Conditions: Primary Myelofibrosis Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis Polycythemia Vera Essential Thrombocythemia
Keywords: Primary Myelofibrosis Post Polycythemia Vera Myelofibrosis Post Essential Thrombocythemia Myelofibrosis Polycythemia Vera Essential Thrombocythemia blood disorders
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
This open-label study is to determine the long-term safety and tolerability of momelotinib in previously enrolled study participants with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), post-essential thrombocythemia myelofibrosis (post-ET MF), polycythemia vera (PV), or essential thrombocythemia (ET), who have tolerated and achieved stable disease or better with momelotinib treatment while enrolled in a previous clinical trial.

Detailed description:

Arms:
arm 1: Participants previously enrolled in Study CCL09191E will receive momelotinib for approximately 4 years. arm 2: Participants previously enrolled in Study YM387-II-02 will receive momelotinib for approximately 4 years. arm 3: Participants previously enrolled in Study GS-US-354-0101 will receive momelotinib for up to 4 years.

Cohort 3 was closed and all enrolled participants were discontinued from this study because parent Study GS-US-354-0101 was terminated. arm 4: Participants previously enrolled in Study GS-US-352-1672 will receive momelotinib for approximately 4 years.

Interventions: intervention 1: Momelotinib
Intervention descriptions: intervention 1: Momelotinib tablets administered orally once daily

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Study Title:
Open-label Study to Assess the Long-term Safety and Efficacy of 
Momelotinib in Subjects with Primary Myelofibrosis, 
Post-polycythemia Vera Myelofibrosis, Post-essential 
Thrombocythemia  Myelofibrosis, Polycythemia Vera or Essential 
Thrombocythemia
Sponsor:
Gilead Sciences, Inc.
IND Number:
EudraCT Number:
101155
2013-004476-36
Indication:
Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, 
Post-essential Thrombocythemia  Myelofibrosis, Polycythemia 
Vera, or Essential Thrombocythemia 
Protocol ID:
GS-US-352-1154
Gilead Clinical Program 
Manager:
Name:
Ori Yellin
Telephone:
+1 (650) 372-7643
Gilead Medical Monitor:
Name:
Jun Kawashima, MD
Telephone:
+1 (650) 524-8930
Fax:
+1 (650) 372-6730
Protocol Version/Date:
Original:
12 December 2013
Amendment 1:
21 July 2014
Amendment 2:
22 August 2014
Amendment 3:
27 July 2015
Amendment 4
06 November 2017
CONFIDENTIALITY STATEMENT
The information contained in this document, particularly unpublished data, is the property or 
under control of Gilead Sciences, Inc., and is provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your staff, and an applicable Institutional 
Review Board or Independent Ethics Committee. The information is only to be used by you in 
connection with authorized clinical studies of the investigational drug described in the protocol. 
You will not disclose any of the information to others without written authorization from 
Gilead Sciences, Inc., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered.
NCT02124746


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TABLE OF CONTENTS
TABLE OF CONTENTS ..............................................................................................................................................2
LIST OF IN-TEXT TABLES........................................................................................................................................5
LIST OF IN-TEXT FIGURES ......................................................................................................................................5
PROTOCOL SYNOPSIS ..............................................................................................................................................6
GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................................11
1.
INTRODUCTION ..............................................................................................................................................13
1.1.
Background ............................................................................................................................................13
1.2.
Momelotinib (MMB) .............................................................................................................................13
1.2.1.
General Information .............................................................................................................13
1.2.2.
Preclinical Pharmacology and Toxicology...........................................................................14
1.2.3.
Clinical Trials of Momelotinib.............................................................................................17
1.3.
Rationale for This Study ........................................................................................................................18
1.3.1.
Dose Justification .................................................................................................................19
1.4.
Compliance ............................................................................................................................................20
1.5.
Other Relevant Clinical Information......................................................................................................20
2.
OBJECTIVES.....................................................................................................................................................21
3.
STUDY DESIGN................................................................................................................................................22
3.1.
Endpoints ...............................................................................................................................................22
3.2.
Study Design..........................................................................................................................................22
3.3.
Study Treatments ...................................................................................................................................22
3.4.
Duration of Treatment............................................................................................................................22
3.5.
Discontinuation Criteria.........................................................................................................................22
3.6.
Source Data............................................................................................................................................22
4.
SUBJECT POPULATION..................................................................................................................................23
4.1.
Number of Subjects and Subject Selection ............................................................................................23
4.2.
Inclusion Criteria....................................................................................................................................23
4.3.
Exclusion Criteria...................................................................................................................................23
5.
INVESTIGATIONAL MEDICINAL PRODUCTS ...........................................................................................25
5.1.
Enrollment and Treatment Assignment..................................................................................................25
5.2.
Description and Handling of MMB........................................................................................................25
5.2.1.
Formulation..........................................................................................................................25
5.2.2.
Packaging and Labeling .......................................................................................................25
5.2.3.
Storage and Handling...........................................................................................................25
5.3.
Dosage and Administration of MMB.....................................................................................................25
5.3.1.
Starting Dose........................................................................................................................25
5.3.2.
Dose Increase Based on Response .......................................................................................26
5.3.3.
Dose Reductions and Rules for Interrupting MMB..............................................................27
5.3.4.
Discontinuing or Interrupting Treatment..............................................................................28
5.4.
Concomitant Medications ......................................................................................................................28
5.4.1.
Proscribed Medication..........................................................................................................28
5.4.2.
Restricted Medications.........................................................................................................29
5.4.3.
Breast Cancer Resistance Protein (BCRP) Substrates..........................................................29
5.4.4.
Organic Anion-Transporting Polypeptide (OATP) Inhibitors..............................................29
5.5.
Accountability for MMB........................................................................................................................30


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6.
STUDY PROCEDURES ....................................................................................................................................31
6.1.
Subject Enrollment and Treatment Assignment.....................................................................................31
6.2.
Study Procedure Description..................................................................................................................31
6.2.1.
Obtain Written Informed Consent........................................................................................31
6.2.2.
Recording Medical History ..................................................................................................32
6.2.3.
Medication History...............................................................................................................32
6.2.4.
Physical Examination and Symptom Assessment................................................................32
6.2.5.
Vital Signs............................................................................................................................32
6.2.6.
Electrocardiogram................................................................................................................32
6.2.7.
Ophthalmic Examination......................................................................................................32
6.2.8.
Laboratory Assessments.......................................................................................................32
6.2.9.
Patient-reported Outcomes Assessments (PRO) ..................................................................33
6.2.10.
Disease Assessment..............................................................................................................34
6.3.
Pretreatment Assessment........................................................................................................................34
6.3.1.
Screening Visit/Enrollment ..................................................................................................34
6.4.
Treatment Assessments..........................................................................................................................35
6.4.1.
Months 1 and 2 (Cohorts 1 and 2 only)................................................................................35
6.4.2.
Months 3 to Early Study Drug Discontinuation (ESDD) visits or End of 
Study ....................................................................................................................................36
6.5.
Unscheduled visits .................................................................................................................................37
6.6.
Post-treatment Follow-up Assessments..................................................................................................37
6.7.
Assessments for Premature Discontinuation from Study.......................................................................38
6.8.
Criteria for Discontinuation of Study Treatment....................................................................................38
6.9.
End of Study...........................................................................................................................................38
7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT...............................................................................39
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse Events.................................39
7.1.1.
Adverse Events.....................................................................................................................39
7.1.2.
Serious Adverse Events........................................................................................................39
7.2.
Assessment of Adverse Events and Serious Adverse Events.................................................................40
7.2.1.
Assessment of Causality for Study Drug and Procedures ....................................................40
7.2.2.
Assessment of Severity ........................................................................................................41
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events and Serious 
Adverse Events to Gilead.......................................................................................................................41
7.4.
Gilead Reporting Requirements.............................................................................................................43
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as Adverse Events or 
Serious Adverse Events..........................................................................................................................43
7.6.
Toxicity Management ............................................................................................................................44
7.7.
Special Situations Reports......................................................................................................................44
7.7.1.
Definitions of Special Situations..........................................................................................44
7.7.2.
Instructions for Reporting Special Situations.......................................................................44
8.
STATISTICAL CONSIDERATIONS................................................................................................................46
8.1.
Analysis Objectives and Endpoints........................................................................................................46
8.1.1.
Analysis Objectives..............................................................................................................46
8.1.2.
Primary Endpoints................................................................................................................46
8.1.3.
Secondary Endpoints............................................................................................................46
8.1.4.
Exploratory Endpoints..........................................................................................................48
8.2.
Analysis Conventions.............................................................................................................................48
8.2.1.
Analysis Sets ........................................................................................................................48
8.3.
Data Handling Conventions ...................................................................................................................48
8.4.
Demographic Data and Baseline Characteristics ...................................................................................48
8.5.
Efficacy Analysis ...................................................................................................................................49


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8.5.1.
Time-to-Event Endpoints .....................................................................................................49
8.5.2.
Categorical Endpoints ..........................................................................................................49
8.5.3.
Continuous Endpoints ..........................................................................................................49
8.6.
Safety Analysis.......................................................................................................................................49
8.6.1.
Extent of Exposure...............................................................................................................49
8.6.2.
Adverse Events.....................................................................................................................50
8.6.3.
Laboratory Evaluations ........................................................................................................50
8.7.
Sample Size............................................................................................................................................51
9.
RESPONSIBILITIES..........................................................................................................................................52
9.1.
Investigator Responsibilities ..................................................................................................................52
9.1.1.
Good Clinical Practice..........................................................................................................52
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval...........................................................................................................52
9.1.3.
Informed Consent.................................................................................................................52
9.1.4.
Confidentiality......................................................................................................................53
9.1.5.
Study Files and Retention of Records ..................................................................................53
9.1.6.
Case Report Forms...............................................................................................................54
9.1.7.
Investigational Medicinal Product Accountability and Return.............................................55
9.1.8.
Inspections............................................................................................................................55
9.1.9.
Protocol Compliance............................................................................................................55
9.2.
Sponsor Responsibilities ........................................................................................................................55
9.2.1.
Protocol Modifications.........................................................................................................55
9.2.2.
Study Report and Publications .............................................................................................56
9.3.
Joint Investigator/Sponsor Responsibilities ...........................................................................................56
9.3.1.
Access to Information for Monitoring..................................................................................56
9.3.2.
Access to Information for Auditing or Inspections ..............................................................56
9.3.3.
Study Discontinuation..........................................................................................................57
10.
REFERENCES ...................................................................................................................................................58
11.
APPENDICES ....................................................................................................................................................60
Appendix 1.
Investigator Signature Page....................................................................................................61
Appendix 2.
Study Procedures Table..........................................................................................................62
Appendix 3.
International Working Group for Myelofibrosis Research and Treatment (IWG-
MRT) consensus criteria for treatment response in myelofibrosis with myeloid 
metaplasia...............................................................................................................................64
Appendix 4.
2013 European LeukemiaNet (ELN) and International Working Group for 
Myelofibrosis Response and Treatment (IWG-MRT) Consensus..........................................66
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations...........................................................................................68
Appendix 6.
ECOG status...........................................................................................................................71


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LIST OF IN-TEXT TABLES
Table 1-1.
Preliminary Data on the Relative Bioavailability of MMB Tablet vs Capsule.......................19
Table 5-1.
Starting Dose of MMB Cohorts 1 and 2.................................................................................26
Table 5-2.
Dose Adjustments of MMB from a Once-daily to a Twice-daily Regimen ...........................27
Table 5-3.
Doses for Restarting MMB after Withholding Treatment for Toxicity..................................28
Table 6-1.
Analytes..................................................................................................................................33
Table 7-1.
Grading of Adverse Event Severity........................................................................................41
Table 7-2.
Grading of Hemoglobin Severity ...........................................................................................43
LIST OF IN-TEXT FIGURES
Figure 6-1.
Initial Study Procedures .........................................................................................................31


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PROTOCOL SYNOPSIS
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Study Title: 
Open-label Study to Assess the Long-term Safety and Efficacy of 
Momelotinib in Subjects with Primary Myelofibrosis, 
Post-polycythemia Vera Myelofibrosis, Post-essential 
Thrombocythemia Myelofibrosis, Polycythemia Vera or Essential
Thrombocythemia
IND Number:
EudraCT Number:
101155
2013-004476-36
Study Centers 
Planned:
Approximately 35 centers in North America, Europe and Australia
Objectives:
The primary objective of this study is to determine the long-term 
safety and tolerability of momelotinib (MMB) in 4 cohorts of 
subjects:

Cohort 1: Subjects who are currently receiving MMB capsules in 
the CCL09101E study for primary myelofibrosis (PMF) and 
post-polycythemia vera/essential thrombocythemia myelofibrosis 
(post-PV/ET MF) whose disease has not progressed on study

Cohort 2: Subjects who are currently receiving MMB capsules in 
the YM387-II-02 study for PMF and post-PV/ET MF whose 
disease has not progressed on study

Cohort 3 was closed and all enrolled subjects were discontinued 
from this study due to limited efficacy of MMB in the treatment 
of PV and ET on GS-US-354-0101.

Cohort 4: Subjects who are currently receiving MMB tablets in 
the GS-US-352-1672 study for PMF and post-PV/ET MF, who 
completed 24 weeks of treatment and have responded to treatment 
while on study, per investigator’s discretion.
The secondary objective of this study is to determine the long-term 
efficacy of MMB in these 4 cohorts of subjects.


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Study Design:
An open-label study for subjects with PMF, post-PV MF, 
post-ET MF, PV, or ET, who have tolerated and achieved stable 
disease or better with MMB treatment while enrolled in a previous 
MMB clinical trial. After screening, subjects in Cohorts 1 and 2 will 
discontinue the MMB capsule and initiate the tablet form of MMB
according to Table 5-1. Subjects in Cohort 4 will discontinue MMB 
tablets from the previous study and initiate MMB tablets in this study.
Number of Subjects 
Planned:
Based on the number of previously enrolled subjects in Cohorts 1,2, 
and 3 including the number of expected subjects in Cohort 4, up to 
105 subjects maybe enrolled:
Cohort 1: 30 subjects enrolled
Cohort 2: 22 subjects enrolled
Cohort 3: 13 subjects enrolled
Cohort 4: 40 subjects expected
Target Population:
Four cohorts of subjects whose disease has not progressed on a 
previous study.
Duration of 
Treatment:
Subjects will continue on MMB for a duration of approximately
4 years from the start of this study or until study termination.
Diagnosis and Main 
Eligibility Criteria:
Inclusion Criteria

Currently enrolled in study CCL09101E, or YM387-II-02, or 
successfully completed 24 weeks of study GS-US-352-1672.

Did not end treatment with MMB for any reason other than to 
enroll in this study

Eastern Cooperative Oncology Group (ECOG) performance status 
of 0, 1, or 2 at enrollment of this study

Negative serum or urine pregnancy test is required for female 
subjects (unless surgically sterile or greater than two years 
post-menopausal)

Male subjects and female subjects of childbearing potential who 
engage in heterosexual intercourse must agree to use protocol 
specified method(s) of contraception as described in Appendix 5

Ability and agreement to attend  protocol-specified visits at the 
study site

Any Grade 3 or 4 non-hematologic toxicity that the investigator 
considers related to previous MMB use must have resolved, 
reverted to Grade 1, or to baseline of the prior study prior to 
Day 1 of this study


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
Able to comprehend and willing to sign the informed consent 
form
Exclusion Criteria

Known hypersensitivity to MMB, its metabolites, or formulation 
excipients

Incomplete recovery from major surgery prior to Day 1 of this 
study

Presence of peripheral neuropathy ≥ Common Terminology 
Criteria for Adverse Events CTCAE Grade 3

Known positive status for human immunodeficiency virus (HIV)
Known chronic active or acute viral hepatitis A, B, or C infection
Study Procedures/
Frequency:
Procedures performed at a regular follow-up visit on subject’s 
previous MMB study may be used to fulfill screening criteria and to 
establish any new medical history on this study.
At Day 1, the starting dose of MMB tablets will be determined per the 
criteria in protocol Section 5.3. All subjects will self-administer 
MMB tablets.
Subjects who have not undergone a bone marrow aspirate/biopsy
within 12 months prior to Day 1 of this study will undergo a bone 
marrow biopsy. The bone marrow aspirate/biopsy will be repeated 
every 24 months and/or at the time of study withdrawal.
Study visits consisting of clinical, laboratory, and disease assessments 
will be completed every 3 months. Cohorts 1 and 2 will have 
2 additional visits at Months 1 and 2. All study required laboratory 
assessments will be performed by Central laboratory and ECG 
assessments will be performed and interpreted by local departments. 
Following treatment, subjects will be followed for safety and disease 
status for a period of 30 days. Subjects who continue treatment with 
MMB in the extended access program following the end of this study 
are not required to complete the 30 day post-treatment follow-up 
assessments.
Test Product, Dose, 
and Mode of 
Administration:
MMB 100 mg, 150 mg, or 200 mg tablet orally self-administered 
once daily (QD).


