Clinical trial NCT02630030
Conditions: Glioblastoma
Sponsor: Emory University
Start date: 2016-03-24; Completion date: 2020-09-03
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase 0 trial studies ixazomib citrate in treating patients with glioblastoma that has spread or returned after period of improvement who are planning to undergo surgery. When given by mouth, ixazomib may be able to reach tumor cells in the brain. Studying samples of tissue, blood, and plasma in the laboratory from patients receiving ixazomib may help doctors learn more about the effects of ixazomib on the cells. It may also help doctors understand how well patients will respond to treatment.

Detailed description:
PRIMARY OBJECTIVES:

I. Measurement of tissue concentration of ixazomib (ixazomib citrate) in a glioblastoma after preoperative administration.

II. Measurement of blood and plasma concentration of ixazomib during surgical sampling after preoperative administration.

SECONDARY OBJECTIVE:

I. Assessment of the safety of ixazomib after single dose administration in glioblastoma patients undergoing surgery for tissue concentration assessment.

OUTLINE:

Patients receive ixazomib orally (PO) 3 hours before surgery.

After completion of study, patients are followed up for 30 days and then periodically thereafter.

Arms: arm 1: Patients receive ixazomib PO 3 hours before surgery.
Interventions: intervention 1: Ixazomib
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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WINSHIP CANCER INSTITUTE OF EMORY UNIVERSITY
INVESTIGATOR-INITIATED STUDY
WITH
MILLENNIUM PHARMACEUTICALS 
INVESTIGATIONAL AGENT:  IXAZOMIB 


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CLINICAL STUDY PROTOCOL 
Takeda Oncology Clinical Study Protocol X16071
Phase 0 Analysis of Ixazomib (MLN9708) in Patients with Glioblastoma
Indication:
Glioblastoma
Phase:
Phase 0
Protocol History
Draft 
Original
26 Jan 2015
DD Month YYYY
Investigator and Study Center:
Jeffrey J. Olson, MD
Department of Neurosurgery
Emory University School of Medicine
1365B Clifton Road, NE
Atlanta, GA 30087
404-778-3091
This is an investigator-initiated study.  The principal investigator, Jeffrey J. Olson (who may 
also be referred to as the sponsor-investigator), is conducting the study and acting as the 
sponsor.  Therefore, the legal/ethical obligations of the principal investigator include both those 
of a sponsor and those of an investigator.


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PROTOCOL SUMMARY 
Study Title:  Phase 0 Analysis of Ixazomib (MLN9708) in Patients with Glioblastoma
Phase:  0
Number of Patients:  3
Study Objectives 
Primary
1. Measurement of tissue concentration of ixazomib in a glioblastoma after preoperative 
administration
2. Measurement of blood and plasma concentration of ixazomib during surgical sampling after 
preoperative administration
Secondary
1. Assessment of the safety of ixazomib after single dose administration in glioblastoma patients 
undergoing surgery for tissue concentration assessment.  
Overview of Study Design:  
This is a surgically based Phase 0 study of MLN9708 administration in 3 patients to 
determine whether its active metabolite MLN2238 can be measured in tumor in individuals 
with glioblastoma.  The primary endpoint centers around MLN2238 concentration 
measurements in the glioblastoma, blood and plasma of these individuals 3 hours after 
administration.  
Study Population:  
Patients with recurrent glioblastoma requiring surgery will be candidates for this study.  The 
specific criteria are as follows:
Key Inclusion Criteria
1. Age 18 or above
2. Recurrent glioblastoma for which surgical resection is indicated
3. Karnofsky Performance Status of 60 or above
4. Platelet count > 100,000
5. ANC > 1,500
6. Hemoglobin > 9 g/dL
7. LFTs < 3 x Upper Limit of Normal for the testing lab
8. Creat < 1.5 mg/dL
Key Exclusion Criteria
1. Grade > 3 peripheral neuropathy or Grade 2 with pain on clinical examination during 
the screening period.
Duration of Study:  
Each individual will begin study activity at the time of Ixazomib administration 3 hours pre-
operatively until about two weeks post-operatively when their staples or sutures are removed.  It is 
estimated one subject will be accrued every two months.  Thus the study duration will be 


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approximately 6 months.  (please note that all serious adverse events must be reported up to 30 
days after the dose of ixazomib as described in Section 8.2: Procedures for Reporting 
Serious Adverse Events).  
STUDY OVERVIEW DIAGRAM 
Consent and 
Screening
Ixazomib 4mg po 
(approximately 3 
hours before 
surgery)
Surgery for 
glioblastoma: Tumor 
and Blood Samples
Suture or Staple 
Removal and Off 
Study
(Approximately 2 
weeks after surgery)


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SCHEDULE OF EVENTS   
Outline of Events
I.
Informed consent process completed
II.
Laboratory screening to confirm or deny eligibility
III.
Ixazomib administration 3 hours prior to surgery
IV.
Surgical resection of tumor
A.
Tumor specimen collection for MLN2238 concentration assessment
B.
Timed blood specimen collection during surgery for MLN2238 concentration 
assessment
V.
Off-study assessment at the time of suture or staple removal
Safety of ixazomib administration will be assessed from the first administration of ixazomib 
until approximately 2 weeks post-operatively.  Attributions of adverse events will be determined 
and recorded by likely source of that event.  
Schedule of Events and Observations
Consent
Screening
Ixazomib 
Administration 
3 Hours Before 
Surgery
Surgery
Postop Day 1
Postop Visit for 
Staple/Suture 
Removal
Reference 
Time Line
14 or fewer 
days before 
date of surgery
After consent 
and prior to 
ixazomib 
administration
1 to 3 hours 
prior to 
surgical 
incision
On average a 
two to four 
hour period of 
time with 
sampling 
occurring as 
clinically safe 
during the 
tumor 
resection
Assessment 12 
to 36 hours 
after the end 
of the surgery
Depending on 
the nature of 
the wound 
repair and 
integrity 
staple/suture 
removal will 
occur 10 to 20 
days after the 
day of surgery
Patient 
Education
x
Laboratory 
screening
x
Observation 
for clinical and 
laboratory 
toxicity using 
standard 
postop 
parameters*
x
x
x
Blood sampling 
just prior to 
incision
x
Blood sampling 
during tumor 
sampling
x
Blood sampling 
during surgical 
closure
x
Tumor 
sampling
x
* Toxicities are to be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.


