Conditions: Multiple Myeloma Kahler Disease Plasma-Cell Myeloma Myelomatosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: no

Brief summary:
This study will look at the safety and tolerability of the new drug MLN9708 in combination with the existing drugs panobinostat and dexamethasone among patients with relapsed or refractory multiple myeloma. This study will also look at the response and clinical benefit of the treatment and the progression-free survival and overall survival of study participants.

Detailed description:
The primary objective of this study is to define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and dexamethasone in patients with relapsed or refractory myeloma.

The secondary objectives of this study are to assess response and clinical benefit response rates according to international uniform response criteria and adapted EBMT criteria, respectively. And to assess progression-free survival (PFS) and overall survival (OS).

Arms:
arm 1: Panobinostat: 20mg, on day 1, 3, 5, 15, 17, 19, 28 Dexamethasone: 20mg, on day 1, 2, 8, 9, 15, 16, 28 MLN9708: 4mg on day 1, 8, 15, 28

Interventions: intervention 1: Panobinostat intervention 2: Dexamethasone intervention 3: MLN9708
Intervention descriptions: intervention 1: 20mg, on day 1, 3, 5, 15, 17, 19, 28 intervention 2: 20mg, on day 1, 2, 8, 9, 15, 16, 28 intervention 3: 4mg on day 1, 8, 15, 28

Protocol document:
Prot_SAP_001.pdf: 
 
 
 
CASE 4A13 A9 04/03/2017 
 
 
 
 
Case CCC Study: CASE 4A13 
Clinical Trial Protocol Number  CLBH589DUS92T 
Title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination with Panobinostat and 
Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma 
ClinicalTrials.gov NCT #: 02057640 
 
Author(s): 
Frederic J. Reu, M.D.  
Principal Investigator 
Co-Principal Investigator 
Jason Valent, M.D. 
Ehsan Malek, MD (University Hospitals) 
Data Coordinator 
Sherry Fada 
Release date 
Amendment 1 
Amendment 2 
Amendment 3 
Amendment 4 
Amendment 5 
Amendment 6 
Amendment 7 
Amendment 8 
Amendment 9 
March 6, 2014 
April 24, 2014 
May 6, 2014 
June 18, 2014 
December 26, 2014 
June 3, 2015 
September 23, 2015 
July 18, 2016 
March 1, 2017 
April 3, 2017 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
2 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
3 
 
PROTOCOL SUMMARY 
Title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination with Panobinostat and 
Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma 
 
Objectives 
The primary objective of this study is to: 
 Define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 
every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and 
dexamethasone in patients with relapsed or refractory myeloma 
 
The secondary objectives of this study are to: 
 Assess response and clinical benefit response rates according to international uniform 
response criteria and adapted EBMT criteria, respectively (see under 8.1) 
 Assess progression-free survival (PFS) and overall survival (OS) 
 
Patient Population 
Specific inclusion and exclusion criteria are detailed in Section 6.1.2 
Number of Patients 
 31 patients (11 in phase I, 20 in phase II) 
Study Design and Methodology 
Phase I: This study will use a modified 3 + 3 design to define the tolerability and safety of 
MLN9708 (ixazomib) administered to at least 6 patients with relapsed or refractory myeloma 
on a day 1,8,15 every 28 day schedule at up to 4mg in combination with fixed doses of 
panobinostat and dexamethasone.  
 
Dose limiting toxicities (DLTs, see under 5.4) will be assessed at the end of the first cycle, on 
day 28. The trial will accrue up to three patients at any given DL who will need to be assessed 
for DLTs before the next three patients can be enrolled. Determination of the highest tolerated 
dose of two tested dose levels will require treatment of at least 6 patients at the respective dose 
level with no more than one patient developing a DLT. 
The first three patients will be treated at DL1. If no patient develops any DLT, the next three 
patients will be enrolled at DL2. If 1 patient develops any DLT, three additional patients will 
be enrolled at DL1. If no more than 1 of 6 patients treated at DL1 develops a DLT, the next 
three patients will be enrolled at DL2. If 2 or more of 2-6 patients treated at DL1 develop DLTs 
further enrollment will be stopped and a change in the protocol will be discussed. If DL2 opens 
to enrollment, and 0-1 of the first three patients develop any DLT, additional three patients will 
be enrolled at DL2 and if no more than 1 of 6 patients treated at DL2 develop any DLT, DL2 
will be considered a tolerated MLN9708 dose and further dose escalation will not be done. If 2 
of three or up to 6 patients enrolled at DL2 develop any DLT, further enrollment at that dose 
level will be stopped and enrollment will continue at DL1 unless 6 patients have already been 
treated at that dose level. If no more than 1 patient treated at DL1 develops any DLT that dose 
level will be considered tolerated and an intermediate dose level may be discussed. If 2 or more 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
4 
 
of up to 6 patients treated at DL1 develop a DLT, further enrollment will be stopped and a 
change in the protocol will be discussed. 
Phase II: Twenty additional patients will be treated at target doses of DL2 which has been found 
to be well tolerated without any DLT in phase I. 
 
Treatments Administered 
 
 
Dose levels 
Dose 
level 
PO Panobinostat 
PO 
MLN9708 
(Ixazomib) 
PO Dexamethasone 
1 
20mg d 1,3,5,15,17,19 q 28 d 3mg d1,8,15 q 28 d 
20mg d 1,2,8,9,15,16 q 
28 d 
2 
20mg d 1,3,5,15,17,19 q 28 d 4mg d1,8,15 q 28 d 
20mg d 1,2,8,9,15,16 q 
28 d 
 
Phase I: Patients will remain on study for six 28-day cycles or until criteria for discontinuation 
(7.6.1) are met, whichever comes earlier. Decisions on subsequent maintenance therapy will at 
the discretion of the treating physician but if the patient’s myeloma is controlled (at least in 
stable disease) panobinostat, dexamethasone, and ixazomib may be continued and will be 
provided free of charge to the patient.  This protocol may be amended to include a formal 
maintenance phase and/or a phase II portion after review of safety and preliminary efficacy data 
and approval by Novartis, Millennium, and the sponsor institution (Cleveland Clinic).  
Phase II: Patients will receive therapy according to DL2 and will remain on study until criteria 
for discontinuation (7.6.1) are met. 
 
Efficacy Data Collected 
The following evaluations will be conducted to assess the efficacy of this regimen: 
Response will be assessed according to international uniform response criteria and clinical 
benefit response according to modified EBMT response criteria (8.1), using myeloma panels 
obtained at the beginning of each cycle that include SPEP, 24 h UPEP, serum and urine IFEs, 
and serum free light chains. In addition, a baseline bone marrow exam and skeletal survey will 
be obtained and repeated as clinically indicated, including repeat bone marrow exam for 
confirmation of complete remission (see also Section 8 schedule of assessments). 
 
Pharmacokinetic/Pharmacodynamic/Pharmacogenomic/Correlative Studies Collected 
None. 
Safety Data Collected 
The following evaluations will be conducted to assess the safety of this regimen: 
 Dose limiting toxicity will be evaluated after the first cycle for patients in phase I 
 Toxicity will be evaluated according to CTCAE version 4.0, weekly during the first 
cycle and whenever the dose of a drug is increased, then at the start of each subsequent 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
5 
 
cycle  
Statistical Procedures 
Due to low patient numbers and short study duration results will only be described. Appropriate 
statistical analysis will be added if the study is extended into a phase II evaluation. 
Phase II: Kaplan-Meier survival and progression-free survival estimates will be calculated. 
Table of contents 
 
PROTOCOL SUMMARY ......................................................................................................... 3 
Table of contents ................................................................................................................. 5 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ....................................................................................................................... 11 
1.1 
Overview of targeted Multiple Myeloma .............................................................. 11 
1.2 
Overview of Panobinostat...................................................................................... 12 
1.2.1 
Anticancer activity of DAC inhibitors .................................................. 12 
1.2.2 
Panobinostat (LBH589) ........................................................................ 13 
1.2.3 
Overview of clinical experience ............................................................ 14 
1.2.4 
Human pharmacokinetics ...................................................................... 18 
1.2.5 
Cardiac Safety ....................................................................................... 20 
1.3 
Overview of MLN9708 (Ixazomib) ....................................................................... 22 
1.3.1 
Scientific Background ........................................................................... 22 
1.3.2 
Nonclinical Pharmacology .................................................................... 22 
1.3.3 
Nonclinical Pharmacokinetics ............................................................... 23 
1.3.4 
Safety Pharmacology ............................................................................ 24 
1.3.5 
In Vivo Toxicology ............................................................................... 24 
1.3.6 
Clinical Experience ............................................................................... 25 
1.3.7 
Pharmacokinetics and Drug Metabolism .............................................. 26 
1.3.8 
Clinical Trial Experience Using the Oral Formulation of MLN9708 ... 26 
1.3.9 
Relapsed and/or Refractory Multiple Myeloma .................................... 31 
1.3.10 
Newly Diagnosed Multiple Myeloma (NDMM) .................................. 34 
1.3.11 
Clinical Trial Experience Using the Intravenous Formulation of 
MLN9708 .............................................................................................. 36 
1.3.12 
Potential Risks of MLN9708 ................................................................ 36 
2 
Study rationale/purpose ..................................................................................................... 38 
3 
Study objectives ................................................................................................................. 39 
3.1 
Primary Objective .................................................................................................. 39 
3.2 
Secondary Objective .............................................................................................. 39 
4 
Study endpoints: ................................................................................................................ 39 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
6 
 
4.1 
Primary endpoints: ................................................................................................. 39 
4.2 
Secondary endpoints: ............................................................................................. 39 
5 
Overall study design, treatment cycles, and study duration .............................................. 40 
5.1 
Study design and treatment cycles ......................................................................... 40 
5.2 
Study duration ........................................................................................................ 40 
5.3 
Dose levels ............................................................................................................. 41 
5.4 
Dose limiting toxicity ............................................................................................ 41 
6 
Study population ................................................................................................................ 42 
6.1.1 
Patient population.................................................................................. 42 
6.1.2 
Inclusion and exclusion criteria ............................................................ 42 
6.2 
Definition Relapsed Myeloma and Refractory Myeloma ...................................... 46 
6.2.1 
Refractory Myeloma ............................................................................. 46 
6.2.2 
Relapsed Myeloma ................................................................................ 46 
7 
Treatments ......................................................................................................................... 47 
7.1 
Investigational therapy ........................................................................................... 47 
7.1.1 
Panobinostat .......................................................................................... 47 
7.1.2 
MLN9708 (Ixazomib) ........................................................................... 48 
7.1.3 
Cardiac precautions ............................................................................... 50 
7.2 
Dexamethasone ...................................................................................................... 50 
7.3 
Mandatory concomitant therapy ............................................................................ 50 
7.4 
Instructions for Initiation of a New Cycle ............................................................. 51 
7.5 
Dose modifications for adverse events .................................................................. 51 
7.5.1 
Dose reduction guidelines ..................................................................... 51 
7.5.2 
Dose Re-Escalation Guidelines ............................................................. 52 
7.5.3 
Dose modifications for study drug-related toxicity (see section 
7.5.4 for dose modifications for prolonged QTc): ................................ 53 
7.5.4 
Dose modifications for prolonged QTcF .............................................. 58 
7.6 
Management of Clinical Events ............................................................................. 61 
7.6.1 
Study drug discontinuation ................................................................... 63 
7.6.2 
Follow-up for toxicities ......................................................................... 64 
7.7 
Other concomitant medications ............................................................................. 64 
7.7.1 
Summary of commonly used allowed supportive concomitant 
medications ........................................................................................... 65 
7.7.2 
Summary of prohibited concomitant medications and supplements ..... 65 
7.7.3 
Anti-coagulant therapy .......................................................................... 67 
7.8 
Precautions and Restrictions .................................................................................. 67 
7.9 
Contraception Requirements ................................................................................. 67 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
7 
 
7.9.1 
CYP2D6 Substrates ............................................................................... 69 
7.9.2 
Drugs that can inhibit/induce CYP3A4/5 ............................................. 69 
7.10 
Treatment compliance ........................................................................................... 70 
8 
Visit schedule and assessments ......................................................................................... 70 
8.1 
Efficacy / response assessments and criteria ......................................................... 71 
8.1.1 
Progressive Disease ............................................................................... 73 
9 
Safety assessments ............................................................................................................. 73 
9.1.1 
Adverse events ...................................................................................... 74 
9.1.2 
Vital signs.............................................................................................. 74 
9.1.3 
Physical examination ............................................................................ 74 
9.1.4 
Laboratory evaluations .......................................................................... 75 
9.1.5 
Serum pregnancy test ............................................................................ 75 
9.1.6 
ECG ....................................................................................................... 75 
9.2 
Drug levels and pharmacokinetic assessments ...................................................... 77 
10 Safety monitoring .............................................................................................................. 77 
10.1 
Novartis Instructions for rapid notification of serious adverse events .................. 77 
10.2 
Millennium Instructions for rapid notification of serious adverse events ............. 78 
10.3 
Any other form deemed appropriate by the sponsor-investigatorAdverse 
Event of Special Interest Definition ...................................................................... 80 
10.4 
Millennium Rules for Monitoring of Adverse Events and Period of 
Observation ............................................................................................................ 80 
10.5 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events .... 81 
10.6 
Millennium Product Complaints ............................................................................ 81 
10.7 
Serious Adverse Events ......................................................................................... 82 
10.8 
Pregnancies ............................................................................................................ 82 
11 Protocol amendments, or changes in study conduct .......................................................... 83 
12 Data review and management ........................................................................................... 83 
12.1 
Data Management .................................................................................................. 83 
12.2 
Analyses and Reporting ......................................................................................... 83 
 
Data Safety Monitoring Plan ................................................................................. 84 
12.3 
Study Monitoring ................................................................................................... 84 
12.3.1 
Investigator Responsibilities ................................................................. 84 
13 Statistical methods ............................................................................................................. 84 
13.1 
Datasets to be Analyzed ......................................................................................... 84 
13.1.1 
Primary objectives and endpoints ......................................................... 84 
13.1.2 
Secondary objectives and endpoints ..................................................... 85 
14 Procedures and instructions ............................................................................................... 85 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
8 
 
14.1 
Publication of results ............................................................................................. 85 
14.2 
Disclosure and confidentiality ............................................................................... 86 
14.3 
Discontinuation of study ........................................................................................ 86 
15 Ethics and Good Clinical Practice ..................................................................................... 86 
15.1 
Institutional Review Board/Independent Ethics Committee ................................. 86 
15.2 
Informed consent ................................................................................................... 87 
15.3 
Investigator and Site Responsibility for Drug Accountability .............................. 87 
15.4 
Record Retention ................................................................................................... 87 
16 USE OF INFORMATION ................................................................................................ 87 
17 References ......................................................................................................................... 88 
18 Appendices ........................................................................................................................ 93 
19 Medications which have a risk of causing Torsades de pointes ventricular arrhythmia 
should be avoided .............................................................................................................. 93 
20 Medications which are known strong CYP3A4/5 inhibitors to be used with caution ....... 95 
21 Medications which are known CYP2D6 substrates to be used with caution .................... 96 
22 Cockroft-Gault estimation of CrCl .................................................................................... 97 
22.1.1 
Millennium Pregnancy Reporting Form ............................................... 98 
23    Summary of Changes ...................................................................................................... 102 
List of abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
absolute neutrophil count 
APL 
acute promyelocytic leukemia 
ASCO 
American Society of Clinical Oncologists 
AST 
aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATRA 
all trans-retinoic acid 
AUC 
area under the curve 
BCR-ABL 
a fusion gene of the BCR and ABL genes 
BUN 
blood urea nitrogen 
CIS 
carcinoma in-situ 
Cmax 
maximum concentration of drug 
CML 
chronic myelogenous leukemia 
CNS 
central nervous system 
CR 
complete response/remission 
CS&E 
clinical safety and epidemiology 
CTCAE 
NCI common terminology criteria for adverse events (version 3.0) 
CTCL 
cutaneous T-cell lymphoma 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
9 
 
CV 
coefficient of variation 
DLT 
dose-limiting toxicity 
DNA 
deoxyribose nucleic acid 
ECG 
12 lead electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eRT 
eResearchTechnology 
FACT 
functional assessment of cancer therapy 
FDA 
food and drug administration 
G-CSF 
granulocyte colony-stimulating factor (e.g. filgrastim) 
GM-CSF 
granulocyte-macrophage colony-stimulating factor (e.g. sargramostim) 
H3, H4 
histones H3, H4 
HAT 
histone acetyltransferase 
HDAC 
histone deacetylase 
HDACi 
histone deacetylase inhibitor 
hERG 
human ether-a-go-go related gene 
HIV 
human immunodeficiency virus 
i.v. 
intravenous(ly) 
ICH 
international conference on harmonization 
IEC 
independent ethics committee 
IRB 
institutional review board 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
mg/m2 
milligrams per square meter 
MM 
Multiple myeloma 
RRMM 
Relapsed or refractory multiple myeloma 
MTD 
maximum tolerated dose 
MUGA 
multiple uptake gated acquisition scan 
MWF 
monday, wednesday, friday 
NCI 
national cancer institute 
NDMM 
Newly diagnosed multiple myeloma 
NHL 
non-hodgkin’s lymphoma 
NIH 
national institutes of health 
PD 
pharmacodynamic 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic 
PLT 
platelet 
PR 
partial response 
REB 
research ethics board 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
10 
 
SAE 
serious adverse event 
SAHA 
suberoylanilide hydroxamic acid 
SD 
stable disease 
SOP 
standard operating procedure 
T4 
thyroxine 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
WBC 
white blood cell 
WNL 
within normal limits 
WOCBP 
women of childbearing potential 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
11 
 
1 
Introduction 
1.1 
Overview of targeted Multiple Myeloma  
Multiple myeloma, a cancer of antibody producing plasma cells, is the second most common 
hematologic 
malignancy 
in 
the 
United 
States. 
Based 
on 
SEER 
data 
(http://seer.cancer.gov/statfacts/html/mulmy.html, accessed 1/31/2013) it is estimated that 
21,700 individuals were diagnosed with multiple myeloma in 2012 and that 10,710 died of the 
disease. Treatment has improved life expectancy with major milestones marked by the 
introduction of oral melphalan therapy in the late 1950s, corticosteroids prednisone or 
dexamethasone shortly thereafter, high dose melphalan with autologous stem cell transplant in 
the 1990s, and discovery of profound antimyeloma effects with the use of “new drugs” 
thalidomide, bortezomib, and lenalidomide around the turn of the century 1. With improved life 
expectancy 
myeloma 
prevalence 
increases 
and 
was 
71,213 
in 
2009 
(http://seer.cancer.gov/statfacts/html/mulmy.html, accessed 1/31/2013). Almost all patients 
still experience disease progression and ultimately their disease becomes refractory to available 
standard therapy which includes various combinations of “new drugs” corticosteroids, and 
conventional chemotherapeutic agents. More recent progress includes development of 
carfilzomib, a second generation proteasome inhibitor which in contrast to bortezomib does not 
cause significant neurotoxicity and produces at least minor responses as single agent in more 
than one third of patients with refractory myeloma 2 leading to FDA approval in 2012. 
Pomalidomide, an analogue of lenalidomide, in combination with dexamethasone yielded about 
similarly promising results in refractory myeloma 3-5 and obtained FDA approval in 2013. 
Despite these developments, the majority of patients with relapsed and refractory multiple 
myeloma do not respond to available therapy creating an unmet need for further drug 
development. One of the mechanisms of increasingly uncontrollable growth of cancer cells 
during clonal evolution as it occurs in most cancers including myeloma is epigenetic silencing 
of genes required for senescence, differentiation, cell death, and immune attack 6. The pan-
histone deactelyase inhibitor panobinostat may restore intrinsic and extrinsic growth control by 
reactivation of respective genes and pathways through its chromatin opening effects and 
enhance cell death induction through inhibition of deacetylation of non-histone proteins. In a 
clinical study that enrolled patients who were refractory to their last bortezomib containing 
regimen, panobinostat added to bortezomib and dexamethasone yielded a remarkable clinical 
benefit response (at least minor response) of about 50% 7. The need for parenteral administration 
and neurotoxic adverse events with the use of bortezomib has led to the development of the oral 
proteasome inhibitor MLN9708 which has shown single agent activity in relapsed and 
refractory myeloma without clinically significant neuropathy 8-10. The maximal tolerated dose 
for MLN9708 when given as a single agent in either a twice-a-week (2mg/m2) 10 or weekly 
(2.97mg/m2) 9 administration schedule has been determined. Dosing of MLN9708 became more 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
12 
 
straightforward after analysis of pharmacokinetic data of patients on IV and PO clinical trials 
revealed that body size only affects distribution but not AUC of MLN9708, allowing 
formulation of fixed tablet strengths 11. In combination with lenalidomide and dexamethasone, 
MLN9708 can safely be given at 4mg weekly for 3 out of 4 weeks 8 and a phase 3 study for 
upfront therapy in transplant-ineligible patients has already opened (NCT01564537). 
Panobinostat may synergize with MLN9708 and dexamethasone in relapsed and refractory 
myeloma in a similar way as with bortezomib. In this study we will investigate whether 
MLN9708 at up to 4mg day 1,8,15 every 28 days can be given safely in combination with a 
fixed dose schedule of panobinostat and dexamethasone, selected based on the experience with 
twice a week bortezomib combination at effective doses but adjusted to the 4 week MLN9708 
schedule. The most refractory myeloma patient population often requires combination of more 
than three agents for disease control. MLN9708, panobinostat, and dexamethasone may serve 
as a platform for addition of agents. Lenalidomide has been shown to synergize with proteasome 
inhibitors and corticosteroids12,13 and to be well tolerated in combination with MLN9708 and 
dexamethasone8. It appears to synergize with histone deacetylase inhibitors as well14 and 
patients with relapsed and refractory Hodgkin’s lymphoma appear to tolerate twice the amount 
of panobinostat proposed here in combination with standard lenalidomide 25mg day 1-21 every 
28 days15. The three-drug oral regimen we propose to develop here may therefore lend itself for 
further intensification by addition of another active compound to treat the most refractory 
myelomas.without need for parenteral administration.  
 
 
1.2 
Overview of Panobinostat 
1.2.1 
Anticancer activity of DAC inhibitors 
Alterations in chromosome structure play critical roles in the control of gene transcription.  
These epigenetic alterations include modification of histones and others proteins by acetylation 
and/or phosphorylation.  Normally, these modifications are balanced finely and are highly 
reversible in normal tissues, but they may be imbalanced and heritable in tumor cells.  DAC 
inhibitors increase histone acetylation, thereby modulating the expression of a subset of genes 
in a coordinated fashion.  Several tumors suppressor genes associated with the malignant 
phenotype are repressed by epigenetic mechanisms in sporadic cancers.  Thus therapy with 
DAC inhibitors may alter tumor phenotype and inhibit growth in such tumors. 
Multiple hallmarks of cancer are regulated by acetylation/deacetylation: 
 
DAC inhibition targets both histone and nonhistone proteins.  Targeting the acetylation 
status of nonhistone, tumor-associated proteins that mediate proliferation may be the 
underlying antitumor mechanism of DAC inhibitors 16. 
 
Nonhistone proteins regulated by acetylation include α-tubulin, p53, HIF-1, and HSP90.  
These proteins are substrates of DACs 17. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
13 
 
 
The ability of a single agent to target multiple molecular features of tumor cells may result 
in good efficacy against a range of different tumor types. 
 
HSP90 is involved in protein stability and degradation; the inhibition of HSP90 affects 
protein turnover in diseases such as multiple myeloma and B-cell malignancies 18 
 
Acetylated HIF-1 is degraded and can no longer act as a tumor growth factor.  Class II 
DAC inhibitors target histone deacetylase (HDAC or DAC) 6, resulting in increased 
acetylation of HIF-1 and decreased vascular endothelial growth factor (VEGF), thereby 
inhibiting angiogenesis 19. 
 
Both acetylation and ubiquitylation often occur on the same lysine residue, but these 
processes cannot occur simultaneously.  Acetylation allows for increased stability, and 
ubiquitylation leads to protein degradation.  Therefore, DACs decrease the half-life of a 
protein by exposing the lysine residue for ubiquitylation 20. 
 
1.2.2 
Panobinostat (LBH589) 
Panobinostat (LBH589) is a deacetylase inhibitor (DACi) belonging to a structurally novel 
cinnamic hydroxamic acid class of compounds.  It is a potent class I/II pan-DAC inhibitor (pan-
DACi) that has shown anti-tumor activity in pre-clinical models and cancer patients.  
Deacetylases (DAC) target lysine groups on chromatin and transcription factors and various 
non-histone proteins such as p53, tubulin, HSP90 and Rb.  Panobinostat is formulated as an oral 
capsule and a solution for intravenous (i.v.) injection.  Both the oral and i.v. formulations are 
currently being investigated in ongoing Phase I and Phase II studies in advanced solid tumors 
and hematological malignancies.   
Inhibition of DAC provides a novel approach for cancer treatment.  Histones are part of the core 
proteins of nucleosomes, and acetylation and deacetylation of these proteins play a role in the 
regulation of gene expression.  Highly charged deacetylated histones bind tightly to the 
phosphate backbone of DNA, inhibiting transcription, presumably, by limiting access of 
transcription factors and RNA polymerases to DNA.  Acetylation neutralizes the charge of 
histones and generates a more open DNA conformation.  This conformation allows transcription 
factors and associated transcription apparatus access to the DNA, promoting expression of the 
corresponding genes.  The opposing activities of two groups of enzymes, histone 
acetyltransferase (HAT) and DAC control the amount of acetylation.  In normal cells a balance 
exists between HAT and DAC activity that leads to cell specific patterns of gene expression.  
Perturbation of the balance produces changes in gene expression. 
Several lines of evidence suggest that aberrant recruitment of DAC and the resulting 
modification of chromatin structure may play a role in changing the gene expression seen in 
transformed cells.  For example, silencing of tumor suppressor genes at the level of chromatin 
is common in human tumors 21-28 and DAC complexes have been shown to be crucial to the 
activity of the AML-specific fusion proteins PLZF-RAR-α, PML-RAR-α, and AML1/ETO 29-
32.  DAC inhibitors (DACi) have been shown to induce differentiation, cell cycle arrest or 
apoptosis in cultured tumor cells, and to inhibit the growth of tumors in animal models 33-39.  In 
addition, DACi have been shown to induce expression of p21, a key mediator of cell cycle arrest 
in G1 phase and cellular differentiation 40-43. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
14 
 
Tumor growth inhibition and apoptosis in response to DACi treatment may also be mediated 
through changes in acetylation of non-histone proteins (e.g., HSP90, p53, HIF-1α, α-tubulin).  
For example, the chaperone protein HSP90 has been shown to be acetylated in cells treated with 
DACi 44-46.  Acetylation of HSP90 inhibits its ability to bind newly synthesized client proteins, 
thus preventing proper client protein folding and function.  In the absence of HSP90 function, 
misfolded proteins are targeted for degradation in the proteasome.  Many proteins that require 
HSP90 association are critical to cancer cell growth, including ErbB1, ErbB2, AKT, Raf, KDR, 
and BCR-ABL.  Acetylation of HSP90 in cells treated with DACi inhibits the chaperone 
function of HSP90, leading to degradation of the client proteins and eventual cell death. 
The potential clinical utility of the use of DACi in cancer therapy was first suggested by the 
activity of the DACi, sodium phenylbutyrate, against acute promyelocytic leukemia (APL).  An 
adolescent female patient with relapsed APL, who no longer responded to all trans-retinoic acid 
(ATRA) alone, achieved a complete clinical remission after treatment with a combination of 
ATRA and the DACi sodium phenylbutyrate 47.   
1.2.3 
Overview of clinical experience 
In clinical studies, both oral and i.v. formulations of panobinostat are being explored for further 
development.  As of 31st December 2009, twenty-six clinical studies, including clinical 
pharmacology (CP), phase I and phase II trials, as well as one recently started randomized phase 
III study, have either been completed or are ongoing. In Table 5-1, “completed” studies are 
studies that have achieved final data base lock; all other studies are identified as “ongoing”. A 
total of 1116 patients were enrolled (248 for i.v. and 868 for oral), received at least one dose of 
panobinostat, and for whom safety data are available. These patients constitute the safety 
population. 
The most common AEs, regardless of their study drug relationship, concern the gastrointestinal 
tract (nausea, diarrhea and vomiting mostly of grade 1/2). For the hematopoietic system, the 
most frequent findings continue to be thrombocytopenia, anemia and neutropenia, mostly of 
grade 3/4, while febrile neutropenia, as expected, has been noted much more frequently in 
patients being treated for hematologic malignancies involving the bone marrow. Additional 
common toxicities include fatigue Grade 3/4 reported with a frequency of 9.2% in an every 
week (QW) dosing schedule vs 15.7% in an every other week (QOW) dosing schedule.  
The most common ECG findings adjudicated by central review included post-baseline increase 
in frequency of sinus tachycardia, T-waves changes (flat, biphasic, inverted), as well as 
depressed ST segment findings. 
The most frequently encountered laboratory abnormalities in both QW and QOW schedules and 
regardless of disease, refer to hematological parameters, including decreased WBC, platelet and 
neutrophil count and hemoglobin. Worsening of these hematologic parameters was more 
evident for the QW schedule and appears to be dose-dependent. Liver function tests alterations 
were mostly of grade 1/2 with either schedule, with grade 3 reported at the highest dose of 60 
mg TIW QW. Decreasing electrolytes and elevated glucose was mostly grade 1/2 worsening 
from baseline, but again increased severity (up to grade 3) was seen at the highest dose of 60 
mg with the QW schedule. 
Thyroid function, as monitored by the measurement of TSH and free T4, did not reveal overt 
hyper- or hypo- thyroidism, with fluctuations in TSH values being within normal limits. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
15 
 