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Cohort 1 and Cohort 2 will be initiated on the tablet form of MMB 
according to the following table:
Previous Capsule Dose of MMB
Initial Tablet Dose of MMB
100 mg QD
100 mg QD
150 mg QD
100 mg QD
200 mg QD
150 mg QD
250 mg QD
150 mg QD
300 mg QD
200 mg QD
50 mg BID
100 mg QD
100 mg BID
150 mg QD
150 mg BID
200 mg QD
200 mg BID
200 mg QD
BID = twice a day; QD = once daily
Cohort 4 will continue the tablet form of MMB at the same dose they 
were receiving in study GS-US-352-1672.
Doses will be adjusted per Section 5.
Criteria for 
Evaluation:
Safety
The primary endpoint is safety. Safety will be evaluated by the 
incidence and severity of adverse events and clinical laboratory 
abnormalities, as defined by Common Terminology Criteria for 
CTCAE v4.03.
Efficacy
Efficacy endpoints are considered secondary and will include:

Overall survival (OS): defined as the interval from the first dose 
of MMB on the previous study until death from any cause 

Progression-free survival (PFS): defined as the interval from the 
first dose of MMB on the previous study until the first 
documentation of definitive progressive disease  or death from 
any cause

Leukemia free survival: defined as the interval from the first dose 
of MMB on the previous study until the first documented 
leukemic transformation or death from any cause

Rate of red blood cells (RBC) transfusion: defined as the average 
number of RBC units per subject month from the first dose of 
MMB in the previous study during the study period

Other cohort-specific endpoints
Pharmacokinetics:
None


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Statistical Methods:
Analysis Methods
Full Analysis Set consists of all subjects who are enrolled into this 
study. This analysis set will be used in the analyses of subject 
characteristics, study drug treatment administration, safety and 
efficacy endpoints.
All study endpoints will be summarized by descriptive statistics. 
Descriptive summaries will be prepared to show sample size, mean, 
standard deviation (SD), 90% confidence intervals (CIs) on the mean, 
median, minimum and maximum for continuous variables and counts, 
percentages and 90% CIs on the percentage for categorical variables. 
Baseline data are defined as the data collected prior to dosing on the 
previous study. All time-to-event endpoints will be analyzed using the
Kaplan-Meier method. The medians and 90% confidence intervals for 
medians of these endpoints will be provided if the medians can be 
estimated. Data will be analyzed according to the nominal visits. 
AEs will be summarized by system organ class, high level term and 
preferred term. Clinical laboratory tests, vital signs, and their changes 
from baseline will be summarized descriptively.
Sample Size
No formal hypothesis testing is planned for this study. Up to 
105 subjects who have previously participated in a Gilead clinical 
trial with MMB will be enrolled.
This study will be conducted in accordance with the guidelines of Good Clinical Practice (GCP) 
including archiving of essential documents.


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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS
C 
degrees Celsius
F
degrees Fahrenheit
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma/serum/peripheral blood mononuclear cell concentration versus 
time curve
BCRP
breast cancer resistance protein
BID
twice a day 
BUN
blood urea nitrogen
CBC
complete blood count
CI
confidence interval
CLcr
creatinine clearance
Cmax
the maximum observed serum/plasma/peripheral blood mononuclear (PBMC) 
concentration of drug
CR
complete remission
CRF
case report form(s)
CRO
contract (or clinical) research organization 
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
cytochrome P450
DOR
duration of response
DSPH
Drug Safety and Public Health
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form(s)
ELN
European LeukemiaNet
EOT
end of treatment
ESDD
early study drug discontinuation
ET
essential thrombocythemia
EudraCT
European clinical trials database
FDA
(United States) Food and Drug Administration
GCP
Good Clinical Practice (guidelines)
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
IB
Investigator’s Brochure 
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IMP
investigational medicinal product


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IRB
institutional review board
IUD
intrauterine device
IWG
International Working Group
IWG-ELN
International Working Group-European  LeukemiaNet
IWG-MRT
International Working Group for Myelofibrosis Response and Treatment
IXRS
interactive voice/web response system
LCM
left costal margin
M
month
mg
milligram
MMB
momelotinib
MPN
myeloproliferative neoplasm
MRI
magnetic resonance image
NOAEL
no observed adverse effect level
ORR
overall response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PGIC
Patients’ Global Impression of Change
PK
Pharmacokinetic
PMF
Primary Myelofibrosis
PR
partial remission
PRO
Patient-reported outcome
PV
polycythemia vera
QD
once daily 
RBC
red blood cell
SAE
serious adverse event
SD
stable disease
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
An estimate of the terminal elimination half-life of the drug in serum/plasma/PBMC, 
calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz)
US
United States
WBC
White blood cell


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1.
INTRODUCTION
1.1.
Background
The myeloproliferative neoplasms (MPN), most notably polycythemia vera (PV), 
essential thrombocythemia (ET), and primary myelofibrosis (PMF) are a diverse but inter-related 
group of clonal disorders of pluripotent hematopoietic stem cells {Tefferi 2008}. The MPN share 
a range of biological, pathological, and clinical features including the relative overproduction of 
one or more cells of hematopoietic origin, growth factor independent colony formation in vitro, 
marrow hypercellularity, extramedullary hematopoiesis, spleno- and hepatomegaly, and 
thrombotic and/or hemorrhagic diatheses {Tefferi 2005}.
In early 2005, several research groups independently reported that a single acquired point 
mutation at codon 617 in JAK2 (V617F mutation), a cytoplasmic tyrosine kinase, was present in 
the majority of patients with the BCR-ABL-negative MPN (ie, PV, ET, and PMF) {Baxter 2005}, 
{James 2005, Kralovics 2005, Levine 2005}. Since then, additional JAK2 and thrombopoietin 
receptor (MPL) mutations have been described in PV and ET/PMF, respectively {Pardanani 
2007, Pardanani 2006, Pikman 2006, Scott 2007}. Studies have shown that these mutations 
cause cytokine independent activation of the JAK-STAT, PI3K, AKT, MAPK, and ERK 
pathways; all of which are implicated in erythropoietin (EPO) receptor signaling. The JAK2
V617F mutation leads to ongoing auto-phosphorylation of JAK2, which on binding to a cytokine 
receptor, promotes STAT recruitment and subsequent STAT phosphorylation {James 2005}. 
This mutation is the likely cause of the hypersensitivity to cytokines that characterizes 
hematopoietic progenitor cells (HPC) from each of the MPNs. 
The occurrence of JAK2 mutations in the majority of patients with PV (almost 100%), 
ET (approximately 60%) or PMF (approximately 60%) has reinforced the putative oncogenic 
role of abnormal JAK-STAT signaling in these disorders {Levine 2007}. As a result, in less than 
5 years from the first description of JAK2V617F {Baxter 2005, James 2005, Kralovics 2005, 
Levine 2005}, small molecule JAK2 inhibitor drugs have been developed {Pardanani 2008} and 
approved {DSM Pharmaceuticals Inc. 2011, Novartis Pharma GmbH 2013}. Results from these 
trials and subsequent approvals have demonstrated efficacy in amelioration of constitutional 
symptoms and reduction of splenomegaly {Pardanani 2011}.
1.2.
Momelotinib (MMB)
1.2.1.
General Information
MMB dihydrochloride (N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-
yl)benzamide, CYT387, GS-0387) is a novel, weakly basic, disubstituted pyrimidine compound 
molecular weight of 487.38 Da. The free base is poorly soluble in water. MMB is presented for 
clinical administration as a dihydrochloride monohydrate salt which shows kinetic solubility in 
water at concentrations up to 60 mg/mL. MMB dihydrochloride is manufactured from a 
pyrimidine scaffold in a five-step process. 


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MMB is a potent and selective small-molecule inhibitor of JAK1 and JAK2 in vitro enzyme and 
cellular assays, with marked disease-modifying properties in ex vivo assays of human erythroid 
cells from PV patients and in a transgenic mouse model of the MPN. In vitro enzyme assays 
demonstrated that MMB is an ATP-competitive inhibitor of JAK1 and JAK2 which is active at 
low nanomolar concentrations. Kinase profiling of MMB indicated that the compound is broadly 
selective for JAK1 and JAK2 over other kinase enzymes, including the closely related 
JAK3 and TYK2. MMB displays potent in vitro inhibitory activity against cells dependent on 
JAK2, including the JAK2V617F mutant which is associated with the etiology of PV and other 
MPNs. 
For further information on MMB, refer to the investigator’s brochure (IB) for MMB.
1.2.2.
Preclinical Pharmacology and Toxicology
1.2.2.1.
Preclinical ADME and Pharmacokinetics (PK)
Equivalent mean maximal plasma concentrations of MMB (~ 700 ng/mL) and comparable 
elimination half-lives (~ 1 hour) were observed in both fed and fasted animals, consistent with 
previous data. There was however a notable prolongation in absorption in fed dogs with a 
delayed Tmax (3h fed vs. 1h fasted). Furthermore, the AUC following dosing to fed dogs was 
approximately double that seen in fasted animal studies suggesting that MMB systemic 
availability is markedly improved when the compound is administered postprandially.
Consistent with the moderate to high bioavailability seen in nonclinical species, MMB shows 
high permeability in vitro across human Caco-2 cell monolayers with low efflux potential. These 
results indicate that MMB is likely to have high permeability across the intestinal mucosa in 
humans and high oral absorption in vivo. 
Data from plasma protein binding studies using rat and human plasma indicate that MMB binds 
extensively to rat plasma proteins (~ 97%) and moderately to human plasma proteins 
(87% to 92%). The mean human blood-to-plasma ratio was determined to be approximately 1.1, 
suggesting similar distribution between the cellular and plasma fractions of blood. The rat 
blood-to-plasma ratio ranged from 0.6 to 0.8 indicating a lesser partitioning into blood cells. 
The systemic clearance of MMB was low in rats and significantly higher in dogs. The 
steady-state volume of distribution in both species substantially exceeded total body water.
Following oral administration as the dihydrochloride salt, MMB showed high bioavailability in 
the rat (50%) and moderate bioavailability in the dog (20%). The PK parameters in both the rat 
and dog indicated that MMB was well absorbed. In the rat, less than 10% of an administered 
dose of MMB was recovered in the urine as parent compound suggesting that urinary excretion 
is a minor clearance route for parent compound.
The distribution of MMB into brain tissue was assessed in Swiss outbred mice following 
intravenous administration (5 mg/kg). The brain-to-plasma ratio for MMB was determined to be 
0.075 and 0.215 at 5 and 60 minutes following MMB administration, respectively, suggesting 
low permeability of MMB across the blood brain barrier.


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Metabolite profiling has identified major putative metabolites from in vitro and in vivo studies.
Metabolite M19 was present in greater amounts in both rat (both dose levels) and dog plasma 
pools, than in the human plasma pool. Metabolites M15, M17, and M20 were present in greater 
amounts in the rat plasma pool (both dose levels), than in the human or dog plasma pools. 
Metabolite M21 was present in human plasma at higher levels than that observed in rat plasma 
(20 mg/kg or 80 mg/kg doses, respectively). Metabolite M21 was not observed in the dog plasma. 
M8 was not observed in either the rat or dog plasma pools. 
The ability of the major drug-metabolizing CYP450 enzymes (CYP1A2, 2A6, CYP2B6, 
CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) to metabolize MMB was 
assessed with recombinant human CYP450 enzymes (Supersomes). These in vitro studies 
demonstrated that MMB exhibits measurable metabolism by CYP3A4.
The potential of MMB to impair the metabolism of other agents by inhibition of major drug 
metabolizing enzymes has also been investigated. The half-maximal inhibitory concentration 
(IC50) of MMB on the six CYP isoforms investigated (CYP1A2, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4) was greater than 25 μM. IC50 of MMB on CYP2B6 was 12.4 μM.
No time dependent inhibition was observed for GS-0387 on CYP1A2 or CYP3A4. MMB is 
therefore unlikely to mediate significant metabolic drug-drug interactions through inhibition of 
these isoforms in vivo. MMB was determined to have the potential to be an inhibitor of 
UGT1A1, a major human uridine diphosphate glucuronosyltransferase enzyme responsible for 
the glucuronidation of bilirubin, with an IC50 of 0.3 μM, but it is not clinically relevant as no 
clinically significant elevation of indirect (unconjugated) bilirubin has been reported in the 
PI/II clinical study.
The potential of major metabolites (M19 and M21) to impair the metabolism of other agents by 
inhibition of drug metabolizing enzymes has also been investigated. The IC50 of MMB on the 
seven CYP isoforms investigated (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, 
and CYP3A4) was greater than 25 μM. No time dependent inhibition was observed for 
M19 and M21 on CYP3A4. M19 and M21 did not show any activation of PXR.
The potential of MMB to inhibit the major drug transporters was studied in cells in which the 
individual transporters were over expressed and the MMB IC50 for the transport of probe 
substrates was determined, where possible.  MMB did not significantly inhibit P-gp, OAT1, 
OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or BSEP mediated transport of probe substrates at 
15 μM. MMB was determined to be an inhibitor of breast cancer resistance protein (BCRP) with 
an IC50 of 2.9 μM.
1.2.2.2.
Nonclinical Toxicology
Nonclinical safety pharmacology and toxicology studies have characterized the safety of MMB
and included both repeat dose toxicology studies and in vitro genotoxicity studies. All pivotal 
toxicology studies, including the genotoxicity studies, were conducted in full compliance with 
Good Laboratory Practice (GLP) regulations (21 CFR 58). The scope of the nonclinical safety 
evaluation is consistent with guidance issued by the International Conference on Harmonisation 
(ICH).


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The potential for MMB to induce hemodynamic or electrocardiogram (ECG) effects was 
evaluated in male beagle dogs following a single oral dose of 5, 30 or 100 mg/kg. Mean arterial 
pressure was decreased at an oral dose of 30 and 100 mg/kg and heart rate was increased at 
100 mg/kg. 
Toxicological findings were principally related to the pharmacological action of the compound, 
as indicated by hematological and organ weight changes related to lymphatic and bone marrow 
tissues. A dose-dependent decrease in body weight gain, correlated with a dose-dependent 
decrease in food consumption, was observed in all studies and considered significant at 
high-dose levels in all studies except the 13-week dog study. Following very high exposure 
levels in the rat 28-day study, some off-target reversible toxicity was observed that included 
changes in the kidney, gastrointestinal tract, heart, and liver, of which none were observed in the 
rat 13-week study or the dog studies. Female reproductive changes were observed only at high 
doses in the rat 28-day study and were reversible. Dose-dependent testicular degeneration was 
observed in rats following 28 days or 13 weeks of repeated dosing. Recovery of testicular 
findings was dependent upon the cycle length of spermatogenesis with reversibility observed 
after a 10-week recovery period (13-week study) but not after a 28-day recovery period 
(28-day study). These changes were not observed above background levels in sexually mature 
dogs consistent with the role of JAK2 in maturation of the reproductive organs {Wu 2005}.
There were several effects observed that could not be readily attributed to JAK1/2 inhibition. 
This potential off-target toxicity was noted in the kidney, heart, and gastrointestinal tract of the 
rat, and gall bladder of the dog. All effects were reversible upon cessation of dosing.
In the 90-day oral rat toxicity study, based upon the significant loss of body weight at 
80 mg/kg/day, the no observed adverse effect level (NOAEL) was determined as 20 mg/kg/day, 
with associated Day 91 AUC0-24 values of 94,200 ng·h/mL in males and 102,000 ng h/mL in 
females. The Cmax values in males and females on day 91 were 6720 and 7290 ng/mL, 
respectively.
In the 3-month dog study, the highest NOAEL was 60 mg/kg/day once daily. Associated 
AUC0-12 values at the NOAEL on Day 91 were 4160 and 3220 ng·h/mL, respectively. The Cmax
values in males and females on day 91 were 1250 and 1150 ng/mL, respectively.
The plasma AUCτ in subjects from Study CCL09101 at 300 mg capsule was 4.3 μg h/mL. 
Therefore, the margin of exposure for the NOAEL in the 90-day toxicity studies to the steady 
state AUC NOAEL is 22 in the rat and 0.8 in the dogs.
An in vitro bacterial reverse mutation assay (Ames test), an in vitro mammalian cell gene 
mutation assay (chromosomal aberration test), and an in vivo rat bone marrow micronucleus 
assay were conducted with MMB. No evidence of mutagenicity or clastogenicity was observed 
indicating a low potential for MMB to cause genotoxicity. 
Preliminary data from a dose range finding embryo-fetal developmental toxicity study in rats are 
available. MMB was orally administered to pregnant rats (7 to 8/group plus additional animals 
for TK evaluations) at 0 (vehicle), 4.3, 17, and 68 mg free base equivalents/kg/day 


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(5, 20, 80 mg/kg/day dihydrochloride salt) from gestation days 6 through 17. Based on the 
preliminary data, no maternal adverse effects and no embryo fetal adverse events (AEs) were 
observed at 4.3 mg/kg/day.  Maternal toxicity was observed at 17 and 68 mg/kg/day. At these 
maternally toxic doses, MMB administration resulted in embryo fetal effects (increase in post 
implantation loss resulting in a reduced number of viable fetuses).  No viable fetuses were 
obtained at 68 mg/kg/day.  At 17 mg/kg/day, there was an increase in the percentage of litters 
with absent innominate artery.  The toxicokinetic data is not yet available from this study. Based 
on the data from non-pregnant female rats, the mean systemic exposure (AUC0-24) at the NOAEL 
is 4-fold higher than the systemic exposure observed in patients administered 300 mg MMB, the 
maximum recommended dose (MRD).  The exposure of MMB in non-pregnant rats at 
17 mg/kg/day, the current minimum effect level, is approximately 23 fold higher than the MRD.
The metabolism of MMB could result in the release of cyanide via metabolite CYC-11384. 
While theoretically possible, the in vitro metabolite profiling studies indicate minimal conversion 
to CYC-11384 (and the consequent liberation of aminoacetonitrile and cyanide). In addition, 
during the first 9 cycles of MMB treatment in the CCL09101 study, elevations above the 
population-based reference ranges which reflect ordinary dietary, occupational and 
environmental exposure to cyanide were observed in 11 subjects (7%). In the majority of these 
cases, values were borderline elevations above the reference range and in no case did thiocyanate 
values ever approach the toxic range. In addition, available data from the extension portion of the 
study (CCL09101E), which includes observation to a maximum of 30 months of dosing, 
continue to demonstrate an absence of significant thiocyanate elevations, with only one 
additional subject with a minor elevation above the reference range. 
The lack of significant drug-induced thiocyanate generation is further strengthened by 
preliminary thiocyanate data collected to 6 months of dosing in the ongoing study YM387-II-02, 
where subjects are treated with higher daily MMB doses in a twice daily dosing regimen. These 
results are consistent with current observations from the core study with only 
1 of 42 subjects (2%) experiencing a minimal elevation above the reference range.
Together, these clinical findings in a comparatively large number of MF subjects indicate that 
any drug-induced thiocyanate generation over the extended MMB dosing period is relatively 
insignificant in comparison with exogenous environmental cyanide exposure and based on the 
currently available data does not appear to compromise the very favorable clinical activity and 
chronic tolerability of the compound.
A more detailed summary of findings from the nonclinical studies is available in the current
IB for MMB. Investigators should refer to this document prior to initiating therapy with MMB.
1.2.3.
Clinical Trials of Momelotinib
Completed and Ongoing Clinical Trials
Please refer to the MMB IB for a listing of completed and ongoing MMB clinical trials.