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TABLE OF CONTENTS
PROTOCOL SUMMARY........................................................................................................3
STUDY OVERVIEW DIAGRAM...........................................................................................4
SCHEDULE OF EVENTS.......................................................................................................5
TABLE OF CONTENTS .........................................................................................................6
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..............................................8
1. BACKGROUND AND STUDY RATIONALE ................................................................12
1.1 Scientific Background ..................................................................................................12
1.1.1 Disease Under Treatment.......................................................................................12
1.1.2 Ixazomib ................................................................................................................12
1.2 Preclinical Experience ..................................................................................................12
1.3 Clinical Experience.......................................................................................................13
1.4 Pharmacokinetics and Drug Metabolism......................................................................14
1.5 Clinical Trial Experience Using the Oral Formulation of Ixazomib............................15
1.6 Relapsed and/or Refractory Multiple Myeloma ...........................................................21
1.7 Newly Diagnosed Multiple Myeloma (NDMM)..........................................................22
1.8 Clinical Trial Experience Using the Intravenous Formulation of Ixazomib ................22
1.9 Study Rationale.............................................................................................................22
1.10 Potential Risks and Benefits.......................................................................................23
2. STUDY OBJECTIVES ......................................................................................................24
2.1 Primary Objectives .......................................................................................................24
2.2 Secondary Objectives ...................................................................................................24
3. STUDY ENDPOINTS........................................................................................................24
3.1 Primary Endpoints ........................................................................................................24
3.2 Secondary Endpoints ....................................................................................................24
4. STUDY DESIGN ...............................................................................................................24
4.1 Overview of Study Design ...........................................................................................24
4.2 Number of Patients .......................................................................................................25
4.3 Duration of Study .........................................................................................................25
4.4 Staggered Enrollment ...................................................................................................25
5. STUDY POPULATION.....................................................................................................25
5.1 Inclusion Criteria ..........................................................................................................25
5.2 Exclusion Criteria.........................................................................................................26
6. STUDY DRUG...................................................................................................................28
6.1 Description of Investigational Agents ..........................................................................28
6.2 Study Drug Administration ..........................................................................................28
6.3 Excluded Concomitant Medications and Procedures ...................................................29
6.4 Permitted Concomitant Medications and Procedures...................................................30
6.5 Precautions and Restrictions.........................................................................................30
6.6 Management of Clinical Events ...................................................................................31
6.7 Preparation, Reconstitution, and Dispensing................................................................34
6.8 Packaging and Labeling................................................................................................34
6.9 Storage, Handling, and Accountability.........................................................................34
6.10 Study Compliance.......................................................................................................35
6.11 Study Treatment ........................................................................................................36


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6.12 Termination of Treatment and/or Study Participation................................................37
7. STATISTICAL AND QUANTITATIVE ANALYSES.....................................................38
7.1 Statistical Methods .......................................................................................................38
7.1.1 Determination of Sample Size...............................................................................38
7.1.2 Populations for Analysis........................................................................................38
7.1.3 Procedures for Handling Missing, Unused, and Spurious Data ............................38
7.1.4 Demographic and Baseline Characteristics ...........................................................39
7.1.5 Pharmacokinetics/Pharmacodynamics/Biomarkers (if applicable).......................39
7.1.6 Safety Analysis ......................................................................................................39
7.1.7 Adverse Event Stopping Rule................................................................................39
7.1.8 Data Safety Monitoring Plan .................................................................................39
8. ADVERSE EVENTS..........................................................................................................40
8.1 Definitions ....................................................................................................................40
8.1.1 Adverse Event Definition ......................................................................................40
8.1.2 Serious Adverse Event Definition .........................................................................40
8.2 Procedures for Reporting Serious Adverse Events.......................................................41
8.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........43
9. ADMINISTRATIVE REQUIREMENTS ..........................................................................44
9.1 Product Complaints ......................................................................................................44
10. REFERENCES .................................................................................................................45
11. APPENDICES..................................................................................................................47
11.1 Eastern Cooperative Oncology Group (ECOG) Scale and Karnofsky Performance 
Status Scale...........................................................................................................47
11.2 Cockcroft-Gault Equation...........................................................................................48
11.3 Pharmacokinetic (PK) Sample Collection and Handling (Mandatory, if Applicable)49


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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
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  


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Abbreviation
Term
CNS
central nervous system
CO2
carbon dioxide
CR
complete response   
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
DDI
drug-drug interaction
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


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Abbreviation
Term
HIV
human immunodeficiency virus
HNSTD
highest nonseverely toxic dose
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
progressive disease (disease progression)
Progressive disease
Pgp
P-glycoprotein
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response 
PRO
patient-reported outcome


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Abbreviation
Term
PSA
prostate-specific antigen
QD
quaque die; each day; once daily
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
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
single-dose time to reach maximum (peak) concentration
UK
United Kingdom
ULN
upper limit of the normal range
US
United States
Vz
volume of distribution in the terminal phase
WBC
white blood cell
WHO
World Health Organization


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   Scientific Background
   1.1.1
Disease Under Treatment
Glioblastoma, the most common primary tumor of the brain in adults, is rarely associated with 
cure or even control.[1]  Advances in surgical care and radiation planning have improved safety, 
and the addition of temozolomide to initial therapy has added some months to overall 
survival.[2] 
At progression bevacizumab extends time to further imaging progression, but not overall 
survival.  Having said this, average overall survivals are still in the range of 12-14 months.  This 
clearly leaves room for improvement by exploring other therapeutic modalities.  Standard 
cytotoxic agents have been studied from a number of standpoints and their effect has probably 
been maximized.[3, 4, 5]  
Bortezomib, a proteasome inhibitor, has been evaluated in preclinical and clinical studies with 
promising results, as a single agent or in combination with temozolomide and radiation therapy. 
As a single agent at recurrence, partial responses have been observed.[6]  Additionally, 
bortezomib appears to enhance radiation effects in these tumors [7, 8].  In a phase I study of 66 
patients with primarily recurrent glioblastoma the maximum tolerated dose in those not taking 
enzyme-inducing anti-seizure drugs was 1.70 mg/ m2 based on grade 3 thrombocytopenia, 
sensory neuropathy and fatigue. In the group taking enzyme-inducing anti-seizure drugs 
escalation was terminated at 2.5 mg/m2 without meeting meet the maximum tolerated dose 
criteria. However, proteasome inhibition in this group did not change at significantly at doses 
above 1.50 mg/m2 for those not taking enzyme-inducing anti-seizure drugs and above 1.90 
mg/m2 for those taking enzyme-inducing anti-seizure drugs.  This suggests that further 
escalations beyond those studied in this protocol would be unlikely to increase the biologic 
effect of this proteasome inhibitor.  Two partial responses were observed.[9]  Based on this 
information there appears to be a potential role for proteasome inhibitors in the management of 
progressive glioblastoma and this warrants the investigation at hand here.=.  
1.1.2         Ixazomib (MLN9708) 
1.2   Preclinical Experience
Please refer to the current ixazomib Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA).