As the number of patients is quite different across doses, the following rules have been applied 
to report these events in the tables below: in doses where the number (n) of patients is ≥25 
patients, AEs reported in ≥10% of patients are listed; in doses where n is <25 patients, AEs 
reported in ≥50% of patients are listed.  If an AE frequency matches the criteria in one dose 
category, the frequency of that event is shown for all doses. Since the dosing in this study will 
follow the three-times-per-week schedule, Table 1-1 below, provides a summary of adverse 
events that occurred in >15% of the patients at any dose. 
Table 1-1All grade adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-week (TIW QW) 
Primary System Organ Class 
Preferred term 
20 
mga 
N = 293 
n    (%) 
30 
mga 
N = 22 
n     (%) 
40 
mga 
N = 163 
n     (%) 
60 
mga
N 
= 
54
n    (%) 
Any primary system organ class 
291( 100.0) 22(100.0) 152(93.3) 54(100.0) 
Blood and lymphatic system disorders 
181(61.8) 17( 77.3) 131( 80.4) 49(90.7) 
Anemia 
60( 20.5) 
9( 40.9) 
51( 31.3) 24(44.4) 
Neutropenia 
52( 17.7) 
4(  18.2) 38( 23.3) 21( 38.9) 
Thrombocytopenia 
122( 42.1) 13( 59.1) 123( 75.5) 31(57.4) 
Gastrointestinal Disorders 
232( 79.2) 21( 95.5) 137( 84.0) 53( 98.1) 
Abdominal pain 
29(  9.9) 
2(  9.1) 
23( 14.1) 17( 31.5) 
Constipation 
42( 14.3) 
2(  9.1) 
27( 16.6) 13( 24.1) 
Diarrhea 
150( 51.2) 15( 68.2) 94( 57.7) 42( 77.8) 
Nausea 
132( 45.1) 11( 50.0) 90( 55.2) 34( 63.0) 
Vomiting 
64( 21.8) 
6( 27.3) 
62( 38.0) 24( 44.4) 
 
General Disorders and Site Conditions 219( 74.7) 17( 77.3) 112( 68.7) 49( 90.7) 
Asthenia 
50( 17.1) 
2(  9.1) 
26( 16.0) 11( 20.4) 
Fatigue 
118( 40.3) 12( 54.5) 66( 40.5) 37( 68.5) 
Edema peripheral 
57( 19.5) 
6( 27.3) 
24( 14.7) 17( 31.5) 
Pyrexia 
59( 20.1) 
8( 36.4) 
4( 25.2) 
20( 37.0) 
 
Investigations 
133( 45.4) 10( 45.5) 52( 31.9) 36( 66.7) 
Blood creatinine increased 
35( 11.9) 
1(  4.5) 
9(  5.5) 
11( 20.4) 
Weight decreased 
42( 14.3) 
6( 27.3) 
20( 12.3) 17( 31.5) 
 
Metabolism and nutrition disorders 
167( 57.0) 13( 59.1) 74( 45.4) 48( 88.9) 
Anorexia 
45( 15.4) 
10( 45.5) 16(  9.8) 
24( 44.4) 
Decreased appetite 
43( 14.7) 
1(  4.5) 
35( 21.5) 12( 22.2) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
16 
 
Primary System Organ Class 
Preferred term 
20 
mga 
N = 293 
n    (%) 
30 
mga 
N = 22 
n     (%) 
40 
mga 
N = 163 
n     (%) 
60 
mga
N 
= 
54
n    (%) 
Hypokalaemia 
31( 10.6) 
6( 27.3) 
22( 13.5) 24( 44.4) 
Musculoskeletal and connective tissue 
disorders 
107( 36.5) 10( 45.5) 59( 36.2) 23( 42.6) 
Back Pain  
33( 11.3) 
3( 13.6) 
14(  8.6) 
9( 16.7) 
Nervous system disorders 
142( 48.5) 13( 59.1) 70( 42.9) 36( 66.7) 
Dizziness 
39( 13.3) 
3( 13.6) 
11(  6.7) 
8( 14.8) 
Dysgeusia 
42( 14.3) 
6( 27.3) 
21( 12.9) 18( 33.3) 
Headache 
46( 15.7) 
5( 22.7) 
27( 16.6) 12( 22.2) 
Respiratory, thoracic and mediastinal 
disorders 
111( 37.9) 10( 45.5) 72( 44.2) 32( 59.3) 
Cough 
30( 10.2) 
5( 22.7) 
29( 17.8) 14( 25.9) 
Dyspnea 
43( 14.7) 
5( 22.7) 
23( 14.1) 13( 24.1) 
Skin and subcutaneous tissue disorders 142( 48.5) 8( 36.4) 
54( 33.1) 26( 48.1) 
Pruritus 
54( 18.4) 
0(  0.0) 
13(  8.0) 
3(  5.6) 
a. Includes patients from [B1101], [B2101], [B2102] Group X and Y, [B2201], [B2202], 
[B2203], [B2211], [B2212], [E2214]; events occurring in ≥10% of patients
A patient with multiple occurrences of an AE in one SOC is counted only once in the 
AE category 
As shown on the above table 1-1, AEs have been reported for 519 patients (97.6% of the safety 
population) for the QW schedule. The most commonly reported AEs across doses were diarrhea 
in 301 patients (56.6%), thrombocytopenia in 289 patients (54.3%), nausea in 267 patients 
(50.2%) and fatigue in 233 patients (43.8%). 
Table 1-2All grade adverse events regardless of causality in patients receiving oral 
panobinostat three-times-a-week every-other-week (TIW QOW) 
Primary 
System 
Organ 
Class
Preferred term 
30 
mga 
N 
= 
28 
n    (%) 
45 
mga
N 
= 
18
n    (%) 
60 
mga
N 
= 
24
n    (%) 
Any primary system organ class 
28(100.0) 
18(100.0) 
24(100.0) 
Blood and lymphatic system disorders 
16( 57.1) 
14( 77.8) 
21( 87.5) 
Anemia 
5( 17.9) 
6( 33.3) 
11( 45.8) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
17 
 
Primary 
System 
Organ 
Class
Preferred term 
30 
mga 
N 
= 
28 
n    (%) 
45 
mga
N 
= 
18
n    (%) 
60 
mga
N 
= 
24
n    (%) 
Neutropenia 
3( 10.7) 
5( 27.8) 
10( 41.7) 
Thrombocytopenia 
10( 35.7) 
10( 55.6) 
14( 58.3) 
Gastrointestinal Disorders 
25( 89.3) 
17( 94.4) 
24(100.0) 
Constipation 
6( 21.4) 
3( 16.7) 
10( 41.7) 
Diarrhea 
15( 53.6) 
11( 61.1) 
16( 66.7) 
Nausea 
17( 60.7) 
9( 50.0) 
19( 79.2) 
Vomiting 
12( 42.9) 
6( 33.3) 
12( 50.0) 
 
General Disorders and Site Conditions 
27( 96.4) 
17( 94.4) 
23( 95.8) 
Asthenia 
5( 17.9) 
5( 27.8) 
4( 16.7) 
Fatigue 
18( 64.3) 
12( 66.7) 
15( 62.5) 
Edema peripheral 
6( 21.4) 
5( 27.8) 
4( 16.7) 
Pyrexia 
11( 39.3) 
9( 50.0) 
10( 41.7) 
 
Investigations 
14( 50.0) 
8( 44.4) 
11( 45.8) 
Weight decreased 
10( 35.7) 
5( 27.8) 
3( 12.5) 
 
Metabolism and nutrition disorders 
22( 78.6) 
9( 50.0) 
18( 75.0) 
Anorexia 
17( 60.7) 
6( 33.3) 
10( 41.7) 
Hypokalaemia 
4( 14.3) 
3( 16.7) 
6( 25.0) 
Musculoskeletal and connective tissue 
disorders 
16( 57.1) 
7( 38.9) 
13( 54.2) 
Arthralgia 
3( 10.7) 
0(  0.0) 
6( 25.0) 
Back Pain  
3( 10.7) 
4( 22.2) 
3( 12.5) 
Pain in extremity 
3( 10.7) 
2( 11.1) 
3( 12.5) 
Nervous system disorders 
17( 60.7) 
6( 33.3) 
14( 58.3) 
Headache 
7( 25.0) 
3( 16.7) 
6( 25.0) 
Respiratory, thoracic and mediastinal 
disorders 
15( 53.6) 
8( 44.4) 
17( 70.8) 
Cough 
5( 17.9) 
4( 22.2) 
7( 29.2) 
Dyspnea 
9( 32.1) 
6( 33.3) 
6( 25.0) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
18 
 
Primary 
System 
Organ 
Class
Preferred term 
30 
mga 
N 
= 
28 
n    (%) 
45 
mga
N 
= 
18
n    (%) 
60 
mga
N 
= 
24
n    (%) 
Skin and subcutaneous tissue disorders 
12( 42.9) 
5( 27.8) 
9( 37.5) 
Pruritus 
5( 17.9) 
1(  5.6) 
3( 12.5) 
Rash 
3( 10.7) 
1(  5.6) 
4( 16.7) 
a. Includes patients from [B1101], [B2101], [B2102] (Group X and Y), [B2201], [B2202], 
[B2203], [B2211], [B2212], [E2214]; events occurring in ≥10% of patients
A patient with multiple occurrences of an AE in one SOC is counted only once in the 
AE category 
As shown on the above Table 1-2, AEs have been reported for 70 patients (100% of the safety 
population) for the QOW schedule. The most commonly reported AEs across doses were fatigue 
and nausea in 45 patients each (64.3% each), diarrhea in 42 patients (60%), thrombocytopenia 
in 34 patients (48.6%) and anorexia in 33 patients (47.1%). 
Of note, the safety profile appears to be qualitatively similar between the two schedules.  At 
present, a quantitative comparison is limited by the significantly different number of patients 
available in both safety populations. 
1.2.4 
Human pharmacokinetics 
After oral administration, panobinostat is rapidly absorbed with no observed lag phase. 
Maximum plasma concentrations were generally reached within 1 hour after oral dosing. The 
absolute bioavailability was 30% (data on file) and the mean (SD) half-life of panobinostat was 
comparable following i.v. and oral dosing ~15.0 (5) hours. Moderate drug accumulation was 
observed with oral three-times-a-week schedule but not with the weekly i.v. schedule (1.4-fold 
drug accumulation with oral three-times-a-week dosing), consistent with the terminal half-life 
of 15 hours and dosing interval. 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
19 
 
Figure 1-1 
Mean panobinostat plasma concentration versus time profiles following 
single oral or intravenous administration 
 
Table 1-3Pharmacokinetic parameters of panobinostat in three ongoing Phase I studies 
[CLBH589A2101], [CLBH589B2101], and [CLBH589B2102] 
Route 
of 
administration 
& 
Dose (No. of patients 
following 
single 
dose) 
Mean (CV%) 
Single 
dose 
Cmax(ng/mL) 
Mean (CV%) 
Single dose 
AUC0-inf (ng*hr/mL) 
Mean (CV%) 
Multiple dose 
AUC0-48 (ng*hr/mL) 
i.v. 20 mg/m2 (n=31) 
784 (45) 
1041 (38) 
n/a 
p.o. 20 mg (n=45) 
22.8 (58) 
194 (58) 
258 (65) 
p.o. 30 mg (n=49) 
36.2 (62) 
267 (54) 
279 (54) 
p.o. 40 mg (n=24) 
58.0 (59) 
329 (77) 
270 (59) 
p.o. 60 mg (n=57) 
66.1 (68) 
362 (62) 
306 (50) 
p.o. 80 mg (n=18) 
63.5 (58) 
397 (49) 
369 (52) 
n/a: not applicable 
with 
weekly 
i.v. 
administration 
 
In vitro experiments suggested that the hepatic oxidative metabolism of panobinostat is 
mediated primarily by cytochrome P450 (CYP)3A4, and to a lesser extent by CYP2D6 and 
CYP2C19. In addition to monooxygenation, hydrolysis of the hydroxamic sid chain (M43.5) 
were also found to be mediated (at least in-part) by the CYPs. These same metabolic pathways, 
were also observed in the recent human ADME and mass balance study [CLBH589B218]. 
0.0
0.1
1.0
10.0
100.0
1000.0
0
5
10
15
20
25
30
35
40
45
50
Time (hr)
20 mg PO
20 mg/m2 IV


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
20 
 
Dose proportionality 
A positive and linear dose-exposure relationship was found following single i.v. administration 
(1.2 to 20 mg/m2, Rs = 0.83; p<0.0001).  After oral dosing with 15 mg to 80 mg of panobinostat, 
dose-proportionality analysis indicated that systemic exposure increased nearly dose-
proportionally at doses below 60 mg and there is less than proportional increase in AUC after 
60 mg and 80 mg doses of panobinostat.  It appears that absorption may become limiting at 
doses ≥ 60 mg of panobinostat.   
Food Effect 
Influence of food on panobinostat PK was evaluated in patients with advanced cancer who 
received 20 mg panobinostat twice a week and were randomized to receive panobinostat under 
fasting, high fat, and normal breakfast conditions [CLBH589B2111]. The overall exposure and 
inter-patient variability (CV 59%) in 34 patients remained unchanged with or without food, 
whereas Cmax was transiently reduced by <45% and Tmax prolonged by food (i.e., both normal 
and high fat breakfast).  Since food did not alter the overall extent of absorption, food is unlikely 
to significantly impact panobinostat’s systemic exposure in cancer patients. The findings from 
this formal food effect are consistent with the results from an earlier pilot food effect 
[CLBH589B2101] arm 1. Therefore, panobinostat can be administered without regard to food 
in future studies. 
1.2.5 
Cardiac Safety 
As of 31 December 2009, cardiac safety data were available for 532 patients in the TIW QW 
dose schedule and 70 patients in the TIW QOW dose schedule.  All of these patients underwent 
intensive pre- and post-dose ECG recording to monitor the occurrence of QTcF changes as well 
as to capture other ECG abnormalities.  There are mounting evidences that the most common 
finding is a QTcF increase of ≤60 msec (CTCAE grade 1) from baseline in both schedules.  The 
absolute maximal QTcF values remain limited to ≤480 msec (grade 1/2).  Higher absolute 
values are infrequent.  Of note a QTcF increase >480 msec has been mostly observed at the 
highest oral dose of 60 mg given TIW QW.  There were no cases of torsade de pointes with 
either schedule for oral panobinostat. 
1.2.5.1 
Relationship between panobinostat plasma concentrations and QTcF 
As presented in Figure 1-2 (i.v.) and Figure 1-3 (po) below, the maximum change of QTcF from 
baseline does not coincide with the peak plasma concentration-time course of panobinostat for 
either route of administrations suggesting a possible delayed effect.   
It is noteworthy (as shown in Table 1-3) that the mean maximum concentration (Cmax) and 
overall exposure (AUC) for the oral formulation is at least 30-fold and 5-fold, respectively 
lower than that has been seen with intravenous panobinostat.  It does not appear that QTcF 
change is directly related to panobinostat plasma concentrations. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
21 
 
Figure 1-2 
QTcF change from baseline over time vs. panobinostat conc-time course 
following the first intravenous panobinostat weekly doses   
 
Figure 1-3 
QTcF change from baseline over time vs. panobinostat conc-time course 
following the first oral panobinostat doses of a MWF schedule 
4
All data points with n>3, all dose levels
QTcF change
PK conc
-10
0
10
20
Time from dose (hr)
0
10
20
30
40
50
0
10
20
30
40
 
 
All data points with n>3, all dose levels
QTcF change
PK conc
-2
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time from dose (hr)
0
10
20
30
40
50
60
0
100
200
300
400
500
600
700


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
22 
 
1.3 
Overview of MLN9708 (Ixazomib) 
1.3.1 Scientific Background 
MLN9708 is Millennium’s next generation small molecule inhibitor of the 20S proteasome that 
is under development for the treatment of nonhematologic malignancies, lymphoma, multiple 
myeloma (MM), and plasma cell dyscrasias. Inhibition of the 20S proteasome has been 
validated as a therapeutic target for the treatment of malignancies using VELCADE 
(bortezomib) for Injection, Millennium Pharmaceuticals, Inc.’s first-in-class proteasome 
inhibitor 48. In an effort to broaden activity against a wider range of tumor types and increase 
activity in tumor types where VELCADE has shown activity, Millennium has developed the 
proteasome inhibitor, MLN9708, formulated for both intravenous (IV) and oral (PO) 
administration. 
 
1.3.2 Nonclinical Pharmacology  
MLN2238 refers to the biologically active, boronic acid form of the drug substance, MLN9708. 
MLN9708 refers to the citrate ester of MLN2238. In water or aqueous systems, the equilibrium 
shifts from MLN9708 to the biologically active boronic acid form MLN2238. All doses and 
concentrations are expressed as the boronic acid, MLN2238. 
 
 
1.3.2.1 
In Vitro Pharmacology 
MLN2238 inhibits β5 site 20S proteasome activity in vitro, with a half-maximal inhibitory 
concentration (IC50) of 3.4 nM. Potency is reduced roughly 10-fold versus β1 (IC50 = 31 nM) 
and 1,000-fold versus β2 (IC50 = 3500 nM). MLN2238 was also tested for inhibition against a 
panel of 103 kinases, 18 receptors (neurotransmitter, ion channel, brain and gut receptors), and 
9 serine proteases. In all cases, the IC50 values were > 10 μM. Proteasome inhibition results in 
the accumulation of poly-ubiquitinated substrates within the cell and leads to cell cycle 
disruption, with concomitant activation of apoptotic pathways and cell death. Consistent with 
inhibition of β5 20S proteasome activity, MLN2238 demonstrated potent activity against 
cultured MDA-MB-231 human breast cancer cells in the WST cell viability assay. 
 
1.3.2.2 
In Vivo Pharmacology 
To determine the activity of MLN2238 in vivo, pharmacodynamic studies were performed in 
immunocompromised mice bearing either CWR22 human prostate or WSU-DLCL2 (human 
diffuse large B-cell lymphoma [DLBCL]) tumors. Xenograft tumor pharmacodynamic 
responses were analyzed by assessing 20S proteasome inhibition and by evaluating levels of 
the protein markers growth arrest and deoxyribonucleic acid (DNA) damage-inducible protein 
34 (GADD34) and activating transcription factor-3 (ATF-3). Increased expression of GADD34 
and ATF-3 is indicative of a downstream biological response to proteasome inhibition. After a 
single dose of MLN2238, a clear dose response was observed in CWR22 xenografts as seen in 
both tumor 20S proteasome inhibition and in changes in GADD34 and ATF-3 expression. In 
WSU-DLCL2 xenografts, greater tumor proteasome inhibition and greater elevation of 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
23 
 
GADD34 and ATF-3 were observed with MLN2238 compared to bortezomib. Additionally, 
MLN2238 demonstrated proteasome inhibition in blood, liver, and tumor tissue after a single 
IV dose of 5, 10, or 14 mg/kg or a single PO dose of 8 or 11 mg/kg to female PHTX-24C 
(primary colon cancer) tumorbearing NCR nude mice. MLN2238 demonstrated strong 
antitumor activity in xenograft models derived from human cancer cell lines or primary human 
tumors. Antitumor activity was demonstrated with subcutaneous (SC) xenografts of CWR22 
prostate, LXFE 409 epidermoid lung carcinoma, and 2 lymphoma models (WSU-DLCL2 and 
PHTX-22L). MLN2238 also showed antitumor activity in a disseminated model of lymphoma 
(OCI-Ly7-7D1-luc cells inoculated intravenously) and in an intraosseous model using MDA-
MB-231 human breast adenocarcinoma cells. In addition, MLN2238 demonstrated antitumor 
activity in mouse models of plasma cell malignancy (PCM): the iMycCα/Bcl-XL genetically-
engineered mouse [GEM] model of de novo PCM and disseminated and intraosseous models 
of PCM generated by IV and intratibial inoculation of the DP54-Luc iMycCα/Bcl-XL mouse 
cell line. In the CWR22 xenograft model, significant antitumor activity was seen with both PO 
and IV dosing, demonstrating that this molecule has antitumor activity when administered via 
different dosing routes. MLN2238 demonstrated stronger antitumor activity than did 
bortezomib in the 3 lymphoma models, the lung carcinoma model, and the breast cancer model, 
and similar antitumor activity to bortezomib in the CWR22 model and the PCM models. In 
summary, MLN2238 is Millennium’s next generation dipeptide boronic acid proteasome 
inhibitor that potently, reversibly, and selectively inhibits the proteasome. There are several 
features of MLN2238 demonstrated in mouse xenograft models, such as sustained 
pharmacodynamic effects and activity in xenograft models that do not respond to bortezomib, 
that suggest that the biodistribution and activity that of MLN2238 may extend beyond that of 
VELCADE. 
 
1.3.3 
Nonclinical Pharmacokinetics 
The pharmacokinetic (PK) properties of MLN2238 were studied in severe combined 
immunodeficient (SCID) mice bearing human CWR22 tumor xenografts, Sprague-Dawley rats, 
beagle dogs, and cynomolgus monkeys. Because of the extensive red blood cell (RBC) 
partitioning of MLN2238, both blood and plasma PK parameters were determined in these 
studies. MLN2238 had a very low blood clearance (CL) and a moderate blood volume of 
distribution at steady-state (Vss) after IV administration. The concentration-versus-time curve 
of MLN2238 displayed a distinct bi-exponential profile, with a steep initial distribution phase 
and a long terminal t1/2 (>24 hr) in all species tested. MLN2238 had higher plasma CL and larger 
plasma Vss than in blood, largely because of the extensive RBC partitioning. The PK properties 
of MLN2238 after oral administration were studied in rats and dogs. The plasma oral 
bioavailability (F) was 41% in rats and nearly 100% in dogs. A clinical prototype formulation 
of the MLN9708 capsule demonstrated that MLN2238 had excellent oral F and an excellent 
absorption profile in dogs. In addition, interindividual variability, as measured by %CV, in Cmax 
and AUC0-24hr after oral administration was low to moderate, similar to that after IV 
administration. The terminal t1/2 after oral administration was also similar to that after IV 
administration. Metabolism appears to be a major route of elimination for MLN2238, and 
urinary excretion of the parent drug was negligible (< 5% of dose). In vitro in liver microsomes, 
the metabolism of MLN2238 was high in mice and low to moderate in all other species studied. 
MLN2238 is metabolized by multiple cytochrome P450 (CYP) isozymes and non-CYP 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
24 
 
enzymes and proteins. The rank order of relative biotransformation activity of each of the 5 
major human CYP isozymes in the in vivo studies was 3A4/5 (34.2%) >1A2 (30.7%)  >2D6 
(14.7%) >2C9 (12.1%) >2C19 (negligible). In SD rats, after a single IV dose of [14C]MLN9708, 
the blood exposure to MLN2238 was the same as that of total radioactivity in the blood, 
indicating that MLN9708 was completely converted to MLN2238 in vivo and the metabolism 
of MLN2238 was extremely slow. MLN2238 is neither an inhibitor of CYP isozymes 1A2, 
2C9, 2C19, 2D6, and 3A4/5 (IC50 >30 μM, with an estimated inhibition dissociation constant 
[Ki] >15 μM), nor a time dependent inhibitor of CYP3A4/5 (up to 30 μM). The potential for 
MLN9708 treatment to produce DDIs via CYP inhibition is inferred to be low. However, there 
may be a potential for DDIs with a concomitant strong CYP3A4/5 or CYP1A2 inhibitor or a 
strong CYP3A4/5 inducer because of the possible contribution of CYP3A4/5- and CYP1A2-
mediated metabolism to the elimination of MLN9708 in humans. Clinical evaluation with 
CYP3A4/5 as a strong inhibitor or inducer is planned. 
 
1.3.4 
Safety Pharmacology 
Evaluation of the effect of MLN9708 on cardiovascular (CV), respiratory, and central nervous 
system (CNS) function was conducted as part of the Good Laboratory Practice (GLP)-compliant 
repeat-dose toxicology studies. In exploratory safety pharmacology studies, MLN2238 was a 
weak inhibitor of the cloned cardiac potassium (K+) human ether à-go-gorelated gene (hERG) 
channel in vitro, with an IC50 of 59.6 μM, which exceeds, by approximately 200-fold, the 
plasma Cmax (111 ng/mL [0.3 μM]) predicted to occur in humans at the optimally efficacious 
dose after IV administration. In the GLP-compliant, 1-cycle PO toxicology study in beagle 
dogs, an increase in QTc was seen in male dogs at nontolerated doses, and a potential increase 
in QTc was seen in male dogs at tolerated doses. However, increased QTc was not seen in 
female dogs at any dose, despite similar plasma Cmax values. Additionally, in GLP-compliant 
2- and 5-cycle IV and 5-cycle PO toxicology studies in beagle dogs, there were no changes in 
electrocardiograms, heart rate, and waveform intervals (PR, QRS, QT, and QTcV), even though 
dogs in the IV studies had higher MLN2238 plasma Cmax values than in the 1-cycle PO study. 
In GLP-compliant PO and IV repeat-dose toxicology studies up to 5 cycles in duration, there 
were no MLN9708-related effects on clinical signs or physical examination findings indicative 
of impaired respiratory or CNS function at tolerated doses. These data suggest that MLN2238 
has a low potential for cardiovascular, CNS, or respiratory alterations. 
 
1.3.5 
In Vivo Toxicology 
 
1.4.1.1 Oral Dosing 
After PO administration of MLN2238, the exposures that were tolerated in rats were similar to 
those tolerated in dogs, indicating similar species sensitivity. Additionally, PO administration 
for 5 cycles to rats and dogs resulted in higher plasma exposures of MLN2238 on Day 94 than 
on Day 0, indicating accumulation of MLN2238. Dose-limiting toxicity (DLT) in the GLP-
compliant PO toxicology studies up to 5 cycles in duration in rats and dogs was primarily due 
to effects in the gastrointestinal (GI) and lymphoid systems. Additionally, at doses below those 
associated with DLT, alterations in leukocyte and coagulation parameters consistent with an 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
25 
 
inflammatory response were seen in both rats and dogs, and neuronal degeneration of the 
sympathetic, dorsal root, and end organ ganglia was seen mainly in dogs (possibly due to higher 
exposures). All of the effects seen in the GLP-compliant PO toxicology studies in both rats and 
dogs at tolerated doses were reversible/reversing and can be monitored in the clinic with routine 
clinical observations (GI disturbances and opportunistic infections secondary to lymphoid 
depletion), clinical pathology assessments (inhibition of erythropoiesis, thrombocytopenia, and 
inflammatory leukogram), and neurologic assessment, as are commonly done for patients 
treated with bortezomib. MLN9708 did not cause significant toxicities that have not been 
previously observed after dosing with bortezomib,11 and the neurologic lesions in these studies 
are similar to what has been described after treatment with bortezomib and are believed to be 
the cause of the peripheral neuropathy observed in patients treated with bortezomib. 
 
 
1.4.1.2 Intravenous Dosing 
After IV administration of MLN2238, the exposures that were tolerated in rats were similar to 
those tolerated in dogs, indicating similar species sensitivity. In GLP-compliant IV toxicology 
studies, the target tissues for dogs and rats were similar and consisted of the bone marrow, 
peripheral ganglia, intestines, and lymphoid tissues. In addition, kidneys, adrenal and lacrimal 
glands (rats) and perianal glands (dogs) were also identified as target organs in the 5-cycle 
studies. The effects seen with the IV studies were largely consistent with the toxicologic effects 
seen with PO dosing; however, the greater severity/frequency or additional target organs seen 
with IV dosing were likely a result of the higher exposures relative to PO dosing. DLT was 
primarily due to GI and lymphoid depletion effects in both rats and dogs, although some of the 
microscopic features in those organs differed between the species. All of the effects seen in the 
GLP-compliant IV toxicology studies in both rats and dogs at tolerated doses were 
reversible/reversing and can be monitored in the clinic. Additionally, these effects were 
consistent with the toxicities associated with and described after treatment with bortezomib 11. 
 