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1.3.
Rationale for This Study
MMB displays potent in vitro inhibitory activity against cells dependent on JAK2, including the 
JAK2V617F mutant which is associated with the etiology of PV and the other MPNs. It has been 
shown to potently inhibit JAK2 signaling and the formation of JAK2V617F mutant myeloid 
colonies in a dose-responsive manner (IC50 = 0.3 M and 1 to 2 μM, respectively), suggesting 
potential activity for the compound in these disease settings. 
MMB demonstrated activity in vivo in JAK2-dependent models. In a study investigating the 
effects of twice daily administered MMB (25 and 50 mg/kg) in a transgenic mouse model of the 
JAK2-mediated human MPN there was significant reduction of leukocyte count into the normal 
range within 1 week of dosing and reduction of erythrocytosis after 6 weeks of dosing. After 
56 days of dosing, the average spleen size was significantly reduced in a dose-dependent manner, 
extra-medullary hematopoiesis was reduced, and normal erythrocytosis was being re-established 
in the bone marrow compartment.
Based on the analysis of clinical study CCL09101 and its extension study CCL09101E, with a 
data cutoff date of April 2013, subjects continued to obtain clinical benefit from treatment with 
MMB with duration of follow-up on-study ranging from 15 to 34 twenty-eight-day cycles.
Clinical benefit was demonstrated by durable decreases in spleen size, anemia response, and 
improved symptoms.  Fifty seven (32.4%) of the spleen evaluable subjects achieved a spleen 
response with a median duration of response of 323.5 days.
Another benefit of MMB was an improvement in anemia related outcomes with a decrease in the 
rate of transfusion dependence and increased hemoglobin. Forty-three (60%) of the transfusion 
dependent subjects achieved a transfusion independence response per International Working 
Group for Myelofibrosis Response and Treatment (IWG-MRT) criteria that lasted at least 
12 weeks (Gale criteria) {Gale 2011}. Eight of the transfusion independent, but anemic subjects 
(20%) achieved a hemoglobin increase of at least 2 g/dL with a minimum duration of at least 
8 weeks. The maximum duration of anemia response has approached 3 years.
MMB administration appears to have been well tolerated overall and with prolonged 
administration in the extension study. Most of the treatment-emergent AEs were reported as 
Grade 1 or mild. The most commonly reported treatment-emergent AEs were thrombocytopenia, 
diarrhea, anemia, dizziness, peripheral neuropathy, and abnormalities in liver/pancreas-related 
lab values, and elevated uric acid lab values. As of April 2013, 28 deaths (16 during the 9 month 
core and 12 during the extension) were reported; however, none of these deaths were reported as 
treatment-related.
At the initial dose escalation phase of the YM387-II-02 study, although no dose limiting 
toxicities were observed, 250 mg twice daily (BID) was not well tolerated and 200 mg BID was 
the dose level chosen for the dose confirmation phase. Preliminary results of the 
YM387-II-02 study, as of a data cut off of 3 September 2013 ,  demonstrated similar safety, 
tolerability, and efficacy to the once daily dosing (n = 61).  Clinical splenic responses in this 
study have been evaluated by physical examination demonstrating a 66.0% spleen response rate 
by 2006 IWG-MRT (n = 50 with spleen > 5 cm at baseline) which lasted at least 8 weeks.


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Magnetic resonance imaging (MRI) evaluation of spleen response was also obtained at 6 months 
in the 58 subjects who had not undergone a previous splenectomy, demonstrating a 46.6% 
spleen response (≥35% reduction in spleen volume by MRI).  Of the 28 subjects who were 
transfusion dependent at baseline, 28.6% (n = 8) achieved a 12-week transfusion independent 
response.
The encouraging nonclinical data coupled with the common occurrence of JAK2 pathway 
aberrations in patients with MPN and a known contribution of the JAK2V617F mutation to 
various phenotypes of these disorders render the JAK2 pathway an attractive and relevant target 
for drug development in other related MPNs such as PV and ET.  
The purpose of this extension study is to continue to collect long-term safety, tolerability, and 
efficacy data from subjects with MPNs who have received a clinical benefit from treatment with 
MMB on a Phase 2 clinical trial.  
1.3.1.
Dose Justification
The starting MMB dose for each subject in this study will correspond to the dose which the 
subject tolerated and which provided clinical benefit in their parent study. The maximum dose 
of 200 mg was selected based on PK results from Study GS-US-352-0102, which compared the 
relative bioavailability of the tablet vs capsule. Dose reductions will be allowed on this study if 
clinically indicated (Section 5.3.3).
PK results from Study GS-US-352-0102 indicate the 200 mg tablet results in equivalent 
exposure (AUC and Cmax) as the 300 mg capsule as shown in Table 1-1.
Table 1-1.
Preliminary Data on the Relative Bioavailability of MMB Tablet vs 
Capsule
PK Parameters
200 mg Tablet:
Mean 
(standard deviation)
300 mg Capsule:
Mean 
(standard deviation)
GMR [%] (90% CI)
Cmax (ng/mL)
324 (188)
356 (196)
92.0 (79.0, 107)
AUCinf (h·ng/mL)
2570 (1670)
2670 (1990)
102 (87.7, 118)
AUClast (h·ng/mL)
2340 (1510)
2440 (1740)
101 (86.8, 116)
The reduced MMB tablet doses of 150 mg and 100 mg represent 25% and 50% dose reductions, 
respectively, compared to the starting tablet dose of 200 mg which provided equivalent 
exposures to the MMB 300 mg capsule. Based on the PK results from Study GS-US-352-0102, 
150 mg and 100 mg tablets resulted in ~70% and ~50% of MMB exposures (AUCinf and Cmax) 
compared to the 300 mg capsule. These reduced tablet doses of MMB are still expected to 
provide efficacy based on previous dose-response analyses, where robust spleen response was 
observed at average daily MMB capsule dose of ≥~150 mg.


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1.4.
Compliance
This study will be conducted in compliance with this protocol, Good Clinical Practice (GCP), 
and all applicable regulatory requirements.
1.5.
Other Relevant Clinical Information
A recent clinical trial of the JAK2 inhibitor fedratinib (SAR302503) in myelofibrosis was halted 
due to reported cases of Wernicke’s encephalopathy. There has been one case of suspected 
Wernicke’s encephalopathy reported in clinical trials with MMB in subjects with myelofibrosis.
Peripheral neuropathy has also been reported as an adverse event. Based on these data, thiamine 
status will be monitored throughout the duration of the study treatment.


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2.
OBJECTIVES
The primary objective of this study is to determine the long-term safety and tolerability of MMB 
in 4 cohorts of subjects: 

Cohort 1: Subjects who are currently receiving MMB capsules in the CCL09101E study for 
PMF and post-PV/ET MF without documented progressive disease 

Cohort 2: Subjects who are currently receiving MMB capsules in the YM387-II-02 study for 
PMF and post-PV/ET MF without documented progressive disease 

Cohort 3 was closed and all enrolled subjects were discontinued from this study due to 
limited efficacy of MMB in the treatment of PV and ET on GS-US-354-0101.

Cohort 4: Subjects who are currently receiving MMB tablets in the GS-US-352-1672 study 
for PMF and post-PV/ET MF, who completed 24 weeks of treatment and have responded to 
treatment, per investigators discretion.
The secondary objective of this study is to determine the long-term efficacy of MMB in these 
4 cohorts of subjects.


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3.
STUDY DESIGN
3.1.
Endpoints
The endpoints for this study are described in Section 8.
3.2.
Study Design
This is an open-label study for subjects with MF, post-PV/ET MF, PV or ET, who have tolerated 
MMB and their corresponding disease has not progressed per 2006 IWG-MRT for MF 
(Appendix 3) or 2013 IWG-ELN and IWG-MRT criteria for PV/ET (Appendix 4) while enrolled 
in the previous study. After screening, subjects in Cohorts 1 and 2 will discontinue the MMB 
capsule and initiate the tablet form of MMB. Subjects in Cohort 4 will discontinue MMB tablets 
from the previous study and initiate MMB tablets in this study at the same dose they were 
receiving in the previous study. Dose adjustments may be made according to Section 5.3.
3.3.
Study Treatments
The study drug in this study is MMB, supplied by Gilead. The formulation and packaging of 
MMB are further described in Section 5.
3.4.
Duration of Treatment
Subjects may participate in this study for approximately 4 years or until study termination. 
3.5.
Discontinuation Criteria
The study may be discontinued at any time based on periodic reviews of safety data by Gilead.
Subject discontinuation criteria are described in Section 6.8.
3.6.
Source Data
Patient reported outcomes data that are collected on paper will be considered source data.
Subject identification number captured by the interactive voice/web response system (IXRS) is
considered source.


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4.
SUBJECT POPULATION
4.1.
Number of Subjects and Subject Selection
Based on the number of enrolled subjects to date in Cohorts 1, 2, and 3, including the number of 
expected subjects in Cohort 4, up to 105 subjects (30 from Cohort 1, 22 from Cohort 2, 13 from 
Cohort 3, and approximately 40 from Cohort 4) may participate in this trial.
4.2.
Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.

Currently enrolled in study CCL09101E, YM387-II-02, or successfully completed 24 weeks 
of study GS-US-352-1672.

Did not end treatment with MMB for any reason other than to enroll in this study

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at enrollment
of this study

Negative serum or urine pregnancy test is required for female subjects (unless surgically 
sterile or greater than two years post-menopausal)

Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use protocol specified method(s) of contraception as described in 
Appendix 5

Ability and agreement to attend to protocol-specified visits at the study site

Any Grade 3 or 4 non-hematologic toxicity that the investigator considers related to previous 
MMB use must have resolved, reverted to Grade 1, or returned to baseline on the prior study 
prior to Day 1 of this study

Able to comprehend and willing to sign informed consent form
4.3.
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.

Known hypersensitivity to MMB, its metabolites, or formulation excipients

Incomplete recovery from major surgery prior to Day 1 of this study


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
Presence of peripheral neuropathy ≥Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3  

Known positive status for human immunodeficiency virus (HIV)

Known chronic active or acute viral hepatitis A, B, or C infection


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5.
INVESTIGATIONAL MEDICINAL PRODUCTS
5.1.
Enrollment and Treatment Assignment
Subjects will be enrolled via IXRS based on their dose on the previous study.
5.2.
Description and Handling of MMB
5.2.1.
Formulation
MMB is supplied as GS-0387-01 (dihydrochloride monohydrate) and is available as 100 mg, 
150 mg, and 200 mg strength (as free base equivalent) tablets. The tablets contain excipients, 
microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, silicon dioxide, 
magnesium stearate, propyl gallate, polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, 
yellow iron oxide, and red iron oxide. MMB 100 mg tablets are round-shaped, film-coated,
brown tablets, MMB 150mg are round or triangle-shaped, film-coated, brown tablets, and MMB 
200 mg tablets, are capsule-shaped, film-coated, brown tablets.
5.2.2.
Packaging and Labeling
MMB tablets are packaged in white, high-density polyethylene (HDPE) bottles. Each bottle 
contains 30 tablets, a silica gel desiccant, and polyester packing material. Each bottle is enclosed 
with a white, continuous thread, child-resistant screw cap with an induction-sealed, 
aluminum-faced liner.
Study drug(s) to be distributed to centers in the US and other participating countries shall be 
labeled to meet applicable requirements of the United States Food and Drug Administration 
(FDA), EU Guideline to Good Manufacturing Practice – Annex 13 (Investigational Medicinal 
Products), and/or other local regulations.
5.2.3.
Storage and Handling
MMB should be stored at controlled room temperature of 25 ºC (77 ºF); excursions are permitted 
between 15 ºC and 30 ºC (59 ºF and 86 ºF). 
Until dispensed to the subjects, all MMB bottles should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure stability and proper identification, the 
drug products should be stored in the containers in which they are supplied.
5.3.
Dosage and Administration of MMB
5.3.1.
Starting Dose
Subjects will self-administer MMB tablets at 100 mg, 150 mg, or 200 mg orally once-daily.
Cohorts 1 and 2 will initiate the tablet form of MMB according to Table 5-1.


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Table 5-1.
Starting Dose of MMB Cohorts 1 and 2
Dose of Capsule
Initial Dose of Tablet
100 mg QD
100 mg QD
150 mg QD
100 mg QD
200 mg QD
150 mg QD
250 mg QD
150 mg QD
300 mg QD
200 mg QD
50 mg BID
100 mg QD
100 mg BID
150 mg QD
150 mg BID
200 mg QD
200 mg BID
200 mg QD
BID = twice a day; QD = once daily
For Cohorts 1 and 2 the starting dose will be assigned by first determining the tablet dose 
corresponding to the capsule dose the subject was receiving prior to drug interruption using 
Table 5-1. The reduced dose can then be determined using Table 5-3. 
Cohort 4 will continue the tablet form dose of MMB they were previously receiving in study 
GS-US-352-1672.  If a toxicity requiring drug interruption during participation in 
GS-US-352-1672 persists for longer than a total of 30 days from the last MMB administration to 
Day 1 of this study, subjects will not be eligible to participate on study in Cohort 4 and will be 
considered screen failures.  Subjects in screening on a drug hold < 30 days whom the 
investigator believes that the toxicity has resolved and that they can join Cohort 4 must seek 
consultation with the study Medical Monitor.
5.3.2.
Dose Increase Based on Response 
Cohorts 1 and 2
If, per the investigator’s judgment, there is evidence of insufficient efficacy that does not meet 
the criteria of 2006 IWG-MRT for Progressive Disease (Appendix 3), and platelet, and 
neutrophil counts are adequate, the MMB dose may be increased in 50 mg increments once-daily 
to a maximum of 200 mg or 300 mg per day depending on the dosing schedule a subject was on 
in the prior study,  in accordance with the following criteria. The MMB dose may not be 
increased after it is reduced due to a Grade 3 or 4 toxicity that the investigator considers related 
to MMB or after a switch to twice-daily dosing (if applicable- Cohorts 1 and 2 only). The MMB 
dose may not be increased during the first 4 weeks of therapy and not more frequently than every 
2 weeks.


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Insufficient efficacy and adequate platelet and neutrophil counts are described as follows:

Insufficient efficacy: Insufficient efficacy is defined as an increase in palpable spleen length 
from the lower of baseline spleen length of the previous study (Study CCL09101 or 
YM387-II-02), or nadir of spleen length while on treatment during the previous study 
(Study CCL09101 or YM387-II-02) or the current study (Study GS-US-352-1154), but has 
not met the criteria for progressive disease. Refer to Appendix 3 for IWG-MRT treatment 
response criteria.

Adequate platelet and neutrophil :
Platelet count 25 x 109/L
Absolute neutrophil count (ANC) 0.75 x 109/L
Subjects, in Cohorts 1 and 2 only, who were receiving a twice-daily regimen of MMB in the 
30 days immediately prior to enrollment in this study will be permitted to resume a twice-daily 
regimen per Table 5-2 if they meet the above criteria for insufficient efficacy and adequate 
platelet and neutrophil counts. These subjects may only resume a twice-daily regimen if they are 
receiving 200 mg once daily or if they were reduced to 150 mg once daily after receiving 200 mg 
once daily in this study. For subjects resuming twice-daily dosing at 100 mg twice daily, dose 
increase to 150 mg twice daily is not permitted.
Cohort 4
Cohort 4 subjects may not dose increase.
Table 5-2.
Dose Adjustments of MMB from a Once-daily to a Twice-daily 
Regimen
Dose at time of Adjustment
Adjusted Dose Regimen
100 mg QD
Not permitted
150 mg QD
100 mg BID
200 mg QD
150 mg BID
5.3.3.
Dose Reductions and Rules for Interrupting MMB
Grade 3 or 4 Drug-related Non-hematologic Toxicities
In the event of a Grade 3 or 4 non-hematologic toxicity that the investigator considers related to 
MMB, dosing will be interrupted for a maximum of 30 days, inclusive of taper, until the toxicity 
resolves or returns to levels at enrollment. Additionally, dosing will be interrupted for any 
bleeding event of a Grade 2 or neuropathy Grade ≥3. Treatment may be restarted within 
30 days per Table 5-3 (MMB). If the toxicity persists beyond 30 days, treatment may be restarted 
contingent on sponsor approval.