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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 RRMM are ongoing.
As of 27 March 2013, preliminary clinical data is available for a total of 653 patients across 13 
studies. The emerging safety profile indicates that ixazomib is generally well tolerated. The 
adverse events (AEs) are consistent with the class-based effects of proteasome inhibition and are 
similar to what has been previously reported with VELCADE though the severity of some, for 
example peripheral neuropathy, is less. While some of these potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, 
dose modification or discontinuation.
Fatigue was the most common AE reported among 384 patients treated in the oral (PO) studies 
(47%). Other common AEs reported in the pooled intravenous (IV) and PO safety populations 
include nausea, thrombocytopenia, diarrhea, and vomiting. Rash is also a commonly reported 
treatment-emergent event; however, there is some variety in its characterization and causality 
resulting in different preferred terms to describe it. A high-level term outline of rash events 
includes rashes, eruptions and exanthems NEC; pruritus NEC; erythemas; papulosquamous 
conditions; and exfoliative conditions. The dose escalation phases of most trials reported in the 
IB have now completed enrollment, and gastrointestinal (GI) symptoms were the common dose-
limiting toxicities (DLTs) when the use of prophylactic anti-emetics was not permitted per 
protocol. In the expansion cohorts or phase 2 cohorts (as per each study), the incidence and 


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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 
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 (t1/2) after multiple dosing of 
approximately 5 to 7 days [10]. 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 [11]. 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  doses of ixazomib.


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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 
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 Error! No text of specified style in document.-1   Clinical Studies of Oral 
Ixazomib
Trial/
Population
Description
Doses Investigated
C16003
RRMM
N = 60
PO, TW, single agent
0.24-2.23 mg/m2 TW
MTD:  2.0 mg/m2
DLT:  rash, thrombocytopenia
Closed to enrollment
C16004
RRMM
N = 60
PO, W, single agent
0.24-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  rash, nausea, vomiting, diarrhea
Closed to enrollment
C16005
NDMM
N = 65
PO, W, combination with LenDex 
28-day cycle
1.68-3.95 mg/m2 W
MTD:  2.97 mg/m2
DLT:  nausea, vomiting, diarrhea, syncope
RP2Da:  4.0 mg fixed (switched to fixed dosing in 
phase 2, equivalent  to 2.23mg/m2)
Closed to enrollment
C16006
NDMM
N = 20
PO, TW (Arm A- 42 day cycle) and 
W (Arm B- 28 day cycle), 
combination with Melphalan and 
Prednisone
Arm Aa:  3-3.7-mg fixed dose TW
DLT:  rash, thrombocytopenia, subileus
Arm Ba:  3-5.5-mg fixed dose, W
DLT:  Esophageal ulcer nausea, vomiting, 
hematemesis, thrombocytopenia, ileus, 
neurogenic bladder
MTD = 3.0 mg
C16007
RRAL
N = 27
PO, W, single agent
4-5.5-mg fixed dosea W
DLT:  thrombocytopenia, diarrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
MTD:  4.0  mg W
C16008
NDMM
N = 64
PO, TW, combination with LenDex 
21-day cycle
3.0-3.7-mg fixed dosea W
MTD:  3.0 mg
Closed to enrollment
C16009
Solid tumors, 
Lymphomas
N = 54
PO, W, single agent
5.5-mg fixed dosea W
C16010
RRMM
N = 200
PO, W, with LenDex versus placebo-
LenDex
4.0 mg W
C16011
RRAL
N = 4
PO, W, with Dex versus physician’s 
choice of a Dex-based regimen
4.0 mg W
C16013
RRMM
PO, W, with LenDex
4.0 mg W


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Table Error! No text of specified style in document.-1   Clinical Studies of Oral 
Ixazomib
Trial/
Population
Description
Doses Investigated
N = 9
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.


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Overview of the Oral Formulation of Ixazomib
The emerging safety profile indicates that ixazomib is generally well tolerated.  The adverse 
events (AEs) are consistent with the class-based effects of proteasome inhibition and are similar 
to what has been previously reported with VELCADE though the severity of some, for example 
peripheral neuropathy, is less.  While some of these potential toxicities may be severe, they can 
be managed by clinical monitoring and standard medical intervention, or, as needed, dose 
modification or discontinuation.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent 
oral ixazomib in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 201 patients have been treated as of 27 
March 2013. These patients have been treated with different doses of ixazomib as they are all 
phase 1 trials. An overview of the most frequent (at least 10%) AEs occurring in the pooled 
safety population from single-agent oral ixazomib Studies (C16003, C16004, C16007, and 
C16009) is shown in Table 1-2.
Table 1-2   
Overall Safety Population: Treatment-Emergent Adverse Events
Reported by ≥ 10% of Patients
Primary System Organ 
Class
IV Studiesa
Oral Studiesb
Total
Preferred Term
N = 146
N = 491
N = 637
Subjects With at Least 1 
TEAE
145 (99)
482 (98)
627 (98)
Gastrointestinal 
disorders 
115 (79)
400 (81)
515 (81)
Nausea 
59 (40)
230 (47)
289 (45)
Diarrhoea 
51 (35)
230 (47)
281 (44)
Vomiting 
60 (41)
181 (37)
241 (38)
Constipation 
36 (25)
134 (27)
170 (27)
Abdominal pain 
28 (19)
60 (12)
88 (14)
General disorders and 
administration site 
conditions
118 (81)
363 (74)
481 (76)
Fatigue 
89 (61)
223 (45)
312 (49)
Pyrexia 
45 (31)
112 (23)
157 (25)
Oedema peripheral 
31 (21)
122 (25)
153 (24)
Asthenia 
10 (7)
74 (15)
84 (13)
Nervous system 
disorders 
87 (60)
272 (55)
359 (56)
Dizziness 
25 (17)
85 (17)
110 (17)
Headache 
31 (21)
74 (15)
105 (16)
Neuropathy peripheral 
17 (12)
81 (16)
98 (15)
Metabolism and 
nutrition disorders 
89 (61)
267 (54)
356 (56)