1.4.2 Genotoxicity 
MLN2238 was not mutagenic in a GLP-compliant bacterial reverse mutation assay (Ames 
assay). 
 
 
1.3.6 
Clinical Experience 
As of 30 April 2012, 382 patients have been treated with MLN9708 across 9 enrolling, 
sponsor-led phase 1 or phase 1/2 studies evaluating both twice-weekly and weekly dosing 
schedules.  MLN9708 is available as an intravenous and oral formulation. Regardless of the 
route of administration in the twice-weekly dosing schedule, MLN9708 is given on Days 1, 4, 
8, and 11 of a 21-day cycle; in the weekly dosing schedule, the drug is given on Days 1, 8, 
and 15 of a 28-day cycle. To date, the development of oral MLN9708 has focused on multiple 
myeloma [relapsed and/or refractory and newly diagnosed] and a different yet related plasma 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
26 
 
cell dyscrasia, systemic light chain (AL) amyloidosis. A clinical pharmacology study looking 
at drug-drug interactions, the effect of food, and bioavailability also uses the oral formulation. 
Details of these trials can be found in ClinicalTrials.gov and the MLN9708 IB.   
1.3.7 
   
Pharmacokinetics and Drug Metabolism 
Clinical IV and PO pharmacokinetic (PK) data show that MLN9708 (measured as the 
biologically active boronic acid form of MLN9708 [MLN2238]) has multi-exponential 
disposition with a rapid initial phase that is largely over by 4 hours.  Oral MLN9708 is rapidly 
absorbed with a median time to first maximum plasma concentration (Tmax) of approximately 
0.5 to 2.0 hours and terminal t1/2 after multiple dosing of approximately 5 to 7 days.[1]  
Results of a population PK analysis (N = 137) show that there is no relationship between body 
surface area (BSA) or body weight and clearance (CL).  Also, based on stochastic simulations 
for fixed dose, exposures are independent of the individual patient’s BSA.[2]  Based on these 
data, a recommendation was made for fixed dosing in clinical trials.  An absolute 
bioavailability of 67% was determined for MLN9708 using the population PK analysis.  See 
the IB for information on the PK for IV doses of MLN9708. 
Metabolism appears to be the major route of elimination for MLN9708, with negligible 
urinary excretion of the parent drug (< 3% of dose).  In vitro studies of liver microsomes show 
that MLN9708 is metabolized by multiple cytochrome P450 enzymes (CYPs) and non-CYP 
enzymes/proteins.  The rank order of relative biotransformation activity of the 5 major human 
CYP isozymes is 3A4 (34.2%) > 1A2 (30.7%) > 2D6 (14.7%) > 2C9 (12.1%) > 2C19 (< 1%).  
MLN9708 is not an inhibitor of CYPs 1A2, 2C9, 2C19, 2D6, or 3A4, nor is it a time-
dependent inhibitor of CYP3A4/5.  The potential for MLN9708 treatment to produce 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 because of the potential for first-pass 
metabolism when MLN9708 is administered via the PO route and because of the moderate 
contribution of CYP3A4- and CYP1A2-mediated metabolism of MLN9708 in human liver 
microsomes.  MLN9708 may be a weak substrate of P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP), and multidrug resistance associated protein (MRP2) efflux pump 
transporters.  MLN9708 is not an inhibitor of P-gp, BCRP, and MRP2.  The potential for 
DDIs with substrates or inhibitors of P-gp, BCRP, and MRP2 is, therefore, inferred to be low. 
1.3.8 
    Clinical Trial Experience Using the Oral Formulation of MLN9708 
In the 7 studies actively enrolling patients to investigate oral MLN9708 in patients with 
differing malignancies (multiple myeloma, AL amyloidosis, nonhematologic cancers, and 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
27 
 
lymphoma), a total of 242 patients have been treated as of 30 April 2012. These patients have 
been treated with different doses of MLN9708, either as a single agent treatment or in 
combination with currently clinically available treatments. Information regarding the ongoing 
studies, patient populations, and doses investigated are included in Table 1-1. 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
28 
 
Table 1-4 
Ongoing Studies of Oral MLN9708 
Trial/ 
Population 
Description 
Doses Investigated 
C16003 
RRMM 
N = 58 
PO, twice weekly (TW), single agent 
0.24-2.23 mg/m2, TW 
MTD:  2.0 mg/m2 
DLT:  rash, thrombocytopenia 
C16004 
RRMM 
N = 52 
PO, weekly (W), single agent 
0.24-3.95 mg/m2, W 
MTD:  2.97 mg/m2 
DLT:  rash, nausea, vomiting, diarrhea 
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 
RP2D*:  4.0 mg fixed (switched to fixed dosing in 
phase 2, relevant to 2.23 mg/m2) 
C16006 
NDMM 
N = 28 
PO, TW (Arm A- 42 day cycle) and W 
(Arm B- 28 day cycle), combination 
with melphalan and prednisone 
Arm A*:  3-3.7 mg, fixed dose, TW 
DLT: rash, thrombocytopenia, subileus 
Arm B*:  5.5 mg, fixed dose, W 
DLT: Esophageal ulcer 
C16007 
RR-AL 
N = 6 
PO, W, single agent 
4-5.5 mg, fixed dose*, W 
MTD: 4 mg 
DLT: thrombocytopenia, dirrhea, dyspnea, acute 
rise in creatinine, cardiac arrest 
 
C16008 
NDMM 
N=11 
PO, TW, combination with LenDex 21 
day cycle 
3.0-3.7 mg fixed dose* W 
MTD: 4 mg 
DLT: 
C16009 
Solid 
tumors, 
Lymphomas 
N = 22 
PO, W, single agent 
5.5 mg fixed dose* W 
C16010 
RRMM 
N = 1 
PO, W, combination with LenDex 
4.0 mg fixed dose* W 
TB-
MC010034 
RRMM 
N = 5 
PO, W, single agent in 1s part of study 
then in combination with LenDex in 2nd 
part 
3.0 mg fixed dose* W 
DLT: thrombocytopenia, nausea, hypertension, 
diarrhea 
Abbreviations:  RRAL = Relapsed or refractory Primary systemic light chain (AL) amyloidosis; BSA = body 
surface area ; DLT = dose-limiting toxicity; IV = intravenuously; LenDex = lenalidomide plus 
dexamethasone; MTD = maximum tolerated dose; NDMM = newly diagnosed multiple myeloma; PO = 
orally; RRMM = relapsed and/or refractory multiple myeloma; RPh2D = recommended phase 2 dose 
* Approximate body surface area (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. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
29 
 
 
Overview of the Oral Formulation of MLN9708 
The emerging safety profile indicates that oral MLN9708 is generally well tolerated with 
predominant toxicities largely reversible, able to be monitored by routine clinical 
examinations and manageable by dose reductions, discontinuation, or standard supportive 
care. From experience from phase 1 through 2 studies the major toxicities can be managed to 
allow repeat treatment cycles over periods extending beyond 24 months.  
In the 4 ongoing studies (C16003, C16004, C16007, and C16009) investigating single-agent 
oral MLN9708 in patients with differing malignancies (multiple myeloma, AL amyloidosis, 
nonhematologic cancers, and lymphoma), a total of 146 patients have been treated as of 30 
April 2012. These patients have been treated with different doses of MLN9708 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 MLN9708 Studies (C16003, C16004, C16007, and 
C16009) is shown in Table 1-2. 
Table 1-5 
Summary of Most Common (At Least 10% of Total) All Grade 
Treatment-Emergent Adverse Events (Oral MLN9708 Single-Agent 
[C16003/4/7/9] Safety Population) 
Primary System Organ Class  
Preferred Term and Incidence 
N=146 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
Gastrointestinal disorders 102 (70) 
Nausea 68 (47); Diarrhoea 55 (38); Vomiting 51 (35); 
Abdominal pain 21 (14); Constipation 21 (14) 
General disorders and administration site conditions 
98 (67) 
Fatigue 71 (49); Pyrexia 31 (21); Oedema peripheral 
15 (10) 
Blood and lymphatic system disorders 77 (53) 
Thrombocytopenia 60 (41); Anaemia 30 (21); 
Neutropenia 23 (16); Leukopenia 15 (10) 
Nervous system disorders 63 (43) 
Headache 20 (14); Dizziness 18 (12) 
Metabolism and nutrition disorders 60 (41) 
Decreased appetite 39 (27) Dehydration 21 (14) 
Respiratory, thoracic and mediastinal disorders 60 
(41) 
Cough 22 (15); Dyspnoea 21 (14) 
Skin and subcutaneous tissue disorders 60 (41) 
Rash macular 17 (12) 
Musculoskeletal and connective tissue disorders 56 
(38) 
Arthralgia 20 (14); Back pain 17 (12) 
Infections and infestations 54 (37) 
Upper respiratory tract infection 21 (14) 
Source: MLN9708 Investigator’s Brochure Edition 6 
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, any event that is considered drug-related regardless of 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
30 
 
the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related.  
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects 
as the denominator 
 
In the 3 studies actively enrolling patients to investigate oral MLN9708 in combination with 
standard combination regimens in patients with newly diagnosed multiple myeloma, a total of 
96 patients have been treated as of 30 April 2012. These patients have been treated with 
different doses of MLN9708 in combination with lenalidomide and dexamethasone in 2 trials 
(C16005 and C16008) and with melphalan and prednisone in 1 trial (C16006). The most 
frequent (at least 10%) adverse events occurring in the pooled safety population from Studies 
C16005, C16006, and C16008 is shown in Table 1-3. In combinations trials, related is defined 
as possibly related to any drug in the combination regimen, not just specifically related to 
MLN9708. 
 
Table 1-6 
Summary of Most Common (At Least 10% of Total) Treatment- 
Emergent Adverse Events (Oral MLN9708 Combination Agent 
[C16005/6/8] Safety Population) 
 
Primary System Organ Class  
Preferred Term and Incidence 
N= 96 
n (%) 
Subjects with at Least One Adverse Event 135 (92) 
 
 
Gastrointestinal disorders 70 (73) 
Nausea 32 (33); Constipation 29 (30); Vomiting 25 
(26) 
Diarrhoea 22 (23) 
General disorders and administration site conditions 
64 (67) 
Fatigue 37 (39); Oedema peripheral 20 (21); Pyrexia 
19 (20) 
Skin and subcutaneous tissue disorders 57 (59) 
Rash 13 (14) 
Nervous system disorders 46 (48) 
Neuropathy peripheral 13 (14); Dysgeusia 12 (13) 
Dizziness 11 (11) 
Musculoskeletal and connective tissue disorders 45 
(47) 
Back pain 18 (19); Muscle spasms 10 (10) 
Blood and lymphatic system disorders 42 (44) 
Thrombocytopenia 28 (29); Anaemia 22 (23);  
Neutropenia 19 (20) 
Infections and infestations 40 (42) 
Upper respiratory tract infection 17 (18);  
Metabolism and nutrition disorders 38 (40) 
Decreased appetite 11 (11) 
Respiratory, thoracic and mediastinal disorders 34 
(35) 
Dyspnoea 13 (14); Cough 11 (11) 
Psychiatric disorders 23 (24) 
Insomnia 15 (16) 
Source: MLN9708 Investigator’s Brochure Edition 6. 
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, any event that is considered drug-related regardless of 
the start date of the event, or any event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
31 
 
Subject Incidence: A subject counts once for each preferred term. Percentages use the number of treated subjects 
as the denominator. 
 
 
 
 
The clinical experience with MLN9708 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 MLN9708, when combined with established therapies, and across the 
malignancies studied (advanced solid tumors [3], non-Hodgkin’s disease, Hodgkin’s disease 
[4], relapsed and/or refractory multiple myeloma [RRMM; 5; 6], relapsed or refractory 
systemic light chain amyloidosis [RRAL; 7], and newly diagnosed multiple myeloma 
[NDMM; 8; 9; 10]) to date. 
 
Though additional data are needed to characterize the clinical benefit of this drug, the 
emerging data supports the ongoing development of MLN9708. 
 
Of particular relevance to this study (C16011) is the clinical experience from Studies C16004 
and C16007 in which single-agent MLN9708 is administered weekly in patients with RRMM 
or RRAL, respectively.  
 
1.3.9 
    Relapsed and/or Refractory Multiple Myeloma 
Study C16004 is an open-label, dose-escalation, phase 1 study of MLN9708 administered 
weekly on Days 1, 8, and 15 of a 28-day cycle in adult patients with RRMM. Patients with 
MM enrolled in the dose-escalation component of the study have relapsed following at least 2 
lines  of therapy, which must have included bortezomib, thalidomide (or lenalidomide), and 
corticosteroids. The dose-escalation phase of the trial has completed. In this study, 2 of 3 
patients experienced protocol-defined DLTs (Grade 3 rash and Grade 3 nausea, vomiting, and 
diarrhea) at a dose of 3.95 mg/m2. As per protocol, subsequent patients were treated at 1 dose 
level below (2.97mg/m2) where 1 of 6 patients experienced a DLT (Grade 3 nausea, vomiting, 
and diarrhea). The MTD of weekly oral MLN9708 was determined to be 2.97 mg/m2. 
Once the MTD was established, cohorts of patients representing the heterogeneous patient 
population currently seen in clinical practice were enrolled in order to further evaluate the 
safety, tolerability, efficacy, PK, and pharmacodynamics of oral MLN9708. The MTD 
expansion cohorts enrolling are: 
1. Relapsed and Refractory expansion cohort [refractory is defined as disease progression 
while on therapy or within 60 days after the last dose of therapy]; 
2. Carfilzomib expansion cohort 
3. Proteasome Inhibitor-Naïve expansion cohort 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
32 
 
4. VELCADE-Relapsed expansion cohort 
Final study results are not available for this ongoing trial, but preliminary data suggest 
MLN9708 has antitumor activity in heavily pretreated MM patients, with durable 
responses/disease control, and is generally well tolerated.[11,12] 
As of the 30 April 2012 data cut, these patients are considered heavily pretreated as evidenced 
by a median number of 4 (range 1–13) prior lines of therapy, with 66% refractory to the last 
line of therapy. Patients have received a median of 2 cycles of therapy (range, 1- 11). Five 
patients have achieved objective response: 1 patient achieved a VGPR and 4 patients achieved 
a PR. Additionally, 15 patients achieved durable disease stabilization for up to 9.5 months. At 
data cut-off, 15 patients remain on treatment; discontinuation of treatment was primarily due 
to progressive disease (69%). 
 
A summary of the safety profile of patients treated in Study C16004 is outlined in Table 1-4. 
Overall, 92% of patients experienced a TEAE of any grade and of any cause. Peripheral 
neuropathy was limited to Grade 1/ 2 in 6 patients, with 3 patients reporting baseline Grade 1 
PN at study entry. 
 
Table 1-7    
Study C16004, Oral MLN9708, Single Agent, Given Weekly:  Most 
Common TEAEs as of 30 April 12 (N= 52) 
Most Common (> 20%) Any Grade and Irrespective 
of Cause 
Thrombocytopenia (54%) 
Fatigue (48%) 
Nausea (44%), diarrhea (44%) 
Vomiting (37%) 
Decreased appetite (33%) 
Rash* (31%) 
Anemia (25%) 
Neutropenia (23%) 
Drug-Related Grade  3 in > 5% of patients 
 
Thrombocytopenia (38%) 
Diarrhea and neutropenia 17% (each), fatigue and 
lymphopenia 10% (each), nausea and decreased 
appetite 8% (each) and vomiting 6% 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
* Rash includes preferred terms of rash macular, rash, maculo-papular, rash morbilliform, rash pruritic, 
pruritus,, rash erythematous, exfoliative rash, and rash popular 
 
 
Dose reductions required were due to AEs that included rash, neutropenia, thrombocytopenia, 
diarrhea, nausea, vomiting, dehydration, hypotension, increase in serum creatinine, abdominal 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
33 
 
pain, ileus, fatigue, and pneumonia. The AEs reported for the 5 patients who were required to 
discontinue treatment included Grade 2 MLN9708-related nausea/vomiting in 1 patient 
treated above the MTD, Grade 3 MLN9708-related diarrhea in a second patient, related Grade 
3 thrombocytopenia, related Grade 2 dyspnea, and notrelated Grade 4 elevation in creatinine(1 
patient each). There were no on-study deaths.  
Study C16007 is evaluating single agent weekly , Day 1, 8, and 15 of a 28-day cycle, oral 
dosing in patients with RRAL after at least 1 prior therapy. The objectives of this study are to 
determine the safety, tolerability, and MTD, as well as to determine hematologic and organ 
response rates in this patient population. The starting dose level was selected from Study 
C16004 as previously described. In Study C16007 the dose was switched from the BSA-based 
dosing to the fixed dose, thereby the 4.0 mg fixed starting dose in Study C16007 corresponds 
to the 2.23 mg/m2 dose (one dose level below MTD) from Study C16004. This study is 
currently enrolling patients in the dose-expansion portion of the trial. 
As of 30 April 2012, 14 patients have been treated in this study. At the first dose level of 4.0 
mg, 1 of 6 patients experienced a protocol-defined DLT (that is, thrombocytopenia that lasted 
more than 2 weeks, which met the definition of a DLT due to the delay in starting Cycle 2). 
As per protocol, the dose was escalated to 5.5 mg for the next cohort of patients where 2 of 5 
patients experienced a DLT (Grade 3 diarrhea, n=1; and Grade 2 dyspnea, Grade 2 acute rise 
in serum creatinine, and Grade 4 cardiac arrest, n=1). The latter patient did not appear to have 
cardiac AL amyloidosis by echocardiogram on study entry, but did have substantial renal 
involvement. After the occurrence of this DLT, diagnoses included cardiac involvement and 
CHF. The MTD of weekly oral MLN9708 was determined to be 4.0 mg. Following the 
establishment of the MTD, patients are currently being enrolled in to 1 of 2 cohorts: 
proteasome inhibitor naïve or proteasome inhibitor exposed.[13] 
As of the 30 April 2012 data cut, the patients enrolled in the study are considered heavily 
pretreated, as evidenced by a median number of 3 prior lines of therapy (range 1–7), with 38% 
and 46% of patients having been previously treated with bortezomib and lenalidomide, 
respectively. To be eligible for the study, patients must have amyloid involvement of the 
heart, kidney, or both; at the data cut the organ involvement distribution was 6, 4, and 4 
patients, respectively. Patients have received a median of 2.5 cycles of therapy (range, 1-12). 
Eight patients remain on treatment. Early signs of activity have been reported. There were 11 
patients who have received at least 1 cycle of therapy with completed response assessments (9 
in the 4.0 mg [MTD] cohort and 2 in the 5.5 mg cohort). The overall hematologic response 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
34 
 
rate at MTD is 56% (5 patients achieved a hematologic response [4 VGPR and 1 PR]; 3 
patients showed no change, and 1 patient had an early progression.  
A summary of the safety profile of patients treated in Study C16007 is outlined in Table 1-5. 
Overall, 86% of patients experienced a TEAE of any grade and of any cause. 
Table 1-8    
Study C16007, Oral MLN9708, Single Agent Given Weekly  Most 
Common TEAEs as of 30April 12 (N = 14) 
Most Common (> 20%) 
Any Grade and Irrespective of Cause 
Nausea (50%) 
Fatigue (36%) 
Thrombocytopenia (29%) 
Diarrhea (29%) 
Decreased Appetite (21%) 
Peripheral Edema (21%) 
Dyspnea (21%) 
Abdominal pain (21%) 
Drug-Related Grade  3 in more than 3 Patients  
Thrombocytopenia 5 patients, rash 3 patients, 
dehydration 2 patients, fatigue 2 patients 
 
Source: MLN9708 Investigator’s Brochure Edition 6 
 
One patient discontinued study drug administration due to a TEAE (patient with DLT of acute 
rise in serum creatinine, dyspnea, and cardiac arrest treated at 5.5 mg, as noted above). No 
death has been reported. 
The potential risks reported with MLN9708 use, pooled from all studies using the oral 
formulations, were anticipated based on preclinical data and previous experience with 
VELCADE and are noted in the MLN9708 IB, SMA, and ICF documents. Regardless of 
whether MLN9708 is administered on the once weekly or twice weekly dosing schedule, there 
is consistency among the type of TEAEs reported, despite some differences in the frequency 
and severity of the reported events. While the predominant potential toxicities may be severe 
in some cases, they are largely reversible, and can be managed by routine clinical monitoring 
and standard medical interventions, which may include dose reductions and supportive care. 
Please refer to the MLN9708 IB and SMA for further information. 
1.3.10 
    Newly Diagnosed Multiple Myeloma (NDMM) 
In Study C16005, MLN9708 is given weekly (Days 1, 8, and 15), in combination with 
lenalidomide (Days 1-21), and dexamethasone (Days 1, 8, 15, and 22) in a 28-day cycle.  
Enrollment to this study is closed.   


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
35 
 
Clinical data as of 30 April 2012 is available.  The MTD in Study C16005 was determined to 
be 2.97 mg/m2 given weekly in a 28-day cycle with LenDex.  The DLTs were urticarial rash, 
dizziness, nausea, orthostatic hypotension, vomiting, diarrhoea, and syncope.  The 
recommended phase 2 dose (RP2D) estimation was established following evaluation of the 
available data from the phase 1 portion of the trial which included, but was not limited to, 
analyses of efficacy results and adverse events (Grade 3/4 AEs, SAEs, all grades peripheral 
neuropathy, and treatment discontinuation).  Given that the dose of MLN9708 at 2.97 mg/m2 
compromised the maximal dosing of lenalidomide and that the dose of 2.23 mg/m2 is very 
tolerable and clinically active, Millennium designated 2.23 mg/m2 as the RP2D after 
evaluation of the data and discussion with investigators.  The RP2D of 2.23 mg/m2 has been 
translated into a fixed dose of 4.0 mg based on the results from the population PK analysis.  
Enrollment in this study has been completed; final study results are not available, but 
preliminary data suggests oral MLN9708 given weekly plus lenalidomide and dexamethasone 
in a 28-day cycle appears well tolerated with manageable toxicity and encouraging antitumor 
activity.   
In Study C16005, 15 of 15 (100%) patients in the dose escalation portion of the study 
experienced at least 1 TEAE irrespective of grade or causality.  At the MTD across all dose 
expansion cohorts 49 of 53 patients (including 3 patients from the dose escalation cohort 
[92%]) reported at least 1 TEAE irrespective of grade or causality.  In the MTD cohorts, 
fatigue was the most common AE reported (38%).  Other common AEs reported include 
nausea (32%), constipation (30%), upper respiratory infection (23%), and peripheral 
oedema (21%).  Skin toxicity, primarily erythematous rash, occurred in 62% of patients (of 
note, rash is an overlapping toxicity with MLN9708 and lenalidomide).  Peripheral 
neuropathy was reported in 13% of patients; Grade 3 in 1 patient.   
A summary of the overall safety profile of patients treated in Study C16005 is outlined in 
Table 1-6.  Overall, 100% of 65 patients experienced at least one TEAE of any grade and of 
any cause.   
Table 1-9    
Study C16005:  Oral MLN9708 Given Weekly in Combination With 
Lenalidomide and Dexamethasone, Most Common TEAEs as of 30 
April 2012 
Most Common (> 20%) Any Grade and Irrespective of 
Cause 
Fatigue (37%) 
Nausea (34%) 
Constipation (31%) 
Vomiting (28%) 
Diarrhoea (26%) 
Thrombocytopenia (23%) 
Upper respiratory tract infection (22%) 
Anaemia and oedema peripheral ( 20% each) 
Drug-Relateda Grade  3 in  2 Patients  
Nausea, vomiting (n=3 each)  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
36 
 
Thrombocytopenia, lymphopenia, rash pruritic (n=2 each ) 
 
Source: MLN9708 Investigator’s Brochure Edition 6. 
a 
Related means to ANY drug in the study drug combination. 
 
The most common drug-related SAEs reported in Study C16005 as of 30 April 2012 include 
pneumonia, infection, diverticulitis, localised infection, gastrointestinal haemorrhage, 
respiratory syncytial virus (RSV) pneumonia faecaloma, pyrexia, pneumonia respiratory 
syncytial viral, non-cardiac chest pain, peripheral oedma, asthenia, hyponatraemia vomiting, 
diarrhoea, nausea, chest pain, dehydration, anemia, dizziness, peripheral sensory neuropathy, 
orthostatic hypotension, embolism, muscular weakness, acute renal failure, blood creatinine 
increased, maculopapular rash, atrial fibrillation, syncope, hypotension, and deep vein 
thrombosis, and back pain.   
As of the clinical data cutoff, 4 patients have discontinued treatment due to TEAEs including 
gastrointestinal haemorrhage, angioedema, syncope, and RSV pneumonia. 
One death was reported for a patient with RSV pneumonia; the event was deemed by the 
investigator to be related to treatment with MLN9708.   
1.3.11 
Clinical Trial Experience Using the Intravenous Formulation of 
MLN9708 
See the IB for descriptions of the 2 ongoing studies investigating IV MLN9708 in advanced 
solid tumors and advanced lymphoma (Studies C16001 and C16002, respectively). 
 
 
 
 
Please refer to the current MLN9708 Investigator’s Brochure (IB) and Safety Management 
Attachment (SMA) for more information. 
 
1.3.12 
Potential Risks of MLN9708  
Safety information from toxicology studies as well as the preliminary safety information gained 
from clinical Studies C16001, C16002, C16003, C16004, C16005, C16006, C16007,  C16008, 
and C16009 has been used to guide the safety evaluation of MLN9708. As of 30 April 2012, 
safety data is available for 382 patients who have received multiple cycles of therapy (between 
1 and 28 cycles of MLN9708 therapy). Adverse events reported in MLN9708 clinical trials are 
generally consistent with the class-based effects of proteasome inhibition and are generally 
similar to what has been previously reported with VELCADE, though the severity of some, for 
example peripheral neuropathy, is less. While some of the potential toxicities may be severe, 
they can be managed by clinical monitoring and standard medical intervention, or, as needed, 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
37 
 
dose modification or discontinuation. Each protocol recommends that patients are monitored 
closely for the anticipated potential toxicities, as well as for any unanticipated toxicities when 
they receive MLN9708, and for at least 30 days after their last dose.  
 
1.3.12.1 Potential Risks by System Organ Class Include: 
 Blood and lymphatic system disorders: Neutropenia, anemia, lymphopenia. Reductions 
in blood counts may predispose patients to an increased susceptibility to infection (see 
Infections and infestations below) and anemia. Reticulocytopenia was described in 
animals and may be associated with anemia. 
 Gastrointestinal disorders: Constipation, intestinal obstruction including ileus and 
intussusception (described in animal studies), abdominal pain. 
 General disorders and administration site conditions: Pyrexia, chills, influenza like 
illness, edema peripheral. 
 Infections and infestations: Pneumonia. Lymphopenia may be associated with increased 
risk of infection, including re-activation of herpes zoster. 
 Investigations: Blood creatinine increased (see Renal and urinary disorders below). 
 Metabolism and nutrition disorders: Decreased appetite, dehydration, electrolyte 
imbalance. 
 Musculoskeletal and connective tissue disorders: Back pain, myalgia, arthralgia, bone 
pain, pain in extremity. 
 Nervous system disorders: Headache, dizziness, neuropathy peripheral (includes pain, 
burning sensation, and numbness), and syncope. In addition, autonomic and motor 
neuropathy may be observed, as both have been reported for VELCADE, another 
proteasome inhibitor. Posterior reversible encephalopathy syndrome (PRES) has been 
reported with MLN9708 (this event was reported after the data cut-off date, 30 April 
2012). PRES has also been reported for VELCADE (refer to VELCADE for Injection 
Package Insert). 
 Renal and urinary disorders: Renal impairment, renal failures, and renal failure acute 
have been reported in association with dehydration due to nausea, vomiting, anorexia, 
and/or diarrhea, the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and/or 
disease progression. In some situations, this has been severe, requiring temporary 
dialysis. 
 Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, upper respiratory tract 
infection, pneumonitis. 
 Skin and subcutaneous tissue disorders: A rare risk is Stevens-Johnson Syndrome, a 
severe, life-threatening or deadly rash with skin peeling and mouth sores, which should 
be managed symptomatically according to standard medical practice. Stevens-Johnson 
syndrome has also been reported for VELCADE (refer to VELCADE for Injection 
Package Insert). It is also reported as risk with lenalidomide, an agent used in the 
treatment of hematologic malignancies including in combination with proteasome 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
38 
 
inhibitors. For more information about this risk with lenalidomide refer to the Revlimid 
(lenalidomide) Package Insert. 
 Vascular disorders: Hypotension, orthostatic hypotension. 
Other: Acute phase response that may result in fever and metabolic changes (observed only in 
nonclinical studies). Infrequent incidences of tumor lysis syndrome have also been reported. 
Supplemental information is provided in the current edition of the IB. 
2 
Study rationale/purpose 
Multiple myeloma refractory to bortezomib and refractory to, relapsed after, or ineligible for 
IMiDs constitutes an unmet medical need with EFS and OS of 5 and 9 months, respectively, 
and response and clinical benefit response rates of 24 and 34%, respectively 49. A recently 
presented study suggests bortezomib refractoriness of multiple myeloma may be overcome by 
combination with panobinostat and dexamethasone. Enrolled patients were refractory to their 
last bortezomib containing regimen and achieved a remarkable response rate of 35% and 
clinical benefit response rate of 53% 7. The oral proteasome inhibitor MLN9708 (ixazomib) 
appears to not only be more convenient than bortezomib but also safer; with an otherwise 
comparable safety profile it has not caused any severe neuropathy at doses that had single agent 
activity in relapsed and refractory multiple myeloma when used in a twice a week dosing 
schedule 10 or administered weekly 9. The MTD for MLN9708 (ixazomib), when given twice a 
week (day 1,4,8,11 every 21 days) to patients with relapsed or refractory multiple myeloma was 
established at 2mg/m2, whereas weekly administration (day 1,8,15 every 28 days) was tolerated 
at higher doses (MTD 2.97mg/m2) in a comparable patient population 9,10. Another study used 
MLN9708 (ixazomib) in a weekly administration schedule (day 1,8,15 every 28 days) in 
combination with lenalidomide (25mg day 1-21 every 28 days) and dexamethasone (40mg once 
a week) in newly diagnosed multiple myeloma 8. This study also found the MTD of MLN9708 
(ixazomib) to be at 2.97mg/m2 but recommended 2.23mg/m2 for phase 2 evaluation because 
of improved tolerance. The most common possibly MLN9708 (ixazomib) related adverse 
events in these studies were thrombocytopenia, neutropenia, fatigue, and gastrointestinal 
adverse events including nausea and diarrhea. Gupta et al. analyzed pharmacokinetic data of 
the active metabolite of MLN9708 (ixazomib) from 4 trials that used either IV or PO dosing. 
Using a non-linear mixed effects modeling approach he found that body size affected only 
volume of distribution but not maximal or AUC concentrations 11. A decision was therefore 
made by the manufacturer Millennium to use flat dosing in future trials, using 2.3mg, 3mg, and 
4mg tablets. 
Here we aim to develop an “all oral” regimen of proteasome and histone deacetylase inhibition 
in combination with dexamethasone for future phase 2 study and as a platform for addition of 
further drugs.  
Phase II extension: Patients in phase I (median age 65, range 50-73, median previous regimens 
5, range 2-10) tolerated treatment without DLT and without non-hematologic severe (grade 3 
or higher) adverse event according to CTCAE vs.4.03. Three patients developed grade 3 
hematologic toxicities (2 neutropenia, 1 thrombocytopenia). Worst diarrhea was grade 1 (n=6), 
worst nausea grade 2 (n=1) and 4 additional patients developed transient grade 1 nausea. Other 
possibly panobinostat or ixazomib related grade 1/2 adverse events included thrombocytopenia 
(n=5), neutropenia (n=3), fatigue (n=2), anemia (n=2), anorexia (n=1) and arthralgia (n=1). 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
39 
 
Median QTcF before treatment start was 405 msec (range 378-430) and increased on average 
by 4.3% (maximally by 13%). One patient developed transient grade 1 QTcF prolongation to 
552 msec. No other cardiac adverse events were observed. Of the 11 patients in phase I, one 
reached PR, two reached MR, and one had stable disease for 6 months. All patients entered the 
study with disease refractory to their last regimen, and in two of the responding patients (1PR, 
1MR) this included a proteasome inhibitor an IMiD, and a glucocorticosteroid (carfilzomib, 
pomalidomide, dexamethasone in the MR patient, bortezomib, dexamethasone, lenalidomide in 
the MR patient). Overall, we are encouraged by activity in extensively pretreated patients and 
by excellent tolerance of this regimen so far. In phase II we aim to extend the study cohort by 
an additional 20 patients who will be treated until progression or other reasons for 
discontinuation arise (7.6.1) to strengthen the safety analysis and obtain a more reliable estimate 
of activity. 
3 
Study objectives 
 
3.1 
Primary Objective 
 Define the tolerability and safety of MLN9708 (ixazomib) administered on a day 1,8,15 
every 28 day schedule up to 4mg in combination with fixed doses of panobinostat and 
dexamethasone in patients with relapsed or refractory myeloma. 
3.2 
Secondary Objective 
 Assess response and clinical benefit response rates according to international uniform 
response criteria and adapted EBMT criteria, respectively (see under 8.1) 
 Assess progression-free survival (PFS) and overall survival (OS) 
 
4 
Study endpoints:   
4.1 
Primary endpoints: 
 Dose limiting toxicity (phase I) and tolerance according to CTCAE vs. 4.03 (phase I 
and II) 
4.2 
Secondary endpoints: 
 Response to panobinostat, dexamethasone, ixazomib (MLN9708) will be assessed 
according to international uniform response criteria and clinical benefit response 
according to modified EBMT response criteria, comparing myeloma panels obtained 
at the beginning of each cycle that include SPEP, 24 h UPEP, serum and urine IFEs, 
and serum free light chains to results at screening. In addition a baseline bone marrow 
exam and skeletal survey will be obtained and repeated as clinically indicated and for 
assessment of complete remission (bone marrow). 
 Progression-free survival will be measured from study entry to progression or death 
of any cause, whichever comes first.  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
40 
 
 Overall survival for all will be measured from study entry to death from any cause. 
5 
Overall study design, treatment cycles, and study duration 
 
5.1 
Study design and treatment cycles 
Phase I: This study will use a modified 3 + 3 design to define the tolerability and safety of 
MLN9708 (ixazomib) administered to at least 6 patients with relapsed or refractory myeloma 
on a day 1,8,15 every 28 day schedule at up to 4mg in combination with fixed doses of 
panobinostat and dexamethasone.  
 