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For any toxicity that does not meet the above criteria and the investigator considers related to 
MMB and is clinically significant, MMB may be interrupted for a maximum of 30 days until the 
toxicity resolves ≤ Grade 1 or baseline, or permanently reduced as per Table 5-3.
Table 5-3.
Doses for Restarting MMB after Withholding Treatment for Toxicity
Dose at time of toxicity
Restarting dose level
200 mg QD
150 mg QD
150 mg QD
100 mg QD
100 mg QD
100 mg QD*
150 mg BID
100 mg BID
100 mg BID
Permanently Discontinue treatment
QD = once daily, BID=twice daily
* If Grade 3 or 4 toxicity recurs after restarting MMB, treatment will be permanently discontinued.
Other Toxicities
Treatment may be interrupted at the investigator’s discretion for up to 30 days, inclusive of taper, 
for any other toxicity. If the toxicity persists beyond 30 days, treatment may be restarted upon 
sponsor approval. Treatment may be restarted at the dose the subject was taking prior to 
interruption or at a reduced dose per Table 5-3, at the investigator’s discretion.
5.3.4.
Discontinuing or Interrupting Treatment
When discontinuing or interrupting treatment, MMB may be reduced to 100 mg once daily for 
1 week prior to stopping treatment, at the choice of the investigator. Treatment may be re-started 
at 100 mg once daily for subjects receiving 100 mg once daily, however if the same Grade 3 or 4 
MMB-related toxicity recurs at the 100 mg once daily dose, MMB will be permanently 
discontinued.
5.4.
Concomitant Medications
5.4.1.
Proscribed Medication
The following are proscribed unless sponsor approval is obtained:

Chemotherapy

Immunomodulators

Systemic corticosteroids (local topical, otic, nasal, ophthalmic, or inhaled corticosteroids are 
permitted)

Hydroxyurea


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
Anagrelide

Androgen for the treatment of myelofibrosis

Interferon 

JAK inhibitors other than the MMB administered in this trial

Experimental therapy other than the MMB administered in this trial

Erythropoiesis stimulating agents

Granulocyte Colony Stimulating Factor (G-CSF) unless administered for the treatment of
neutropenic fever

Thrombopoietins

Any other investigational treatment or procedure
5.4.2.
Restricted Medications
CYP3A4 Inhibitors/Inducers

Strong CYP3A4 inducers (eg, carbamazepine, phenytoin, St. John’s Wort) may decrease
MMB exposure and should be excluded

Moderate inducers of CYP3A/2C8/2C19 may decrease MMB exposure and alternative 
medications should be considered if clinically appropriate when co-administered with MMB
5.4.3.
Breast Cancer Resistance Protein (BCRP) Substrates
In vitro, MMB was determined to be an inhibitor of BCRP. Results from a clinical drug-drug 
interaction study suggested that multiple doses of MMB at 200 mg increased the exposure 
(Cmax and AUC) of rosuvastatin (a BCRP substrate) by approximately 3 fold. Plasma exposures 
of BCRP substrates may increase when administered with MMB. As such, where appropriate, 
dose modification or alternative medications as clinically appropriate may be considered when 
co-administered with MMB.
5.4.4.
Organic Anion-Transporting Polypeptide (OATP) Inhibitors
MMB was determined to be a substrate of OATP1B1 and OATP1B3. A single dose of rifampin 
(potent inhibitor of OATP1B1 and OATP1B3) increased MMB Cmax by ~40% and 
AUCinf by ~56%. Care should be exercised when MMB is co-administered with OATP 
inhibitors.
Refer to Investigator Brochure of MMB for more details. Refer to prescribing information of 
co-administered drugs prior to administration.


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5.5.
Accountability for MMB
The investigator is responsible for ensuring adequate accountability of all used and unused 
MMB. This includes acknowledgement of receipt of each shipment of MMB 
(quantity and condition). All used and unused MMB dispensed to subjects must be returned to 
the site.
MMB accountability records will be provided to each study site to:

Record the date received and quantity of MMB.

Record the date, subject number, and the MMB bottle number dispensed.

Record the date, quantity of used and unused MMB returned, along with the initials of the 
person recording the information.
The methods of MMB return and destruction are described in Section 9.1.7.


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6.
STUDY PROCEDURES
The study procedures to be conducted for each subject enrolled in the study are presented in 
tabular form in Appendix 2 and described in the text that follows. Additional information is 
provided in the study procedures manual.
The investigator must document any deviation from protocol procedures and notify the sponsor 
or contract research organization (CRO).
The initial study procedures to be conducted for each subject enrolled in the study are presented 
in Figure 6-1.
Figure 6-1.
Initial Study Procedures

Steps 1 through 5 may occur on the same or different days, but must occur sequentially

The maximum amount of time allowed from step 1 to step 5 is 30 days 

Results from laboratory assessments and procedures performed up to 30 days prior to step 5
(eg, results from procedures performed during the previous study or as part of the subject’s 
routine care (if documentation is available) may be utilized for determining eligibility)
6.1.
Subject Enrollment and Treatment Assignment
A subject will be considered enrolled once enrolled in IXRS. It is the responsibility of the 
investigator to ensure that each subject is eligible for the study before enrollment. Details 
regarding treatment assignment and dosing are in Section 5.3.
6.2.
Study Procedure Description
6.2.1.
Obtain Written Informed Consent
All subjects must personally sign and date the institutional review board / independent ethics 
committee (IRB/IEC) approved informed consent form before any study procedures are 
performed (Section 9.1.3).


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6.2.2.
Recording Medical History
Medical history from the previous study will not be reported in the electronic case report form 
(eCRFs) for this study. Any ongoing AE from the previous study at the time of enrollment in this 
study will be considered medical history on this study and should be reported in the eCRFs and 
followed to resolution.
6.2.3.
Medication History
A current list of ongoing medications will be obtained prior to enrollment and recorded on the 
eCRF.
6.2.4.
Physical Examination and Symptom Assessment
At all study visits, the physical examination will be an interim examination to monitor for any 
changes and will include vital signs, weight, clinical signs, symptoms, and palpable spleen 
length, measured with a ruler. The physical exam will include assessment of splenomegaly and 
hepatomegaly. Breast, genital, and rectal examinations are not required at any study visit unless 
warranted in the opinion of the investigator. Weight should be collected with the subject standing 
without shoes.
6.2.5.
Vital Signs
Vital signs will include pulse, systolic and diastolic blood pressure, and body temperature. They
should be collected per institutional guidelines.
6.2.6.
Electrocardiogram
A single 12-lead ECG will be collected at each applicable study visit per guidelines. ECGs will 
be read locally and the results will be reported in the eCRFs. The investigator will review all 
ECGs and retain the tracing with the source documents. Following completion of a thorough 
QT study and a review of cardiovascular-related events, ECG monitoring may be discontinued in 
this study.
6.2.7.
Ophthalmic Examination
An eye exam will be performed to assess for cataracts and visual acuity. All assessments will be 
performed in accordance with standard practice.
6.2.8.
Laboratory Assessments
All samples collected in this study for laboratory assessments will be sent to the central 
laboratory with the exception of urine pregnancy test which will be completed at the site.
Screening laboratory samples should be obtained within 30 days prior to the first dose of MMB 
taken on this study. Local laboratory CBC assessments may be collected for dose adjustments 
throughout the study. 


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The central laboratory will be responsible for chemistry, CBC, coagulation, urinalysis, and serum 
pregnancy testing per Table 6-1. Any samples collected per the Schedule of Assessments 
(Appendix 2) may be analyzed for any tests necessary to ensure subject safety. Specific 
instructions for processing, labeling, and shipping samples will be provided in a central 
laboratory manual. The date and time of sample collection will be reported to the central 
laboratory.
Table 6-1.
Analytes
Chemistry
Urinalysis
Hematology and Coagulation
Other Analytes
Albumin
Alkaline phosphatase
ALT
AST
Amylase
Bicarbonate
BUN
Calcium
Chloride
Creatininea
GGT
Glucose
LDH
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin
Total protein
Uric acid
Color and appearance
Specific gravity
pH
Occult blood
Protein
Glucose
Bilirubin
Leukocyte esterase
Ketones
Nitrite
Urobilinogen
Microscopicc
Urine beta hCGb
RBC
Hemoglobin
Hematocrit
Platelets
WBC
Differential
Neutrophils
Bands/stabs
Eosinophils
Basophils
Lymphocytes
Monocytes
% blasts
ANC
PT (INR)
PTT
Serum beta hCGb
Thiamine status
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; 
GGT = gamma-glutamyl transpeptidase; LDH = lactate dehydrogenase; PT = prothrombin time; 
PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell; hCG=human chorionic gonadotropin
Note: Additional components, abnormal, and/or atypical cells will also be reported if present
a
Estimated creatinine clearance/glomerular filtration rate will be calculated based on the Cockroft-Gault formula
b
If applicable and either urine or serum HCG is acceptable
c
Reflex testing based on other abnormalities
6.2.9.
Patient-reported Outcomes Assessments (PRO)
PRO assessments completed at study visits should be completed prior to any other visit 
assessments on the visit day.
The Patients’ Global Impression of Change (PGIC) will be used to assess patient reported 
outcome.
The PGIC is a single-item questionnaire to assess change in patient status over time. The 
questionnaire will be completed at each visit. 


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6.2.10.
Disease Assessment
6.2.10.1.
Treatment Response Assessment
Cohorts 1, 2, and 4
Treatment response for Cohorts 1, 2, and 4 will be assessed using the 2006 IWG criteria for 
treatment response in myelofibrosis (Appendix 3). The criteria classify treatment response based 
on laboratory (eg, bone marrow histology, hematology), physical examination 
(eg, splenomegaly), and symptoms assessments. Spleen and liver assessments will not require 
radiographic confirmation.
6.2.10.2.
Bone Marrow Aspirate and Biopsy
Bone marrow aspirate/biopsy samples will be assessed by a local hematopathologist for grading 
of bone marrow fibrosis. Unstained slides should be made available to the sponsor for central
review, if requested. Grading of bone marrow fibrosis will include assessments of reticulin
(eg silver stain) and collagen fibrosis (eg, trichrome stain). Results from assessment of bone 
marrow aspirate/biopsy samples obtained as part of the subject’s routine medical care may be 
used if the documentation is available.
6.2.10.3.
Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG performance status is an investigator assessment of the impact of the disease on the 
subject’s activities of daily living. It is assessed on a 6-point scale as described in Appendix 6
{Oken 1982}.
6.2.10.4.
Transfusion Recording
Subjects in all cohorts will record transfusion events in a diary throughout the study. The diary 
will include instructions for the transfusion clinic to provide the date, type (eg, whole blood, 
packed cells), and number of units of the transfusion. Transfusion events which occur prior to 
Day 1 of this study will be reported on the appropriate eCRF page for the previous study. 
Transfusion events which occur after administration of the first dose of MMB on this study will 
be reported on the transfusion eCRF for this study. The hemoglobin value at the time of the 
transfusion will be reported on the eCRF as an observational component of the study.
6.3.
Pretreatment Assessment
6.3.1.
Screening Visit/Enrollment
The screening date will be defined as the date the subject signs the informed consent form (ICF).  
Results from procedures performed within 30 days prior to Day 1 may be used to determine 
eligibility for this study and receiving drug.  The maximum time allowed between consenting 
and the first dose of MMB on this study is 30 days. The following will be performed or 
documented at screening:

Informed consent

PGIC


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
Current medications

Physical examination and symptoms assessment 

Vital signs

Single 12-lead ECG 

ECOG performance status

Bone marrow aspirate/biopsy (not required if previously completed within 12 months of 
first dose of MMB on this study and the data are available for reporting to the eCRF)

Laboratory assessments and blood sampling
Chemistry 
Thiamine status 
Complete Blood Count (CBC) and differential
Coagulation 
Urinalysis 
Serum or urine pregnancy test, if applicable

Transfusion recording
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will discontinue 
the MMB received for their previous study and start their assigned dose of MMB tablets for this 
study.
If the MMB received per the previous study is held due to toxicity during the screening period
the subject may delay screening for up to 30 days from the End of Treatment (EOT) visit on their 
previous study as long as all enrollment criteria are met.
6.4.
Treatment Assessments
6.4.1.
Months 1 and 2 (Cohorts 1 and 2 only)
As all subjects in Cohorts 1 and 2 are transitioning from MMB capsules to tablets and some 
subjects are transitioning from twice-a-day  to once-daily dosing, 2 additional study visits at 
Months 1 and 2, within a window of ± 7 days, will evaluate dose adjustments based on tolerance 
and response. The following will be completed at these visits:

Physical examination and symptoms assessment 

Vital signs


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
Single 12-lead ECG

Laboratory assessments and blood sampling
Chemistry 
Thiamine status (Repeat if sample was not able to be analyzed during 
Screening/Enrollment visit)
CBC and differential

Transfusion recording

Response assessment

AEs and concomitant medications

MMB accountability and dispensing
6.4.2.
Months 3 to Early Study Drug Discontinuation (ESDD) visits or End of 
Study 
On-study visits during this period will occur every 3 months within a window of ± 7 days. The 
following procedures will be completed at each visit, unless otherwise specified.

PGIC

Physical examination and symptoms assessment 

Vital signs

Single 12-lead ECG

Laboratory assessments and blood sampling
Chemistry
Thiamine status
CBC and differential
Coagulation 
Urinalysis 
Urine pregnancy test


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
ECOG performance status 

Transfusion recording

Response assessment

Bone marrow aspirate/biopsy (Months 24 and 48 only)

Ophthalmic Examination (Month 6, 12 and annually thereafter and at the Month 48/ESDD
visit if not done within the previous 6 months)

AEs and concomitant medications

MMB accountability and dispensing
6.5.
Unscheduled visits
Unscheduled visits may occur at any time during the study. Vital signs, laboratory assessments, 
ECG, and physical examination may be conducted at these visits.
6.6.
Post-treatment Follow-up Assessments
A safety follow-up visit is required for subjects at approximately 30 days after ending treatment.
Subjects who continue treatment with MMB in the extended access program following the end of 
this study are not required to complete the 30 day post-treatment follow-up assessments.
The following procedures will be completed 30 days after the subject’s last dose of MMB, within 
a window of 7 days:

PGIC

Physical examination and symptoms assessment

Vital signs

Single 12-lead ECG

ECOG performance status

Laboratory assessments
Chemistry
Thiamine Status
CBC and differential


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Coagulation 
Urinalysis 
Urine pregnancy test

Transfusion recording

AEs and Concomitant medications
6.7.
Assessments for Premature Discontinuation from Study
If a subject discontinues study dosing (for example, as a result of an AE), every attempt should 
be made to keep the subject in the study and continue to perform the required study-related 
follow-up and procedures (see Section 6.6). If this is not possible or acceptable to the subject or 
investigator, the subject may be withdrawn from the study.
6.8.
Criteria for Discontinuation of Study Treatment
Study medication may be discontinued in the following instances:

Intercurrent illness that would, in the judgment of the investigator, affect assessments of 
clinical status to a significant degree. Following resolution of intercurrent illness, the subject 
may resume study dosing at the discretion of the investigator

Toxicity that, in the judgment of the investigator, compromises the ability to continue 
study-specific procedures or is considered to not be in the subject’s best interest

Disease progression

Subject request to discontinue for any reason

Subject noncompliance

Pregnancy during the study; refer to Appendix 5

Discontinuation of the study at the request of Gilead, a regulatory agency or an 
institutional review board or independent ethics committee (IRB/IEC)
6.9.
End of Study
All treatment-emergent AEs and laboratory abnormalities present at the end of study are to be 
followed until resolution or the event is determined to be irreversible by the investigator. End of 
study for a subject is defined as the date of the last study-related procedure or protocol-defined 
follow-up contact.


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7.
ADVERSE EVENTS AND TOXICITY MANAGEMENT
7.1.
Definitions of Adverse Events, Adverse Reactions, and Serious Adverse 
Events
7.1.1.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. AEs may also include pre- or post-treatment complications that 
occur as a result of protocol specified procedures, lack of efficacy, overdose, drug abuse/misuse 
reports, or occupational exposure. Preexisting events that increase in severity or change in nature 
during or as a consequence of participation in the clinical study will also be considered AEs.
An AE does not include the following:

Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion.
The condition that led to the procedure may be an AE and must be reported.

Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
first dose of MMB on the previous study, are considered medical history. If they occurred 
during the previous  study , prior to the first dose of MMB on this study, but have not 
resolved, they are considered medical history on this study

Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions)

Overdose without clinical sequelae
7.1.2.
Serious Adverse Events
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as an event 
that, at any dose, results in the following:

Death

Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.)