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Decreased appetite 
56 (38)
120 (24)
176 (28)
Dehydration 
25 (17)
61 (12)
86 (14)
Primary System Organ 
Class
IV Studiesa
Oral Studiesb
Total
Hypokalaemia 
11 (8)
57 (12)
68 (11)
Blood and lymphatic 
system disorders 
88 (60)
256 (52)
344 (54)
Thrombocytopenia 
65 (45)
161 (33)
226 (35)
Anaemia 
28 (19)
114 (23)
142 (22)
Neutropenia 
16 (11)
103 (21)
119 (19)
Lymphopenia 
16 (11)
61 (12)
77 (12)
Skin and subcutaneous 
tissue disorders 
84 (58)
255 (52)
339 (53)
Rash (all terms) 
73 (50)
197 (40)
270 (42)
Rash maculo-papular 
21 (14)
60 (12)
81 (13)
Rash macular 
15 (10)
56 (11)
71 (11)
Musculoskeletal and 
connective tissue 
disorders
78 (53)
249 (51)
327 (51)
Back pain 
27 (18)
88 (18)
115 (18)
Arthralgia 
17 (12)
72 (15)
89 (14)
Pain in extremity 
21 (14)
66 (13)
87 (14)
Respiratory, thoracic 
and mediastinal 
disorders
87 (60)
228 (46)
315 (49)
Cough 
32 (22)
94 (19)
126 (20)
Dyspnoea 
31 (21)
80 (16)
111 (17)
Infections and 
infestations 
48 (33)
244 (50)
292 (46)
Upper respiratory 
tract infection 
12 (8)
94 (19)
106 (17)
Psychiatric disorders 
32 (22)
151 (31)
183 (29)
Insomnia 
14 (10)
89 (18)
103 (16)
Source: \biostatistics\MLNM9708\IB\2014\Tables\T14.1.3-TEAE_Pct10_Pooled and
\biostatistics\MLNM9708\IB\2014\Tables\T14.6.2-TEAE_AESI_Rash; data cutoff 27 March 2014.
Treatment emergent is defined as any AE that occurs after administration of the first dose of any study drug 
through 30 days after the last dose of any study drug.
A subject counts once for each preferred term and system organ class. Percentages use the number of treated 
subjects as the denominator.
a Studies C16001 and C16002.
b Studies C16003, C16004, C16005, C16006, C16007, C16008, C16009, C16013, C16015, C16017, C16018,
and TB-MC010034.
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 maculopapulara
29 (17)
 Rash maculara
22 (13)
Musculoskeletal and connective tissue 
disorders
99 (57)
 Back pain
42 (24)
 Pain in extremity
31 (18)
 Arthralgia
22 (13)
Respiratory, thoracic and mediastinal 
disorders
80 (46)
 Cough
36 (21)
 Dyspnoea
26 (15)


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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 [12], non-Hodgkin’s disease, Hodgkin’s disease [13], relapsed and/or 
refractory multiple myeloma [RRMM; , 14, 15], relapsed or refractory systemic light chain 
amyloidosis [RRAL; 16], and newly diagnosed multiple myeloma [NDMM;  17, 18, 19]) 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.(, 20, 
21)  Study C16004 is an open-label, dose escalation, phase 1 study of ixazomib dosing on a 
weekly schedule on Days 1, 8, and 15 of a 28-day cycle in adults patients with RRMM.( 22, 23, 


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24)  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 IB and SMA for further information. 
1.8      Clinical Trial Experience Using the Intravenous Formulation of Ixazomib
See the IB for descriptions of the 2 studies that investigated IV ixazomib in advanced solid 
tumors and advanced lymphoma (Studies C16001 and C16002, respectively).
1.9
Study Rationale
Glioblastoma, the most common primary tumor of the brain in adults, is rarely associated with 
cure or even control.  Advances in surgical care and radiation planning have improved safety, 
and the addition of temozolomide to initial therapy has added some months to overall survival. 
At progression bevacizumab extends time to further imaging progression, but not overall 


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survival.  Having said this, average overall survivals are still in the range of 12-14 months.  This 
clearly leaves room for improvement by exploring other therapeutic modalities.  Standard 
cytotoxic agents have been studied from a number of standpoints and their effect has probably 
been maximized. 
Thus, alternative agents, either targeted to critical pathways related to tumor growth, or 
interrupting normal tumor cellular metabolism provide promising alternatives.  One of these 
strategies is altering the normal function of the 20S proteasome subunit.  Ixazomib has a shorter 
20S proteasome dissociation half-life than bortezomib, which plays an important role in 
improving tissue distribution. Direct comparison with bortezomib has revealed that Ixazomib 
has an improved pharmacokinetic and pharmacodynamic profile and shows superior antitumor 
activity in both solid tumor and hematologic xenograft models, and shows antitumor activity 
when administered via multiple dosing routes and regimens.  Although bortezomib has not been 
shown to have single agent efficacy in glioblastomas, the characteristics of ixazomib may be 
advantageous.  It has not been determined as to whether or not the active metabolite of ixazomib 
reaches these tumors effectively.  Preclinical models of glioblastoma, though very interesting, 
do not easily recapitulate the human situation in terms of size, tumor heterogeneity or effects of 
systemic metabolism.  In order to address this question directly, a phase 0 study of ixazomib is 
proposed here to answer this question prior to moving forward with more advanced phase 
studies.   
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
1. Measurement of tissue concentration of ixazomib in a glioblastoma after preoperative 
administration
2. Measurement of blood and plasma concentration of ixazomib during surgical sampling 
after preoperative administration
2.2   Secondary Objectives
1. Assessment of the safety of MLN9708 after single dose administration in glioblastoma 
patients undergoing surgery for tissue concentration assessment.  
3.   
STUDY ENDPOINTS
3.1   Primary Endpoints 
Determination of brain tumor tissue, blood and plasma concentrations ixazomib
3.2   Secondary Endpoints
Determination of the safety of MLN9708 after single dose administration in glioblastoma 
patients undergoing tumor resection
4.   
STUDY DESIGN 
4.1   Overview of Study Design
Individuals who are candidates for surgery for recurrent (or progressive) glioblastoma will be 
considered for participation in this study.  Those deemed by the PI to be potential candidates 
will be counseled and provided a consent.  Those signing a consent will then undergo eligibility 
screening.  Those eligible will receive 4 mg of Ixazomib orally 3 hours prior to surgery and be 
on study as of that day.  Tumor samples will be obtained at the time of surgery and provided to 
Covance for MLN2238 assay.  Also during the surgery, blood samples will be obtained at the 
time of induction, one and two hours later and provided to Covance for ixazomib assay in both 
blood and plasma.  At the time of return to the outpatient clinic the individual will be assessed 
for safetyrelated to Ixazomib administration.  At that point the individual will be off study.  
Adverse events are followed and reported for 30 days after drug administration.  The subject 
will continue to follow-up with their surgeon and oncologist as per standard care for their 
circumstance and therapy dictates and the adverse events will be captured at those follow-up 
visits.  


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4.2   Number of Patients
Three patients will be enrolled in this study.  Enrollment will commence at the time of Ixazomib 
administration.  
4.3   Duration of Study
This investigation will enroll approximately 1 patient every 2 months with completion expected 
6 months after Winship Cancer Center checklists are completed.  For the individuals enrolled, 
study activity will last from the day of surgery until the day the sutures or staples are removed.  
The average time period for the wound to heal well enough for suture or staple removal is 10-17 
days depending on the nature of the surgical wound. (please note that all serious adverse events 
must be reported up to 30 days after the dose of ixazomib as described in Section 8.2: 
Procedures for Reporting Serious Adverse Events).  The subject will continue to follow-up with 
their surgeon and oncologist as per standard care for their circumstance and therapy dictates and 
the adverse events will be captured at those follow-up visits.  
4.4   Staggered Enrollment
Patients will be enrolled in a staggered fashion with ≥ 4 weeks between each patient dosed.
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 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:

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 


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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 previous diagnosis of a recurrent or progressive glioblastoma for 
which surgical resection is now indicated. 
5. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status 0, 1, or 2 or (Karnofsky Performance Status of 60 or above).
6. Patients must meet the following clinical laboratory criteria:

Absolute neutrophil count (ANC) 1,500/mm3 and platelet count 100,000/mm3.  
Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 
days before study enrollment.

