortes J, Giles F, Faderl S, Jabbour E, et al. Results of 
intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia 
or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 
2006 Mar 1;106(5):1090-8. PubMed PMID: 16435386. 
 
4. 
Burnett AK, Milligan D, Prentice AG, Goldstone AH, McMullin MF, Hills RK, et al. 
A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid 
for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not 
considered fit for intensive treatment. Cancer. 2007 Mar 15;109(6):1114-24. PubMed 
PMID: 17315155. 
 
5. 
Roboz GJ. Current treatment of acute myeloid leukemia. Current opinion in 
oncology. 2012 Nov;24(6):711-9. PubMed PMID: 23014187. 
 
6. 
Derolf AR, Kristinsson SY, Andersson TM, Landgren O, Dickman PW, Bjorkholm 
M. Improved patient survival for acute myeloid leukemia: a population-based study of 9729 
patients diagnosed in Sweden between 1973 and 2005. Blood. 2009 Apr 16;113(16):3666- 
72. PubMed PMID: 19020306. 


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11. 
APPENDICES 
 
11.1   Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work) 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55. 


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12.COCKCROFT-GAULT EQUATION 
 
 
For males: 
 
 
 
Creatinine Clearance = (140-age[years] weight [kg]) 
72 (serum creatinine[mg/dL]) 
 
OR 
 
(140–age[years] weight [kg]) 
0.81 (serum creatinine[mol/L]) 
 
 
 
For females: 
 
 
Creatinine Clearance = 0.85 (140-age[years] weight [kg]) OR 0.85 (140-age[years] weight 
[kg]) 72 (serum creatinine[mg/dL])  
0.81 (serum creatinine[mol/L]) 
 
 
 
 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.