In-patient hospitalization or prolongation of existing hospitalization

Persistent or significant disability/incapacity


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
A congenital anomaly/birth defect

A medically important event or reaction: such events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. Medical and 
scientific judgment must be exercised to determine whether such an event is reportable under 
expedited reporting rules. Examples of medically important events include intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; and development of drug dependency or 
drug abuse. For the avoidance of doubt, infections resulting from contaminated medicinal 
product will be considered a medically important event and subject to expedited reporting 
requirements.
7.1.2.1.
Protocol-Specific Serious Adverse Event Instructions
To maintain the integrity of the study, the following events that are assessed as unrelated to 
MMB by the investigator will not be considered SAEs:
Cohorts 1, 2, and 4:

Progression of MF (including leukemia)

Death related to progression of MF (per IWG criteria)

Death related to MF (not meeting IWG criteria for disease progression)
7.2.
Assessment of Adverse Events and Serious Adverse Events
The investigator or qualified subinvestigator is responsible for assessing AEs and SAEs for 
causality and severity, and for final review and confirmation of accuracy of event information 
and assessments.
7.2.1.
Assessment of Causality for Study Drug and Procedures
The investigator or qualified subinvestigator is responsible for assessing the relationship to 
MMB therapy using clinical judgment and the following considerations:

No: Evidence exists that the AE has an etiology other than the MMB. For SAEs, an 
alternative causality must be provided (eg, pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication).

Yes: There is reasonable possibility that the event may have been caused by the 
investigational medicinal product (IMP).
It should be emphasized that ineffective treatment should not be considered as causally related in 
the context of AE reporting. 


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The relationship to study procedures (eg, invasive procedures such as venipuncture or biopsy) 
should be assessed using the following considerations:

No: Evidence exists that the AE has an etiology other than the study procedure.

Yes: The AE occurred as a result of protocol procedures, (eg, venipuncture)
7.2.2.
Assessment of Severity
The severity of AEs will be graded using the CTCAE Version 4.03. For each episode, the highest 
severity grade attained should be reported.
If a CTCAE criterion does not exist, the investigator should use the grade or adjectives:
Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or 
Grade 5 (fatal) to describe the maximum intensity of the AE. For purposes of consistency with 
the CTCAE, these intensity grades are defined in Table 7-1.
Table 7-1.
Grading of Adverse Event Severity
Grade
Adjective
Description
Grade 1 
Mild
Sign or symptom is present, but it is easily tolerated, is not expected to have a 
clinically significant effect on the subject’s overall health and well-being, does not 
interfere with the subject’s usual function, and is not likely to require medical 
attention.
Grade 2 
Moderate
Sign or symptom causes interference with usual activity or affect clinical status, 
and may require medical intervention.
Grade 3 
Severe
Sign or symptom is incapacitating or significantly affects clinical status and likely 
requires medical intervention and/or close follow-up.
Grade 4 
Life-threatening
Sign or symptom results in a potential threat to life.
Grade 5 
Fatal
Sign or symptom results in death.
The distinction between the seriousness and the severity of an AE should be noted. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed in Section 7.1.2.
7.3.
Investigator Requirements and Instructions for Reporting Adverse Events 
and Serious Adverse Events to Gilead.
All SAEs, regardless of cause or relationship, that occur after the subject first consents to 
participate in the study (ie, signing the informed consent) and throughout the duration of the
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database. 
All AEs resulting from protocol-associated procedures must be reported to the CRF/eCRF 
database as instructed, starting from the time the subject first consents to participate in the study 
and throughout the duration of the study.


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All AEs, regardless of cause or relationship, that occur from the first dose of MMB in this study 
until 30 days after the last administration must be reported to the eCRF database as instructed.
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of MMB, regardless of causality, should also be reported. 
All AEs should be followed up until resolution if possible. If by the last day on study 
(including the off-study medication follow-up period) the AE has not resolved, then the AE will 
be followed up until the investigator and/or Gilead Sciences determine that the subject's 
condition is stable. However, Gilead Sciences may request that certain AEs be followed until 
resolution.
Investigators are not obligated to actively seek SAEs after the post-treatment follow-up period or 
30 days after the last dose of MMB (whichever is later). However, if the investigator learns of 
any SAEs that occur after study participation has concluded and the event is deemed relevant to 
the use of MMB, he/she should promptly document and report the event to Gilead DSPH or to 
the designated CRO.

All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined 
in the CRF/eCRF completion guideline.

SAEs will be reported using an electronic SAE (eSAE) system. Gilead will provide training 
and account information.
Electronic Serious Adverse Event (eSAE) Reporting Process 
Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines.
If for any reason it is not possible to record the SAE information electronically, ie, the eCRF 
database is not functioning, record the SAE on the paper SAE reporting form and submit within 
24 hours as described above.
As soon as it is possible to do so, any SAE reported via paper must be transcribed into the eCRF 
Database according to instructions in the eCRF completion guidelines.
If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary.
All AEs and SAEs will be recorded in the CRF/eCRF database within the timelines outlined in 
the CRF/eCRF completion guideline.
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers.


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Additional information may be requested to ensure the timely completion of accurate safety 
reports.
Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s CRF/eCRF and the event description section of the SAE 
form.
7.4.
Gilead Reporting Requirements
Depending on relevant local legislation or regulations, including the applicable US FDA Code of 
Federal Regulations, the EU Clinical Trials Directive (2001/20/EC) and relevant updates, and 
other country-specific legislation or regulations, Gilead may be required to expedite to 
worldwide regulatory agencies reports of SAEs, SADRs, or suspected unexpected serious 
adverse reactions (SUSARs). In accordance with the EU Clinical Trials Directive (2001/20/EC), 
Gilead or a specified designee will notify worldwide regulatory agencies and the relevant IEC in 
concerned Member States of applicable SUSARs as outlined in current regulations.
Assessment of expectedness for SAEs will be determined by Gilead using reference safety 
information specified in the IB or relevant local label as applicable. 
All investigators will receive a safety letter notifying them of relevant SUSAR reports. The 
investigator should notify the IRB or IEC of SUSAR reports as soon as is practical, where this is 
required by local regulatory agencies, and in accordance with the local institutional policy. 
7.5.
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (eg, clinical chemistry, hematology, and urinalysis) that require medical or surgical 
intervention or lead to MMB interruption or discontinuation must be recorded as an AE, as well 
as an SAE, if applicable. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (ie, anemia) not the laboratory result (ie, decreased hemoglobin).
Severity should be recorded and graded according to the CTCAE Version 4.03 except for 
anemia (hemoglobin) which will be graded using the CTCAE Version 3.0 as defined in 
Table 7-2.
Table 7-2.
Grading of Hemoglobin Severity
Grade (CTCAE 3.0)
1
2
3
4
5
<LLN – 10.0 g/dL
<LLN – 6.2 mmol/L
<LLN – 100 g/L
<10.0 – 8.0 g/dL
<6.2 – 4.9 mmol/L
<100 – 80 g/L
<8.0 – 6.5 g/dL
<4.9 – 4.0 mmol/L 
<80 – 65 g/L
<6.5 g/dL
<4.0 mmol/L
<65 g/L
Death
For AEs associated with laboratory abnormalities, the event should be graded on the basis of the 
clinical severity in the context of the underlying conditions; this may or may not be in agreement 
with the grading of the laboratory abnormality.


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7.6.
Toxicity Management
Dosing requirements for certain toxicities are specified in Section 5.3.4. The investigator may 
contact the medical monitor to review toxicities that are not directly discussed in the protocol.
Laboratory abnormalities (eg, thiamine deficiency) identified at Screening/Baseline and during 
study participation should be treated at the investigator’s discretion.
7.7.
Special Situations Reports
7.7.1.
Definitions of Special Situations
Special situation reports include all reports of medication error, abuse, misuse, overdose, lack of 
effect reports, and pregnancy reports regardless of an associated AE.  Also includes reports of
adverse reactions in infants following exposure from breastfeeding, and reports of adverse 
reactions associated with product complaints and reports arising from occupational exposure.
A pregnancy report is used to report any pregnancy following maternal or paternal exposure to 
the medicinal product.
Medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the health care provider, subject, or consumer.
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by a 
subject.
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information.
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator has 
reason to suspect that the subject has taken the additional dose(s).
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product.
7.7.2.
Instructions for Reporting Special Situations
7.7.2.1.
Instructions for Reporting Pregnancies
The investigator should report all pregnancies that are identified after the subject first consents to 
participate in the study (ie, signs the informed consent) and throughout the study, including the 
post study drug follow-up period, to the Gilead DSPH using the pregnancy report form within 
24 hours of becoming aware of the pregnancy. Refer to Section 7.3 and the CRF/eCRF 
completion guidelines for full instructions on the mechanism of pregnancy reporting.


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The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons.
Any premature termination of pregnancy (eg, a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term.
A spontaneous abortion is always considered to be an SAE and will be reported as described in 
Sections 7.1.1 and 7.1.2. Furthermore, any SAE occurring as an adverse pregnancy outcome post 
study must be reported to Gilead DSPH.
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH. Pregnancies of female partners of male study subjects 
exposed to Gilead or other study drugs must also be reported and relevant information should be 
submitted to or Gilead DSPH using the pregnancy and pregnancy outcome forms within 
24 hours. Monitoring of the subject should continue until the conclusion of the pregnancy. If the 
end of the pregnancy occurs after the study has been completed, the outcome should be reported 
directly to Gilead DSPH. 
Refer to Appendix 5 for Pregnancy Precautions, Definition for Female of Childbearing Potential, 
and Contraceptive Recommendations.
7.7.2.2.
Reporting Other Special Situations
All other special situation reports must be reported on the special situations report form and 
forwarded to the designated CRO or Gilead DSPH within 24 hours of the investigator becoming 
aware of the situation. These reports must consist of situations that involve MMB, but do not 
apply to concomitant medications. Except for situations that result in AEs, special situations 
involving concomitant medications will not be reported. Any inappropriate use of medications 
prohibited by this protocol should not be reported as “misuse,” but may be more appropriately 
documented as a protocol deviation.
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE CRF/eCRF and/or the SAE report form. Details of the symptoms 
and signs, clinical management, and outcome will be reported, when available.


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8.
STATISTICAL CONSIDERATIONS
8.1.
Analysis Objectives and Endpoints
8.1.1.
Analysis Objectives
The primary objective of this study is to determine the long term safety and tolerability of 
momelotinib (MMB) in 4 cohorts of subjects: 

Cohort 1: Subjects who are currently receiving MMB capsules in the CCL09101E study for 
PMF and post-PV/ET MF without documented progressive disease 

Cohort 2: Subjects who are currently receiving MMB capsules in the YM387-II-02 study for 
PMF and post-PV/ET MF without documented progressive disease 

Cohort 3 was closed and all enrolled subjects were discontinued from this study due to 
limited efficacy of MMB in the treatment of PV and ET on GS-US-354-0101.

Cohort 4: Subjects who are currently receiving MMB tablets in the GS-US-352-1672 study 
for PMF and post-PV/ET MF without documented progressive disease.
The secondary objective of this study is to determine the long-term efficacy of MMB in these 
4 cohorts of subjects.
8.1.2.
Primary Endpoints
The primary endpoint is safety. Safety will be evaluated by the incidence and severity of adverse 
events and clinical laboratory abnormalities, as defined by CTCAE v4.03.
8.1.3.
Secondary Endpoints
The secondary endpoints are all efficacy-related endpoints and no analyses/summaries of 
efficacy endpoints will be performed for Cohort 3 subjects as Cohort 3 was closed and all 
enrolled subjects were discontinued from this study due to limited efficacy of MMB in the 
treatment of PV and ET on study GS-US-354-0101.
Secondary endpoints are:

Overall survival (OS): defined as the interval from the first dose of MMB on the previous 
study until death from any cause

Progression-free survival (PFS): defined as the interval from the first dose of MMB on the 
previous study until the first documentation of definitive progressive disease or death due to 
any cause
Progressive Disease (Cohorts 1 and 2) defined as (Appendix 3):
o
Leukemic transformation confirmed by a bone marrow blast count of ≥20%, OR


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o
Peripheral blood blast count of ≥ 20% associated with an absolute blast count of 
≥1 x 10 9 /L that lasts for a at least 8 weeks, OR
o
Progressive splenomegaly defined as:

Appearance of new splenomegaly that is palpable > 5 cm below the 
left costal margin (LCM), OR

A ≥ 100% increase in palpable spleen length below LCM, for baseline palpable 
splenomegaly of previous study that measured >5 and <10 cm below LCM, OR

A ≥ 50% increase in palpable spleen length below LCM, for baseline 
splenomegaly of previous study that measured ≥ 10 cm below LCM

Leukemia-free survival:  defined as the interval from the first dose of MMB on the previous
study until the first documented leukemic transformation or death from any cause

Rate of RBC transfusion:  defined as the average number of RBC units per subject month 
from the first dose of MMB on the previous study during the study period
Other secondary endpoints specific to Cohorts 1 and 2:

Duration of splenic response: defined as the interval from the first onset of splenic response 
(in the previous study or this study) to the earliest date of loss of splenic response which 
persists for at least 4 weeks or death from any cause. Splenic response is defined 
as > 50% reduction in palpable splenomegaly of a spleen that is ≥ 10 cm below the LCM at 
baseline or a spleen that is palpable at > 5 cm below the LCM at baseline becomes not 
palpable.

Duration of transfusion independence response: defined as the interval from the first onset 
date of transfusion independence (in the previous study or this study) to the earliest onset 
date of transfusion dependence or death from any cause, among those subjects who are 
transfusion dependent at baseline. Transfusion independence is defined as absence of RBC 
transfusions for ≥ 12 weeks.

Duration of anemia response: defined as the interval from the first onset of anemia 
response (in the previous study or this study) to the earliest date of loss of anemia response
which persists for at least 4 weeks or death from any cause. Anemia response is defined as
≥2g/dL increase in hemoglobin for baseline transfusion independent subjects with baseline 
hemoglobin level of < 10g/dL, or becoming transfusion independent for those who were 
transfusion dependent at baseline for ≥12 weeks.
Secondary endpoints specific to Cohort 4 are:

Transfusion response rate: defined as becoming not transfusion dependent for ≥ 12 weeks 
at any time from the first dose of MMB on the previous study until end of this study.


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8.1.4.
Exploratory Endpoints
Exploratory endpoints are:

Change in hemoglobin level over time

Change in patient global impression of change (PGIC) over time 
8.2.
Analysis Conventions
8.2.1.
Analysis Sets
8.2.1.1.
Full Analysis Set
The Full Analysis Set consists of all subjects who are enrolled into this study. The Full Analysis 
Set will be used for demographic and baseline characteristics, medical and disease history, study 
treatment administration and compliance, and efficacy and safety analyses.
8.3.
Data Handling Conventions
Unless otherwise specified, data will be summarized and analyzed by each cohort separately.
Within each cohort, data will be summarized by the initial dose in the parent study (CCL09101 
for Cohort 1).
In general, the baseline value used in each analysis will be the baseline defined in the previous 
study. Analyses will be based upon the observed data unless methods for handling missing data 
are specified. If there is a significant degree of non-normality, analyses may be performed on 
log-transformed data or nonparametric tests may be applied, as appropriate.
Unless otherwise specified, all analyses will be 2-sided at the 0.1 level of significance.
The following censoring conventions will be applied for time-to-event endpoints:

Duration of response: Data from subjects who remain response will be censored at the date of 
last visit.

Progression-free survival: Data from surviving, non-progressing subjects will be censored at 
the last adequate response assessment date prior to the initiation of myelofibrosis 
(Cohorts 1, 2, and 4) treatment other than MMB or the last time that lack of definitive 
progression was objectively documented.

Overall survival: Data from surviving subjects will be censored at the date of last contact.
8.4.
Demographic Data and Baseline Characteristics
Demographic and baseline characteristics will be summarized using standard descriptive 
methods.  Demographic summaries will include sex, race/ethnicity, and age.


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8.5.
Efficacy Analysis
There is no primary efficacy endpoint in this study. Safety summaries will be generated to 
evaluate the primary objective.   There will be no efficacy analyses for Cohort 3 subjects as 
Cohort 3 was closed and all enrolled subjects were discontinued from this study.
8.5.1.
Time-to-Event Endpoints 
Progression-free survival, duration of response, leukemia-free survival and overall survival will 
be described in the appropriate analysis set using Kaplan-Meier methods. The survival functions 
will be plotted and median survival times will be presented with corresponding 90% CIs.
8.5.2.
Categorical Endpoints
Categorical endpoints will be described. Response rates will be presented with corresponding 
exact 90% CIs.
Rate of RBC transfusion will be summarized descriptively.
8.5.3.
Continuous Endpoints
Continuous endpoints will be summarized descriptively over time. Both changes from baseline 
to each subsequent time point and best overall on-study changes will be evaluated. Means and 
standard errors will be presented.
8.6.
Safety Analysis
All safety data collected on or after the date that MMB was first dispensed in the previous study 
up to the date of last dose of MMB plus 30 days will be summarized. Events occurred on or after 
the first dose date of MMB in the current study may also be summarized separately.
8.6.1.
Extent of Exposure
A subject’s extent of exposure to MMB data will be generated from the MMB administration 
data. Exposure data will be summarized.
Descriptive information will be provided by cohort regarding the number of doses of MMB
prescribed, the total number of doses taken, the percent of expected doses taken, the number of 
days of MMB, and the number and timing of prescribed dose modification and interruptions.
Compliance will be described in terms of the proportion of MMB actually taken based on 
returned pill count relative to the amount that was dispensed (taking into account 
physician-prescribed modification and interruptions).