Hemoglobin > 9 g/dL

Total bilirubin 1.5 the upper limit of the normal range (ULN).

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)3ULN for 
the lab utilized.

Creatinine < 1.5 mg/dL

Calculated creatinine clearance  30 mL/min (see Section 11.2).
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 pregnancy test during the 


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screening period. 
2. Failure to have fully recovered (ie,  Grade 1 toxicity) from the reversible effects of 
prior chemotherapy.
3. Major surgery, including craniotomy, within 14 days before enrollment.
4. Radiotherapy of brain tumor within 3 months before enrollment. 
5. Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment.
6. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months.
7. Systemic treatment, within 14 days before the first dose of ixazomib, with strong 
inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of 
CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, 
nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, 
carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort.
8. Ongoing or active systemic infection, active hepatitis B or C virus infection, or known 
human immunodeficiency virus (HIV) positive.
9. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
10. Known allergy to any of the study medications, their analogues, or excipients in the 
various formulations of any agent.
11. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of ixazomib including difficulty swallowing.
12. 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.
13. Patient has  Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical 


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examination during the screening period.
14. Participation in other clinical trials utilizing other therapeutic investigational agents not 
included in this trial, within 30 days of the start of this trial and throughout the duration 
of this trial. 
15. Patients that have previously been treated with ixazomib, or participated in a study with 
ixazomib whether treated with ixazomib or not.
6.   
STUDY DRUG
6.1
Description of Investigational Agents
Ixazomib Capsules
The ixazomib drug product is provided in strengths of 4.0-, 3.0-, and 2.3-mg and 2.0-, 0.5-, 
and 0.2 mg capsules as the active boronic acid. The different dose strengths are differentiated 
by both capsule size and color as described below:
Dose Strength
Capsule Size
Capsule Color
4.0 mg
Size 4
Ivory
3.0 mg
Size 3
Light gray
2.3 mg
Size 2
Light pink
2.0 mg
Size 2
Swedish orange
0.5 mg
Size 3
Dark green
0.2 mg
Size 4
White opaque
For additional details, please see the ixazomib IB.
6.2   Study Drug Administration
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).


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Capsules of ixazomib will also be referred to as study drug.  Study drug will be supplied by 
Millennium as capsules of 0.2-, 0.5-, and 2.0 mg, or as capsules of 2.3-, 3.0- and 4.0 mg 
ixazomib. 
The prescribed administration of the ixazomib dose in this study is one 4.0 mg dose 
approximately 3 hours prior to surgery.  No further doses of ixazomib will be administered.   
The dose will be dispensed by the Emory University Hospital Research Pharmacy and 
administered by the PI who will document the time of administration, the dose, and toleration of 
the dose in the operative dictation.  The patient will be in the preoperative waiting room and 
then the preoperative holding area after administration while being prepared for surgery.  As 
there is only one dose used in this study, and it will be documented as part of the surgical 
procedure, no drug diary will be used.  
Patients will 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) 
as they will have been NPO since midnight on the day surgery in preparation for general 
anesthesia.  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.  
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.
Anesthetic agents, corticosteroids, anticonvulsants, antibiotics and other supportive agents will 
be administered during and after the surgical procedure (respecting those not allowed in the 
exclusion criteria list item number 8 above).  
6.3   Excluded Concomitant Medications and Procedures
The following medications are prohibited from 14 days prior to the dose of ixazomib to 7 days 
after the dose of ixazomib, ie. the study period.
Systemic treatment with any of the following metabolizing enzyme inhibitors is not permitted 
during the study period as these drugs may interfere with the evaluation of the pharmacokinetics 
of ixazomib:

Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin


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
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 
during the study period, unless there is no appropriate alternative medication for the patient’s 
use as these drugs may interfere with the evaluation of the pharmacokinetics of ixazomib:

Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, and 
phenobarbital
Excluded foods and dietary supplements include St. John’s wort and Ginkgo biloba
6.4   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.

Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines.

Supportive measures consistent with optimal patient care may be given throughout the 
study.
6.5   Precautions and Restrictions 

Fluid deficit should be corrected before initiation of treatment and during treatment with 
ixazomib.
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 


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reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days 
after the last dose of study drug, or 

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.)
6.6
 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


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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. 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 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 


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areas of the body or oral or topical antihistamines).  A rare risk is Stevens-Johnson Syndrome, a 
severe and potentially life-threatening rash with skin peeling and mouth sores, which should be 
managed symptomatically according to standard medical practice.  Punch biopsies for 
histopathological analysis are encouraged at the discretion of the investigator.
Thrombocytopenia
Blood counts should be monitored regularly as outlined in the protocol with additional testing 
obtained according to standard clinical practice. Thrombocytopenia may be severe but has been 
manageable with platelet transfusions according to standard clinical practice. 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 regularlyfollowing administration of ixazomib.  Neutropenia 
may be severe but has been manageable.  Growth factor support is not required but may be 
considered according to standard clinical practice.  
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 ixazomib 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 


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adjustments of their concomitant medications during the course of the trial.  Fluid deficit should 
be corrected before initiation of ixazomib 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.
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.
6.7
Preparation, Reconstitution, and Dispensing
Ixazomib is an anticancer drug and as with other potentially toxic compounds caution should be 
exercised when handling ixazomib capsules.
6.8
Packaging and Labeling
The study drug ixazomib capsules will be provided by Millennium.  The study drug will be 
labeled and handled as open-label material, and packaging labels will fulfill all requirements 
specified by governing regulations.  
The capsules are individually packaged using cold-form foil-foil blisters that are in a child-
resistant carton.  There are 3 capsules in each wallet/carton. 
6.9
Storage, Handling, and Accountability
Upon receipt at the investigative site, ixazomib should remain in the blister and carton provided 
until use or until drug is dispensed. The container should be stored at the investigative site 
refrigerated (36°F to 46°F, 2°C to 8°C). Ensure that the drug is used before the retest expiry date 
provided by Millennium. Expiry extensions will be communicated accordingly with updated 
documentation to support the extended shelf life.


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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. 
6.10      Study Compliance
Not applicable in this study. 