Dose limiting toxicities (DLTs, see under 5.4) will be assessed at the end of the first cycle, on 
day 28. The trial will accrue up to three patients at any given DL who will need to be assessed 
for DLTs before the next three patients can be enrolled. Determination of the highest tolerated 
dose of two tested dose levels will require treatment of at least 6 patients at the respective dose 
level with no more than one patient developing a DLT. 
 
The first three patients will be treated at DL1. If no patient develops any DLT, the next three 
patients will be enrolled at DL2. If 1 patient develops any DLT, three additional patients will 
be enrolled at DL1. If no more than 1 of 6 patients treated at DL1 develops a DLT, the next 
three patients will be enrolled at DL2. If 2 or more of 2-6 patients treated at DL1 develop DLTs 
further enrollment will be stopped and a change in the protocol will be discussed. If DL2 opens 
to enrollment, and 0-1 of the first three patients develop any DLT, additional three patients will 
be enrolled at DL2 and if no more than 1 of 6 patients treated at DL2 develop any DLT, DL2 
will be considered a tolerated MLN9708 dose and further dose escalation will not be done. If 2 
of three or up to 6 patients enrolled at DL2 develop any DLT, further enrollment at that dose 
level will be stopped and enrollment will continue at DL1 unless 6 patients have already been 
treated at that dose level. If no more than 1 patient treated at DL1 develops any DLT that dose 
level will be considered tolerated and an intermediate dose level may be discussed. If 2 or more 
of up to 6 patients treated at DL1 develop a DLT, further enrollment will be stopped and a 
change in the protocol will be discussed. 
 
Phase II: Twenty additional patients will be treated at target doses of DL2 which has been found 
to be well tolerated without any DLT in phase I. 
 
 
5.2 
Study duration 
Phase I: Patients will remain on study for six 28-day cycles or until criteria for discontinuation 
(7.6.1) are met, whichever comes earlier. Decisions on subsequent maintenance therapy will at 
the discretion of the treating physician. If the patient’s myeloma is controlled in at least stable 
disease panobinostat may be continued free of charge to the patient. Follow up after completion 
of cycle 6 is at the discretion of the treating physician but if panobinostat is continued, 
monitoring for electrolyte abnormalities, especially potassium and magnesium, at a frequency 
appropriate for the respective patient, is recommended.  This protocol may be amended to 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
41 
 
include a formal maintenance phase and/or a phase II portion after review of safety and 
preliminary efficacy data. 
Phase II: Patients will receive therapy according to DL2 and will remain on study until criteria 
for discontinuation (7.6.1) are met. 
 
 
5.3 
Dose levels 
Dose levels are defined in table Table 5-1 
Dose 
level 
PO Panobinostat 
PO 
MLN9708 
(Ixazomib) 
PO Dexamethasone 
1 
20mg d 1,3,5,15,17,19 q 28 d 3mg d1,8,15 q 28 d 
20mg d 1,2,8,9,15,16 q 
28 d 
2 
20mg d 1,3,5,15,17,19 q 28 d 4mg d1,8,15 q 28 d 
20mg d 1,2,8,9,15,16 q 
28 d 
 
5.4 
Dose limiting toxicity 
 
Dose limiting toxicity (DLT) will be assessed during the first cycle and be defined as the 
following drug-related adverse events according to CTCAE version 4.03 (if an adverse event is 
attributed to progressive disease, it will not be counted as DLT): 
 Grade 4 or higher neutropenia or thrombocytopenia that does not resolve to grade 3 or 
lower within 7 days after detection while MLN9708 (ixazomib) and panobinostat are 
held. 
 Use of G-CSF or platelet transfusions in cycle one 
 Neutropenic fever (with grade 3 or grade 4 neutropenia) 
 QTcF increase to > 480 msec that persists > 7 days after withholding panobinostat and 
MLN9708 
 Any grade 3 or higher non-hematologic adverse events except: 
o 
Nausea, vomiting, diarrhea, or electrolyte abnormalities that can be reduced to 
grade 2 with supportive measures within 7 days 
 
 
Patients who cannot be assessed for DLT due to progressive disease or other reasons will be 
replaced. Patients who develop a DLT may remain on study. 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
42 
 
6 
Study population 
Patients with relapsed or refractory myeloma after at least two previous regimens including a 
proteasome inhibitor and an IMiDTM seen at the Cleveland Clinic Taussig Cancer Center will 
be screened for enrollment. Approximately 700 patients with multiple myeloma are seen each 
year at this site and approximately 600 have relapsed or refractory myeloma. The study will be 
offered to our partner institution within the Case Comprehensive Cancer Center, the Seidman 
Cancer Center of University Hospitals and Case Western University, where approximately 100 
patients with relapsed or refractory multiple myeloma are seen each year. Participation is 
expected and would not alter per patient costs. We have accrued 11 patients to phase I in about 
12 months and expect to enroll to phase II at a faster pace since no interruptions for DLT 
assessments will be required. We anticipate it will take about 18 months to accrue additional 20 
patients to phase II. . 
6.1.1 
Patient population 
Eleven patients have been enrolled to phase I and an additional 20 patients are planned for phase 
two totaling 31 patients for the entire study. 
6.1.2 
Inclusion and exclusion criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. Results of all baseline evaluations, which assure that 
all inclusion and exclusion criteria have been satisfied, must be reviewed by the Principal 
Investigator prior to enrollment of that patient. In addition, the patient must be thoroughly 
informed about all aspects of the study, including the study visit schedule and required 
evaluations and all regulatory requirements for informed consent. The written informed consent 
must be obtained from the patient prior to enrollment. The following criteria apply to all patients 
enrolled onto the study unless otherwise specified. 
Inclusion criteria  
1. Male or female patients aged ≥ 18 years old 
2. Ability to provide written informed consent obtained prior to participation in the study and 
any related procedures being performed 
3. Patients must carry a diagnosis of symptomatic multiple myeloma according to international 
myeloma working group criteria 50 and have relapsed or refractory disease according to 
international uniform response criteria and must have previously received therapy with a 
proteasome inhibitor and an IMiDTM 51,52(see also 6.2). 
4. Must have measurable disease defined as any of the following: Serum m-spike > 1g/dL, 24 
h urine m-spike of at least 200mg/d, involved serum free light chains > 100mg/L with 
abnormal serum free light chain ratio, bone marrow plasma cells of at least 30% 
5. ECOG PS < 2 
6. No gastro-intestinal condition, that in the opinion of the treating physician or the principal 
investigator significantly limits oral absorption 
7. No serious uncontrolled coexisting medical condition 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
43 
 
8. Patients must meet the following laboratory criteria: 
 ANC ≥ 1.0 x 109/L without use of pegfilgrastim in the preceding 21 days and without 
non-pegylated G-CSF or GM-CSF within 7 days prior to study entry 
 Hemoglobin ≥ 8 g/dl (may be after transfusion of packed red blood cells or use of 
erythropoiesis stimulating agents)  
 Platelets ≥ 70x 109/L without platelet transfusion 7 days prior to study entry 
 AST and ALT ≤ 2.5 x ULN  
 Serum bilirubin  1.5 x ULN 
 Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be 
achieved with repletion or other supportive medications like potassium sparing 
diuretics) Creatinine clearance  30 mL/min according to Cockroft-Gault formula (see 
Section 22) 
 Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone 
supplements to treat underlying hypothyroidism. 
9. Baseline MUGA or ECHO must demonstrate LVEF ≥ 45% 
10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test 
within 7 days prior to start of study treatment 
11. Male patients, even if surgically sterilized (i.e., status post vasectomy), have to either: 
 
Agree to practice effective barrier contraception during the entire study treatment period 
and through 4 months after the last dose of study treatment, OR 
 
Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception. 
12. Female patients have to fulfill one of the following: 
 
Be postmenopausal for at least 1 year before the Screening visit, OR 
 
Be surgically sterile, OR 
 
If of childbearing potential, agree to practice 2 effective methods of contraception, 
at the same time, from the time of signing the informed consent through 90 days 
after the last dose of study treatment 
 
Oral contraceptives are generally metabolized by CYP3A4. Since the induction 
potential of panobinostat to induce CYP3A4 is unknown, patients who are using oral 
contraceptives as a method of contraception, and are sexually active, should use 
another effective contraceptive method, AND Must also adhere to the guidelines of 
any treatment-specific pregnancy prevention program, if applicable, OR 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
44 
 
 
Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods 
of contraception.) 
13.  At least 7 days must have passed since the last treatment with lenalidomide, pomalidomide, 
thalidomide, proteasome inhibitors, or low dose cyclophosphamide (up to 50mg daily), at 
least 21 days must have passed since the last treatment with daratumumab, elotuzumab, 
investigational therapy and most conventional chemotherapy including cyclophosphamide 
above 50mg per dose, bendamustine, doxorubicin, cisplatin, and etoposide; and at least 35 
days since the last treatment with melphalan. 
 
Exclusion criteria 
1. Prior anti-cancer treatment with MLN9708 (ixazomib), HDAC, DAC, HSP90 inhibitors or 
valproic acid 
2.   Prior participation in a randomized controlled study that included MLN9708 (ixazomib)  in 
one of the treatment arms independent of whether assigned to MLN9708 (ixazomib) or not 
3.   Patients who will need valproic acid for any medical condition during the study or within 5 
days prior to first panobinostat treatment 
4.   Female patients who are lactating or have a positive serum pregnancy test during the 
screening period. 
5.   Impaired cardiac function or clinically significant cardiac diseases, including any one of 
the following: 
 History or presence of sustained ventricular tachyarrhythmia. (Patients with a history of 
atrial arrhythmia are eligible) 
 Any history of ventricular fibrillation or torsade de pointes 
 Bradycardia defined as HR< 50 bpm. Patients with pacemakers are eligible if HR ≥ 50 
bpm. 
 Screening ECG with a QTcF > 470 msec (QTcF=QT/3√RR). If potassium or magnesium 
blood levels are below normal limits, consider repeating ECG after correction of these 
electrolytes. 
 Right bundle branch block + left anterior hemiblock (bifascicular block) 
 Patients with myocardial infarction or unstable angina  ≤ 6 months prior to starting study 
drug 
 Other clinically significant heart disease (e.g., CHF NY Heart Association class III or 
IV , uncontrolled hypertension, history of labile hypertension, or history of poor 
compliance with an antihypertensive regimen) 
6.  Impairment of GI function or GI disease that may significantly alter the swallowing  
absorption of  panobinostat and MLN9708 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
45 
 
7.    Patients with diarrhea > CTCAE (version 4.03) grade 2 
8.  Patient has  Grade 3 peripheral neuropathy, or > Grade 2 with pain on clinical examination 
during the screening period. 
9.  Patients with known metastasis of malignant plasma cells to the central nervous system (if 
not suspected no specific testing is required) 
10.  Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes 
or active or uncontrolled infection) including abnormal laboratory values, that could cause 
unacceptable safety risks or compromise compliance with the protocol 
11.  Patients using medications that have a relative risk of prolonging the QT interval or inducing 
torsade de pointes if treatment cannot be discontinued or switched to a different medication 
prior to starting study drug. If an alternative medication that does not risk QT prolongation 
can safely be used in the opinion of the treating physician and the treatment is changed to 
that medication, the patient may be enrolled. 
12.  Patients who have not passed the nadir of bone marrow suppression from previous anti-
myeloma therapy yet. If in doubt, serial CBCs with differential should be obtained. 
13.  The corticosteroids prednisone and dexamethasone may be continued until the day before 
treatment start if all related adverse events are controlled at CTCAE version.4.03 grade < 1. 
14.  Patients who have received radiation therapy to more than half of the pelvis or more than half 
of the spine within < 2 weeks prior to starting study treatment; or who have not yet recovered 
from side effects of such therapies. 
15.  Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who 
have not recovered from side effects of such therapy 
16.  Systemic treatment, within 14 days before study enrollment, 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. 
17.  Ongoing or active systemic infection, known human immunodeficiency virus (HIV) positive, 
known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis. 
18.  Concurrent diagnosis of another malignancy if either systemic treatment or surgery is 
expected to be required within 2 years from study entry. 
19.  Known allergy to any of the study medications, their analogues, or excipients in the various 
formulations of any agent. 
20.  Patients with any significant history of non-compliance to medical regimens or unwilling or 
unable to comply with the instructions given to him/her by the study staff. 
21.  Infection requiring systemic antibiotic therapy or other serious infection within 14 days 
before study enrollment unless the patient is felt to have fully recovered and any antibiotics 
that are continued are either beta lactam antibiotics or are specifically allowed on study 
according to 7.7.1  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
46 
 
22.  Participation in other clinical trials, including those with other investigational agents not 
included in this trial, within 21 days of the start of this trial and throughout the duration of 
this trial. 
 
 
6.2 
Definition Relapsed Myeloma and Refractory Myeloma 
An ASH/FDA panel has recommended to include clinical criteria to define relapsed myeloma 
and to separately analyze data for the relapsed as opposed to the refractory group of patients 52. 
In accordance with this consensus statement, International Myeloma Working Group diagnostic 
criteria 50, and the international uniform response criteria 51 the following definitions will be 
used: 
 
6.2.1 Refractory Myeloma 
Biochemical or clinical evidence of loss of disease control within 60 days after the last therapy. 
Any of the following defines refractory myeloma: 
1. Progressive disease (see 8.1.1) on prior therapy 
2. Best response to prior therapy was stable disease (see 8.1) 
3. Progressive disease (see 8.1.1) within 60 days of the last therapy 
 
6.2.2 Relapsed Myeloma 
Not fulfilling criteria for refractory disease and at least one biochemical and at least one 
clinical criterion fulfilled indicating recurrence of disease more than 60 days after the last 
therapy:  
One or more biochemical criteria for recurrent disease: 
An increase of 25% from lowest response value in any one or more of the following, verified 
on two consecutive measurements: 
1. Serum M-component (absolute increase must be >0.5 g/100 ml) * 
2. Urine M-component (absolute increase must be >200mg per 24 h) 
3. Only in patients without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels (absolute increase must be >100 mg/l) 
4. Bone marrow plasma cell percentage (absolute % must be >10%) 
 
AND one or more clinical criteria for recurrent disease: 
 
Any of the following: 
1. Definite development of new bone lesions or soft tissue plasmacytomas 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
47 
 
2. Definite increase in the size of existing bone lesions or soft tissue plasmacytomas. A 
definite increase is defined as a 50% (and at least 1 cm) increase as measured serially 
by the sum of the products of the cross-diameters of each measurable lesion 
3. Development of hypercalcemia (corrected serum calcium >11.5mg / 100ml) that can be 
attributed solely to the plasma cell proliferative disorder 
4. Decrease of hemoglobin by at least 2g/dL below the best independent value (without 
ESA or blood transfusion for at least 28 days) since the  end of previous therapy or new 
decrease in HgB below 10g/dL or to 2g/dL below the lower limit of normal 
5. New increase in serum creatinine to > 2mg/dL, or increase by 2mg/dL attributed to 
myeloma progression 
 
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, verified 
on two consecutive measurements, is sufficient as a biochemical criterion for recurrent 
disease. 
 
 
7 
Treatments 
7.1 
Investigational therapy 
7.1.1 
Panobinostat 
Panobinostat (also known as LBH589) will be provided by Novartis. Oral panobinostat will be 
supplied as 5-mg, 15-mg,  or 20-mg pink/opaque-colored, hard gelatin capsules. 
 Medication labels will comply with US legal requirements and be printed in English. They will 
supply no information about the patient. The storage conditions for study drug will be described 
on the medication label. 
During the study, panobinostat will be administered orally as once daily dose of 20 mg. 
according to the schedule in 5.3.  
Patients should be instructed to take their once-a-day oral dose of panobinostat at the same time 
each morning. Each dose of panobinostat should be taken with an 8 oz / 240 ml glass of water 
after a meal. Patients should be instructed to swallow the capsules whole and not chew them. 
Patients must avoid grapefruit or grapefruit juice and seville (sour) oranges during the entire 
study. 
On the days of ECG monitoring, drug administration should be supervised by study center 
personnel and administration time should be recorded.  Subsequently, ECGs should be 
performed at the predefined time points.) 
If the patient forgets to take his/her dose during the morning on scheduled treatment day, then 
he/she should take panobinostat (LBH589) on that same day within 12 hours after the missed 
dose if possible. After more than 12 hours, that day’s dose should be withheld, and the patient 
should wait to take LBH589 until the next scheduled treatment day (i.e., patients should be 
instructed not to try to make-up the missed dose after 12 hours). The patient should then 
continue treatment with the original dosing schedule 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
48 
 
The investigator should instruct the patient to take the study drug exactly as prescribed (promote 
compliance). All dosages prescribed and dispensed to the patient and all dose changes during 
the study should be recorded. 
 
7.1.2 
MLN9708 (Ixazomib) 
 
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified sub investigator(s).  Patients should be monitored 
for toxicity, as necessary, and doses of MLN9708 should be modified as needed to 
accommodate patient tolerance to treatment; this may include symptomatic treatment, dose 
interruptions, and adjustments of MLN9708 dose (see under 7.5). 
7.1.2.1 
MLN9708 (Ixazomib) Administration  
Capsules of MLN9708 will be supplied by Millennium as capsules of 2.3 mg, 3.0 mg, and 4.0 
mg MLN9708. 
The prescribed administration of MLN9708 doses and schedules in this study are outlined in 
5.3 
Patients should be instructed to swallow MLN9708 capsules whole, with water, and not to 
break, chew, or open the capsules.  Study drug should be taken on an empty stomach (no food 
or drink) at least 1 hour before or 2 hours after a meal.    A total of approximately 8 ounces (240 
mL) of water should be taken with each  capsule.   
Missed doses can be taken as soon as the patient remembers if the next scheduled dose is 
72 hours or more away.  A double dose should not be taken to make up for a missed dose.  If 
the patient vomits after taking a dose, the patient should not repeat the dose but should resume 
dosing at the time of the next scheduled dose. 
 
7.1.2.2 
MLN9708 Destruction 
 
Investigational MLN9708 (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. 
7.1.2.3 
Packaging, and Labeling of MLN9708 
For blistered material, the capsules are packaged in cold form foil-foil blisters with a paper 
backing for child-resistance. 
MLN9708 is an anticancer drug and as with other potentially toxic compounds caution should 
be exercised when handling MLN9708 capsules. 
The study drug MLN9708 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 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
49 
 
specified by governing regulations.  The formulation consists of 0.5-, and 2.0-mg capsules for 
oral administration. 
MLN9708 capsules should be stored unopened at 2°C to 8°C (36°F-46°F).  The capsules are 
individually packaged in cold form foil-foil blisters in a child-resistant package.   The 0.2-, 0.5-
, and 2.0 mg capsules are in 1  4 blister strips that are individually perforated.  The strips (1  
4) are placed in cartons containing 6 strips (24 total capsules) of the same strength. The 2.3-, 
3.0-, and 4.0 mg capsules are supplied as a 1 x 3 blister card in a child-resistant cardboard wallet. 
Storage, Handling, and Accountability 
Upon receipt at the investigative site, MLN9708 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). All excursions should be brought to Millennium’s 
attention for assessment and authorization for continued use. Ensure that the drug is used before 
the retest expiry date provided by Millennium. Expiry extensions will be communicated 
accordingly with updated documentation to support the extended shelf life. 
In countries where local regulations permit, MLN9708 capsules dispensed to the patient for 
take-home dosing should remain in the blister packaging and refrigerated as noted above until 
the point of use. The investigative site is responsible for providing the medication to the patient 
in the correct daily dose configurations. Approval for any patient for take-home medication 
must be discussed with Millennium in order to ensure the greatest conformity with repackaging, 
labeling, and patient compliance. Comprehensive instructions should be provided to the patient 
in order to ensure compliance with dosing procedures. Patients who are receiving take-home 
medication should be given only 1 cycle of medication at a time. Patients should be instructed 
to store the medication refrigerated (36°F to 46°F, 2°C to 8°C) for the duration of each cycle. 
Patients should be instructed to return their empty blister packs to the investigative site, rather 
than discarding them. Reconciliation will occur accordingly when the patient returns for their 
next cycle of take-home medication. Any extreme in temperature should be reported as an 
excursion and should be dealt with on a case-by-case basis. 
Because MLN9708 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 (e.g., from a broken capsule), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of contact 
with the eyes, copious amounts of water should be used to flush the eyes for at least 15 minutes. 
Medical personnel should be notified. Patients are to be instructed on proper storage, 
accountability, and administration of MLN9708, including that MLN9708 is to be taken as 
intact capsules. 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
50 
 
7.1.3 
Cardiac precautions 
All patients must have an assessment of serum potassium, magnesium, and calcium (total 
corrected for albumin, or ionized calcium) ≤ 72 hours prior to the administration of oral 
panobinostat on day 1 of cycle 1 and the results must all be ≥ LLN before the first dose of 
panobinostat is administered. Throughout the study serum biochemistry values including serum 
potassium, calcium, and magnesium will be monitored closely. On any day and time in which 
serum potassium, calcium, and magnesium are assessed, if the value is < LLN, then the patient’s 
potassium, calcium,  or magnesium should be immediately supplemented following the 
availability of that laboratory result, in order to minimize the time patients have low values. 
Patients must then undergo a repeat biochemistry test to demonstrate values ≥ LLN. These 
values must be ≥ LLN before the patient is re-dosed with oral panobinostat. 
Patients must be instructed to not take panobinostat if their most recent biochemistry values 
demonstrates potassium, calcium, or magnesium < LLN. At a minimum, potassium, 
magnesium, and calcium will be checked according to the protocol. More frequent testing 
should be done if clinically indicated, e.g. patient has had prior low values, patient is taking 
medications (e.g., diuretics) that can result in lowering of their potassium, magnesium, or 
calcium levels. 
 
7.2 
Dexamethasone  
Dexamethasone will be prescribed as 4mg tablets and charged to the patient’s insurance. 
Dexamethasone tablets should be taken after breakfast with approximately 8 ounces (240 mL) 
of water. Missed doses can be made up until 72h from the next planned dose. Adherence will 
be evaluated together with adherence to investigational therapy. 
 
 
 
 
7.3 
Mandatory concomitant therapy 
 
7.3.1.1 
Herpes prophylaxis 
The risk for shingles is increased with proteasome inhibition and can be decreased with 
prophylactic acyclovir 53. All patients will receive prophylaxis with acyclovir 400mg orally 
twice a day or valacyclovir 1000mg orally once a day. If the creatinine clearance of a patient 
drops below 30ml/min while a patient is on study, acyclovir should be reduced to 200mg twice 
a day and valacyclovir to 500mg orally once a day. 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
51 
 
7.4 
Instructions for Initiation of a New Cycle 
A new course of treatment may begin on the scheduled Day 1 of a new cycle (cycle 2 and 
beyond) if: 
 ANC ≥ 1.0 x 109/L (G-CSF and GM-CSF are allowed to achieve this threshold) 
 Platelets ≥ 50x 109/L, without platelet transfusion for > 72h 
 AST and ALT ≤ 3 x ULN  
 Serum bilirubin  3 x ULN 
 Serum potassium ≥ LLN and serum magnesium ≥ LLN (electrolyte levels may be 
achieved with repletion or other supportive medications like potassium sparing 
diuretics) 
 QTcF < 480 msec if ECG obtained (mandatory before cycle 2) 
 Any non-hematologic drug-related adverse events that may have occurred have resolved 
to ≤ grade 1 or baseline severity. Physician discretion may be used in initiating the next 
cycle of treatment if the only toxicities that have not resolved to ≤ grade 2 severity are 
dexamethasone-related toxicities. 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated at least 
weekly and a new cycle of treatment will not be initiated until the toxicity has resolved as 
described above. If a prolonged QTcF prevents re-initiation of therapy for more than 7 days the 
patient will be taken off study. For phase I patients only: If other criteria to initiate a new cycle 
are not met by 14 days after the planned start of a new cycle patients also go off study. 
 
 
7.5 
Dose modifications for adverse events 
7.5.1 
Dose reduction guidelines 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to keep the patient on study drugs. If administration of panobinostat, 
MLN9708 (ixazomib), or dexamethasone must be interrupted because of unacceptable toxicity, 
drug dosing will be interrupted or modified according to guidelines outlined below.  Clinical 
judgment may be used when deciding which drug to hold or modify in scenarios that are not 
covered below. Also, if the treating physician feels dose reduction by one level will not suffice 
to avoid recurrence of an observed profound adverse event, dose reduction by more than one 
dose level or before the severe adverse event occurs is allowed. If an adverse event is felt not 
related to study drug but continued use of study drugs may worsen the adverse event, holding 
the respective study drug until resolution of the adverse event without dose reduction at re-
initiation of therapy is allowed. Toxicity will be assessed using the NIH-NCI Common 
Terminology 
Criteria 
for 
Adverse 
Events, 
version 
4.03 
(CTCAEv4.03, 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf). 
All 
interruption or changes to study drug administration must be recoded. 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
52 
 
7.5.2 
Dose Re-Escalation Guidelines 
If an entire cycle was tolerated without need for dose reduction and it is felt that the patient may 
tolerate a re-escalation of study therapy due to improved disease control or optimized supportive 
measures, doses may be increased by one level per cycle for either ixazomib (MLN9708) or 
panobinostat with or without concurrent increase of dexamethasone up to maximally starting 
dose level. 
Table 7-1    
Dose modification (DM) levels for adverse events attributed to MLN9708 
DM Level 
 
MLN9708 dose modification dependent on starting dose (maintain schedule of 
administration on  day 1,8,15 every 28 days in all DM levels) 
Starting dose 
0 
3mg 
4mg 
-1 
2.3mg 
3mg 
- 2 
Discontinue MLN9708 
2.3mg 
-3 
 
Discontinue MLN9708 
 
Table 7-2    
Dose modification (DM) levels for adverse events attributed to panobinostat 
DM Level 
Panobinostat dose (maintain schedule of administration on d 
1,3,5,15,17,19 q 28 d in all DM levels) 
0 
20mg 
-1 
15mg 
-2 
10mg 
-3 
 5mg 
-4 
Discontinue panobinostat 
 
Dose modification (DM) levels for adverse events attributed to panobinostat and MLN9708 
Modify dosing schedules as outlined in table 7-1 and 7-2 alternating between panobinostat and 
MLN9708, starting with panobinostat 
 
Table 7-3    
Dose modification (DM) levels for adverse events attributed to 
dexamethasone 
DM Level 
Dexamethasone 
0 
20mg d 1,2,8,9,15,16 q 28 d 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
53 
 
-1 
20mg d 1,8,15,22 q 28 d 
-2 
16mg d 1,8,15.22 q 28 d 
-3 
12mg d 1,8,15,22 q 28 d 
-4 
Discontinue dexamethasone 
 
 
 
 
7.5.3 
Dose modifications for study drug-related toxicity (see section 7.5.4 for dose 
modifications for prolonged QTc):  
The criteria for dose modifications for study drug-related toxicity are detailed in table 7-4. 
 