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8.6.2.
Adverse Events
All AEs will be listed. The focus of AE summarization will be on treatment-emergent AEs. 
A treatment-emergent AE is defined as an AE that occurs or worsens in the period from the 
first dose of MMB in the previous study to 30 days after the last dose of MMB.
AEs will be classified using Medical Dictionary for Regulatory Activities (MedDRA)
(http://www.meddramsso.com) with descriptions by System Organ Class (SOC), High-Level 
Group Term (HLGT), High-Level Term (HLT), Preferred Term (PT), and Lower-Level Term
(LLT). The severity of AEs will be graded by the investigator according to the CTCAE,
Version 4.03, whenever possible. If a CTCAE criterion does not exist for a specific type of AE, 
the grade corresponding to the appropriate adjective will be used by the investigator to describe 
the maximum intensity of the AE: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (life threatening), or Grade 5 (fatal). The relationship of the AE to the MMB will be 
categorized as related or unrelated.
Treatment-emergent AEs will be summarized. Summary tables will be presented to show the 
number of subjects reporting treatment-emergent AEs by severity grade and corresponding 
percentages. A subject who reports multiple treatment-emergent AEs within the same PT (or 
SOC) is counted only once for that PT (or SOC) using the worst severity grade. AE descriptions 
will be presented by decreasing frequency for a given SOC, HLT and PT. Separate listings and 
summaries will be prepared for the following types of treatment emergent AEs:

Study-drug-related AEs

AEs that are Grade ≥ 3 in severity

AEs leading to MMB interruption and/or dose modification

AEs leading to MMB discontinuation

SAEs
8.6.3.
Laboratory Evaluations
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. 
The focus of laboratory data summarization will be on treatment-emergent laboratory 
abnormalities. A treatment-emergent laboratory abnormality is defined as an abnormality that, 
compared to baseline, worsens by 1 grade in the period from the first dose of MMB in the 
previous study to 30 days after the last dose of MMB. If baseline data are missing, then any 
graded abnormality (ie, an abnormality that is Grade 1 in severity) will be considered treatment 
emergent.


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Hematological, serum biochemistry, and urine data will be programmatically graded according 
to CTCAE severity grade, when applicable. For parameters for which a CTCAE scale does not 
exist, reference ranges from the central laboratory will be used to determine programmatically if 
a laboratory parameter is below, within, or above the normal range for the subject’s age, sex, etc.
Hematological and serum biochemistry and their changes from baseline will be summarized by 
visit. Summary tables will be presented for each relevant assay to show the number of subjects 
by CTCAE severity grade with corresponding percentages. For parameters for which a CTCAE 
scale does not exist, the frequency of subjects with values below, within, and above the normal 
ranges will be summarized. Subjects will be characterized only once for a given assay, based on 
their worst severity grade observed during a period of interest (eg, during the study or from 
baseline to a particular visit).
Shift tables for hematology and serum biochemistry will also be presented by showing change in 
CTCAE severity grade from baseline to the worst grade post-baseline. For parameters for which 
a CTCAE scale does not exist, shift tables will be presented showing change in results from 
baseline to the worst grade post baseline. Separate listings and summaries will be prepared for 
laboratory abnormalities that are Grade 3 in severity.
8.7.
Sample Size
No formal hypothesis testing is planned for this study. Up to 105 subjects who have previously 
participated in a Gilead clinical trial with MMB will be enrolled.


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9.
RESPONSIBILITIES
9.1.
Investigator Responsibilities
9.1.1.
Good Clinical Practice
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and 
South Africa), ICH guidelines, or with the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the study subject. These 
standards are consistent with the European Union Clinical Trials Directive 2001/20/EC and 
Good Clinical Practice Directive 2005/28/EC.
The investigator will ensure adherence to the basic principles of GCP, as outlined in 
21 CFR 312, subpart D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, 
and 21 CFR, part 56, 1998.
The investigator and all applicable subinvestigators will comply with 21 CFR, Part 54, 1998, 
providing documentation of their financial interest or arrangements with Gilead, or proprietary 
interests in the investigational drug under study. This documentation must be provided prior to 
the investigator’s (and any subinvestigator’s) participation in the study. The investigator and 
subinvestigator agree to notify Gilead of any change in reportable interests during the study and 
for 1 year following completion of the study. Study completion is defined as the date when the
last subject completes the protocol-defined activities.
9.1.2.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
Review and Approval
The investigator (or sponsor as appropriate according to local regulations) will submit this 
protocol, informed consent form, and any accompanying material to be provided to the subject 
(such as advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) to an IRB (for studies conducted in the United States) or IEC (for studies 
conducted outside of the United States). The investigator will not begin any study subject 
activities until approval from the IRB or IEC has been documented and provided as a letter to the 
investigator.
Before implementation, the investigator will submit to and receive documented approval from 
the IRB or IEC any modifications made to the protocol or any accompanying material to be 
provided to the subject after initial approval, with the exception of those necessary to reduce 
immediate risk to study subjects.
9.1.3.
Informed Consent
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 


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investigator must use the most current IRB-/ IEC-approved consent form for documenting 
written informed consent. Each informed consent (or assent as applicable) will be appropriately 
signed and dated by the subject or the subject’s legally authorized representative and the person 
conducting the consent discussion, and also by an impartial witness if required by local 
requirements. 
9.1.4.
Confidentiality
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only subject date of birth (where allowed), 
another unique identifier (as allowed by local law) and an identification code will be recorded on 
any form or biological sample submitted to the sponsor, IRB/IEC, or laboratory. Laboratory 
specimens must be labeled in such a way as to protect subject identity while allowing the results 
to be recorded to the proper subject. Refer to specific laboratory instructions. 
NOTE: The investigator must keep a screening log showing codes, names, and addresses for all 
subjects screened and for all subjects enrolled in the trial. Subject data will be processed in 
accordance with all applicable regulations. 
The investigator agrees that all information received from Gilead, including but not limited to the
IB, this protocol, CRF/eCRF, the IP, and any other study information, remain the sole and 
exclusive property of Gilead during the conduct of the study and thereafter. This information is 
not to be disclosed to any third party (except employees or agents directly involved in the 
conduct of the study or as required by law) without prior written consent from Gilead. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain.
9.1.5.
Study Files and Retention of Records
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following two categories: (1) investigator’s study file, and 
(2) subject clinical source documents.
The investigator’s study file will contain the protocol/amendments, CRF and query forms, 
IRB/IEC and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence.
The required source data should include sequential notes containing at least the following 
information for each subject:

Subject identification (name, date of birth, gender);

Documentation that subject meets eligibility criteria, ie, history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria);

Documentation of the reason(s) a consented subject is not enrolled;


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
Participation in study (including study number);

Study discussed and date of informed consent;

Dates of all visits;

Documentation that protocol specific procedures were performed;

Results of efficacy parameters, as required by the protocol;

Start and end date (including dose regimen) of MMB, including dates of dispensing and 
return;

Record of all AEs and other safety parameters (start and end date, and causality and 
severity);

Concomitant medication (including start and end date, dose if relevant; dose changes);

Date of study completion and reason for early discontinuation, if it occurs.
All clinical study documents must be retained by the investigator until at least 2 years or 
according to local laws, whichever is longer, after the last approval of a marketing application in 
an ICH region (ie, United States, Europe, or Japan) and until there are no pending or planned 
marketing applications in an ICH region; or, if no application is filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and regulatory 
authorities have been notified. Investigators may be required to retain documents longer if 
specified by regulatory requirements, by local regulations, or by an agreement with Gilead. The 
investigator must notify Gilead before destroying any clinical study records.
Should the investigator wish to assign the study records to another party or move them to another 
location, Gilead must be notified in advance.
If the investigator cannot provide for this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Gilead to store 
these records securely away from the site so that they can be returned sealed to the investigator 
in case of an inspection. When source documents are required for the continued care of the 
subject, appropriate copies should be made for storage away from the site.
9.1.6.
Case Report Forms
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRF should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of 
safety data.  Subsequent to data entry, a study monitor will perform source data verification 
within the EDC system. Original entries as well as any changes to data fields will be stored in 
the audit trail of the system.  Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that 
the forms have been reviewed, and that the entries accurately reflect the information in the 


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source documents. The eCRF capture the data required per the protocol schedule of events and 
procedures. System-generated or manual queries will be issued to the investigative site staff as 
data discrepancies are identified by the monitor or internal Gilead staff, who routinely review the 
data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update 
(eg, data entry error). At the conclusion of the trial, Gilead will provide the site with a read-only 
archive copy of the data entered by that site. This archive must be stored in accordance with the 
records retention requirements outlined in Section 9.1.5.
9.1.7.
Investigational Medicinal Product Accountability and Return
Gilead recommends that used and unused IMP supplies (MMB is the IMP for this study) be 
returned to the shipping facility from which it came for eventual destruction. The study monitor 
will provide instructions for return. If return is not possible, the study monitor will evaluate each 
study center’s IMP disposal procedures and provide appropriate instruction for destruction of 
unused IMP supplies. If the site has an appropriate standard operating procedure (SOP) for drug 
destruction as determined by Gilead QA, the site may destroy used (empty or partially empty) 
and unused IMP supplies in accordance with that site’s approved SOP. A copy of the site’s 
approved SOP will be obtained for central files. 
If IMP is destroyed on site, the investigator must maintain accurate records for all IMP
destroyed. Records must show the identification and quantity of each unit destroyed, the method 
of destruction, and the person who disposed of the IMP. Upon study completion, copies of the 
IMP accountability records must be filed at the site. Another copy will be returned to Gilead.
The study monitor will review IMP supplies and associated records at periodic intervals.
9.1.8.
Inspections
The investigator will make available all source documents and other records for this trial to 
Gilead’s appointed study monitors, to IRBs or IECs, or to regulatory authority or health authority 
inspectors.
9.1.9.
Protocol Compliance
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol.
9.2.
Sponsor Responsibilities
9.2.1.
Protocol Modifications
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by Gilead. The investigator must submit all protocol modifications to the IRB or IEC
in accordance with local requirements and receive documented approval before modifications 
can be implemented.


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9.2.2.
Study Report and Publications
A clinical study report (CSR) will be prepared and provided to the regulatory agency(ies). 
Gilead will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases.
Investigators in this study may communicate, orally present, or publish in scientific journals or 
other scholarly media only after the following conditions have been met:

the results of the study in their entirety have been publicly disclosed by or with the consent of 
Gilead in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years

The investigator will submit to Gilead any proposed publication or presentation along with 
the respective scientific journal or presentation forum at least 30 days before submission of 
the publication or presentation. 

No such communication, presentation, or publication will include Gilead’s confidential 
information (see Section 9.1.4).
The investigator will comply with Gilead’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary.
9.3.
Joint Investigator/Sponsor Responsibilities
9.3.1.
Access to Information for Monitoring
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the 
CRF/eCRF.
The monitor is responsible for routine review of the CRF/eCRF at regular intervals throughout 
the study to verify adherence to the protocol and the completeness, consistency, and accuracy of 
the data being entered on them. The monitor should have access to any subject records needed to 
verify the entries on the CRF/eCRF. The investigator agrees to cooperate with the monitor to 
ensure that any problems detected through any type of monitoring (central, on site) are resolved.
9.3.2.
Access to Information for Auditing or Inspections
Representatives of regulatory authorities or of Gilead may conduct inspections or audits of the 
clinical study. If the investigator is notified of an inspection by a regulatory authority the 
investigator agrees to notify the Gilead medical monitor immediately. The investigator agrees to 
provide to representatives of a regulatory agency or Gilead access to records, facilities, and 
personnel for the effective conduct of any inspection or audit.


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9.3.3.
Study Discontinuation
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should 
this be necessary, both parties will arrange discontinuation procedures and notify the appropriate 
regulatory authority(ies), IRBs, and IECs. In terminating the study, Gilead and the investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.


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10.
REFERENCES
Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, et al. Revised response 
criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-
MRT consensus project. Blood 2013;121 (23):4778-81.
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of 
the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365 
(9464):1054-61.
DSM Pharmaceuticals Inc. JAKAFI™ (ruxolitinib) tablets, for oral use. US Prescribing 
Information. Greenville, NC. Revised November.  2011:
Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et al. What are RBC-
transfusion-dependence and -independence? Leuk Res 2011;35 (1):8-11.
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal 
JAK2 mutation leading to constitutive signalling causes polycythaemia vera. 
Nature 2005;434 (7037):1144-8.
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function 
mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352 
(17):1779-90.
Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy 
of myeloproliferative disorders. Nature reviews. Cancer 2007;7 (9):673-83.
Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in 
the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and 
myeloid metaplasia with myelofibrosis. Cancer cell 2005;7 (4):387-97.
Novartis Pharma GmbH. Jakavi 5 mg tablets. EU SmPC. Nuremberg Germany. Revised April.  
2013:
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5 (6):649-55.
Pardanani A. JAK2 inhibitor therapy in myeloproliferative disorders: rationale, preclinical 
studies and ongoing clinical trials. Leukemia 2008;22 (1):23-30.
Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy 
of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011;29 
(7):789-96.


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Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic 
correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia 
vera. Leukemia 2007;21 (9):1960-3.
Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 
mutations in myeloproliferative and other myeloid disorders: a study of 1182 
patients. Blood 2006;108 (10):3472-6.
Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel 
somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 
2006;3 (7):e270.
Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations 
in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356 
(5):459-68.
Tefferi A. Myeloproliferative Disorders: Essential Thrombocythemia and Primary Myelofibrosis 
[Abstract 177]. Myeloproliferative Disorders 2008:1280.
Tefferi A, Barbui T. bcr/abl-negative, classic myeloproliferative disorders: diagnosis and 
treatment. Mayo Clin Proc 2005;80 (9):1220-32.
Tefferi A, Barosi G, Mesa RA, Cervantes F, Deeg HJ, Reilly JT, et al. International Working 
Group (IWG) consensus criteria for treatment response in myelofibrosis with 
myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment 
(IWG-MRT). Blood 2006;108 (5):1497-503.
Wu J, Jester WF, Jr., Orth JM. Short-type PB-cadherin promotes survival of gonocytes and 
activates JAK-STAT signalling. Developmental biology 2005;284 (2):437-50.


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11.
APPENDICES
Appendix 1.
Investigator Signature Page
Appendix 2.
Study Procedures Table
Appendix 3.
International Working Group for Myelofibrosis Research and Treatment (IWG-
MRT) consensus criteria for treatment response in myelofibrosis with myeloid 
metaplasia
Appendix 4.
2013 European LeukemiaNet (ELN) and International Working Group for 
Myelofibrosis Response and Treatment (IWG-MRT) Consensus
Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing Potential, and 
Contraceptive Recommendations
Appendix 6.
ECOG status




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Appendix 2.
Study Procedures Table
Screening/
enrollment
Months 1&2
(Cohorts 1 & 2 
only)
3
M
6
M
9
M
12
M
15
M
18
M
21
M
24 
M
27
M
30
M
33
M
36
M
39
M
42
M
45
M
48 M+/Q3 Months/
ESDD
Post-treatment 
Follow uph
Informed Consent
X
General and Safety Assessments
Medication History
X
Physical Examination  and 
Symptoms Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ophthalmic Examination
X
X
X
X
Xa
Response Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE/Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease Assessments
PGIC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transfusion Recording
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Bone Marrow 
Aspirate/Biopsy 
Xb
X
Xg
Serum / Urine Pregnancy 
Testc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Thiamine status 
X
Xf
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CBC and Differential
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening/
enrollment
Months 1&2
(Cohorts 1 & 2 
only)
3
M
6
M
9
M
12
M
15
M
18
M
21
M
24 
M
27
M
30
M
33
M
36
M
39
M
42
M
45
M
48 M+/Q3 Months/
ESDD
Post-treatment 
Follow uph
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
MMB Accountability and 
Dispensing 
Xd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xe
a
EOT/Early Withdrawal if not done within the previous 6 months
b
Bone Marrow biopsy at screening if not performed within 12 months of Day 1.
c
For women of childbearing age only. Serum or urine testing at screening only. Urine pregnancy test for other visits.
d
Dispensing only
e
Accountability only at ESDD visit or final study visit
f
Thiamine levels may be repeated if sample was not able to be analyzed during Screening/Enrollment Visit
g
Bone marrow biopsy to be performed at month 48 only, not required for Q3 Months visits or ESDD visit
h
Subjects who continue treatment with MMB in the extended access program following the end of the study are not required to complete the 30 day post-treatment follow-up 
assessments.