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6.11
Study Treatment
Schedule of Events and Observations
Consent
Screening
Ixazomib 
Administration 
3 Hours Before 
Surgery
Surgery
Postop Day 1
Postop Visit for 
Staple/Suture 
Removal
Reference 
Time Line
14 or fewer 
days before 
date of surgery
After consent 
and prior to 
ixazomib 
administration
1 to 3 hours 
prior to 
surgical 
incision
On average a 
two to four 
hour period of 
time with 
sampling 
occurring as 
clinically safe 
during the 
tumor 
resection
Assessment 12 
to 36 hours 
after the end 
of the surgery
Depending on 
the nature of 
the wound 
repair and 
integrity 
staple/suture 
removal will 
occur 10 to 20 
days after the 
day of surgery
Patient 
Education
x
Laboratory 
screening
x
Observation 
for clinical and 
laboratory 
toxicity using 
standard 
postop 
parameters*
x
x
x
Blood sampling 
just prior to 
incision
x
Blood sampling 
during tumor 
sampling
x
Blood sampling 
during surgical 
closure
x
Tumor 
sampling
x
* Toxicities are to be assessed according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.
Informed Consent Process:  Patients with recurrent glioblastoma who need surgery will be 
presented the concept of this study and its pro’s and con’s.  They will then receive a consent 
form and be allowed to review it.  They will then be allowed to ask questions and provided these 
are satisfactorily answered sign consent.  This process may take one or more days.
Screening:  After signing informed consent there will be determination of performance status, 
CBC, Complete Metabolic Panel, Na/K/Glucose/Chloride/Bun/Cr, PT/PTT/INR, Urinalysis, & 
Serum pregnancy test.


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Ixazomib Administration:  4.0 mg Ixazomib administration orally with 8 oz of water 3 hours 
prior to projected surgery start time.  The individual will be observed for evidence of treatment-
emergent adverse events. This will be recorded as the on study time.  Accurate recording of the 
time of ixazomib administration will be made in the patient’s clinical records.
Surgery:  One red top tube of blood will be collected at the time of surgical incision, tumor 
sampling and wound closure.  The time of each sampling will be recorded.  The tumor will 
sampled at three different sites and the timing of the sampling will be recorded.  
Post Op Day 1:  General and neurologic exam observations will be collected and laboratory 
evaluations performed with be collected and recorded.
Post Op Visit for Staple/Suture Removal:  The subject will undergo standard staple/suture 
removal, with observations from the general and neurologic exam being collected for 
assessment of potential Ixazomib toxicity.  The patient will be the off study point and visit 
(please note that all serious adverse events must be reported up to 30 days after the dose of 
ixazomib as described in Section 8.2: Procedures for Reporting Serious Adverse Events).  The 
subject will continue to follow-up with their surgeon and oncologist as per standard care for 
their circumstance and therapy dictates and the adverse events will be captured at those follow-
up visits.  
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

Protocol violation

Lost to follow-up

Progressive disease

Study terminated 

Other
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.  If the patient is unable have surgery after the drug 


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administration or us unable to come to the off study suture/staple removal visit they will be 
withdrawn from the study and replaced until three patient complete follow-up through the off 
study visit.
7.   
STATISTICAL AND QUANTITATIVE ANALYSES
7.1   Statistical Methods
This will be a phase 0 study designed to assess whether or not Ixazomib reaches glioblastoma 
tissue in measurable concentrations.  The drug concentration results and clinical observations 
after administration will be tabulated and summarized with simple descriptive statistics. The 
relationship between patient’s demographic, tumor and drug concentration results will be 
assessed with Pearson’s correlation coefficient and tested with Wald’s test. In addition, the 
mean and standard error of the concentrations will be estimated using a random-effects model to 
account for the within-patient correlation of the tumor biopsy samples. Given the limited 
number of observations, a relatively simple covariance matrix (e.g. compound symmetry) will 
be assumed.  
    7.1.1
Determination of Sample Size
The sample size will be three cases.  This is based on clinical judgment believing this will 
provided enough data to account for tumor inter-tumor heterogeneity.  To assist in addressing 
tumor heterogeneity three samples from different portions of the tumor will be obtained in each 
case and their location described in the operative report.  
Should a patient fail to be able to take the preoperative Ixazomib dose, undergo the surgery for 
tumor resection, have useful surgical samples obtained or be unable to reach the postoperative 
visit for suture/staple removal the patient will be removed from study and a replacement patient 
will be recruited.  
   7.1.2
Populations for Analysis
Patients to be enrolled will be have recurrent or progressive glioblastoma for which surgical 
resection is indicated and have a Karnofsky Performance Status of 60 (ECOG 2) or above.  
   7.1.3
Procedures for Handling Missing, Unused, and Spurious Data
If there is reason to believe that there is a problem with handling of the tumor specimens likely 
to render their pharmacokinetic analysis inaccurate the data from this subject will be discarded 
and a replacement subject recruited.  Similarly, if pharmacokinetic or safety data is missing on a 
subject, and is irretrievable for technical or other reasons, a replacement subject will be 
recruited. 


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   7.1.4
Demographic and Baseline Characteristics
The baseline clinical observations will be provided with simple descriptive statistics and tables 
of observations. 
   7.1.5
Pharmacokinetics/Pharmacodynamics/Biomarkers (if applicable)
The primary objective of this study is measurement of tumor tissue concentrations of ixazomib  
in a glioblastoma after preoperative administration.  This will be done in one point in time 
(during surgery) and from multiple spots in the tumor for each of the three participants.  The 
sample from each site within each tumor will be analyzed separately.  These results will allow 
simple descriptive statistics of the concentration data but no formal pharmacokinetic parameters 
will be calculated.  
   7.1.6
Safety Analysis
Safety will be assessed with routine postoperative laboratory, vital sign, neurologic exam, and 
imaging through the day of staple or suture removal.  This data will be collected and any 
adverse events (as defined below) graded and their relationship to the Ixazomib administration 
determined.  
   7.1.7
Adverse Event Stopping Rule
For any toxicity ≥ one grade above baseline for any pre-existing adverse events (AEs), and any 
new grade ≥ 2 AEs study accrual will be suspended.  The study team will review the data to 
determine the proper course of action. These actions may include further adverse event 
monitoring and evaluation to assess attribution of the adverse event observed, continued 
suspension of accrual pending study modification, dose modification, and closure of the trial.
   7.1.8
Data Safety Monitoring Plan
Winship Cancer Institute’s Data and Safety Monitoring Committee (DSMC) will review toxicity 
and safety data for each subject following completion of the 2 week post-operative/off-study 
visit.  The sponsor-investigator is responsible for providing adverse event data to the DSMC for 
review.  Should any SAEs occur, from first dose of study drug through 30 days post-
administration, the sponsor-investigator will halt enrollment and notify DSMC of event 
occurrence.  Any SAE, regardless of relationship to the study drug, will be reported to the 
DSMC for review prior to enrollment of subsequent patients to evaluate the safety of trial 
continuation.  