Table 7-4    
Criteria for dosing delays, dose-reductions, and re-initiation of treatment 
due to study drug-related toxicity (excluding QT prolongation) 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
HEMATOLOGICAL TOXICITIES 
Thrombocytopenia 
Grade 4 (< 25 x 109/L) 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until platelets have increased to> 50 
x 109/L, then reduce dose of one of 
these drugs by one level per cycle  
starting with panobinostat until 
panobinostat is at 10mg, then 
alternate 
with 
ixazomib 
dose 
reductions 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
54 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
Neutropenia (ANC) 
Grade 4 (ANC < 0.5 x 109/L) Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
and consider use of G-CSF or GM-
CSF until the ANC has increased to 
> 0.5 x 109/L , then reduce dose of 
one of these drugs by one level per 
cycle starting with  panobinostat 
until panobinostat is at 10mg, then 
alternate 
with 
ixazomib 
dose 
reductions. If neutropenia was the 
only reason for dose reduction, 
consider maintaining the same dose 
level with prophylactic use of G-CSF 
or GM-CSF in the next cycle when 
neutrophil counts decrease below 1 x 
109/L.  
Febrile neutropenia 
(ANC < 1.0 x 109/L, fever ≥ 
38.5°C) 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
and consider use of G-CSF or GM-
CSF until fever resolved and ANC ≤ 
grade 2, then reduce dose of one of 
these drugs by one level per cycle 
starting with  panobinostat until 
panobinostat is at 10mg, then 
alternate 
with 
ixazomib 
dose 
reductions.   


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
55 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
NON-HEMATOLOGICAL TOXICITIES 
CARDIAC 
Cardiac - Prolonged QT interval** 
Please refer to Section 7.5.4. 
PERIPHERAL NEUROPATHY 
Grade 1-2 with clinically significant impact on 
quality of life 
Consider 
holding 
ixazomib 
(MLN9708) 
and 
restarting 
at 
reduced level upon satisfactory 
improvement 
Grade 3 
Hold ixazomib (MLN9708) and 
restart 
at 
reduced 
level 
upon 
resolution to Grade ≤ 1 or baseline. 
Grade 4 
Permanently discontinue ixazomib 
(MLN9708) 
RASH 
Grade 2 
Symptomatic recommendations as 
per section 7.6 
GASTROINTESTINAL 
Diarrhea 
Grade 2 (4-6 stools/day 
over baseline, etc.) despite 
the 
use 
of 
optimal 
antidiarrheal medications 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until resolved to ≤ grade 1, or 
baseline, then restart at unchanged 
dose levels at the first occurrence. If 
this adverse event recurs at grade 2 in 
subsequent cycles reduce dose by 
one 
level 
alternating 
between 
panobinostat and MLN9708, starting 
with panobinostat.  
Grade 3 (≥ 7 stools/day over 
baseline, etc.) despite the 
use of optimal antidiarrheal 
medications 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until resolved to ≤ grade 1, or 
baseline, then reduce dose by one 
level 
alternating 
between 
panobinostat and MLN9708, starting 
with panobinostat.  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
56 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
Grade 4 (life-threatening 
consequences, 
hemodynamic 
collapse, 
etc.) despite the use of 
optimal 
antidiarrheal 
medications 
Take patient off study. 
Nausea/vomiting 
Grade 1 & 2 not requiring 
treatment 
or 
controlled 
using standard anti-emetics 
Maintain 
dose 
levels 
of 
panobinostat, 
MLN9708, 
and 
dexamethasone. 
Grade 3 or 4 vomiting or 
Grade 3 nausea that cannot 
be controlled despite the 
use of standard anti-emetics 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until resolved to ≤ grade 1, or 
baseline, then reduce dose by one 
level 
alternating 
between 
panobinostat and MLN9708, starting 
with panobinostat.  
FATIGUE 
Fatigue 
Grade 
3 
(fatigue 
not 
relieved by rest limiting 
self-care activities of daily 
life) 
Temporarily 
discontinue 
panobinostat dosing until resolved to 
≤ grade 2 (fatigue not relieved by rest 
limiting instrumental activities of 
daily life), or baseline, then reduce 
dose by one level 
alternating 
between 
panobinostat 
and 
MLN9708, 
starting 
with 
panobinostat.  
HEPATIC 
Total Bilirubin 
Grade 3-4 (> 3 x ULN) 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until resolved to ≤ grade 2, or 
baseline, then reduce dose by one 
level 
alternating 
between 
panobinostat and MLN9708, starting 
with panobinostat.  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
57 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
AST/SGOT, ALT/SGPT 
> 5-10 x ULN 
Temporarily 
discontinue 
panobinostat and MLN9708 dosing 
until resolved to ≤ grade 1 (or ≤ grade 
2 if liver infiltration with myeloma is 
present), or baseline, then: 
 If resolved within 7 days, then: 
 restart 
panobinostat 
and 
MLN9708 at unchanged dose 
levels 
If resolved in more than 7 days, then 
reduce dose by one level alternating 
between 
panobinostat 
and 
MLN9708, 
starting 
with 
panobinostat.  
> 10 x ULN 
Temporarily 
discontinue 
panobinostat dosing until resolved to 
≤ grade 1, or baseline, then reduce 
dose by one level 
alternating 
between 
panobinostat 
and 
MLN9708, 
starting 
with 
panobinostat.  
Other NON-HEMATOLOGICAL TOXICITIES 
Grade 2 with clinically significant impact on quality 
of life 
Consider holding study drug(s) felt 
to be responsible and restarting at 
reduced level and/or with improved 
supportive 
measures 
upon 
satisfactory improvement. 
Grade 3  
Hold study drug(s) felt to be 
responsible and restart at reduced 
dose level upon resolution to Grade 
≤ 1 or baseline. 
Grade 4 
Strongly 
consider 
permanently 
discontinuing study drug(s) felt to be 
responsible but resuming at reduced 
dose upon resolution to < grade 1 or 
baseline is allowed if clinical 
judgment suggests net benefit from 
continued treatment. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
58 
 
Worst Toxicity 
CTCAE Grade* unless otherwise specified (Value) 
Dose Modification Guidelines 
At any time during a cycle of 
therapy (including intended day of 
dosing) 
All dose modifications should be based on the worst preceding toxicity. 
* Common Terminology Criteria for Adverse Events (CTCAE Version 4) 
 ** It is critical that electrolyte abnormalities be followed closely and corrected prior to dosing 
*** See also concomitant medication Section 7.7 
 
 
7.5.4 
Dose modifications for prolonged QTcF 
All cardiac events should be treated as per the local standard of care and referred to a specialist 
if clinically indicated. Initial assessments will be made by the treating physician based on the 
QTc calculated by the ECG machine according to the Bazett formula (QTcB=QT/√RR). Any 
panobinostat dosing or withholding decisions will only be made after calculation of the QTcF 
according to the following formula QTcF=QT/3√RR by trained research nurses or the principal 
investigator. If a patient cannot be dosed due to prolonged QTcF for more than 7 days since last 
dose, patient should be discontinued from study. 
 
Table 7-5    
Dose modifications for prolonged QTcF 
ECGs 
to 
be 
performed 
at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy 
(including intended day of dosing) 
Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: 
𝑸𝑻𝒄𝑭= 𝑸𝑻 (𝒎𝒔𝒆𝒄)/√𝑹𝑹
𝟑
(𝒔𝒆𝒄 
Pre-panobinostat-
dose on cycle 1, day 
1: 
3 ECGs separated by 
5-10 
minutes, 
obtained 
prior 
to 
panobinostat dosing. 
Average QTcF > 470 
msec 
Check and correct the patient’s serum 
potassium, 
magnesium, 
and 
calcium 
immediately, as well as evaluate con-meds 
that can prolong (or is known to be associated 
with) QTc interval. 
 
Repeat 3 pre-panobinostat-dose ECGs. 
If the 3 pre-panobinostat-dose ECGs: 
Do not meet criteria again, discontinue 
patient from study. 
Do meet criteria for dosing; administer study 
drug treatment. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
59 
 
ECGs 
to 
be 
performed 
at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy 
(including intended day of dosing) 
Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: 
𝑸𝑻𝒄𝑭= 𝑸𝑻 (𝒎𝒔𝒆𝒄)/√𝑹𝑹
𝟑
(𝒔𝒆𝒄 
Pre-panobinostat-
dose on day 5, cycle 
1, and on day 1 of 
subsequent cycles: 
3 ECGs separated by 
5-10 
minutes, 
obtained 
prior 
to 
panobinostat dosing 
Average QTcF: 
≥ 481 msec to < 500 
msec 
OR 
> 60 msec increase 
from 
baseline 
average 
Check and correct the patient’s serum 
potassium, 
magnesium, 
and 
calcium 
immediately, as well as evaluate con-meds. 
 
Delay panobinostat dose at least 3 days, hold 
MLN9708, and repeat 3 pre-panobinostat-
dose ECGs. 
 
If the repeat 3 pre-panobinostat-dose ECGs: 
Do not meet pre-panobinostat-dose ECG 
criteria again, discontinue patient from study. 
Do meet pre-panobinostat-dose ECG criteria 
for dosing and QT prolongation determined 
to be related to study drug, resume study drug 
treatment with a panobinostat dose reduction 
of 5 mg. If however, it was determined that 
the QT prolongation was secondary to 
electrolyte 
abnormalities 
or 
con-meds, 
continue at the same dose level upon 
correction of the electrolyte imbalance or 
discontinuation of the offending con-med. 
Repeat ECGs - pre-panobinostat-dose (x3), 
3-hours post-panobinostat-dose (x3), on the 
next scheduled panobinostat dosing day. 
Pre-panobinostat-
dose on cycle 1, day 
5 and on day 1 of 
subsequent cycles: 
3 ECGs separated by 
5-10 
minutes, 
obtained 
prior 
to 
panobinostat dosing 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum 
potassium, 
magnesium, 
and 
calcium 
immediately. 
Discontinue patient from study therapy. 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds: 
Omit panobinostat and next MLN9708 dose. 
On the next scheduled panobinostat dosing 
day continue at the same dose level. Repeat 
ECGs - pre-panobinostat-dose (x3), 3-hours 
post-panobinostat-dose (x3), on the next 
scheduled dosing day. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
60 
 
ECGs 
to 
be 
performed 
at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy 
(including intended day of dosing) 
Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: 
𝑸𝑻𝒄𝑭= 𝑸𝑻 (𝒎𝒔𝒆𝒄)/√𝑹𝑹
𝟑
(𝒔𝒆𝒄 
Post-panobinostat 
dose on cycle 1, days 
1 and 5: 
3 ECGs separated by 
5-10 
minutes, 
obtained 3 hours +/- 
0.5 
hours 
after 
panobinostat dosing: 
 
Average QTcF ≥ 481 
msec to < 500 msec 
OR 
> 60 msec increase 
from baseline 
Check and correct the patient’s serum 
potassium, 
magnesium, 
and 
calcium 
immediately, as well as evaluate con-meds. 
Monitor ECG hourly or by telemetry until 
at least 2 consecutive hourly ECGs 
performed at least 6 hours post dose show 
QTcF < 481. 
Next scheduled panobinostat dosing day: 
repeat 3 pre-panobinostat-dose ECGs. 
If these 3 pre-panobinostat-dose ECGs: 
Do not meet pre-panobinostat-dose ECG 
criteria for dosing (average QTcF ≤ 480 
msec), discontinue patient from study. 
Do meet pre-panobinostat-dose ECG criteria 
for dosing (average QTcF ≤ 480 msec) and 
QT prolongation determined to be related to 
study drug, resume study drug treatment with 
a panobinostat dose reduction of 5 mg. If 
however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities or con-meds, continue at the 
same dose level if responsible con-meds 
could be stopped and any electrolyte 
abnormalities are corrected. Repeat ECGs - 
pre-panobinostat-dose (x3), 3-hours post-
panobinostat-dose (x3) on the next scheduled 
dosing day. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
61 
 
ECGs 
to 
be 
performed 
at 
specified time point 
Abnormality Noted 
Dose Modification Guideline - 
At any time during a cycle of therapy 
(including intended day of dosing) 
Dose modifications are based on local readings of the average QTcF* of triplicate ECGs. 
*QTcF: Heart rate corrected QT interval using the Fredericia formula: 
𝑸𝑻𝒄𝑭= 𝑸𝑻 (𝒎𝒔𝒆𝒄)/√𝑹𝑹
𝟑
(𝒔𝒆𝒄 
Average QTcF ≥ 500 
msec 
Check and correct the patient’s serum 
potassium, 
magnesium, 
and 
calcium 
immediately. 
 
Discontinue patient from study therapy and 
monitor ECG hourly or by telemetry until at 
least 2 consecutive hourly ECGs performed 
at least 6 hours post dose show QTcF < 480. 
 
If however, it was determined that the QT 
prolongation was secondary to electrolyte 
abnormalities 
or 
con-meds: 
omit 
panobinostat and MLN9708 dose. On the 
next scheduled dosing day continue at the 
same dose level. Repeat ECGs - pre-
panobinostat-dose 
(x3), 
3-hours 
post-
panobinostat-dose 
(x3), 
on 
the 
next 
scheduled dosing day. 
 
 
7.6 
   Management of Clinical Events 
Infections 
Mild infections may be treated with concurrent oral antibiotics of the beta-lactam class, with 
azithromycin or levofloxacin, or with other antibiotics taking possible pharmacokinetic 
interactions with panobinostat and MLN9708 into account. Infections that are associated with 
fever (temperature 38C on two consecutive measurements or one temperature of 38.5 C or 
higher) or with other concerning clinical signs or symptoms require holding all study drugs until 
the infection is controlled. 
Nausea and/or Vomiting 
Standard anti-emetics, including 5-HT3 antagonists, are recommended for emesis occurring 
upon treatment initiation; prophylactic anti-emetics may also be considered.  Dexamethasone 
should not be administered as an anti-emetic.  Fluid deficits should be corrected before initiation 
of study drug and during treatment. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
62 
 
Diarrhea 
Diarrhea should be managed according to standard clinical practice, including the 
administration of antidiarrheals once infectious causes are excluded.  Fluid intake should be 
maintained to avoid dehydration.  Fluid deficits should be corrected before initiation of 
treatment and during treatment. 
Erythematous Rash With or Without Pruritus 
As with VELCADE, rash with or without pruritus has been reported with MLN9708, primarily 
at the higher doses tested.  The rash may range from some erythematous areas to macular and/or 
small papular bumps that may or may not be pruritic over a few areas of the body or more 
generalized, or it may have been transient and resolved either spontaneously or with standard 
symptomatic measures such as oral or topical antihistamines.  Prophylactic measures should 
also be considered if a patient develops a rash (e.g., using a thick, alcohol-free emollient cream 
on dry areas of the body).  In the case of rash, the use of a topical or oral steroid (e.g., prednisone 
≤ 10 mg per day or equivalent) is permitted. A rare risk is Stevens-Johnson Syndrome, a severe, 
life-threatening or deadly rash with skin peeling and mouth sores, which should be managed 
symptomatically according to standard medical practice.  
 
Thrombocytopenia 
Thrombocytopenia has been reported with MLN9708 and panobinostat.  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.  MLN9708 administration should 
be modified as noted as per dose modification recommendations in Table 3-2 and Table 7-4 
when thrombocytopenia occurs.  Therapy can be reinitiated at a reduced level upon recovery of 
platelet counts. 
Neutropenia 
Neutropenia has been reported with MLN9708 and panobinostat.  Blood counts should be 
monitored regularly as outlined in the protocol with additional testing obtained according to 
standard clinical practice.  GM-CSF and G-CSF may be used to shorten neutropenic periods 
and to maintain dose level of study drugs if neutropenia is the only reason for dose reduction 
according to table Table 7-4 and at the discretion of the treating physician.  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
63 
 
Fluid Deficits 
Dehydration should be avoided because MLN9708 and panobinostat may cause vomiting, 
diarrhea, and dehydration.  Two cases of acute renal failure have been reported in patients 
treated at or above the MTD with IV administration of MLN9708.  There has been no treatment-
related renal failure reported in patients treated with PO MLN9708.  Fluid deficits should be 
corrected before initiation of study drug and during treatment.  Until further information is 
available, intake of NSAIDs while on this protocol should be avoided. 
Hypotension 
Symptomatic hypotension and orthostatic hypotension have been reported with MLN9708. 
Blood pressure should be closely monitored while the patient is on study treatment and fluid 
deficit should be corrected as needed, especially in the setting of concomitant symptoms such 
as nausea, vomiting, diarrhea, or anorexia. Patients taking medications and/or diuretics to 
manage their blood pressure (for either hypo- or hypertension) should be managed according to 
standard clinical practice, including considerations for dose adjustments of their concomitant 
medications during the course of the trial.  
Posterior Reversible Encephalopathy Syndrome  
One case of posterior reversible encephalopathy syndrome (PRES) has been reported with 
MLN9708.  While this case ultimately resolved, PRES has also been reported rarely with 
another proteasome inhibitor, VELCADE.  PRES is characterized by headache, seizures and 
visual loss, as well as abrupt increase in blood pressure.  Prompt diagnosis and initiation of 
antihypertensive and anticonvulsant therapy are important to prevent irreversible end-organ 
damage. 
 
7.6.1 
Study drug discontinuation 
It will be documented whether or not each patient completed the clinical study. If for any patient 
either study treatment or observations were discontinued, the reason will be recorded in the 
source documents and within ONCORE.  
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: 
1. Disease progression, this always requires removal from study 
2. Adverse event(s) 
3. Abnormal laboratory value(s) 
4. Abnormal test procedure result(s) 
5. For phase I patients only: Dosing delay of > 21 days (= unable to receive study therapy for 
22 days including any therapy held during a cycle)  
6. For phase I patients only: Delay of a cycle by > 14 days from the intended day of the next 
scheduled dose, counted from the start of the previous cycle. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
64 
 
7. Protocol violation 
8. Subject withdrew consent 
9. Lost to follow-up 
10. Administrative problems 
11. New anti-myeloma therapy started 
12. Study Termination 
13. Death  
7.6.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to a possibly study-
drug related adverse event or abnormal laboratory value must be followed until resolution to 
CTCAE V 4.03 grade 2 or 30 days post last study drug administration, whichever comes first.  
If a patient requires a dose delay of > 14 days from the intended day of the next scheduled dose, 
then the patient must be discontinued from the study. All patients will be followed for adverse 
events and serious adverse events for at least 4 weeks following the last dose of any study drug.  
7.7 
Other concomitant medications 
Patients must be instructed not to take any additional medications (including over-the-counter 
products) during the trial without prior consultation with the investigator. All medications taken 
within 30 days of screening should be recorded. If concomitant therapy must be added or 
changed, the reason and name of the drug/therapy should be recorded. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient are allowed, including IV bisphosphonates and drugs given prophylactically (e.g. 
antiemetics) with the following exceptions: 
 Any medications listed in Section 19 which may cause QTc prolongation or inducing 
torsades de pointes should not be used.  
 Any medications that have the potential to alter serum electrolytes (e.g., diuretics) should 
be monitored very closely for electrolyte abnormalities as these can contribute to the risk of 
QT prolongation and ventricular arrhythmias.  
 No other investigational therapy should be given to patients 
 No anticancer agents other than the study medications administered as part of this study 
protocol should be given to patients. If such agents are required for a patient then the patient 
must first be withdrawn from the study. 
 Leukocyte growth factors (e.g. G-CSF and GM-CSF) are not to be administered 
systematically but may be prescribed by the investigator for severe neutropenia if this is 
thought to be appropriate, see also for guidance under table 7-4..  
 Medications known to be substrates of the isoenzyme CYP2D6 should be used with caution 
with panobinostat as panobinostat can inhibit isoenzyme CYP2D6 at low micromolar 
ranges. Please refer to Section 21 for the list of  CYP2D6 substrates.  . 
 Concomitant use of CYP3A4 inhibitors with panobinostat should be used with caution due 
to a potential increase in panobinostat exposure during concomitant treatment with these 
drugs.   


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
65 
 
 Oral contraceptives are generally metabolized by CYP3A4.  Since the induction potential 
of panobinostat to induce CYP3A4 is unknown, patients who are using oral contraceptives 
as a method of contraception, and are sexually active, should use another effective 
contraceptive method. 
 
7.7.1 
Summary of commonly used allowed supportive concomitant 
medications 
 
While a heightened awareness about possible pharmacokinetic and pharmacodynamic 
interactions should be maintained with any medication used concomitantly with study drugs the 
following are generally considered safe due to lack of reported interaction or large therapeutic 
window despite possible interaction: 
 HT3 blockers (with caution, D/C if followed by QTcF prolongation), metoclopramide, 
and prochlorperazine 
 Loperamide, diphenoxylate/atropine 
 Azithromycin, 
levofloxacin, 
pefloxacin, 
ofloxacin, 
tosufloxacin, 
difloxacin, 
temafloxacin, fleroxacin, acrosoxacin, and nalidixic acid are allowed 
 Acetaminophen and opioid analgesics other than methadone 
 Regular orange juice and dihydropyridine calcium channel blockers (e.g. amlodipine, 
felodipine, nicardipine, nifedipine) are allowed 
 IV bisphosphonates 
 G-CSF, GM-CSF: Their use is allowed and should follow institutional practice and 
guidance outlined in table 7-4,  alternative usage may be reviewed with  Millennium 
and  Novartis.  
 Erythropoietin will be allowed in this study. Its  use should follow published 
guidelines and/or institutional practice. 
 Patients should be transfused with red cells and platelets as clinically indicated and 
according to institutional guidelines. 
 Antiviral therapy such as acyclovir may be administered if medically appropriate. 
 
 
7.7.2 
Summary of prohibited concomitant medications and supplements 
 
The following contains commonly used medications that should not be used during this study 
due to either pharmacokinetic interactions or pharmacodynamically based increased risk for 
adverse events. It is not inclusive. See Sections 19-21 for more information. 
 Grapefruit or grapefruit juice and seville (sour) oranges (regular orange juice is allowed) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
66 
 
 Non-steroidal anti-inflammatory agents (NSAIDs) should be avoided if possible due to 
risk for kidney dysfunction in myeloma but if clinical judgement strongly argues for 
their use patients can remain on study while receiving NSAIDs 
 Other antineoplastic agents 
 Other investigational agents 
 Aprepitant 
 All Class IA antiarrhythmics: quinidine, procainamide, disopyramide, any other class 
IA antiarrhythmic drug 
 All Class III antiarrhythmics: amiodarone, sotalol, bretylium, disopryramide, dofetilide, 
ibutilide, any other class III antiarrhythmic drug 
 Calcium channel blockers: diltiazem, verapamil 
 The following Antibiotics: Erythromycin, clarithromycin, telithromycin (azithromycin 
is allowed), enoxacin, sparfloxacin, ciprofloxacin, voriconazole, ketoconazole, and 
posaconazole 
 Antipsychotics/antidepressants: thioridazine, mesoridazine, chlorpromazine, pimozide, 
fluvoxamine, nefazodone 
 Antimalarials: halofantrine, chloroquine 
 Miscellaneous 
drugs: 
arsenic 
trioxide, 
astemizole, 
bepridil, 
domperidone, 
levomethadyl, methadone, pentamidine, droperidol 
 Strong inhibitors of CYP1A2:  fluvoxamine, enoxacin, ciprofloxacin 
 Strong inhibitors of CYP3A:  clarithromycin, telithromycin, itraconazole, voriconazole, 
ketoconazole, nefazodone, and posaconazole 
 Strong CYP3A inducers:  rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, 
and phenobarbital 
 The dietary supplements St John’s wort and Ginkgo biloba are not permitted. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
67 
 
The following procedures are prohibited during the study: 
 Any antineoplastic treatment with activity against MM except for drugs in this 
treatment regimen. 
 Radiation therapy (the requirement for local radiation therapy generally indicates 
disease progression).Platelet transfusions can be given as clinically indicated but 
eligibility for starting a new cycle needs to be determined after at least 72 h without 
platelet transfusion and eligibility for inclusion in this trial needs to be determined after 
at least 7 days without platelet transfusion. Adjuvant hormone therapy for breast or 
prostate cancer. 
 
7.7.3 
Anti-coagulant therapy 
Panobinostat and MLN9708 therapy is commonly associated with mild to moderate degree of 
thrombocytopenia.  This may lead to an increase in the risk of bleeding with concomitant 
sodium warfarin (Coumadin®).  It is recommended that patients who require anticoagulation 
therapy while on panobinostat therapy use low molecular weight heparin (LMWH).  However, 
if the use of LMWH is not feasible, patients on sodium warfarin may continue such therapy 
while on study but for such patients, a close and frequent monitoring of the coagulation 
parameters, including PT/INR should be followed and they should be maintained within a 
therapeutic range.  The dose of sodium warfarin may be adjusted as needed while on study. 
 
7.8 
Precautions and Restrictions 
 Fluid and electrolyte deficits should be corrected before and throughout treatment. 
 Nonsteroidal anti-inflammatory drugs (NSAIDs) risk for  nephrotoxicity is increased in 
patients with multiple myeloma, underlying kidney dysfunction, and dehydration. 
NSAIDs should generally be avoided in patients with multiple myeloma, especially if 
other risk factors co-exist.  
7.9 
    
Contraception Requirements 
The effects of MLN9708 and panobinostat on human pregnancy or development of the embryo 
or fetus are unknown.  Therefore, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  
Nonsterilized female patients of reproductive age and male patients should use effective 
methods of contraception through defined periods during and after study treatment as specified 
below. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
68 
 
Female patients must meet the following eligibility criteria: 
 Are postmenopausal for at least 1 year before the screening visit, OR 
 Are surgically sterile, OR 
 Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.) 
 Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable, OR 
 If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, for at least 28 days before starting study drug through 
90 days after the last dose of study treatment. 
o The 2 methods of reliable contraception must include 1 highly effective method 
and 1 additional effective (barrier) method.  Females of childbearing potential 
must be referred to a qualified provider of contraceptive methods if needed.  The 
following are examples of highly effective and additional effective methods of 
contraception: 
Highly effective methods: 
 Intrauterine device (IUD) 
 Hormonal (injections, implants) 
 Tubal ligation 
 Partner’s vasectomy 
Additional effective methods: 
 Male condom 
 Diaphragm 
 Cervical Cap 
Male patients, even if surgically sterilized (i.e., status post vasectomy), must meet the following 
eligibility criteria: 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
69 
 
 Agree to practice true abstinence when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.), 
OR 
 Agree to practice effective barrier contraception during the entire study treatment period 
and through 4 months after the last dose of study treatment if their partner is of 
childbearing potential, even if they have had a successful vasectomy. 
 Must also adhere to the guidelines of any treatment-specific pregnancy prevention 
program, if applicable. 
 