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Appendix 3.
International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT) consensus criteria for treatment response in 
myelofibrosis with myeloid metaplasia
Complete remission (CR)
i.
Complete resolution of disease-related symptoms and signs including 
palpable hepatosplenomegaly.
ii.
Peripheral blood count remission defined as hemoglobin level at least 
110 g/L, platelet count at least 100 x 109/L, and absolute neutrophil count
(ANC) at least 1.0 x 109/L. In addition, all 3 blood counts should be no 
higher than the upper normal limit. a
iii. Normal leukocyte differential including disappearance of nucleated red 
blood cells, blasts, and immature myeloid cells in the peripheral smear, in 
the absence of splenectomy. 
iv. Bone marrow histologic remission defined as the presence of age-adjusted 
normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis 
grade no higher than 1.b
Partial remission (PR)
Requires all of the above criteria for CR except the requirement for bone 
marrow histologic remission. However, a repeat bone marrow biopsy is required 
in the assessment of PR and may or may not show favorable changes that do not 
however fulfill criteria for CR.
Clinical improvement (CI)
Requires one of the following in the absence of both disease progression (as 
outlined below) and CR/PR assignment (CI response is validated only if it lasts 
for no fewer than 8 weeks):
i.
A minimum 20-g/L increase in hemoglobin level or becoming transfusion 
independent (applicable only for subjects with baseline hemoglobin level of 
less than 100 g/L).
ii.
Either a minimum 50% reduction in palpable splenomegaly of a spleen that 
is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at 
baseline becomes not palpable. c
iii. A minimum 100% increase in platelet count and an absolute platelet count 
of at least 50 000 x 109/L (applicable only for subjects with baseline platelet 
count below 50 x 109/L).
iv.
A minimum 100% increase in ANC and an ANC of at least 0.5 x 109/L 
(applicable only for subjects with baseline ANC below 1 x109/L).
Progressive disease (PD) 
Requires 1 of the following: d
i.
Progressive splenomegaly that is defined by the appearance of a previously 
absent splenomegaly that is palpable at greater than 5 cm below the left 
costal margin or a minimum 100% increase in palpable distance for baseline
splenomegaly of 5-10 cm or a minimum 50% increase in palpable distance 
for baseline splenomegaly of greater than 10 cm.
ii.
Leukemic transformation confirmed by a bone marrow blast count of at 
least 20%.
iii. An increase in peripheral blood blast percentage of at least 20% that lasts 
for at least 8 weeks.
Stable disease (SD)
None of the above.
Relapse (Loss of CR, PR, or CI)
Subject with CR or PR is considered to have undergone relapse when he or she 
no longer fulfills the criteria for even CI. 


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a
Because of subjectivity in peripheral blood smear interpretation, CR does not require absence of morphologic abnormalities 
of red cells, platelets, and neutrophils
b
In patients with CR, a complete cytogenetic response is defined as failure to detect a cytogenetic abnormality in cases with a 
pre-existing abnormality. A partial cytogenetic response is defined as 50% or greater reduction in abnormal metaphases. In 
both cases, at least 20 bone marrow- or peripheral blood-derived metaphases should be analyzed. A major molecular 
response is defined as the absence of a specific disease-associated mutation in peripheral blood granulocytes of previously 
positive cases. In the absence of a cytogenetic/molecular marker, monitoring for treatment-induced inhibition of endogenous 
myeloid colony formation is encouraged. Finally, baseline and posttreatment bone marrow slides are to be stained at the 
same time and interpreted at one sitting by a central review process
c
In splenectomized patients, palpable hepatomegaly is substituted with the same measurements
d
It is acknowledged that worsening cytopenia might represent progressive disease, but its inclusion as a formal criterion was 
avoided because of the difficulty distinguishing disease-associated from drug-induced myelosuppression. However, a 
decrease in hemoglobin level of 20 g/L or more, a 100% increase in transfusion requirement, and new development of 
transfusion dependency, each lasting for more than 3 months after the discontinuation of protocol therapy, can be considered 
disease progression
e
Progressive splenomegaly only applies to those subjects who were on IP treatment for at least 7 days prior without dose 
interruption during those prior 7 days
{Tefferi 2006}


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Appendix 4.
2013 European LeukemiaNet (ELN) and International Working 
Group for Myelofibrosis Response and Treatment (IWG-MRT)
Consensus
Response Criteria for ET
Complete Remission
A
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large 
symptoms improvement,† AND
B
Durable* peripheral blood count remission, defined as: platelet count ≤400 ×109/L, WBC count 
<10 × 109/L, absence of leukoerythroblastosis, AND
C
Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, 
AND
D
Bone marrow histological remission defined as disappearance of megakaryocyte hyperplasia 
and absence of >grade 1 reticulin fibrosis.
Partial Remission
A
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, and large 
symptoms improvement, AND
B
Durable* peripheral blood count remission, defined as: platelet count ≤400 × 109/L, WBC count 
<10 × 109/L, absence of leukoerythroblastosis, AND
C
Without signs of progressive disease, and absence of any hemorrhagic or thrombotic events, 
AND
D
Without bone marrow histological remission, defined as the persistence of megakaryocyte 
hyperplasia.
                       No Response
A
Any response that does not satisfy partial remission
                                  Progressive Disease
A
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia


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Response Criteria for PV
Complete Remission
A
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large 
symptoms improvement† AND
B
Durable* peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND
C
Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND
D
Bone marrow histological remission defined as the presence of age-adjusted normocellularity 
and disappearance of trilinear hyperplasia, and absence of >grade 1 reticulin fibrosis
Partial Remission
A
Durable* resolution of disease-related signs including palpable hepatosplenomegaly, large 
symptoms improvement† AND
B
Durable* peripheral blood count remission, defined as Ht lower than 45% without 
phlebotomies; platelet count ≤400 × 109/L, WBC count <10 × 109/L, AND
C
Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND
D
Without bone marrow histological remission defined as persistence of trilinear hyperplasia.
                   No Response
A
Any response that does not satisfy partial remission
                          Progressive Disease
A
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or acute leukemia‡
{Barosi 2013}


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Appendix 5.
Pregnancy Precautions, Definition for Female of Childbearing 
Potential, and Contraceptive Recommendations
1) Pregnancy and Contraception Requirements for Males and Females of Childbearing 
Potential 
The risks of treatment with MMB during pregnancy have not been evaluated. Data available at 
this time suggest that this drug does not have a drug-drug interaction (DDI) with hormones used 
for contraception. Please refer to the latest version of the investigator’s brochure for additional 
information.
2) Definition of Female of Childbearing Potential
For the purposes of this study, a female subject of childbearing potential is a nonmenopausal 
female who has not had a hysterectomy, bilateral oophorectomy, or medically documented 
ovarian failure. This definition includes a pubertal female who has not yet started menstruating. 
A woman who has had a tubal sterilization is considered to be of childbearing potential.
A female subject may be considered menopausal in either of the following conditions:

Surgical menopause: Appropriate medical documentation of prior complete bilateral 
oophorectomy (ie, surgical removal of the ovaries and occurring at the age at which the 
procedure was performed)

Spontaneous menopause: Permanent cessation of previously occurring menses as a result of 
ovarian failure with documentation of hormonal deficiency by a certified health care 
provider. The worldwide mean age of spontaneous menopause is 49.24 (SD 1.73) years

A hormonal deficiency should be properly documented in the case of suspected spontaneous 
menopause as follows:
If age 54 years and with the absence of normal menses: serum follicle stimulating 
hormone (FSH) level elevated to within the postmenopausal range based on the 
laboratory reference range where the hormonal assay is performed
If age <54 years and with the absence of normal menses: negative serum or urine 
human chorionic gonadotropin (hCG) with concurrently elevated serum FSH level in the 
postmenopausal range, depressed estradiol (E2) level in the postmenopausal range, and 
absent serum progesterone level, based on the laboratory reference ranges where the 
hormonal assays are performed
3) Contraceptive Requirements 
Male subjects and female subjects of childbearing potential who engage in intercourse must 
agree to utilize protocol specified methods of contraception from the screening/enrollment visit 
throughout the study period; female subjects for 30 days and male subjects for 90 days following 
the last dose of study drug. Female study subjects who are not heterosexually active must 


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provide periodic confirmation of continued abstinence from heterosexual intercourse and regular 
pregnancy testing while taking IMP. The investigator will counsel subjects on the protocol 
specified method(s) for avoiding pregnancy in case the subject chooses to engage in heterosexual 
intercourse.
If tubal sterilization is via the Essure procedure, verification of tubal blockage by 
hysterosalpingogram (HSP) must be performed approximately 3 months after microinsertion. 
Prior to verification, Essure is not considered a reliable form of contraception and the 
contraception methods described below must be used. Female subjects who utilize hormonal 
contraceptives as one of their birth control methods must have used the same method for at least 
3 months before study dosing.
Female subjects of childbearing potential must have a negative serum pregnancy test at screening 
and a negative urine pregnancy test at baseline (Day 1) prior to receiving the first dose of study 
drug. Lactating females must discontinue nursing before IMP administration.
Appendix Table 1.
Protocol Specified Contraceptive Methods
Single Methods
Combination Methods
Intrauterine Devices (IUDs)

Copper T 380A IUD

LNg 20 IUD
Progesterone

Implant

Injection
Tubal Sterilization
Vasectomy with Documented 
Azoospermia 3 months After the 
Procedure
Estrogen and Progesterone plus Barrier

Combined oral contraceptives plus barrier

Transdermal patch plus barrier

Vaginal ring plus barrier
Two Barrier Methods

Diaphragm/spermicide plus condom
Acceptable barrier methods include diaphragm (with spermicide) and the male condom.
The investigator will counsel all subjects on the most effective method(s) for avoiding pregnancy 
during the study.
4) Additional Requirements for Male Subjects
Male subjects must agree to use condoms during heterosexual intercourse and avoid sperm 
donation while enrolled in the study and for at least 90 days after administration of the last dose 
of IMP.


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5) Procedures to be Followed in the Event of Pregnancy
Subjects should be instructed to notify the investigator if they become pregnant at any time 
during the study, or if they become pregnant within 30 days of last study drug dose. If a subject 
does become pregnant or suspects that she may have become pregnant while in this study, the 
investigator, in consultation with the medical monitor, will decide whether the benefit of 
continuation of the study outweighs any potential risk to the pregnant subject or her offspring.
The investigator should counsel the subject regarding the possible effects of study drug exposure 
on the fetus and the need to inform the study site of the outcome of the pregnancy.
Instructions for reporting pregnancy and pregnancy outcome are outlined in Section 7.7.2.1.


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Appendix 6.
ECOG status
Grade
ECOG
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 selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
{Oken 1982}

SAP_001.pdf: 
CONFIDENTIAL 
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STATISTICAL ANALYSIS PLAN 
Study Title: 
Open-label Study to Assess the Long-term Safety and 
Efficacy of Momelotinib in Subjects with Primary 
Myelofibrosis, Post-polycythemia Vera Myelofibrosis, Post-
essential Thrombocythemia Myelofibrosis, Polycythemia 
Vera or Essential Thrombocythemia
Name of Test Drug: 
Momelotinib (MMB) 
Study Number: 
GS-US-352-1154 
Protocol Version: 
Amendment 4 
Protocol Date: 
06 November 2017 
Analysis Type: 
Final Analysis  
Analysis Plan Version: 
Final 
Analysis Plan Date: 
26Apr2019 
Analysis Plan Author: 
Brian Pierce 
CONFIDENTIAL AND PROPRIETARY INFORMATION 
NCT02124746


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LIST OF ABBREVIATIONS ................................................................................................................................ 4 
1. 
INTRODUCTION ......................................................................................................................................... 5 
1.1. 
Study Objectives ............................................................................................................................... 5 
1.2. 
Study Design ..................................................................................................................................... 6 
1.3. 
Sample Size and Power ..................................................................................................................... 8 
2. 
TYPE OF PLANNED ANALYSIS ............................................................................................................... 9 
3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ..................................................................... 10 
3.1. 
Analysis Sets ................................................................................................................................... 10 
3.1.1. 
Full Analysis Set ........................................................................................................... 10 
3.1.2. 
Combined Safety Analysis Set ...................................................................................... 10 
3.1.3. 
Rollover Safety Analysis Set ......................................................................................... 11 
3.2. 
Subject Groups ................................................................................................................................ 11 
3.3. 
Strata and Covariates ...................................................................................................................... 11 
3.4. 
Examination of Subject Subsets ...................................................................................................... 11 
3.5. 
Multiple Comparisons ..................................................................................................................... 11 
3.6. 
Missing Data and Outliers ............................................................................................................... 11 
3.6.1. 
Missing Data ................................................................................................................. 11 
3.6.2. 
Outliers .......................................................................................................................... 12 
3.7. 
Data Handling Conventions and Transformations .......................................................................... 12 
3.8. 
Visit Windows ................................................................................................................................ 12 
3.8.1. 
Definition of Study Day ................................................................................................ 12 
3.8.2. 
Analysis Visit Windows ................................................................................................ 13 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis 
Visit Window ................................................................................................................ 13 
4. 
SUBJECT DISPOSITION ........................................................................................................................... 15 
4.1. 
Subject Enrollment .......................................................................................................................... 15 
4.2. 
Disposition of Subjects ................................................................................................................... 15 
4.3. 
Extent of Exposure .......................................................................................................................... 15 
4.3.1. 
Duration of Exposure to Study Drug ............................................................................. 15 
4.3.2. 
Adherence with Study Drug Regimen ........................................................................... 16 
4.3.2.1. 
Average Daily Dose ................................................................................. 16 
4.3.2.2. 
On-Treatment Adherence ......................................................................... 17 
4.4. 
Protocol Deviations ......................................................................................................................... 17 
5. 
BASELINE DATA ...................................................................................................................................... 18 
5.1. 
Demographics ................................................................................................................................. 18 
5.2. 
Other Baseline Characteristics ........................................................................................................ 18 
5.3. 
Medical History .............................................................................................................................. 18 
6. 
EFFICACY ANALYSES ............................................................................................................................ 19 
6.1. 
Primary Efficacy Endpoint .............................................................................................................. 19 
6.2. 
Secondary Efficacy Endpoints ........................................................................................................ 19 
6.2.1. 
Definition of Secondary Efficacy Endpoints ................................................................. 19 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints ................................................... 20 
6.2.2.1. 
Overall Survival ....................................................................................... 20 
6.2.2.2. 
Progression-free Survival ......................................................................... 21 
6.2.2.3. 
Leukemia-free Survival ........................................................................... 21 
6.2.2.4. 
Rate of RBC transfusion .......................................................................... 21 
6.2.2.5. 
Duration of Splenic/Anemia Responses................................................... 21 


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6.2.2.6. 
Transfusion Response Rate ...................................................................... 21 
6.2.2.7. 
Overall Response Rate per Physician Assessment ................................... 21 
6.3. 
Exploratory Efficacy Endpoints ...................................................................................................... 22 
6.3.1. 
Definition of Exploratory Efficacy Endpoints .............................................................. 22 
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints ................................................. 22 
7. 
SAFETY ANALYSES................................................................................................................................. 23 
7.1. 
Adverse Events and Deaths ............................................................................................................. 23 
7.1.1. 
Adverse Event Dictionary ............................................................................................. 23 
7.1.2. 
Adverse Event Severity ................................................................................................. 23 
7.1.3. 
Relationship of Adverse Events to Study Drug ............................................................. 23 
7.1.4. 
Serious Adverse Events ................................................................................................. 23 
7.1.5. 
Treatment-Emergent Adverse Events ........................................................................... 24 
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events ................................. 24 
7.1.5.2. 
Newly Onset Adverse Events .................................................................. 24 
7.1.5.3. 
Incomplete Dates ..................................................................................... 24 
7.1.6. 
Summaries of Adverse Events and Deaths .................................................................... 25 
7.1.6.1. 
Summaries of AE Incidence .................................................................... 25 
7.1.6.2. 
Summaries of Exposure-Adjusted AE Incidence ..................................... 27 
7.2. 
Laboratory Evaluations ................................................................................................................... 27 
7.2.1. 
Summaries of Numeric Laboratory Results .................................................................. 27 
7.2.2. 
Graded Laboratory Values ............................................................................................ 28 
7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities ...................................... 28 
7.2.2.2. 
Summaries of Laboratory Abnormalities ................................................. 28 
7.3. 
Body Weight and Vital Signs .......................................................................................................... 29 
7.4. 
Prior and Concomitant Medications ................................................................................................ 29 
7.4.1. 
Prior Medications .......................................................................................................... 29 
7.4.2. 
Concomitant Medications ............................................................................................. 29 
7.5. 
Electrocardiogram Results .............................................................................................................. 30 
7.6. 
Changes From Protocol-Specified Safety Analyses ........................................................................ 30 
8. 
REFERENCES ............................................................................................................................................ 31 
9. 
SOFTWARE ................................................................................................................................................ 32 
10. SAP REVISION .......................................................................................................................................... 33 
11. APPENDICES ............................................................................................................................................. 34 
Appendix 1.  
Leukemic Transformation MST AEs ............................................................................ 35 
Appendix 2. 
Peripheral Neuropathy SMQ AEs ................................................................................. 37 
Appendix 3. 
Cataract MST AEs ........................................................................................................ 40 
Appendix 4. 
International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT) consensus criteria for treatment response in myelofibrosis with myeloid 
metaplasia 41 
 


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LIST OF ABBREVIATIONS 
 
BMI 
Body mass index 
BPM 
Beats per minute 
CDER 
Center for Drug Evaluation and Research 
CHMP 
Committee for Medicinal Products for Human Use 
CPMP 
Committee for Proprietary Medicinal Products 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
DAVG 
Difference between time-weighted average post-baseline and baseline 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
FR 
Federal Register 
HLT 
High level term 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ITT 
Intent to treat 
IVRS/IWRS 
Interactive voice/web response system 
LLT 
Lower level term 
MedDRA 
Medical dictionary for regulatory activities 
PT 
Preferred term 
SAP 
Statistical analysis plan 
SOC 
System organ class 
TFLs 
Tables, figures, and listings 
WHO 
World Health Organization 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical analysis methods and data 
presentations to be used in tables, figures, and listings (TFLs) in the clinical study report 
(CSR) for Study GS-US-352-1154 (also referred to Rollover Study in this document). This 
SAP is based on the study protocol amendment dated 06 November 2017 and the electronic 
case report form (eCRF). Any changes made after the finalization of the SAP will be 
documented in the CSR. 
As subjects in GS-US-352-1154 study were rolled-over from different previous studies, this 
statistical analysis plan (SAP) describes the statistical analysis for data collected in both the 
current and previous studies: 
Cohort 1: CCL09101, CCL09101E, GS-US-352-1154 
Cohort 2: YM387-II-02, GS-US-352-1154  
Cohort 3: GS-US-354-0101, GS-US-352-1154  
Cohort 4: GS-US-352-1672, GS-US-352-1154 
This SAP also describes analyses for GS-US-352-1154 study only. 
 