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8.   
ADVERSE EVENTS  
8.1   Definitions
8.1.1       Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that has 
increased in severity or frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  
8.1.2   
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time 
of the event.  It does not refer to an event which hypothetically might have caused death 
if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 


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suspected transmission via a medicinal product of an infectious agent.   Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (eg, prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.  
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous.  The 
general term severe is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor medical significance (such as a Grade 3 
headache).  This is NOT the same as serious, which is based on patient/event outcome or action 
criteria described above, and is usually associated with events that pose a threat to a patient’s 
life or ability to function.  A severe AE (Grade 3 or 4) does not necessarily need to be 
considered serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is 
considered Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) 
serves as a guide for defining regulatory reporting obligations.
8.2    Procedures for Reporting Serious Adverse Events
AEs may be spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures.  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. 
AEs which are serious must be reported to Millennium Pharmacovigilance (or designee) from 
the first dose of study drug through 30 days after administration of the last dose of ixazomib. 
Any SAE that occurs at any time after completion of ixazomib treatment or after the designated 
follow-up period that the sponsor-investigator and/or sub-investigator considers to be related to 
any study drug must be reported to Millennium Pharmacovigilance (or designee).  In addition, 
new primary malignancies that occur during the follow-up periods must be reported, regardless 
of causality to study regimen, for a minimum of three years after the last dose of the 
investigational product, starting from the first dose of study drug. All new cases of primary 
malignancy must be reported to Millennium Pharmacovigilance (or designee).   


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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, Jeffrey J. Olson, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events 
(SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.   
Regardless of expectedness or causality, all SAEs (including serious pretreatment events) must 
also be reported in English to Millennium Pharmacovigilance (or designee):
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event
All other serious (non-fatal/non life threatening) events within 4 calendar days of the 
sponsor-investigator’s observation or awareness of the event
See below for contact information for the reporting of SAEs to Millennium Pharmacovigilance.  
The sponsor-investigator must fax or email the SAE Form per the timelines above.  A sample of 
an SAE Form will be provided.  
The SAE report must include at minimum:

Event term(s)

Serious criteria

Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version 4.0, as a guideline, whenever 
possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. [25]

Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to study drug administration. 
Follow-up information on the SAE may be requested by Millennium.  


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Intensity for each SAE, including any lab abnormalities, will be determined by using the NCI 
CTCAE version 4.0.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html.
Relationship to all study drugs for each SAE will be determined by the investigator by 
responding yes or no to the question: Is there a reasonable possibility that the AE is associated 
with the study drug(s)?
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study product(s), as soon as 
possible but no later than 4 calendar days of such communication.
SAE and Pregnancy Reporting Contact Information
Fax Number: 1-800-963-6290
Email: TakedaOncoCases@cognizant.com
Suggested Reporting Form:  
•
SAE Report Form (provided by Millennium)
•
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm
•
Any other form deemed appropriate by the sponsor-investigator
8.3    Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study 
or within 90 days after the last dose, she must inform the investigator immediately and 
permanently discontinue study drug.  The sponsor-investigator must immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or designee 
(see Section 8.2).  The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor-investigator must also immediately fax a completed Pregnancy Form to 
the Millennium Department of Pharmacovigilance or designee (see Section 8.2).  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
Suggested Pregnancy Reporting Form:


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Confidential                                                           44                                DRAFT VERSION: 8/23/2015

Pregnancy Report Form (provided by Millennium)  
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,

Phone: 1-877-TAKEDA7 (1-877-825-3327)

E-mail: medicalinformation@tpna.com

FAX: 1-800-247-8860

Hours: Mon-Fri, 8 a.m. – 6 p.m. ET
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to Millennium Pharmacovigilance


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Takeda Oncology Clinical Study Protocol [X16071]
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10   
REFERENCES   
1.
Darefsky AS, King JT, Jr., Dubrow R. Adult glioblastoma multiforme survival in the 
temozolomide era: a population-based analysis of Surveillance, Epidemiology, and End Results 
registries. Cancer. Apr 15 2012;118(8):2163-2172.
2.
Koshy M, Villano JL, Dolecek TA, et al. Improved survival time trends for glioblastoma using 
the SEER 17 population-based registries. J Neurooncol. Mar 2012;107(1):207-212.
3.
Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with 
irinotecan in recurrent glioblastoma. J Clin Oncol. Oct 1 2009;27(28):4733-4740.
4.
Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by 
bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. Feb 
10 2009;27(5):740-745.
5.
Chamberlain MC, Johnston SK. Salvage therapy with single agent bevacizumab for recurrent 
glioblastoma. J Neurooncol. Jan 2010;96(2):259-269.
6.
Phuphanich S, Supko JS, Carson KA, Grossman SA,  Nabors LB, Mikkelsen T, Lesser G, 
Rosenfeld S, Desideri S, Olson JJ:  Phase 1 clinical trial of bortezomib in adults with recurrent 
malignant glioma.  J Neurooncol (2010) 100:95–103.  
7.
Styczynski J; Olszewska-Slonina D; Kolodziej B; Napieraj M; Wysocki M:  Activity of 
bortezomib in glioblastoma.  Anticancer Research. 26(6B):4499-503, 2006.
8.
Kubicek GJ; Werner-Wasik M; Machtay M; Mallon G; Myers T; Ramirez M; Andrews D; 
Curran WJ Jr; Dicker AP:  Phase I trial using proteasome inhibitor bortezomib and concurrent 
temozolomide and radiotherapy for central nervous system malignancies.  International Journal 
of Radiation Oncology, Biology, Physics. 74(2):433-9, 2009.  
9.
Phuphanich S, Supko JG, Carson KA, Grossman SA, Nabors LB, Mikkelsen T, Lesser G, 
Rosenfeld R, Desideri S, Olson JJ:  Phase 1 clinical trial of bortezomib in adults with recurrent 
malignant glioma.  J Neurooncol, 100: 95-103, 2010.  
10.
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. in 52nd ASH Annual Meeting and Exposition, 2010. 116(21): p. abstr 1813.
11.
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; p. abstr 1433
12.
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
13.
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.
14.
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.
15.
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 10-13 Dec; San Diego, CA; 
p. abstr 816..
16.
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.
17.
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 


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           46                                DRAFT VERSION: 8/23/2015
Untreated Multiple Myeloma (MM) in 54th ASH Annual Meeting and Exposition. 2012. Atlanta, 
Georgia.
18.
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 17th EHA Annual Congress. 2012. Amsterdam, 
the Netherlands.
19.
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.
20.
Richardson P, Baz R, Wang L, Jakubowiak A, Berg D, Liu G, et al. Investigational Agent 
MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory 
Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation 
Study In: 53rd ASH Annual Meeting and Exposition; 2011 10-13 Dec; San Diego, CA; p. abstr 
301.
21.
Lonial S, Baz R, Wang M, Talpaz M, Liu G, Berg D, 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). J Clin Oncol (ASCO Meeting Abstracts) 2012;30(15 
suppl):abstr 8017.
22.
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Berg D, 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 10-13 Dec; San Diego, CA; p. abstr 816.
23.
Kumar S, Bensinger W, Reeder C, Zimmerman T, Berenson J, Liu G, et al. Weekly dosing of the 
investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory 
multiple myeloma (MM): A phase I study. Journal of Clinical Oncology 2012 ASCO Annual 
Meeting Proceedings 2012:Abstract 8034.
24.
Kumar S, Niesvizky R, Berdeja J, Bensinger W, Zimmerman T, Berenson J, et al. Safety and 
Pharmacokinetics of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, Alone and 
in Combination. Clinical Lymphoma Myeloma and Leukemia 2013;13(Supplement 1):S154; 
abstr P-230
25.
Common Terminology Criteria for Adverse Events (CTCAE). 2010.