7.9.1 
CYP2D6 Substrates 
In in vitro assays, panobinostat was shown to inhibit the cytochrome P450 isoenzyme  CYP2D6 
at low micromolar ranges, thereby suggesting a potential risk of drug-drug interactions with 
concomitant medications that are also metabolized by CYP2D6.  A clinical drug-drug 
interaction study with dextromethorphan (a CYP2D6 probe drug) and panobinostat is currently 
ongoing in cancer patients.  In the meantime, medications that are known to be CYP2D6 
substrates should be used with caution when given concomitantly with panobinostat.  Patients 
must be carefully monitored for signs of toxicity as a result of concomitant medication which 
may require dose titration or reduction of the CYP2D6 substrate as medically necessary.  Please 
see 
Appendix 
1 
and 
refer 
to 
the 
following 
website: 
http://medicine.iupui.edu/flockhart/table.htm for a list of substrates of CYP2D6. 
7.9.2 
Drugs that can inhibit/induce CYP3A4/5 
7.9.2.1 
Drugs that can inhibit CYP3A4/5 
Panobinostat is metabolized in vitro by CYP3A4/5. A clinical drug-drug interaction study with 
ketoconazole and panobinostat has recently been completed. The less than 2-fold increase in 
panobinostat AUC upon co-administration with ketoconazole suggests that CYP3A 
contribution to the total clearance of panobinostat is low.  The observed interaction is not 
considered clinically relevant, as panobinostat doses at least 2-fold greater than 20 mg (40 and 
60 mg) have been safely administered in patients.  CYP3A4 inhibitors should have no major 
impact on the exposure of panobinostat and may be co-administered when medically necessary. 
7.9.2.2 
Drugs that are potent CYP3A4/5 inducers 
As it is with other medications that are metabolized by CYP3A4, clinical judgment is to be 
exercised when potent CYP3A4 inducers are concomitantly taken with panobinostat. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
70 
 
7.10 
Treatment compliance 
Records of study medication used, dosages administered, and intervals between visits will be 
recorded during the study. Drug accountability will be noted and patients will be asked to return 
all unused study medication. 
8 
Visit schedule and assessments 
Table 8-1    
Schedule of Assessments* 
Examinations 
Screening 
Cycle 1 
Cycles 2 and 
beyond 
Study 
exit 8 
 
D-7 to D1 
D1 
D5 
Weekly 
D 1 
Weekly 
 
Informed consent 
X 
 
 
 
 
 
 
Background information 1 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Bone marrow examination 
2 
X 
 
 
 
 
 
 
Skeletal survey 3 
X 
 
 
 
 
 
 
Echocardiogram or MUGA 
scan 3 
X 
 
 
 
 
 
 
Vital signs 4 
 
X 
 
X 
X 
 
X 
History & Physical 
examination 
X 
X 
 
X 
X 
 
X 
ECG 5 
X 
X 
X 
 
X5 
 
 
CBC/Diff 
X 
X 
 
X 
X 
X10 
X 
PTT, INR 
X 
 
 
 
 
 
 
CMP,, magnesium 
X 
X 
 
X 
X 
X10 
X 
Response parameters 
SPEP, 24h UPEP, sFLCs, 
serum and urine IFE 
X 
 
 
 
X 
 
X 
TSH, free T3, FTI 
x 
 
 
 
Cycle 
4X9 
 
X 
Pregnancy testing 6 
X 
 
 
 
X 
 
 
Compliance review/drug 
calendar 7 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
* Unless noted otherwise all visits and assessments should occur on the scheduled day +/- 3 days but 
a new cycle may not begin unless ECG and electrolyte assessment has been completed within 24h prior 
to day one dosing and criteria are met for the start of a new cycle (7.4). 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
71 
 
1) Background information. The treating physician is responsible for comprehensive assessment of 
background information as it relates to eligibility for this trial. The following will be recorded on the CRFs: 
Year and month symptomatic myeloma was diagnosed, cytogenetic findings at diagnosis (karyotype, 
FISH, gene expression profile as available), beta 2 microglobulin, serum albumin, and LDH levels at 
diagnosis, number of prior therapies, and responses to prior therapies. Past medical history, past 
surgical history, and allergies as recorded in patient’s charts 6 month prior to enrollment and all 
concomitant medications at the time of enrollment will also be recorded. 
2) Bone marrow examinations: In general this will only be done once at screening or within 28 days prior 
to study entry but for patients who appear to have reached a complete remission based on blood and 
urine studies it will be repeated for confirmation. Patients who have measurable disease only in the bone 
marrow will have bone marrow examinations after cycle 2 and at the end of the study. Additional bone 
marrow examinations may be obtained as clinically indicated.  3) Skeletal survey and left ventricular 
ejection fraction determination by Echocardiogram or MUGA scan: Within 28 days prior to study entry. 
4) Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on patients 
after at least 3 minutes in the sitting position 
5) ECGs: 
 
On Screening: One ECG 
 
On day 1 and 5 of cycle 1: Pre-dose: One ECG, Post-dose at 3 hours ± 0.5 hour: One ECG 
 
On day 1 of cycle 2: Pre-dose: One ECG 
 
Additional ECGs as detailed under 7.5.4 may be necessary if QTcF prolongation prevents 
dosing of panobinostat and MLN9708 or if felt clinically necessary for other reasons 
6) Pregnancy tests for females of childbearing potential.  A female of childbearing potential (FCBP) is a 
sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has 
not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time 
in the preceding 24 consecutive months). All females of childbearing potential should complete a serum 
pregnancy test within 7 days prior to the administration of study drugs on day 1 of cycle 1. The pregnancy 
test should be repeated in week 1 of every cycle (except for cycle 1).  
7) Compliance review / study calendar: Nurses review medication compliance based on study calendar 
patients fill out. 
8) Study exit: Visits and assessments at study exit should occur within 3 days prior and 7 days after the 
end of the previous cycle or within 7 days after the decision to remove the patient from study. If grade > 
3 non-hematologic adverse events or grade 4 neutropenia or thrombocytopenia are present at study 
exit, the respective adverse events should be followed weekly until resolution to grade 2 for non-
hematologic adverse events and grade 3 for neutropenia and thrombocytopenia or until 30 days from 
last treatment have elapsed. 
9) Thyroid function tests should be obtained at study entry, at about 3 months from study entry, ideally  
after the third 28-day cycle, whenever there is clinical suspicion for hypothyroidism, and at the 
completion of this study unless it has been obtained within 30 days prior to study exit. 
10) Weekly CBC/diff, CMP, and magnesium until completion of cycle 2, then as clinically indicated 
 
8.1 
Efficacy / response assessments and criteria 
Baseline assessments must occur within  7 days of protocol therapy initiation as indicated in 
Section 8, schedule of assessments. Response assessments include serum protein 
electrophoresis (SPEP), serum free light chains (sFLCs), 24 h urine protein electrophoresis with 
m-spike (24h UPEP), serum and urine immunofixation, and, for confirmation of complete 
remission and to monitor asecretory myeloma; bone marrow examinations. 
Efficacy assessments are scheduled to occur after each cycle except for bone marrow 
examinations which are done only for confirmation of complete remission (once) and in patients 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
72 
 
with measurable disease restricted to bone marrow plasma cell percentage, where bone marrow 
is obtained after cycle 2 and at study completion. 
All response categories require two consecutive blood and urine assessments (bone marrow 
biopsies do not need to be repeated) and no evidence for progressive or new bone lesions if 
radiographic studies were performed. Radiographic studies are not required for response 
assessment but should be obtained when there is clinical suspicion for progressive bone disease. 
The time point myeloma response parameters first fall into respective response levels is 
recorded as the time a response is achieved once a consecutive set of tests confirmed the 
response. For response categories > PR the confirmatory test may be obtained at any time but 
will generally be obtained at the start of the next cycle unless there is a clinical reason to obtain 
earlier; for MR consecutive tests have to confirm MR over a period of at least 6 weeks. 
 
Complete response (CR) 
Negative immunofixation of serum and urine (or normal 
sFLC ratio if the only measurable disease outside of the 
bone marrow is by sFLCs) and disappearance of any soft 
tissue plasmacytomas, and <5% plasma cells in bone 
marrow 
 
Stringent CR (sCR) 
 
CR as defined above plus normal sFLC ratio and 
absence 
of 
clonal 
cells 
in 
bone 
marrow 
by 
immunohistochemistry or immunofluorescence 
 
Very good partial response (VGPR) Serum 
and 
urine 
M-component 
detectable 
by 
immunofixation but not on electrophoresis or 
>90% or greater reduction in serum M-component plus 
urine M-component <100mg per 24 h or >90% reduction 
in the difference between involved and uninvolved serum 
free light chains if this is the only measurable disease 
outside of the bone marrow 
 
Partial response (PR)  
>50% reduction of serum M protein and reduction in 24-
h urinary M protein by >90% or to <200mg per 24 h, if 
the serum and urine M protein are unmeasurable, a >50% 
decrease in the difference between involved and 
uninvolved sFLC levels is required in place of the M 
protein criteria, if the only measurable disease is in the 
bone marrow, a >50% reduction in bone marrow plasma 
cells is required, provided the baseline percentage was 
>30%. In addition to the above criteria, if present at 
baseline, a >50% reduction in the size of soft tissue 
plasmacytomas is required. 
 
Minor response (MR) 
>25% but <49% reduction of serum M protein and 
reduction in 24 h urine M protein by 50–89%, which still 
exceeds 200mg per 24 h. In addition to the above criteria, 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
73 
 
if present at baseline, 25–49% reduction in the size of soft 
tissue plasmacytomas is also required. No increase in size 
or number of lytic bone lesions (development of 
compression fracture does not exclude response). 
 
Stable disease (SD)  
Not meeting criteria for sCR, CR, VGPR, PR, MR, or 
progressive disease (see under 5.9.1). 
 
8.1.1 
Progressive Disease 
Progressive disease (PD) is defined according to the international uniform response criteria 
(Durie et al. Leukemia 20:1467-73, 2006, ERRATUM Durie et al. Leukemia 21:1134, 2007) 
and requires any of the following, confirmed on two consecutive assessments: 
An increase of 25% from lowest response value in any one or more of the following: 
 Serum M-component (absolute increase must be >0.5 g/100 ml) * 
 Urine M-component (absolute increase must be >200mg per 24 h) 
 Only in patients without measurable serum and urine M-protein levels: the difference 
between involved and uninvolved FLC levels (absolute increase must be >100 mg/l) 
 Bone marrow plasma cell percentage (absolute % must be >10%) 
 
And / or: 
 Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
 Development of hypercalcemia (corrected serum calcium >11.5 mg/100 ml) that can be 
attributed solely to the plasma cell proliferative disorder 
 
*: If the starting serum m-protein level is >5g/dL an absolute increase of >1g/dL, verified on 
two consecutive measurements, is sufficient to define progressive disease. 
 
The decision as to when to repeat the assessment to document progressive disease will be left 
at the discretion of the treating physician, there is no need to wait until the next scheduled 
response assessment. 
9 
Safety assessments 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of hematology, blood chemistry and urine values, vital 
signs, ECOG performance status, and the regular physical examinations and ECG assessments.  
Adverse events will be assessed according to the Common Toxicity Criteria for Adverse Events 
(CTCAE) version 4.0.  CTCAE v4.03 can be accessed on the NIH/NCI website at  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf))  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
74 
 
9.1.1 
Adverse events 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded and followed as appropriate. 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient during or between visits or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. the severity grade (mild, moderate, severe) or (grade 1-4) 
2. its relationship to the study drug(s) (suspected/not suspected) 
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study 
drug permanently discontinued due to this adverse event; concomitant medication taken; 
non-drug therapy given; hospitalization/prolonged hospitalization) 
5. whether it constitutes a serious adverse event (SAE) 
All adverse events should be treated appropriately. Such treatment may include changes in study 
drug treatment including possible interruption or discontinuation, starting or stopping 
concomitant treatments, changes in the frequency or nature of assessments, hospitalization, or 
any other medically required intervention. Once an adverse event is detected, it should be 
followed until its resolution, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigators’ Brochures for panobinostat and MLN9708 or will be communicated 
between IB updates in the form of Investigator Notifications. This information will be included 
in the patient informed consent and should be discussed with the patient during the study as 
needed. 
9.1.2 
Vital signs 
Vital sign assessment consists of height (first visit), pulse, blood pressure, respiration rate, 
temperature and weight. Blood pressure, pulse and respiration rate should be measured on 
patients after at least 3 minutes in the sitting position 
9.1.3 
Physical examination 
Physical examination will be performed which must comprise a total body examination (general 
appearance, skin, neck, including thyroid, eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities and basic nervous system). 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
75 
 
Significant findings made after the start of study drug which meet the definition of an Adverse 
Event must be recorded. 
 
9.1.4 
Laboratory evaluations 
Laboratory evaluation should be done at baseline (within ≤ 72 hours prior to dosing prior to the 
first administration of study drugs, during the course of the study and at the time of the study 
treatment completion visit. Results must be reviewed prior to administering panobinostat 
(LBH589) and ixazomib (MLN9708). More frequent examinations may be performed if 
medically indicated; results should be recorded.  
Hematology 
Hematology must include hemoglobin, hematocrit, platelets, total white blood cell count 
(WBC) and differential. The coagulation profile includes a prothrombin time or International 
Normalized Ratio (INR) and activated partial thromboplastin time. 
Blood chemistry 
Biochemistry includes the following parameters: BUN, creatinine, sodium, potassium, chloride, 
CO2 (HCO3), glucose, calcium, albumin, total protein, total bilirubin, alkaline phosphatase, 
AST/SGOT, ALT/SGPT, and magnesium (where indicated in 8).  If total bilirubin is greater 
than the upper limit of normal, direct and indirect bilirubin should be performed. 
Thyroid function test 
Thyroid Stimulating Hormone (TSH), free T3, and FTI will be measured at baseline, about 3 
months after study entry (+/- 14 days), at the study completion, and as deemed clinically 
necessary during the course of the study. 
 
9.1.5 
Serum pregnancy test 
All females of childbearing potential should complete a serum pregnancy test within 7 days 
prior to the administration of study drugs on day 1 of cycle 1. The pregnancy test should be 
repeated in week 1 of every cycle (except for cycle 1). Postmenopausal women must have been 
amenorrheic for ≥ 12 months in order to be considered “of non-childbearing potential”. 
 
9.1.6 
ECG 
See Section 7.1.3 (Cardiac precaution) Section 7.5.4 (Dose modification for prolonged 
QTc) for guidelines on the required close monitoring of patients’ serum biochemistry values 
(in particular, potassium and magnesium) and the requirement for rapid correction of low 
values). 
A screening 12-lead ECG will be performed to assess study eligibility. Additional 12-lead ECGs 
will be performed at a minimum at scheduled time points as indicated in Section 8. For all 
patients, a 12-lead ECGsmust be performed on cycle 1 day 1 prior to the first administration of  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
76 
 
study drugs or within 24 hours prior to that day. This is necessary to get an accurate baseline 
QTcF calculation. 
Table 9-1 
Cardiac assessment monitoring schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 
Day of cycle 
ECG monitoring a 
 
Screening b 
Single ECG to assess eligibility 
Cycle 1 
1, 5 
Pre-dose: 
Single 12 lead ECG 
 
1, 5 
3 hours post dose: 
Single 12 lead ECG 
Cycle 2  
1 
Pre-dose: 
Single 12 lead ECG 
a Refer to Table 6-7 for the recommended dose modifications due to QTc interval prolongation 
b The screening ECGs will be analyzed locally to assess eligibility of the patient. (Note: the mean QTc 
interval at baseline must be ≤ 470 msec for the patient to be eligible for participation in the trial) 
Note: If no significant QTcF prolongation is noted during the first 4 cycles, the QTc monitoring is no 
longer required and may be performed at the Investigator’s discretion, if medically indicated. 
 
9.1.6.1 
Performance status 
Performance status will be assessed according to the ECOG Performance Status Scale: 
 
 
SCORE 
DESCRIPTION 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work. 
2 
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 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
77 
 
4 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead. 
 
9.1.6.2 
Special tests 
No special tests will be obtained. Routine standard myeloma tests will be obtained as 
outlined in Section 8. 
9.2 
Drug levels and pharmacokinetic assessments 
No pharmacokinetic studies are planned. 
10 
Safety monitoring 
10.1 
Novartis Instructions for rapid notification of serious 
adverse events 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form as outlined per contractual agreement; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The investigator must assess and 
record the relationship of each SAE to each specific study treatment (if there is more than one 
study treatment), complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department. 
The  telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E) are included in the contractual agreement. The original copy of the 
SAE Report Form and the fax confirmation sheet should be kept with the case report form 
documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
78 
 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis Drug 
Safety and Epidemiology (DS&E) department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator Notification 
(IN), to inform all investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC or as 
per national regulatory requirements in participating countries. 
10.2 
Millennium Instructions for rapid notification of serious 
adverse events 
All serious adverse events (SAEs) (regardless of expectedness or causality) must be reported to 
Millennium Pharmacovigilance (or designee).  See also Novartis Instructions for rapid 
notification of serious adverse events for the reporting of SAEs. 
The sponsor-investigator is responsible to meet all regulations and requirements applicable to 
the sponsor-investigator. 
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 must be reported to Millennium Pharmacovigilance (or designee).  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 1 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.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures. 
 
This is an investigator-initiated study.  The principal investigator, Jason Valent (who may also 
sometimes 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. 
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 10.7) must 
be reported by the sponsor- to the Millennium Pharmacovigilance or designee by faxing the 
SAE Report using the US FDA MedWatch 3500A Form : 
Fatal and Life Threatening SAEs within 24 hours but no later than 4 calendar days 
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 
 
The SAE report must include at minimum: 
 Event term(s) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
79 
 
 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 specified in the protocol, as a guideline, whenever 
possible.  The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 Causality of the event(s): Sponsor-investigator’s or sub-investigator’s determination 
of the relationship of the event(s) to study drug administration.  
 
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure that 
the SAE reports are sent to Millennium Pharmacovigilance or designee from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-investigator 
so that the sponsor-investigator can meet his/her foregoing reporting obligations to Millennium 
Pharmacovigilance.  Millennium Pharmacovigilance (or designee) may request follow-up 
information to a reported SAE or serious pretreatment event, which the sponsor-investigator 
will be responsible for providing to Millennium Pharmacovigilance or designee. 
Millennium will provide a sample SAE Report Form representative of the information 
Millennium Pharmacovigilance may request in follow-up.   
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the patient was enrolled in the study are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the study (e.g., surgery was performed earlier or 
later than planned). 
 
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of 
the event to study procedures. 
 
Intensity for each AE, including any lab abnormality, will be determined by using the NCI 
CTCAE, version 4.0 as a guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html    
Relationship to study drug administration will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to study product(s), as soon as 
possible but no later than 4 calendar days of such communication. 
SAE and Pregnancy Reporting Contact Information 
Millennium Pharmacovigilance or Designee 
FAX Number 1-800-963-6290 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
80 
 
Email: TakedaOncoCases@cognizant.com 
Reporting Form:   
 US FDA MedWatch 3500A: 
 http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm  
10.3 
Any other form deemed appropriate by the sponsor-
investigatorAdverse Event of Special Interest Definition 
Adverse Events of Special Interest (AESIs) are a subset of AEs that are to be reported to 
Millennium on a quarterly basis by the sponsor-investigator. Millennium will provide the 
current list of AESIs and updates to the list will be distributed to the sponsor-investigator as 
appropriate 
 
10.4 
 Millennium Rules for Monitoring of Adverse Events and 
Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
 
AEs will be reported from the first dose of MLN9708 through 30 days after 
administration of the last dose of MLN9708. In addition, skeletal-related events that occur 
during the follow-up periods must be reported from the first dose of MLN9708 through death 
or termination of the study by the sponsor-investigator or Millennium. 
 
Serious pretreatment events will be reported to Millennium Pharmacovigilance or 
designee from the time of the signing of the informed consent form (ICF) up to first 
dose of MLN9708. 
 
Related and unrelated SAEs will be reported to Millennium Pharmacovigilance or 
designee from the first dose of MLN9708 through 30 days after administration of the 
last dose of MLN9708. 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). In 
addition, new primary malignancies that occur during the treatment or follow-up periods must 
be reported, regardless of causality to study regime.  All new cases of primary malignancy must 
be reported to Millennium Pharmacovigilance (or designee). Follow up for detection of second 
primary malignancies beyond the planned study is not required; however, if the sponsor-
investigator learns about the occurrence of a second primary malignancy in one of the study 
subjects within 3 years after the last study drug administration he must report the event to 
Millennium Pharmacovigilance (or designee). 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
81 
 
10.5 
Procedures for Reporting Drug Exposure during 
Pregnancy and Birth Events 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is participating in this study, or 
within 28 days of the subject’s last dose of MLN9708, are considered immediately reportable 
events. Study drug(s) is to be discontinued immediately. Millennium or designee must also be 
contacted immediately by faxing a completed Pregnancy Form to the Millennium Department 
of Pharmacovigilance. The pregnancy must be followed for the final pregnancy outcome. The 
pregnancy, suspected pregnancy, or positive pregnancy test must be reported to MPI/PPD Drug 
Safety immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form. 
 
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling. 
The Sponsor-Investigator will follow the female subject until completion of the pregnancy, and 
must notify MPI/PPD Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form. 
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Sponsor-Investigator should report the abnormal outcome as an AE. If the abnormal outcome 
meets any of the serious criteria, it must be reported as an SAE to MPI/PPD Drug Safety 
immediately by facsimile, or other appropriate method, as soon as possible but no later than 5 
calendar days of the Sponsor-Investigator’s knowledge of the event using the SAE Report Form, 
or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Sponsor-Investigator 
suspects is related to the in utero exposure to the IP should also be reported to MPI/PPD Drug 
Safety immediately by facsimile, or other appropriate method, as soon as possible but no later 
than 5 calendar days of the Sponsor-Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking study drug must notify the Sponsor-Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. Millennium or designee must 
also be contacted immediately by faxing a completed Pregnancy Form to the Millennium 
Department of Pharmacovigilance. Every effort should be made to follow the pregnancy for the 
final pregnancy outcome. 
10.6 
Millennium Product Complaints 
    
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
82 
 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals who 
identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product should 
be maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG)  
(US and International) 
 
Product complaints in and of themselves are not AEs.  If a product complaint results in an SAE, 
an SAE form should be completed and sent to PPD (refer to Section 8.2). 
 
 
10.7 
Serious Adverse Events 
Serious adverse event (SAE) is defined as one of the following: 
• 
Is fatal or life-threatening 
• 
Results in persistent or significant disability/incapacity 
• 
Constitutes a congenital anomaly/birth defect 
• 
Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization,  
• 
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• 
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
conditionNote that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above is 
not a serious adverse event 
10.8 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis (and Millennium, see under 10.5) within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
83 
 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the panobinostat any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.Pregnancy outcomes must be 
collected for the female partners of any males who took study treatment in this study. Consent 
to report information regarding these pregnancy outcomes should be obtained from the mother. 
11 
Protocol amendments, or changes in study conduct 
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed by Novartis, Millennium, and the sponsor-investigator before 
implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation or the scientific quality of the study require additional approval by the IRB at each 
study center. A copy of the written approval of the IRB must be provided to Novartis and 
Millennium. Examples of amendments requiring such approval are: 
1. increases in drug dose or duration of exposure of subjects, 
2. significant changes in the study design (e.g. addition or deletion of a control group), 
3. increases in the number of invasive procedures, 
4. addition or deletions of a test procedure required for monitoring of safety. 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator or by Novartis in the interests of preserving the safety of all patients 
included in the trial.  If an immediate change to the protocol is felt to be necessary by the 
investigator and is implemented for safety reasons Novartis must be notified and the IRB at the 
center must be informed immediately.   Amendments affecting only administrative aspects of 
the study do not require formal protocol amendments or IRB approval but the IRB must be kept 
informed of such administrative changes. Examples of administrative changes not requiring 
formal protocol amendments and IRB approval include: 
1. 
changes in the staff used to monitor trials 
2. 
minor changes in the packaging or labeling of study drug. 
Any departures from the protocol must be fully documented in the source documents. 
12 
Data review and management 
12.1 
Data Management 
12.2 
Analyses and Reporting 
Oncore will be used for data entry and analysis. Data will be analyzed and reported in abstract 
form after the last patient has completed the first cycle and a full manuscript will be submitted 
once the last patient has gone off this up to 6 month duration study. In addition, interim 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
84 
 
reports may be submitted as abstracts.Data Safety Monitoring PlanThis protocol will adhere to 
the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in 
accordance with NCI regulations.  
12.3 
Study Monitoring 
Internal monitoring by quality control teams of the Cleveland Clinic Taussig Cancer Institute 
and the Seidman Cancer Center of University Hospitals of Case Western University will occur 
as per Case Comprehensive Cancer Center standard operating procedures for monitoring of 
investigator initiated trials QA-8.1.0. 
12.3.1 Investigator Responsibilities 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) 
and in the US Code of Federal Regulations. 
Investigators must enter study data onto CRFs or other data collection system.  The Investigator 
will permit study-related audits by Novartis and Millennium or its representatives, IRB/EC 
review, and regulatory inspection(s) (e.g., FDA, EMEA, TPP), providing direct access to the 
facilities where the study took place, to source documents, to CRFs, and to all other study 
documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some 
time during audits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) 
for source data verification.  The data collection must be completed prior to each visit and be 
made available to the Novartis and Millennium so that the accuracy and completeness may be 
checked. 
13 
Statistical methods 
13.1 
Datasets to be Analyzed 
13.1.1 
Primary objectives and endpoints 
13.1.1.1 Dose limiting toxicity 
This study will use a 3 + 3 design (see under 5) to estimate whether select doses of MLN9708 
up to a maximal target dose, chosen based on available data from other studies, are tolerated 
when combined with fixed doses of panobinostat and dexamethasone. Tolerance will be based 
on the ratio of patients developing dose limiting toxicity (DLT). Dose increase is allowed if 0 
or 3 patients or 1 of 6 patients develop DLTs, while confirmation of a given dose level as 
tolerated requires treatment of at least 6 patients with no more than one patient developing a 
DLT. 
 
Dose limiting toxicity (DLT) will be assessed during the first cycle and be defined as the 
following drug-related adverse events according to CTCAE version 4.03 (if an adverse event is 
attributed to progressive disease, it will not be counted as DLT): 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
85 
 
 Grade 4 or higher neutropenia or thrombocytopenia that does not resolve to grade 3 or 
lower within 7 days after detection while MLN9708 (ixazomib) and panobinostat are 
held. 
 QTcF increase to > 480 msec that persists > 7 days after withholding panobinostat and 
MLN9708 
 Any grade 3 or higher non-hematologic adverse events except: 
o 
Nausea, vomiting, diarrhea, or electrolyte abnormalities that can be reduced to 
grade 2 with supportive measures within 7 days 
 
Patients who cannot be assessed for DLT due to progressive disease or other reasons will be 
replaced. 
13.1.1.2 Safety 
Data from all subjects who receive any protocol therapy will be included in the safety analyses. 
Subjects who entered the study and did not receive any protocol therapy and had this confirmed, 
will not be evaluated for safety. Adverse events will be recorded during the entire study, weekly 
during the first cycle, and at the start of each cycle for subsequent cycles. Toxicity will be 
graded according to CTCAE v.4.0 whenever possible and reported in a descriptive way. 
 
13.1.2 
Secondary objectives and endpoints 
13.1.2.1 Response 
The response rate (RR= sCR+CR+VGPR+PR) and clinical benefit response rate 
(CBRR=sCR+CR+VGPR+MR) will be calculated for the entire study group, and for individual 
dose levels. Since the number of patients treated at any given dose level will be small, any report 
will mainly list the number of responses but may also mention the percentage of patients 
achieving a response.  
 
13.1.2.2 PFS and OS 
Progression-free survival will be measured from study entry to progression or death of any 
cause, whichever comes first. Overall survival for all will be measured from study entry to death 
from any cause. Due to small sample size and limit of treatment duration to six months only 
observed PFS and OS will be reported for patients participating in phase I. For patients who 
enter on phase II  the Kaplan-Meier method will be used to estimate PFS and OS. 
 
14 
Procedures and instructions 
14.1 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and Millennium and prior to any outside submission.  Novartis and 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
86 
 
Millennium must receive copies of any intended communication in advance of publication (at 
least fifteen working days for presentational materials and abstracts and thirty working days for 
manuscripts).   These requirements acknowledge Novartis’ and Millennium’s responsibility to 
provide peer input regarding the scientific content and conclusions of such publications or 
presentations.  Principal Investigation/Institution shall have the final authority to determine the 
scope and content of its publications, provided such authority shall be exercised with reasonable 
regard for the interests of Novartis and Millennium and, in accord with the trial contract and 
shall not permit disclosure of Novartis or Millennium confidential or proprietary information. 
14.2 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis and Millennium in strict 
confidence and to request similar confidentiality from his/her staff and the IRB/IEC/REB. Study 
documents provided by Novartis (investigators' brochures and other material) will be stored 
appropriately to ensure their confidentiality. The information provided by Novartis to the 
investigator may not be disclosed to others without direct written authorization from Novartis, 
except to the extent necessary to obtain informed consent from patients who wish to participate 
in the trial. 
14.3 
Discontinuation of study 
Novartis and Millennium reserve the right to discontinue any study under the conditions 
specified in the clinical trial agreement. 
15 
Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in Novartis and  Millennium standard operating procedures and: 
1. 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. Directive 
91/507/EEC, the Rules Governing Medicinal Products in the European Community. 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 
56 concerning informed consent and IRB regulations). 
3. 
Declaration of Helsinki and amendments, concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
The investigator agrees to adhere to the instructions and procedures described in it and thereby 
to adhere to the principles of Good Clinical Practice that it conforms to. 
15.1 
Institutional Review Board/Independent Ethics 
Committee 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee/Research Ethics Board (IRB/IEC/REB). A signed and 
dated statement that the protocol and informed consent have been approved by the 
IRB/IEC/REB must be given to Novartis and Millennium before study initiation. Any 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
87 
 
amendments to the protocol, other than administrative ones, must be reviewed by Novartis and 
Millennium and approved by this committee. 
15.2 
Informed consent 
The investigator must explain to each subject (or legally authorized representative) the nature 
of the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved and any discomfort it may entail. Each subject must be informed that 
participation in the study is voluntary and that he/she may withdraw from the study at any time 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If the subject cannot read or sign 
the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the investigator with it for IRB/IEC/REB approval. 
15.3 
Investigator and Site Responsibility for Drug 
Accountability 
Accountability for the study drug at all study sites is the responsibility of the principal 
investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site, inventory 
at the site, use by each patient, and amount returned to Millennium and/or Novartis or a 
designee or disposal of the drug (if applicable and if approved by Millennium and/or 
Millennium) will be maintained by the clinical site.  Accountability records will include dates, 
quantities, lot numbers, expiration dates (if applicable), and patient numbers.   
15.4 
Record Retention 
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory and IRB requirement(s).   
16     USE OF INFORMATION 
All information regarding MLN9708 supplied by Millennium to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from Millennium.  It is 
understood that there is an obligation to provide Millennium with complete data obtained 
during the study.  The information obtained from the clinical study will be used toward the 
development of MLN9708 and may be disclosed to regulatory authority(ies), other 
investigators, corporate partners, or consultants as required. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
88 
 
Upon completion of the clinical study and evaluation of results by Millennium, the hospital or 
institution and/or investigator may publish or disclose the clinical trial results pursuant to the 
terms contained in the applicable Clinical Trial Agreement.    
 
 
17 
References 
 
1. 
Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008;111(6):2962-2972. 
2. 
Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-
171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. Oct 4 
2012;120(14):2817-2825. 
3. 
Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in 
myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing 
strategies in dual-refractory disease. Blood. Sep 15 2011;118(11):2970-2975. 
4. 
Leleu X, Attal M, Arnulf B, et al. Pomalidomide plus low dose dexamethasone is active 
and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 
2009-02. Blood. Jan 14 2013. 
5. 
Richardson PG, Siegel D, Baz R, et al. Phase I study of pomalidomide MTD, safety and 
efficacy in patients with refractory multiple myeloma who have received lenalidomide 
and bortezomib. Blood. Dec 14 2012. 
6. 
Saunthararajah Y, Triozzi P, Rini B, et al. p53-Independent, normal stem cell sparing 
epigenetic differentiation therapy for myeloid and other malignancies. Semin Oncol. Feb 
2012;39(1):97-108. 
7. 
Richardson PG, Alsina M, Weber D, et al. PANORAMA 2: Panobinostat Combined 
with Bortezomib and Dexamethasone in Patients with Relapsed and Bortezomib-
Refractory Multiple Myeloma Blood (ASH Annual Meeting Abstracts) 120: Abstract 
1852. 2012. 
8. 
Kumar SK, Berdeja JG, Niesvizky R, et al. A Phase 1/2 Study of Weekly MLN9708, an 
Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and 
Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM). Blood 
(ASH Annual Meeting Abstracts) 120: Abstract 332. 2012. 
9. 
Kumar S, Bensinger WI, Reeder CB, 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 Blood (ASH Annual Meeting 
Abstracts) 118: Abstract 816. 2011. 
10. 
Richardson PG, Baz R, Wang L, 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 Blood (ASH Annual Meeting Abstracts) 2011 118: Abstract 301. 2011. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
89 
 
11. 
Gupta N, Saleh M, Venkatakrishnan K. Flat-Dosing Versus BSA-Based Dosing for 
MLN9708, An Investigational Proteasome Inhibitor: Population Pharmacokinetic (PK) 
Analysis of Pooled Data From 4 Phase-1 Studies. Blood (ASH Annual Meeting 
Abstracts) 2011 118: Abstract 1433. 2011. 
12. 
Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in 
combination with lenalidomide and low-dose dexamethasone as a frontline treatment 
for multiple myeloma. Blood. Aug 30 2012;120(9):1801-1809. 
13. 
Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and 
dexamethasone combination therapy in patients with newly diagnosed multiple 
myeloma. Blood. Aug 5 2010;116(5):679-686. 
14. 
Siegel DS, Laura McBride L, Bilotti E, et al. Vorinostat Overcomes Lenalidomide-
Dexamethasone 
and 
Lenalidomide-Bortezomib-Dexamethasone 
Resistance 
In 
Relapsed/Refractory Multiple Myeloma. Blood (ASH Annual Meeting Abstracts) 116: 
Abstract 3065. 2010. 
15. 
Christian B, Kopko A, Fehniger TA, Bartlett NL, Kristie A. Blum KA. A Phase I Trial 
of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with 
Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL). Blood 
(ASH Annual Meeting Abstracts). 2012;120: Abstract 1644. 
16. 
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone 
deacetylases and cancer: causes and therapies. Nat Rev Cancer. Dec 2001;1(3):194-202. 
17. 
Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone 
proteins. Gene. Dec 19 2005;363:15-23. 
18. 
Aoyagi S, Archer TK. Modulating molecular chaperone Hsp90 functions through 
reversible acetylation. Trends Cell Biol. Nov 2005;15(11):565-567. 
19. 
Diaz-Gonzalez JA, Russell J, Rouzaut A, Gil-Bazo I, Montuenga L. Targeting hypoxia 
and angiogenesis through HIF-1alpha inhibition. Cancer Biol Ther. Oct 
2005;4(10):1055-1062. 
20. 
Walsh CT, Garneau-Tsodikova S, Gatto GJ, Jr. Protein posttranslational modifications: 
the chemistry of proteome diversifications. Angew Chem Int Ed Engl. Dec 1 
2005;44(45):7342-7372. 
21. 
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of 
demethylation and histone deacetylase inhibition in the re-expression of genes silenced 
in cancer. Nat Genet. Jan 1999;21(1):103-107. 
22. 
Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation 
indicates a tumor suppressor role for p15INK4B. Cancer Res. Feb 15 1996;56(4):722-
727. 
23. 
Herman JG, Latif F, Weng Y, et al. Silencing of the VHL tumor-suppressor gene by 
DNA methylation in renal carcinoma. Proceedings of the National Academy of Sciences 
of the United States of America. 1994;91(21):9700-9704. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
90 
 
24. 
Herman JG, Merlo A, Mao L, et al. Inactivation of the CDKN2/p16/MTS1 gene is 
frequently associated with aberrant DNA methylation in all common human cancers. 
Cancer Res. Oct 15 1995;55(20):4525-4530. 
25. 
Herman JG, Umar A, Polyak K, et al. Incidence and functional consequences of hMLH1 
promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A. Jun 9 
1998;95(12):6870-6875. 
26. 
Merlo A, Herman JG, Mao L, et al. 5' CpG island methylation is associated with 
transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human 
cancers. Nature medicine. 1995;1(7):686-692. 
27. 
Pratt WB, Ruddon RW, Ensminger WD, al. e. The anticancer drugs. 1994;Oxford 
University Press;3-16. 
28. 
Szyf M. DNA methylation properties: consequences for pharmacology. Trends 
Pharmacol Sci. Jul 1994;15(7):233-238. 
29. 
Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant recruitment 
of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid 
leukemia fusion partner ETO. Mol Cell Biol. Dec 1998;18(12):7185-7191. 
30. 
Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-
alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. Feb 19 
1998;391(6669):815-818. 
31. 
Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Jr., Evans RM. Role of the histone 
deacetylase complex in acute promyelocytic leukaemia. 
Nature. Feb 19 
1998;391(6669):811-814. 
32. 
Redner RL, Wang J, Liu JM. Chromatin remodeling and leukemia: new therapeutic 
paradigms. Blood. Jul 15 1999;94(2):417-428. 
33. 
Itazaki H, Nagashima K, Sugita K, et al. Isolation and structural elucidation of new 
cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor 
agents. J Antibiot (Tokyo). Dec 1990;43(12):1524-1532. 
34. 
Medina V, Edmonds B, Young GP, James R, Appleton S, Zalewski PD. Induction of 
caspase-3 protease activity and apoptosis by butyrate and trichostatin A (inhibitors of 
histone deacetylase): dependence on protein synthesis and synergy with a 
mitochondrial/cytochrome c-dependent pathway. Cancer Res. Sep 1 1997;57(17):3697-
3707. 
35. 
Sugita K, Koizumi K, Yoshida H. Morphological reversion of sis-transformed NIH3T3 
cells by trichostatin A. Cancer Res. Jan 1 1992;52(1):168-172. 
36. 
Yoshida H, Sugita K. A novel tetracyclic peptide, trapoxin, induces phenotypic change 
from transformed to normal in sis-oncogene-transformed NIH3T3 cells. Jpn J Cancer 
Res. Apr 1992;83(4):324-328. 
37. 
Yoshida M, Beppu T. Reversible arrest of proliferation of rat 3Y1 fibroblasts in both 
the G1 and G2 phases by trichostatin A. Exp Cell Res. Jul 1988;177(1):122-131. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
91 
 
38. 
Yoshida M, Hoshikawa Y, Koseki K, Mori K, Beppu T. Structural specificity for 
biological activity of trichostatin A, a specific inhibitor of mammalian cell cycle with 
potent differentiation-inducing activity in Friend leukemia cells. J Antibiot (Tokyo). Sep 
1990;43(9):1101-1106. 
39. 
Yoshida M, Nomura S, Beppu T. Effects of trichostatins on differentiation of murine 
erythroleukemia cells. Cancer Res. Jul 15 1987;47(14):3688-3691. 
40. 
Biggs JR, Kudlow JE, Kraft AS. The role of the transcription factor Sp1 in regulating 
the expression of the WAF1/CIP1 gene in U937 leukemic cells. J Biol Chem. Jan 12 
1996;271(2):901-906. 
41. 
Nakano K, Mizuno T, Sowa Y, et al. Butyrate activates the WAF1/Cip1 gene promoter 
through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem. Aug 29 
1997;272(35):22199-22206. 
42. 
Sambucetti LC, Fischer DD, Zabludoff S, et al. Histone deacetylase inhibition 
selectively alters the activity and expression of cell cycle proteins leading to specific 
chromatin acetylation and antiproliferative effects. J Biol Chem. Dec 3 
1999;274(49):34940-34947. 
43. 
Sowa Y, Orita T, Minamikawa S, et al. Histone deacetylase inhibitor activates the 
WAF1/Cip1 gene promoter through the Sp1 sites. Biochem Biophys Res Commun. Dec 
8 1997;241(1):142-150. 
44. 
Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824 down-
regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, 
gemcitabine, and epothilone B. Mol Cancer Ther. Oct 2003;2(10):971-984. 
45. 
Nimmanapalli R, Fuino L, Bali P, et al. Histone deacetylase inhibitor LAQ824 both 
lowers expression and promotes proteasomal degradation of Bcr-Abl and induces 
apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-
blast crisis cells. Cancer Res. Aug 15 2003;63(16):5126-5135. 
46. 
Yu X, Guo ZS, Marcu MG, et al. Modulation of p53, ErbB1, ErbB2, and Raf-1 
expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst. Apr 3 
2002;94(7):504-513. 
47. 
Warrell RP, Jr., He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of 
transcription in acute promyelocytic leukemia by use of an inhibitor of histone 
deacetylase. J Natl Cancer Inst. Nov 4 1998;90(21):1621-1625. 
48. 
Gupta N, Liu G, Berg D, Kalebic T, Gomez-Navarro J. Clinical Pharmacokinetics of 
Intravenous and Oral MLN9708, An Investigational Proteasome Inhibitor: An Analysis 
of Data From Four Phase 1 Monotherapy Studies. Blood (ASH Annual Meeting 
Abstracts) 2010 116: Abstract 1813. 2010. 
49. 
Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple 
myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter 
international myeloma working group study. Leukemia. May 2012;26(5):1153. 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
92 
 
50. 
Criteria for the classification of monoclonal gammopathies, multiple myeloma and 
related disorders: a report of the International Myeloma Working Group. Br J Haematol. 
Jun 2003;121(5):749-757. 
51. 
Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the 
uniform reporting of clinical trials: report of the International Myeloma Workshop 
Consensus Panel 1. Blood. May 5 2011;117(18):4691-4695. 
52. 
Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new 
drug approvals for myeloma. Leukemia : official journal of the Leukemia Society of 
America, Leukemia Research Fund, U.K. 2008;22(2):231-239. 
53. 
Chanan-Khan A, Sonneveld P, Schuster MW, et al. Analysis of herpes zoster events 
among bortezomib-treated patients in the phase III APEX study. J Clin Oncol. Oct 10 
2008;26(29):4784-4790. 
 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
93 
 
18 
Appendices 
19 
Medications which have a risk of causing Torsades de pointes ventricular 
arrhythmia should be avoided 
Patients who are currently receiving treatment of the medications in Table 19-1 and cannot 
either discontinue from this treatment or switch to an alternative medication prior to enrollment 
in a panobinostat clinical study, will be excluded from the study.  Patients may not begin 
panobinostat treatment with any of the medications listed in Table  unless this is discussed with 
the Sponsor and an approval is granted by the Sponsor. The sponsor may agree to temporarily 
discontinue panobinostat treatment (e.g., for 72 hours) during administration with these drugs 
or withheld medications in Table 19-1 for at least 72 hours when panobinostat is to be 
administered.   
 
NOTE: It is of great importance to avoid combining drugs listed below in Table 19-1 and Table 
20-1 (CYP3A inhibitors) especially in the presence of electrolyte abnormalities, notably 
decreased potassium or magnesium levels commonly associated with diuretic usage. 
In generally, medications listed in Table 19-1 should be avoided while medications listed in 
Tables 20-1 and Table 21-1 are to be used with caution when co-administered with 
panobinostat.  Please select the most stringent recommendation for concomitant medications 
(i.e., to be avoided) which are common among the tables (e.g., erythromycin, clarithromycin) 
Table 19-1 
Medications which have a risk of causing Torsades de pointes to be avoided 
All Class IA antiarrhythmics  
 quinidine 
 procainamide 
 disopyramide 
 any other class IA antiarrhythmic drug 
All Class III antiarrhythmics  
amiodarone 
sotalol 
bretylium 
disopryramide 
dofetilide 
ibutilide 
any other class III antiarrhythmic drug 
Antibiotics 
Macrolide antibiotics* 
 erythromycin 
 clarithromycin 
 telithromycin 
Quinolone antibiotics* 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
94 
 
sparfloxacin 
Antipsychotics 
thioridazine 
mesoridazine 
chlorpromazine 
pimozide 
Antimalarials 
 halofantrine 
 chloroquine 
Miscellaneous drugs 
 arsenic trioxide 
 astemizole 
 bepridil 
 domperidone 
 levomethadyl 
 methadone 
 pentamidine 
 droperidol 
 
*Note: azithromycin, levofloxacin, pefloxacin, ofloxacin, tosufloxacin, 
difloxacin, temafloxacin, fleroxacin, acrosoxacin, and nalidixic acid are 
allowed. 
 
This is not a comprehensive list of medications which may prolong the QT interval or have a 
risk of causing Torsades de pointes. This list of medications was developed in collaboration 
with an external cardiology consultant, and represents those medications which are deemed to 
have an unacceptable risk of co-administration with panobinostat. 
The following website may be referenced as a supplemental guide for drugs which have been 
associated with Torsades de pointes or prolonging the QT interval but at this point lack 
substantial evidence for causing Torsades de pointes: 
http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm#. 
Medications listed on the website which do not appear in Table 19-1 above may be used with 
caution at the discretion of the investigators.  
The serotonin (5HT3) antagonists, often used as antiemetics, such as ondansetron dolasetron, 
(also are known CYP2D6 substrates, see Table 21-1), or granisetron have been associated with 
Torsades de points and QT prolongation but have not been shown to cause Torsades de pointes. 
Therefore, 5HT3 antagonists are not per se prohibited but close monitoring for signs and 
symptoms of QT prolongation is recommended.  Caution is to be exercised when using these 
or other agents that may prolong QT intervals in combination with panobinostat.  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
95 
 
20 
Medications which are known strong CYP3A4/5 inhibitors to be used 
with caution 
Panobinostat is a substrate of CYP3A4 with minor involvement of CYP2D6, and CYP2C19 in  
in vitro evaluation of its metabolism. Thus, a clinical drug-drug interaction study was conducted 
using ketoconazole, a strong CYP3A inhibitor, in combination with panobinostat in study 
CLBH589B2110.  
Multiple ketoconazole doses at 400 mg increased Cmax and AUC of panobinostat by 1.6- and 
1.8-fold, respectively, but with no change in Tmax or half-lives in 14 cancer patients. The less 
than 2-fold increase in panobinostat AUC upon co-administration of a strong CYP3A inhibitor 
is considered a weak drug inhibition and not clinically relevant, as panobinostat doses at least 
2-fold greater than the evaluated 20 mg dose (i.e., 40 mg and 60 mg) have been safely 
administered in patients. Thus, co-administration of panobinostat with a moderate or weak 
CYP3A inhibitor is allowed. However, clinical monitoring of signs and symptoms of 
panobinostat treatment related adverse events is recommended when long-term (≥ 1 week) 
concomitant administration of any strong CYP3A inhibitors and panobinostat is medically 
indicated or investigated in a clinical study.  
Patients with impaired liver function (as defined by NCI CTEP criteria)1 are recommended not 
to receive panobinostat concomitantly with strong CYP3A inhibitors because potential 
interaction has not been established in this population. 
Table 20-1   Medications which are known strong CYP3A4/5 inhibitors to be used with 
caution 
Macrolide antibiotics* 
 clarithromycin 
 telithromycin 
 troleandomycin  
 erythromycin 
Antifungals (azoles)* 
 ketoconazole 
 itraconazole  
 fluconazole  
Antidepressants 
 nefazodone 
Calcium channel blockers* 
 diltiazem 
 verapamil 
HIV protease inhibitors: 
 indinavir 
 nelfinavir 
 ritonavir 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
96 
 
 saquinavir  
 Miscellaneous drugs or products 
 aprepitant 
 grapefruit product or juice 
* azithromycin, regular orange juice and dihydropyridine calcium channel 
blockers (e.g. amlodipine, felodipine, nicardipine, nifedipine) are allowed. 
This is not a comprehensive list of medications which may inhibit CYP3A4/5.  Additional 
updated versions with moderate and weak CYP3A inhibitors, which are meant to be used as a 
guide, may be found at the following website: http://medicine.iupui.edu/clinpharm/DDIs 
 
21 
 Medications which are known CYP2D6 substrates to be used 
with caution 
Panobinostat was also shown to be a CYP2D6 inhibitor (Ki 0.17 µM) in vitro.  Thus, clinical 
drug-drug interaction study with panobinostat as CYP2D6 inhibitor and dextromethorpan as 
CYP2D6 substrate was recently conducted in study CLBH589B2109. 
Multiple panobinostat doses increased Cmax and AUC of dextromethorphan by a mean of 1.8- 
and 1.6-fold respectively, but with no change in Tmax in 17 cancer patients.  An approximately 
2-fold increase in dextromethorphan AUC upon co-administration with panobinostat indicated 
that in vivo CYP2D6 inhibition of panobinostat is weak.  
As the study was conducted using a sensitive CYP2D6 substrate which resulted in a weak 
inhibition, drugs with a large therapeutic index such as anti-emetics, anti-hypertensives, and 
anti-depressants are generally safe to be co-administered with panobinostat.  
Patients should be carefully monitored for potential signs and symptoms of toxicity and may 
require dose titration or dose reduction of a sensitive CYP2D6 substrate which also have a 
narrow therapeutic window (e.g., the ratio of toxicity exposure is ≤ 2-fold higher than the 
efficacious or therapeutic exposure).  
Table 21-1    Medications which are known CYP2D6 substrates to be used with caution 
Beta blockers (listed below): 
Antipsychotics (listed below): 
carvedilol 
aripiprazole 
metoprolol 
haloperidol 
propafenone 
perphenazine 
timolol 
risperidone 
Antidepressants (listed below): 
thioridazine 
amitriptyline 
zuclopenthixol 
chlormipramine 
amphetamine  


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
97 
 
desipramine 
alprenolol 
imipramine 
bufuralol 
fluoxetine 
chloropheniramine 
paroxetine 
Antiarrhythmics (listed below): 
venlafaxine 
quinidine 
bupropion 
lidocaine 
duloxetine  
mexiletine 
Antiemetics (listed below): 
propafenone 
dolasetron 
Others: 
ondansetron 
oxycodone 
metoclopramide 
codeine 
 
hydrocodone 
 
terbinafine 
 
promethazine 
 
tamoxifen 
 
tramadol 
This is not a comprehensive list of CYP2D6 substrates.  Additional updated versions of this list, 
which are meant to be used as a guide, may be found at the following website: 
http://medicine.iupui.edu/clinpharm/DDIs Synold TW, Takimoto CH, Doroshow JH, Gandara 
D, Mani S, Remick SC, Mulkerin DL, Hamilton A, Sharma S, Ramanathan RK, Lenz HJ, 
Graham M, Longmate J, Kaufman BM, Ivy SP. Dose-Escalating and Pharmacological Study of 
Oxaliplatin in Adult Cancer Patients with Impaired Hepatic Function: A National Cancer 
Institute Organ Dysfunction Working Group Study, Clin Cancer Res. 2007 13; 3660  
 
 
 
22 
Cockroft-Gault estimation of CrCl 
 
Cockcroft-Gault estimation of creatinine clearance (CrCl):  
(Cockcroft, 1976; Luke 1990) 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)__           
   (Males) 
 
72 x (serum creatinine, mg/dL) 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
98 
 
 
CrCl (mL/min) =  
    (140 –age) x (weight, kg)_    x 0.85         
   (Females) 
 
72 x (serum creatinine, mg/dL) 
 
 
22.1.1 
Millennium Pregnancy Reporting Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
100 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
101 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
102 
 
Summary of Changes: 
 
April 24, 2014: Amendment 1 
 Cover page:  added Dr. Campagnaro as UH investigator 
 Section 7.6.1: pg. 61 changed CRF to Oncore 
 Section 8:  pg. 69 -70 changes on the schedule of assessments and foot notes for some 
additional clarifications 
 Pgs. 76-87  administrative changes brought to our attention  
 
May 6, 2014: Amendment 2 
 Table 7.5 
pg. 57 the parameters for QTCF was changed to >=481 since it would 
otherwise contradict parameters to start a new cycle (7.4; QTCF <=480 = grade 1). 
 Table 8.1 
pg. 69 myeloma parameters removed from day 1 cycle one in schedule 
of assessments (table 8.1) since they are already included in screening (day -7 to 1) 
and do not need to be repeated for any safety concerns    
 
June 18, 2014: Amendment 3 
 Section 10.4 pg. 82 Added: Follow up for detection of second primary malignancies 
beyond the planned study is not required; however, if the sponsor-investigator learns 
about the occurrence of a second primary malignancy in one of the study subjects within 
3 years after the last study drug administration he must report the event to Millennium 
Pharmacovigilance (or designee). 
 
December 26, 2014: Amendment 4 
Cover:  Replaced Dr. Campagnaro with Dr. William as UH PI 
 
1. 5.4:  Dose Limiting Toxicities: Pg. 42 
 Use of G-CSF or platelet transfusions in cycle one 
 Neutropenic fever (with grade 3 or grade 4 neutropenia) 
 
2. 6.1.2: Inclusion/Exclusion: Pg. 45 and 46 
 Updated Inclusion Criteria # 12 
 added Inclusion criteria # 13 
 Updated Exclusion Criteria # 1 
 Added # 2 
 Updated #’s 5, 6 and 9 
 deleted Exclusion criteria # 11 (was added to Inclusion) 
 
3. 7.1.3: Cardiac Precautions – Pg. 51 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
103 
 
 deleted phosphorus  
 
4. 7.4:  Instructions for Initiation of a New Cycle: Pg. 52 
 Platelets ≥ 50x 109/L, without platelet transfusion for > 72h 
 
5. 7.5.4: Dose Modifications for Prolonged QTcF: Pg. 58-63 
 Tables Updated  
 
6. 7.6.1:  Drug Discontinuation: Pg. 66 
 Dosing delay of > 21 days (= unable to receive study therapy for 22 days 
including any therapy held during a cycle) 
 Delay of a cycle by > 14 days from the intended day of the next scheduled dose, 
counted from the start of the previous cycle. 
 
7. 7.7.2: Summary of Prohibited Concomitant Medications and Supplements: Pg. 68 
 Non-steroidal anti-inflammatory agents (NSAIDs) should be avoided if possible 
due to risk for kidney dysfunction in myeloma but if clinical judgement strongly 
argues for their use patients can remain on study while receiving NSAIDs 
 Platelet transfusions can be given as clinically indicated but eligibility for 
starting a new cycle needs to be determined after at least 72 h without platelet 
transfusion and eligibility for inclusion in this trial needs to be determined after 
at least 7 days without platelet transfusion. 
 
8. 8.0:  Visit Schedule and Assessments: Pg. 73 
 Added Physical Exam at Screening 
 Deleted Weekly ECGs (typo) 
 Updated ISTAT BMP info. 
 Updated CMP info. 
 Footnote #5 regarding ECGs updated 
 
9. 9.1.6: ECG Assessments: Pg. 79 
 Updated tables for ECG from 3 to 1  
 
10. 10.0:  Safety Monitoring: Pg. 81-88 
 Multiple updates for Novartis and Millennium Reporting Requirements 
 
June 3, 2015: Amendment 5 
 Cover:  Replaced Dr. William with Dr. Malek as UH PI 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
104 
 
 Pg. 3 Dose Levels:  Patient may continue on Panobinostat behind cycle 6 if disease 
is at least stable disease free of charge. 
 Pg. 39  Section 5.2: Study Duration:  
 If the patient’s myeloma is controlled in at least stable disease panobinostat 
may be continued free of charge to the patient. Follow up after completion of 
cycle 6 is at the discretion of the treating physician but if panobinostat is 
continued, monitoring for electrolyte abnormalities, especially potassium and 
magnesium, at a frequency appropriate for the respective patient, is 
recommended.   
 This protocol may be amended to include a formal maintenance phase and/or a 
phase II portion after review of safety and preliminary efficacy data. 
 Pg. 69 Visit Schedule and Assessments 
 Deleted iSTAT BMP weekly and made CMP weekly instead 
 
September 23, 2015: Amendment 6 
 
 Page 1 Increase # of patients to an additional 20 in the Phase 2 
 Section 2 Page 40 
Rationale for Phase 2 
 Section 6 Page 44 
Study Population 
 Section 6.1.2 Page 44-46 
Inclusion Criteria items 3, 8 and 13 
 Section 6.1.2 Page 48 Exclusion Criteria item 21 
 Section 8 Page 74-75 Visit schedule and assessments 
 
July 18, 2016: Amendment 7 
 Pg. 43  Inclusion Criteria #13 (Added Dara and Elot) At least 7 days must have 
passed since the last treatment with lenalidomide, pomalidomide, thalidomide, 
proteasome inhibitors, or low dose cyclophosphamide (up to 50mg daily), at least 21 
days must have passed since the last treatment with daratumumab, elotuzumab, 
investigational therapy and most conventional chemotherapy including 
cyclophosphamide above 50mg per dose, bendamustine, doxorubicin, cisplatin, and 
etoposide; and at least 35 days since the last treatment with melphalan. 
 Pg. 50 Section 7.4 Instructions for Initiation of a New Cycle (these were 
previously deleted in Amendment 6, however we missed a section 
 Deleted:  total serum calcium [corrected for serum albumin] or ionized 
calcium ≥LLN 
 Clarified:  QTcF < 480 msec if ECG obtained (mandatory before cycle 2) 
 
March 1, 2017: Amendment 8 
 
 Cover Page: Adding NCT # 


 
Confidential 
  
 
CASE 4A13 A9 04/03/2017 
 
105 
 
 Footer: Updated 
 Addendum: Summary of Changes 
 
April 3, 2017 
 Cover Page: PI from Dr. Reu to Dr. Valent 
 Footer Updated 
 
 
 
 

ICF_000.pdf: 
PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 1 of 16 
 
CONSENT FOR CANCER RESEARCH  
 
Project Title: A Phase I/II Study of MLN9708 (Ixazomib) in Combination with Panobinostat 
and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma 
 
Principal Investigator: JASON VALENT, MD  216-445-7238 
SUB-INVESTIGATOR:      EHSAN MALEK, MD 216-844-3951 
Study Coordinator:   Sherry Fada  216-445-6235 
 
 
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, University 
Hospitals and Case Western Reserve University (CWRU) through the NIH National Cancer Institute 
(NCI) designated Case Comprehensive Cancer Center (CaseCCC).  The goal of this collaboration is to 
enhance cancer treatment and research in Northeast Ohio.  This study is being offered at Cleveland 
Clinic (CC) and University Hospitals (UH).  
 
1.  Introduction 
You are being invited to take part in a research study, also known as a clinical study.  Before you decide 
it is important for you to understand why the research is being done and what it will involve.  Please 
take time to read the following information carefully and discuss it with friends, relatives and others if 
you wish.    
Please ask questions if there is anything that is not clear or if you would like more information.  Take 
time to decide whether or not you wish to take part.  This copy of the information sheet is yours to keep. 
Before agreeing to participate in this study, it is important that the following explanation of the research 
study be read and understood.  This form describes the purpose, procedures, benefits, risks, discomforts, 
and precautions of the study.  It also describes alternative procedures available and the right to withdraw 
from the study at any time.  It is important to understand that no guarantee or assurance can be made as 
to the results.  It is also understood that refusal to participate in this study will not influence your rights 
to receive standard treatment or other therapies. 
 
You have been asked to participate in the research study under the direction and medical supervision of 
Dr. Jason Valent, located at the Cleveland Clinic Taussig Cancer Institute and Dr. Ehsan Malek oversees 
study activities at University Hospitals Seidman Cancer Center.  Other professionals working with Dr. 
Valent, Dr. Malek as study staff may assist or act for them.   
 
Conflict of Interest Disclosure 
One or more of the Investigators conducting this study serve as paid speakers, consultants or advisory 
committee members for the company that is paying for this research or a company that makes products 
used in this study.  These financial interests are within permissible limits established by the Cleveland 
Clinic Conflict of Interest Policy.  If you have any questions regarding conflicts of interest, please ask 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 2 of 16 
 
your study doctor or call the Cleveland Clinic Institutional Review Board at 216.444-2924 or University 
Hospitals Institutionals Review Boards at 216.844.1529. 
 
2. Purpose 
 
You have been asked to participate in this research study because you have multiple myeloma that has 
relapsed after previous treatment or did not respond to the last treatment.  Current therapy for your 
disease includes lenalidomide (Revlimid ®), thalidomide (Thalomid ®), pomalidomide (Pomalyst ®), 
dexamethasone (e.g. Decadron ®), prednisone, bortezomib (Velcade ®), carfilzomib (Kyprolis ®), 
chemotherapeutic agents like cyclophosphamide (Cytoxan ®) or liposomal doxorubicin (Doxil ®) alone 
or in various combinations.  
 