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           47                                DRAFT VERSION: 8/23/2015
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. 
Karnofsky Performance Status Scale
The following table presents the Karnofsky performance status scale1:
Points
Description
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or to do active work
60
Requires occasional assistance but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled; hospitalization indicated.  Death not imminent
20
Very sick; hospitalization necessary; active support treatment necessary
10
Moribund; fatal processes progressing rapidly
0
Dead

1
Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an 
examination of its reliability and validity in a research setting.  Cancer 1984;53:2002-2007.


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           48                                DRAFT VERSION: 8/23/2015
11.2  
Cockcroft-Gault Equation
For males:
Creatinine Clearance = (140-age[years]  weight [kg])
OR
(140–age[years]  weight [kg])
72  (serum creatinine[mg/dL])
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.


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Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           49                                DRAFT VERSION: 
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11.3   Pharmacokinetic (PK) Sample Collection and Handling (Mandatory, if 
Applicable)
Materials and Labeling
Blood samples for PK assessment must be collected in 3-mL Vacutainer tubes containing 
K2EDTA as the anticoagulant.  Resulting blood and plasma PK samples must be stored in 
plastic storage tubes with caps.  No blood collection tubes with separation gel should be 
used.
Collected tumor samples will be dissected to a size of roughly 200-300 mg.  The samples are 
weighed, wrapped in aluminum foil, and flash frozen on a dry ice acetone bath. The frozen 
samples are stored at -70 C and shipped on dry ice to the CRO for bioanalysis.  
.  All containers and tubes must be labeled.  The printed information must include the study 
number, patient identification number, treatment period, and scheduled sampling day and 
time.  No other information will be written on the labels.
Preparation of Plasma Pharmacokinetic Samples
1. Draw blood into labeled and chilled 3 mL lavender top K2EDTA Vacutainer tube. 
2.  Mix the blood with the anticoagulant by gently inverting the tube 8-10 times and 
immediately place on wet ice.  
3.  Centrifuge the blood samples for 10 minutes at 1006g at 4º C in a refrigerated 
centrifuge within 10 mins of sample collection 
4.  Immediately following centrifugation, gently remove the plasma from the packed 
cells and aliquot into two transfer vial filled with lyophilized citric acid. Each aliquot 
should contain exactly 0.5 mL of plasma.
5. Vortex split tubes thoroughly. Any remaining plasma post split1/split 2 sample 
aliquots should be discarded following appropriate biohazard disposal procedures.
NOTE: If < 0.5 mL plasma is obtained post centrifugation, do not process or store 
split1 or split2, record split1: ISV (Insufficient Sample Volume), split2: ISV. If < 1.0 
mL plasma is obtained post centrifugation, process and store split1 according to 
procedure; do not process or store split2, record split 2: ISV. Discard remaining 
plasma using appropriate biohazard waste disposal procedures.
6. Replace cap on tube and freeze the samples immediately at -70°C


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           50                                DRAFT VERSION: 
8/23/2015
Note:  No more than 60 minutes should elapse between blood collection and freezing 
the plasma samples.
7. Keep samples frozen at -70°C or lower until shipment.
Note:  Wet ice is defined as a mixture of ice and water
Radius of 
rotation 
(rotor arm 
length) (cm)
RPM speed 
needed to 
achieve 1000g
4
4743
5
4242
6
3873
7
3585
8
3354
9
3162
10
3000
11
2860
12
2738
13
2631
14
2535
15
2449
Excel formula if rotor length not listed in above table:
RPM = SQRT(( 1006/(0.00001118*rotor length in cm))
Questions regarding handling the plasma pharmacokinetic specimens should be addressed to 
the contact person designated by Millennium.
Shipment of Pharmacokinetic Tissue and Blood Samples
All pharmacokinetic samples must be sent to the bioanalytical laboratories specified below 
in a single shipment at the end of the study or in multiple shipments as agreed upon with the 
lab (MLN9708 PK samples currently have 618 days of stability and will need to be analyzed 
before reaching the end of their stability).  An inventory list must be included with each 
shipment.  The inventory list must note each specimen drawn for each patient, and note any 
missing specimens.
The investigator must follow the instructions below:

For all international shipments, a courier will be designated.

Notify the bioanalytical laboratories and the designated courier at least 24 hours in 


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           51                                DRAFT VERSION: 
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advance of the planned shipment.  Provide the designated courier with the 
appropriate account number to be used, if applicable.

Samples should be shipped via overnight delivery only on Monday through 
Wednesday, excluding holidays.

Double-bag the frozen samples for each patient in bags that can withstand dry ice 
conditions.

Pack the frozen samples in sufficient quantity of dry ice in appropriate containers, to 
maintain a frozen state for at least 3 days.

Avoid direct contact between sample bags and dry ice by separating them with a dry 
ice resistant material (eg, newspaper).

For all biological samples, follow the International Air Transport Association 
(IATA) regulations for shipment.

Ensure that the total package weight does not exceed 27.2 kg (60 pounds).

Label the package with the sponsor-investigator name and study number.

Include a return address (which includes the investigator’s name) on the outside of 
each shipping container.

Comply with all courier regulations for the shipment of biological specimens 
(include all paperwork).

Retain all documents indicating date, time, and signature(s) of person(s) making the 
shipment in the study files.
As soon as shipment day and air bill number(s) are available, the site must call or fax the 
bioanalytical laboratories.  The call or fax must specify the study number, number of 
packages shipped, the number of pharmacokinetic samples, and the time of shipment pick-
up.
Ship To:
Covance
115 Silvia Street


Emory University IRB ____
Takeda Oncology Clinical Study Protocol [X16071]
Confidential                                                           52                                DRAFT VERSION: 
8/23/2015
West Trenton, NJ 08628, USA
ATTN: Sample Management
Phone # 609-434-0044 X113
christina.lohman@labcorp.com
james.albanese@labcorp.com
batesc1@labcorp.com