The purpose of this research is to evaluate the use of MLN9708 (Ixazomib ®) in combination with 
panobinostat and dexamethasone.  This study will primarily seek to find an appropriate dose of 
MLN9708 (Ixazomib ®) (one that is not too toxic) for combination with fixed doses of panobinostat and 
dexamethasone. MLN9708 (Ixazomib ®) works in a similar way as bortezomib (Velcade ®) and 
carfilzomib (Kyprolis ®), but while these two drugs have to be given by injection, MLN9708 (Ixazomib 
®) can be taken by mouth. Other studies with MLN9708 (Ixazomib ®) have already shown that it has 
activity in myeloma and suggested less side effects on nerves than with bortezomib (Velcade ®). 
Panobinostat is a drug that acts by a unique mechanism to kill cancer cells, especially refractory 
myeloma cells. It was therefore used in combination with bortezomib (Velcade ®) and dexamethasone 
in patients with multiple myeloma that was refractory to bortezomib (Velcade ®). Promising results with 
about half of the patients reaching at least some degree of a response encouraged us to conduct the 
current study to establish a similar regimen without need for injections.  The Phase I portion of the study 
has been completed. 
 
The Phase II portion of the study will enroll up to 20 patients, who will be monitored for toxicity and 
efficacy.  
Duration 
As long as your myeloma responds you may stay on study until disease progression. Monitoring for toxicity and 
efficacy with laboratory tests and physical exams will be weekly during the first 28-day cycle, after that blood 
tests will be continued during cycle 2. After cycle 2 blood tests and physical exams will be monthly.  
 
3.  Study Procedures 
 
You will be asked to take MLN9708 (Ixazomib ®) on days 1, 8, and 15 of each 28-day cycle of therapy, 
Panobinostat will be 3 times a week every other week and dexamethasone the day of and after 
MLN9708 (Ixazomib ®).   
In order to determine if the study is appropriate for your participation and to obtain a new baseline status 
of your myeloma and of your organs that could possibly be affected by side effects, some tests must be 
done and you must meet certain criteria.  
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 3 of 16 
 
These tests will include standard tests and research related tests. 
 
Standard of care tests: 
· Complete Physical Examination (measuring your heart rate, blood pressure, temperature, height, 
weight, and body surface area, inquire about prescription, over-the-counter medication, vitamins, 
nutritional supplements, natural and herbal products) 
· Serum Chemistry (to check your general body functions) 
· Complete Blood Count (CBC) (to check your blood count) 
· Bone marrow biopsy and aspirate (to determine percent plasma cell involvement) 
· Skeletal survey (to detect any fractures or tumors of the bone; the standard set of X-rays includes 
X-rays of the skull, entire spine, pelvis, ribs, legs and  arms) 
· For females of childbearing potential a pregnancy blood test 
· Myeloma blood and urine tests (from a 24hour urine collection) 
 
Research related tests: 
· Electrocardiogram (to check your heart function) 
· Thyroid function blood test 
· Magnesium blood test 
 
The charts below shows what will happen to you during the first cycle and future treatment cycles.  The 
left-hand column shows the day in the cycle and the right-hand column tells you what to do on that day. 
 
Cycle One: 
Day 
What you do 
Screening- Anytime 
within 7 days of 
starting study 
· Get physical examination, routine blood tests, Thyroid function 
blood test, Myeloma blood and urine tests (from a 24hour urine 
collection), Electrocardiogram, bone marrow biopsy/aspirate 
(after that the bone marrow is only repeated for confirmation of 
complete remission or in rare myelomas that do not produce 
enough myeloma proteins to allow response assessment with  
blood and/or urine tests), skeletal survey, and pregnancy tests 
for females of childbearing potential  
Day 1 
 
· Get physical examination and routine blood tests  
· Myeloma blood and urine tests 
· Pregnancy test for females of childbearing potential every week 
for the first 28 days 
· Electrocardiogram: Pre-dose: 1 ECGs , 1 Post-dose at 3 hours 
Day 5 
· Routine blood tests  
· Electrocardiogram: Pre-dose (only panobinostat is taken on that 
day): 1 ECGs, 1 Post-dose at 3 hours 
Weekly 
· Get physical examination and routine blood tests  
  
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 4 of 16 
 
Cycle 2: 
Day  
What you do 
Day 1 
· Get physical examination and routine blood tests  
· Myeloma blood and urine tests 
· Pregnancy test for females of childbearing potential every 28 
days if you have regular or no menstrual cycles or every 14 
days if you have irregular menstrual cycles 
· Thyroid function test  (every 3 months) 
· Electrocardiogram: Pre-dose: 1 ECGs  
Weekly 
· Get  routine blood tests  
 
 
Cycle 3 and Beyond: 
Day  
What you do 
Day 1 
· Get physical examination and routine blood tests  
· Myeloma blood and urine tests 
· Pregnancy test for females of childbearing potential every 28 
days if you have regular or no menstrual cycles or every 14 
days if you have irregular menstrual cycles 
· Thyroid function test  (after 3 cycles: Day 1 of Cycle 4) 
· Electrocardiogram: Pre-dose: 1 ECGs  
 
 
 
Discontinuation Procedures: 
Standard of care tests: 
· 
Complete Physical Examination (measuring your heart rate, blood pressure, temperature, 
height, weight, and body surface area, inquire about prescription, over-the-counter medication, 
vitamins, nutritional supplements, natural and herbal products) 
· 
Serum Chemistry (to check your general body functions) 
· 
Complete Blood Count (CBC) (to check your blood count) 
· 
Myeloma blood and urine tests (from a 24hour urine collection) 
Research tests: 
·    Thyroid function blood test 
·    Magnesium blood test 
 
4.  Risks 
There is always a risk involved in taking any drugs, but you will be carefully monitored for any 
problems and you are encouraged to report anything that is bothering you.  There may be risks or side 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 5 of 16 
 
effects of the study drugs that are unknown or cannot be predicted at this time.  You should not hesitate 
to report anything that upsets you or may be troubling you to your Study Doctor, even if you do not 
think it is connected to taking the study drugs.  If you have any questions you should contact Dr. Jason 
Valent at 216-445-7238 or Dr. Ehsan Malek at 216-844-3951. 
Steps will be taken to prevent or reduce any discomfort or risk.  You understand that there may be risks 
and discomforts that are unknown.  You may experience all, some or none of these side effects listed.  
You will be asked to contact your study doctor for any problems or questions that arise at any time 
during your treatment, so that measures can be started to prevent or decrease serious problems.  If, 
during the course of treatment, your doctor becomes aware of additional toxic or therapeutic effects, 
your doctor will discuss them with you. 
MLN9708 (Ixazomib): 
 
There are risks to taking part in any research study.  During the study, you may have problems or 
discomforts and risks from MLN9708, MLN9708 and other drug combinations, and/or study 
procedures.   The more commonly occurring discomforts and risks are listed below, as are the rare but 
serious discomforts and risks.  You should discuss these with your study doctor. There is always the 
possibility that unknown risks may occur, however your doctor will watch closely for problems or 
discomforts and risks.  Many discomforts and risks go away shortly after treatment is stopped or with 
treatment for the discomforts and risks, but in some cases discomforts and risks may be serious, long-
lasting or permanent and may even result in hospitalization. There is also the risk of death.   
 
If any discomforts and risks occur, you must tell your study doctor or study staff, even if you do 
not think they are related to the study drug.  
   
POTENTIAL DISCOMFORTS AND RISKS OF MLN9708 
 
Based on studies of MLN9708, it is possible to predict some of the discomforts and risks.  However, it is 
possible that MLN9708 may cause risks that have not yet been observed in patients.   
 
The following risks might be seen: 
 
o Low platelet count which may increase the chance of bleeding; (33%) 
o Skin rash which may range from some red areas, small flat spots, or small raised bumps that may 
or may not be itchy in a few areas or all over the body (45%) 
o Feeling tired or weak (48%) 
o Nausea (41%) 
o Vomiting (30%) 
o Diarrhea (39%) 
o Numbness or tingling or pain feelings in hands and feet (21%) 
o Fever (21%) 
o Constipation (21%) 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 6 of 16 
 
o Lowered red cells or anemia which may make you feel tired; (22%) 
o Lowered white blood cells called neutrophils that may increase your risk of infection (19%) and 
may be associated with fever (<1%) 
o Distortion of the sense of taste i.e. an abnormal or impaired sense of taste. (7%) 
o 
Trouble falling asleep, staying asleep, or both (15%) 
 
Other discomforts and risks reported in studies with MLN9708, which may have been due to the 
patient’s disease, MLN9708, other medications, or some combination of these include: 
 
o Not feeling like eating (13%) 
o Electrolyte imbalance (blood chemical imbalance) (18%) 
o Loss of water from the body (dehydration) because of vomiting and/or loose stools (11%) 
o High blood creatinine and renal failure which means your kidneys are having trouble working 
well; Patients who had lost body water (dehydration) because of vomiting and/or loose stools 
have had high levels of creatinine indicating that the kidneys were failing to function adequately. 
In some severe situations, less kidney function may require temporary treatment with a machine 
that supports the function of the kidney (dialysis) (3%) 
o Headache (13%) 
o Flu-like symptoms and other upper respiratory tract infections (17%) 
o Feeling short of breath (14%) 
o Lung infections including pneumonia or pneumonitis (7%) 
o Cough (12%) 
o Chills (6%) 
o Pain in the abdomen (11%) or back (15%) 
o Swelling or fluid buildup in the arms or legs (20%) 
o General aches or pains in muscles, joints, bones, or arms and legs (11%) 
o Feeling dizzy (13%) 
o Lowered blood pressure (12%) that can commonly cause you to feel light headed, faint or pass 
out when you stand up (4%) 
o Lowered white blood cells called lymphocytes (10%) 
o Pain (muscular) in extremities (10%) 
 
Some discomforts and risks that occur with lesser frequency (<1%) than those mentioned above, should 
be noted because they are severe, life-threatening or fatal.  With limited experience, we do not know if 
MLN9708 causes such problems.  Stevens Johnson’s Syndrome, a severe, life-threatening or deadly 
condition that may involve rash, skin peeling and mouth sores has been reported in ongoingMLN9708 
studies.  Stevens Johnson Syndrome is a disorder of the immune system, which differs from a regular 
skin rash.  
 
In addition posterior reversible encephalopathy syndrome has also been reported with MLN9708 with 
lesser frequency (<1%). This condition affects the brain and may cause headaches, changes in your 
vision, changes in your mental status, or seizures (fits), but is usually reversible.   
Additionally, it is worth noting that: 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 7 of 16 
 
 
· MLN9708 is similar to the drug known as VELCADE ® (bortezomib) for Injections, which is 
approved for the treatment of multiple myeloma (a cancer of the plasma cell), as well as mantle 
cell lymphoma (a cancer of the lymph nodes) in patients who have received at least one prior 
therapy. 
· MLN9708should not be taken if you have ever had an allergic reaction to boron or boron 
containing products. As of April 3, 2014 the only FDA approved boron containing drug is 
Velcade but new boron containing drugs are in development and boron can be found in some 
herbal medicines. If you have an allergy against another medication and you are not sure if it 
contains boron please consult your physician. 
·  The following side effects have been reported with VELCADE use and therefore may also be a 
risk with MLN9708: 
o Reactivation of the herpes virus infection such as herpes zoster (shingles) that can 
sometimes cause local pain that may last after recovery from the skin rash and does not go 
away for some time;  and 
o Rapid death of cancer cells that may let large amounts of their contents into the blood that 
injure organs, such as kidneys (this is referred to as tumor lysis syndrome).  Your study 
doctor can talk with you about other common side effects with VELCADE use.  
 
· The more severe but rare side effects seen with VELCADE, include but are not limited to,  
worsening of your heart function (congestive heart failure), disorders that could affect the 
function of your lung that could be serious enough to result in death, and liver failure. Your 
doctor can talk to you further about the risks of VELCADE. 
 
· Other drugs and supplements may affect the way MLN9708 works.  Tell your doctor about all 
drugs and supplements you are taking while you are in this study. 
 
· Although increased risk for second primary malignancies (another form of cancer) associated 
with the use of MLN9708 or bortezomib has not been detected, Millennium Pharmaceutical does 
require investigators to report any known occurrences up to three years after your last treatment.  
Should you develop a secondary malignancy, please notify the physician’s office who treated 
you on this study. 
 
One fatal case of progressive multifocal leukoencephalopathy (PML) has been reported with MLN9708 
in an oncology patient who had previously received a medication associated with PML. PML is a rare, 
serious infection of the brain that is caused by a virus. Persons with a weakened immune system may 
develop PML. PML can result in death or severe disability. It is not known whether MLN9708 may 
have contributed to the development PML in this patient  
 
 
 
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 8 of 16 
 
Panobinostat: 
At least 30% 
· Lowering in the blood levels of disk-like bodies (known as platelets) which assist your blood 
in clotting. When platelets are low, there is a risk of bleeding and bruising. Sometimes, when 
the platelet count is very low, doctors will order a transfusion of platelets through your vein 
(intravenously, commonly called IV). 
· Mild to moderate nausea, vomiting, and diarrhea, which can be controlled with other 
medicines. Sometimes, doctors order fluids to be given through your vein (intravenously, 
commonly called IV)  
· Decreased appetite 
· Feeling weak or tired 
Other side-effects which have been reported include: 
· Lowering of red blood cell count (anemia), which makes patients feel tired. Doctors 
sometimes give patients with lowered red blood cell count an IV transfusion of red blood 
cells.  
· Lowering of white blood cell count, which may lower your ability to fight infections.  
· Changes in the balance of minerals (called electrolytes) in the blood, such as sodium, 
potassium, calcium, magnesium and phosphate  
· Changes in blood sugar levels 
· Changes in the creatinine level, which might be a sign of a problem with the kidneys 
· Changes in how electricity is conducted in the heart, which can cause abnormal heart beat 
patterns, which sometimes can be life-threatening or even cause death 
· Changes in the way the thyroid works 
Other side-effects reported included:  
· blood clots that can travel in the blood to the brain (a stroke) or lungs 
· pain in the back, arms, legs, muscles, joint and bones 
· headache 
· coughing 
· shortness of breath 
· dizziness 
· constipation 
· fever 
· abdominal pain 
· swelling in the legs or eye 
· itchiness 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 9 of 16 
 
Dexamethasone: 
The most common side effects of dexamethasone include infection, insomnia, seizures, muscle 
weakness, particularly the thigh muscles, irritability and mood swings, dependence with lack of 
energy, lightheadedness, and low blood pressure upon discontinuation, , weight gain, increased 
appetite, diabetes mellitus (high blood sugar), high blood pressure, thromboembolism (blood clot 
formation in a large blood vessel and distribution of pieces of blood clots that break off via the blood 
stream, usually to the lungs), peptic ulcers, pancreatitits (inflammation of the pancreas), infection in 
your mouth and fluid retention. 
For more information about any of the risks and side effects, ask the Study Doctor. 
Possible Side effects of blood draws 
The risk of blood drawing commonly includes discomfort, pain, redness, swelling, and/or bruising 
where the blood is taken from your arm.  Sometimes bleeding can occur at the place where blood is 
drawn.  Fainting and infection are rare occurrences. 
Possible Side effects of bone marrow aspiration and biopsy 
With the bone marrow aspiration and biopsy you may feel a slight burning sensation with the local 
anesthetic. Pressure may be felt as the needle is inserted into the bone. There is a sharp sucking 
sensation as the marrow is aspirated, which lasts for only a few moments. 
There may be some bleeding, swelling, and bruises at the puncture site. More serious risks, such as 
serious bleeding or infection, are very rare. Bleeding may be stopped with direct pressure and a cool 
compress to the area as soon as possible to reduce swelling. Do not place ice directly on the skin. 
Radiation Risks (X-ray/Chest X-ray/Skeletal Survey): 
While you are in this research study, chest x-rays and skeletal surveys (x-rays of the bones) may be 
used to evaluate your disease.  The total amount of radiation that you will get from these tests is 
relatively small and is not likely to be harmful to you or affect your disease. 
12-Lead Electrocardiogram 
An electrocardiogram — also called an ECG or EKG — records these electrical signals as they travel 
through your heart. Your doctor can look for patterns among these heartbeats and rhythms to diagnose 
various heart conditions.  An electrocardiogram is a painless, noninvasive way to diagnose many 
common types of heart disease.   An electrocardiogram is a safe procedure. There may be minor 
discomfort when the electrodes are removed. Rarely, a reaction to the electrodes may cause redness or 
swelling of the skin.  
 
If any physician other than the study physician prescribes medication for you, even if it is for another 
condition, you must inform the study staff.  In addition, you must report all over the counter 
medications, herbal preparations and nutritional supplements that you are taking. This is important 
because the interaction of some medications and supplements may cause serious side effects. 
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 10 of 16 
 
Reproductive Health/Sexual Activity 
 
Pregnancy Risk: 
Female subjects: We do not know if the study drugs MLN9708 and panobinostat will affect mother’s 
milk or an unborn child. Because of the potential for serious adverse reactions in infants, breast-
feeding should be discontinued before starting treatment.  There are no adequate and well-controlled 
studies in pregnant women.   
Therefore, breast-feeding and pregnant women are not allowed to take part in the study.  Due to 
unknown risks and potential harm to the unborn child/ infant from study therapy, you should not 
become pregnant or nurse a baby while on this study.   
 
You must have a negative pregnancy test prior to enrolling in the study. 
 
Unless you cannot have children because of surgery or other medical reasons (you had an effective 
tubal ligation, or had the ovaries or the uterus removed; or you are post-menopausal), you must use 
two effective methods of birth control from the time of signing the informed consent form, for the 
entire study drug treatment period (including interruptions in treatment), and for 90 days after 
completing study drug treatment.  It is strongly recommended that at least one of these two methods be 
highly effective (see examples below). 
 
Highly effective methods 
Other 
effective 
methods 
(barrier 
methods) 
Intra-uterine devices (IUD)         
Latex or non-latex condom with or without 
a spermicidal agent 
Hormonal 
(birth 
control 
pills/oral 
contraceptives, injectable contraceptives, 
contraceptive patches, or contraceptive 
implants) 
Diaphragm with spermicide; Cervical cap 
with 
a 
spermicide; 
Sponge 
with 
a 
spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the 
same time are recommended.  
 
You must use birth control methods as directed above, unless you completely avoid having 
heterosexual intercourse. 
 
Male subjects: We do not know if using MLN9708 and panobinostat will affect sperm.  Therefore, 
due to potential risk, you should not get your partner pregnant during the study drug treatment period 
(including interruptions in treatment).  Even if you are surgically sterilized (i.e. have had a vasectomy) 
you must agree to use an appropriate method of barrier contraception (latex or non-latex condom with 
a spermicidal agent) during the entire study drug treatment period, and for 90 days after completing 
study drug treatment.  Or, you should completely avoid having heterosexual intercourse. 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 11 of 16 
 
 
Highly effective methods 
Other 
effective 
methods 
(barrier 
methods) 
Vasectomy         
Latex or non-latex condom  with or without 
a spermicidal agent   
 
Diaphragm with spermicide; Cervical cap 
with spermicide; Sponge with spermicide 
If one of the highly effective methods cannot be used, using two effective methods at the 
same time are recommended.  
 
All subjects (male or female):  If you or your partner becomes pregnant during this study, you must tell 
the study doctor immediately.  The doctor will advise you of the possible risks to your unborn child and 
discuss options for managing the pregnancy with you.  For female subjects who become pregnant while 
on this study, the study drug will be stopped immediately and we will ask to follow the pregnancy until 
conclusion. 
 
If you do not understand what any of these discomforts and risks mean, please ask the study doctor or 
study staff to explain these terms to you. 
 
5. Benefits 
 
You may or may not receive any benefits from your participation in this study.  By taking part in this 
study you may contribute new information that will help and benefit other people who have a similar 
medical problem in the future  
6. Alternatives to Participation 
 
If you do not take part in this study, you have several alternatives to choose from, including the 
following that you should discuss with your doctor: 
· Getting treatment or care for your cancer without being in a study such as: 
o Chemotherapy 
o Bone marrow or stem cell transplantation 
o Radiation therapy 
o High-dose myeloablative therapy – High-dose chemotherapy 
o Glucocorticoids like dexamethasone or prednisone with or without lenalidomide  
o Other anti-myeloma drugs like bortezomib (Velcade®) or thalidomide (Thalomid®) 
o Ixazomib and Panobinostat are now commercially available 
· Taking part in another study 
· Getting no treatment 
· Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, 
appetite problems and other problems caused by the cancer.  It does not treat the cancer 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 12 of 16 
 
directly, but instead tries to improve how you feel.  Comfort care tries to keep you as active 
and comfortable as possible.  
 
You should talk to your doctor about your choices for managing your healthcare needs before you decide if you 
will take part in this study 
 
7. Costs and Compensation 
Millennium will provide MLN9708 (Ixazomib) and Novartis will provide Panobinostat free of charge. 
You and/or your insurance company will not be charged for any treatments or tests performed strictly 
for this study, that are not considered to be standard of care for myeloma.  You and/or your insurance 
company are responsible for the costs of any other treatments, diagnostic and laboratory studies, hospital 
or clinic visits done while you are on the study.  You will not be paid to participate, however we will 
provide parking passes. 
For more information on clinical trial and insurance coverage, you can visit the National Cancer Institute’s 
(NCI) website at  
http://cancer.gov/clinicaltrials/understanding/insurance-coverage   
You can print a copy of the ‘Clinical Trials and Insurance Coverage’ information from this website.  Another 
way to get information is to call 1-800-4-CANCER (1-800-422-6237) and ask NCI for a free copy.  
 
8.  Research-Related Injury 
 
If you experience physical injury or illness as a result of participating in this research study, medical care 
is available at the Cleveland Clinic or elsewhere; however, the Cleveland Clinic has no plans to provide 
free care or compensation for lost wages.  You are not waiving any legal rights by signing this form. 
 
If injury occurs as a result of your involvement in this research, medical treatment is available from 
University Hospitals or another medical facility but you/your medical insurance will be responsible for the 
cost of this treatment.  A research injury is an injury that happens as a result of taking part in this research 
study.  If you are injured by a medical treatment or procedure that you would have received even if you 
weren’t in the study, that is not considered a “research injury”. There are no plans for payment of medical 
expenses or other payments, including lost wages, for any research related injury.  To help avoid injury, it 
is very important to follow all study directions.  Novartis will not pay any money to you or your medical 
bills.  Millennium will not pay any money to you or your medical bills. 
 
Further information about research-related injuries is available by contacting the Cleveland Clinic 
Institutional Review Board at 216-444-2924 or University Hospitals Cleveland Medical Center’s Research 
Subject Rights phone line at 216-983-4979. 
 
9.  Privacy and Confidentiality 
 
This section explains how your medical and health records might be used and disclosed if you agree to 
participate in this study.  If you do not sign this form you will not be able to participate in this study. 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 13 of 16 
 
Steps will be taken to maintain the confidentiality of your study records.  Agents of the United States 
Food and Drug Administration, governmental agencies in other countries where the study drug may be 
considered for approval, Novartis Oncology and its authorized agents, their agent or designee, and 
Millennium Pharmaceutical, Inc. and its authorized agents will be allowed to inspect sections of your 
medical and research records related to this study. The data from the study may be published; however, 
you will not be identified by name.   
 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a Research 
Study  
 
If you volunteer to participate in this research, your protected health information (PHI) that identifies 
you will be used or disclosed to Jason Valent, MD, Ehsan Malek, MD and their research staff at 
Cleveland Clinic and University Hospitals Cleveland Medical Center for the purposes of this research 
and to Case Western Reserve University for administration. 
 
The PHI that we may use or disclose (release) for this research may include your name, address, phone 
number, date of birth, Social Security number, information from your medical record, lab tests, or 
certain information relating to your health or condition.. 
 
Some of the tests and procedures done solely for this research study may also be placed in your medical 
record so other doctors know you are in this study.  Upon completion of the study, you may have access 
to the research information that is contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be looked at by other 
groups involved with the study such as the Cleveland Clinic Institutional Review Board, University 
Hospitals Institutional Review Board and the Case Comprehensive Cancer Center Protocol Review and 
Monitoring Committee.  Your PHI may also be used by and/or disclosed (released) to: 
 
· 
The drug supplier of panobinostat, (Novartis Pharmaceuticals)and its authorized 
representatives 
· 
The drug supplier of MLN9708 (Ixazomib), (Millennium Pharmaceutical, Inc.)and its 
authorized representatives 
· 
The Food and Drug Administration 
· 
Governmental agencies in other countries where the study drug may be considered for 
approval 
· 
The Department of Health and Human Services 
· 
Your insurance company  
· 
The National Committee for Quality Assurance 
· 
The Cleveland Clinic and/or University Hospitals Cleveland Medical Center  
· 
Case Comprehensive Cancer Center members and collaborators 
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 14 of 16 
 
Once your personal health information is released it may be re-disclosed without your permission and no 
longer protected by privacy laws. 
 
Your research information may be used and disclosed indefinitely, but you may stop these uses and 
disclosures at any time by writing to Jason Valent, MD, The Cleveland Clinic, 9500 Euclid Avenue, 
Cleveland, Ohio  44195 or Ehsan Malek, MD at University Hospitals Cleveland Medical Center, 11100 
Euclid Avenue, Cleveland, Ohio   44106.  Your participation in the research will stop, but any 
information previously recorded about you cannot be removed from the records and will continue to be 
used as part of this research.  Also, information already disclosed outside the Cleveland Clinic cannot be 
retrieved.  This will not affect your rights to treatment or benefits outside the research study.    
 
The Cleveland Clinic and/or University Hospitals will not use your information collected in this study 
for another research purpose without your written permission; unless the Cleveland Clinic Institutional 
Review Board (IRB) assures your privacy and confidentiality is protected.  The IRB is a committee 
whose job it is to protect the safety and welfare of research subjects. 
 
By signing this informed consent form, you are authorizing such access to your research and medical 
record information.  If you choose not to sign this consent form, you will not be able to participate in 
this research study.  This Authorization does not have an expiration date. 
 
10.  Voluntary Participation 
 
Your participation in this research study is voluntary.  Choosing not to participate will not alter your usual 
health care or involve any penalty or loss of benefits to which you are otherwise entitled.  If you decide to 
join the study, you may withdraw at any time and for any reason without penalty or loss of benefits.  If 
information generated from this study is published or presented, your identity will not be revealed.   
 
In the event new information becomes available that may affect the risks or benefits associated with this 
study or your willingness to participate in it, you will be notified so that you can decide whether or not to 
continue participating.   
 
Termination of Participation 
 
You understand that your participation is voluntary and you may refuse to participate.  You may 
discontinue your participation AT ANY TIME, without penalty or loss of benefits to which you are 
otherwise entitled.  You also understand that the investigator has the right to withdraw you from the 
study AT ANY TIME.  You understand that your withdrawal from the study may be for reasons related 
solely to you (e.g. not following study-related directions from the Investigator; a serious adverse 
reaction) or because the entire study has been terminated.  You understand that the study or the 
Investigator’s participation in the study may be terminated at any time. 
 
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 15 of 16 
 
11.  Questions About the Research 
 
If you have any questions, you can ask the Principal Investigator and/or research staff.  JASON VALENT, MD  216-
445-7238 OR EHSAN MALEK, MD 216-844-3951. 
 
Emergency and After-hours Contact Information 
 
If you are a Cleveland Clinic patient, you should contact the page operator at (216) 444-2200 or toll free at 
(800) 223-2273, and ask for the oncologist (cancer doctor) that is on call. 
 
If you are a University Hospitals patient, and you need to contact study staff outside normal business hours, you 
may contact 216-844-3951 and you will be transferred to the answering service, which can put you in contact 
with Dr. Malek or the oncologist on call. 
 
If you have questions about your rights as a research subject, you may contact the Institutional Review Board 
(IRB) at Cleveland Clinic IRB 216-444-2924 or University Hospitals Cleveland Medical Center’s Research 
Subjects Rights Phone line at 216-983-4979. 
 
Where Can I Get More Information? 
 
You may call the National Cancer Institute’s Cancer Information Services at: 
 
1-800-4-CANCER (1-800-422-6237)  
 
You may also visit the NCI website at http://cancer.gov 
· For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials 
· For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo 
 
You will get a copy of this form.  If you want more information about this study, ask your study doctor.   
 
US National Institutes of Health (NIH) Clinical Trial Database 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will 
not include information that can identify you. At most, the Web site will include a summary of study 
results. You can search this Web site at any time. 
 
 
 
 
 
 
 
 
 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018


PRMC #: CASE4A13 
Protocol Number/Version Date: US92T                                                 03April2017  
Consent Descriptor: Main ICF      
 03April2017 
 
Page 16 of 16 
 
12.  Signature 
 
Signing below indicates that you have been informed about the research study in which you voluntarily agree to 
participate; that you have asked any questions about the study that you may have; and that the information given 
to you has permitted you to make a fully informed and free decision about your participation in the study.  By 
signing this consent form, you do not waive any legal rights, and the investigator(s) or sponsor(s) are not 
relieved of any liability they may have.  A signed copy of this consent form will be provided to you. 
 
 
 
Signature of Participant 
 
 
 
Date 
 
   Printed Name of Participant 
 
I have discussed the information contained in this document with the participant and it is my opinion 
that the participant understands the risks, benefits, alternatives and procedures involved with this 
research study. 
 
 
 
Signature of Person Obtaining Consent 
            Date 
 
 
 
 
 
 
Printed Name of Person Obtaining Consent 
CCF IRB #: 14-346
Approval Date: 4/20/2017
Expiration Date: 3/27/2018