1.1. Study Objectives 
The primary objective of this study is to determine the long-term safety and tolerability of 
MMB in 4 cohorts of subjects:  
 
 Cohort 1: Subjects who are currently receiving MMB capsules in the CCL09101E 
study for PMF and post-PV/ET MF without documented progressive disease. 
 Cohort 2: Subjects who are currently receiving MMB capsules in the YM387-II-02 
study for PMF and post-PV/ETMF without documented progressive disease. 
 Cohort 3 was closed and all enrolled subjects were discontinued from this study due 
to limited efficacy of MMB in the treatment of PV and ET on GS-US-354-0101. 
 Cohort 4: Subjects who are currently receiving MMB tablets in the GS-US-352-1672 
study for PMF and post-PV/ET MF, who completed 24 weeks of treatment and have 
responded to treatment, per investigators discretion.  
 
The secondary objective of this study is to determine the long-term efficacy of MMB in these 
4 cohorts of subjects. 


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1.2. Study Design 
This is an open-label study for subjects with MF, post-PV/ET MF, PV or ET, who have 
tolerated MMB and their corresponding disease has not progressed per 2006 IWG-MRT 
criteria for MF or 2013 IWG-ELN and IWG-MRT criteria for PV/ET while enrolled in the 
parent study. After screening, subjects in Cohorts 1 and 2 will discontinue the MMB capsule 
and initiate the tablet form of MMB. Subjects in Cohort 4 will discontinue MMB tablets from 
the parent study and initiate MMB tablets in this study at the same dose they were receiving 
in the parent study. Subjects in Cohort 3 enrolled to this study under the original protocol and 
protocol amendments 1 and 2, where they discontinued MMB tablets from the parent study 
and initiated MMB tablets in this study. On 20 March 2015 parent study GS-US-354-0101 
was terminated due to limited efficacy. All subjects in Cohort 3 were discontinued from GS-
US-352-1154.  
MMB dose adjustments may be made in this study. Subjects may participate in this study for 
approximately 4 years or until study termination. 
Schedule of Assessments 
Procedures performed at a regular follow-up visit on subject‟s previous MMB study may be 
used to fulfill screening criteria and to establish any new medical history on this study. At 
Day 1, the starting dose of MMB tablets will be determined per the criteria in protocol 
Section 5.3. All subjects will self-administer MMB tablets. Subjects who have not undergone 
a bone marrow aspirate/biopsy within 12 months prior to Day 1 of this study will undergo a 
bone marrow biopsy. The bone marrow aspirate/biopsy will be repeated every 24 months 
and/or at the time of study withdrawal. Study visits consisting of clinical, laboratory, and 
disease assessments will be completed every 3 months. Cohorts 1 and 2 will have 2 
additional visits at Months 1 and 2. All study required laboratory assessments will be 
performed by Central laboratory and ECG assessments will be performed and interpreted by 
local departments. Following treatment, subjects will be followed for safety and disease 
status for a period of 30 days. Subjects who continue treatment with MMB in the extended 
access program following the end of this study are not required to complete the 30-day post-
treatment follow-up assessments. 


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Randomization Study is Open-Label and set in approximately 35 centers in North 
America, Europe and Australia.  
Study 
Duration 
Subjects will continue on MMB for a duration of approximately 4 years 
from the start of this study or until study termination. 
 
 


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1.3. Sample Size and Power 
Planned Sample Size 
Based on the number of previously enrolled subjects 
in Cohorts 1,2, and 3 including the number of 
expected subjects in Cohort 4, up to 105 subjects may 
be enrolled: 
Cohort 1: 30 subjects enrolled 
Cohort 2: 22 subjects enrolled 
Cohort 3: 13 subjects enrolled 
Cohort 4: 40 subjects expected 
Power Statement 
No formal hypothesis testing is planned for this 
study.  
 


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2. 
TYPE OF PLANNED ANALYSIS 
2.1. 
Interim Analyses  
An interim analysis was conducted using data collected by 23 June 2016 to support an 
intended MMB marketing application. Cohorts 1 and 2 were included in the interim analysis. 
Due to the limited efficacy, the parent study GS-US-354-0101 was terminated on 20 March 
2015. All subjects who enrolled to GS US 352-1154 study from GS US 354-0101 (Cohort 3) 
were discontinued. Due to the small number of subjects and the limited exposure to MMB, 
subjects in Cohort 3 were not included in the interim analysis. No subject enrolled in Cohort 
4 by data cutoff date for the interim analysis. 
2.2. 
Final Analysis 
After all subjects have either discontinued or completed the study, outstanding data queries 
have been resolved or adjudicated as unresolvable, and the data have been cleaned and 
finalized, the final analysis of the data will be performed. Final analysis will include all 
subjects with MF who enrolled to GS-US-352-1154 study from CCL09101, CCL09101E 
(Cohort 1), YM387-II-02 (Cohort 2), and GS-US-352-1672 (Cohort 4).  
 


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3. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Analysis results will be presented using descriptive statistics. For categorical variables, the 
number and percentage of subjects in each category will be presented; for continuous 
variables, the number of subjects (n), mean, standard deviation (StD) or standard error (SE), 
median, first quartile (Q1), third quartile (Q3), minimum, and maximum will be presented. 
For efficacy analysis and other analyses based on combined data from parent studies and 
GS-US-352-1154, the analysis results will be presented by cohort. Analyses based on 
GS-US-352-1154 study data only are conducted by the initial dose level received in this 
study regardless of any dose modification occurring during the study. 
By-subject listings will be presented for all subjects in the Rollover Safety Analysis Set and 
sorted by subject ID number, visit date, and time (if applicable). Data collected on log forms, 
such as AEs, will be presented in chronological order within the subject. The dose level to 
which subjects were initially assigned will be used in the listings. Age, sex at birth, race, and 
ethnicity will be included in the listings, as space permits.  
Only subjects with MF (Cohort 1, 2, and 4) will be included in the safety and efficacy 
analysis for this study. Cohort 3 subjects were discontinued from GS-US-352-1154 study due 
to limited efficacy in the parent study. All data from Cohort 3 will be listed separately.   
 
3.1. Analysis Sets 
Analysis sets define the subjects to be included in an analysis. Analysis sets and their 
definitions are provided in this section. The analysis set will be identified and included as a 
subtitle of each table, figure, and listing. 
For each analysis set, the number and percentage of subjects eligible for inclusion, as well as 
the number and percentage of subjects who were excluded, will be summarized by dose 
level. 
3.1.1. 
Full Analysis Set 
The Full Analysis Set includes all enrolled subjects in studies CCL09101, YM387-II-02, and 
GS US 352 1672 who received at least one dose of MMB and had at least one post-baseline 
efficacy assessment. The FAS will be used for all Secondary and Exploratory Efficacy 
assessments. 
3.1.2. 
Combined Safety Analysis Set 
The Combined Safety Analysis Set includes all enrolled subjects in studies CCL09101, 
YM387-II-02, and GS US 352 1672 who received at least one dose of MMB. Select safety 
assessments will be analyzed using the Combined Safety Analysis Set. 


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3.1.3. 
Rollover Safety Analysis Set 
The Rollover Safety Analysis Set includes all subjects who are enrolled in GS-US-352-1154 
study excluding subjects enrolled in Cohort 3. Only subjects with MF are included in the 
Rollover Safety Analysis Set which is equivalent to Full Analysis Set (FAS) defined in the 
protocol as all subjects who are enrolled to the study in Cohorts 1, 2, and 4. This analysis set 
will be used for demographic and baseline characteristics, study treatment administration and 
compliance, and safety analyses. 
3.2. Subject Groups 
For analyses based on the combined data from parent studies and GS-US-352-1154, subjects 
will be grouped according to the cohort and median average daily dose defined in 
Section 4.3.2.1. For analyses based on the GS-US-352-1154 data only, subjects will be 
grouped according to the initial dose level assigned in this study. 
 
3.3. Strata and Covariates 
This study does not use a stratified randomization schedule when enrolling subjects. No 
covariates will be included in efficacy and safety analyses. 
3.4. Examination of Subject Subsets 
There are no prespecified subject subgroupings for efficacy and safety analyses. 
3.5. Multiple Comparisons 
Adjustments for multiplicity will not be made, because no formal statistical testing will be 
performed in this study. 
3.6. Missing Data and Outliers 
3.6.1. 
Missing Data 
A missing datum for a given study visit window may be due to: 
1. a visit occurring in the window but data were not collected or were unusable, 
or 
2. a visit not occurring in the window, or 
3. a subject permanently discontinuing from study before reaching the window. 
In general, missing data will not be imputed unless methods for handling missing data are 
specified. Exceptions are presented in Sections 4.3.1, 4.3.2 and 7.1.5.2. 


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The handling of missing or incomplete dates for adverse event onset date is described in 
Section 7.1.5.3. 
3.6.2. 
Outliers 
Outliers will be identified during the data management and data analysis process, but no 
sensitivity analyses will be conducted. All data will be included in the data analysis. 
3.7. Data Handling Conventions and Transformations 
In general, age (in years) on the first dosing date of study drug will be used for analyses and 
presentation in listings. The baseline value used in efficacy analysis or other analyses based 
on combined data will be the baseline defined in the parent study. For analyses based on GS-
US-352-1154 study data only, the baseline value will be the baseline defined in the study.  
The following censoring convention will be applied for time-to-event endpoints: 
• 
Duration of response: Data from subjects who remain a responder will be censored at 
the date of last visit. 
• 
Progression-free survival: Data from surviving, non-progressing subjects will be 
censored at the last adequate response assessment date prior to the initiation of myelofibrosis 
treatment other than MMB or the last time that lack of definitive progression was objectively 
documented. 
 
• 
Overall survival: Data from subjects who remained alive while on study will be 
censored at the date of last contact. 
By-subject listings will be sorted by subject ID number, visit date, and time (if applicable). 
Data collected on log forms, such as adverse events (AEs), will be presented in chronological 
order within subject. The dose level to which subjects were originally assigned will be used 
in the listings. 
3.8. Visit Windows 
3.8.1. 
Definition of Study Day 
Study day will be calculated from the first dosing date of study drug and derived as follows: 
 For post-dose study days: Assessment Date – First Dosing Date + 1 
 For days prior to the first dose: Assessment Date – First Dosing Date  
Therefore, for the analysis of the combined data, study day 1 is the day of first dose of study 
drug in parent study. For the analysis of GS-US-352-1154 study only, study day 1 is the day 
of first dose of study drug in GS-US-352-1154 study. 


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3.8.2. 
Analysis Visit Windows 
The nominal visit as recorded on the CRF will be used when data are summarized by visit. 
Any data relating to unscheduled visits will not be assigned to a particular visit or time point. 
However, the following exceptions will be made: 
 An unscheduled visit prior to the first dosing of study drug in parent study and 
GS-US-352-1154 study may be included in the calculation of the baseline value for 
parent study and GS-US-352-1154 study, respectively. 
 Unscheduled visits after the first dosing of study drug will be included in determining the 
maximum postbaseline toxicity grade. 
 For subjects who prematurely discontinued from the study, early termination (ET) data 
will be summarized as a separate visit, labeled as “Early Termination Visit” 
 For subjects who prematurely discontinued the study/treatment, end of study or early 
study drug discontinuation (ESDD) visit data will be included to derive last visit in study 
and best overall response. 
 Data collected on a follow-up visit will be summarized as a separate visit and labeled 
“Follow-up Visit.” 
 Data obtained after the follow-up visit or last dose date plus 30 days (whichever is later) 
will be excluded from the summaries but will be included in the listings. 
3.8.3. 
Selection of Data in the Event of Multiple Records in an Analysis Visit 
Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value, whereas 
a time-to-event analysis would not require 1 value per analysis window. 
 
If multiple valid, non-missing, continuous measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed: 
 In general, the baseline values for combined data and GS-US-352-1154 study data will be 
the last non-missing value on or prior to the first dosing date or on first dosing date and 
prior to dosing of study drug in parent study and GS-US-352-1154 study, respectively 
unless specified differently. If multiple measurements occur on the same day, the last 
non-missing value prior to first dosing date of study drug will be considered as the 
baseline value. If these multiple measurements occur at the same time or the time is not 
available, the average of these measurements (for continuous data) will be considered the 
baseline value. 


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 For postbaseline values: 
 The record closest to the nominal day for that visit will be selected. 
 If there are 2 records that are equidistant from the nominal day, the later record will 
be selected. 
 If there is more than 1 record on the selected day, the average will be taken, unless 
otherwise specified. 
If multiple valid, non-missing, categorical measurements exist in an analysis window, 
records will be chosen based on the following rules if a single value is needed: 
 The last available record on or prior to first dosing date of study drug in parent study and 
GS-US-352-1154 study will be selected as baseline values for combined data and 
GS-US-352-1154 study data, respectively. If there are multiple records with the same 
time or no time recorded on the same day, the value with the lowest severity will be 
selected (eg, normal will be selected over abnormal for safety electrocardiogram [ECG] 
findings). 
 For postbaseline visits, if there are multiple records with the same time or no time 
recorded on the same day, the value with the worst severity within the window will be 
selected (eg, abnormal will be selected over normal for safety ECG findings). 
 


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4. 
SUBJECT DISPOSITION 
4.1. Subject Enrollment 
A summary of subject enrollment will be provided by dose level per investigator within a 
country and overall. The summary will present the number and percentage of subjects 
enrolled. For each column, the denominator for the percentage calculation will be the total 
number of subjects analyzed for that column. Subjects will be considered enrolled once 
enrolled in IXRS. 
4.2. Disposition of Subjects 
A summary of subject disposition will be provided by dose level and cohort. This summary 
will present the number of subjects enrolled and the number of subjects in each of the 
categories listed below: 
 Rollover Safety Analysis Set 
 Completed Month 48 or later of study treatment 
 Discontinued study drug with reasons for discontinuation of study drug 
 Completed Month 48 or later 
 Discontinued the study with reasons for discontinuation of study 
Subjects who completed Month 48 visit or later will be considered study/drug completers. A 
by-subject listing of study/drug completion information including the reason for premature 
study withdrawal/study drug termination will be provided by subject identification (ID) 
number in ascending order to support the above summary tables. 
The denominator for the percentages of subjects in each category will be the number of 
subjects in the Rollover Safety analysis set.  
4.3. Extent of Exposure 
Extent of exposure to study drug during GS-US-352-1154 study will be examined by 
assessing the total duration of exposure to study drug and the level of adherence to the study 
drug specified in the protocol. 
4.3.1. 
Duration of Exposure to Study Drug 
Total duration of exposure to study drug in GS-US-352-1154 study will be defined as last 
dosing date minus first dosing date in this study plus 1, regardless of any temporary 


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interruptions in study drug administration, and will be expressed in months using up to 1 
decimal place (eg, 4.5 months). If the last study drug dosing date is missing: 
 If the study drug is permanently withdrawn, the latest date among the study drug end 
date will be used. 
 If the study drug completion status is unknown the date of death will be used for 
analysis. 
 If the stop date is partial then the stop date will be imputed with the earliest of the last 
day of the month (if only day is missing) or the last month of the year (if day and 
month are missing), or the death date if applicable. 
The total duration of exposure to study drug in GS-US-352-1154 study will be summarized 
using descriptive statistics by dose level for the Rollover Safety Analysis Set. 
The total duration of exposure to study drug during parent and GS-US-352-1154 studies will 
also be summarized using descriptive statistics, which is defined as last dosing date in this 
study minus first dosing date in parent study plus 1, regardless of any temporary interruptions 
in study drug administration. Summaries will be presented by cohort and median average 
daily dose for the Rollover Safety Analysis Set.   
The number and percentage of subjects who had dose increase and/or dose reduction will be 
provided in terms of frequency count (n) and percentage (%). Reasons for dose 
increase/reduction will be summarized. 
4.3.2. 
Adherence with Study Drug Regimen 
The total number of tablets administered will be summarized using descriptive statistics (n, 
mean, StD, median, min-max) by dose level for GS-US-352-1154 study. The total number of 
tablets administered during parent and GS-US-352-1154 studies will also be summarized 
using descriptive statistics (n, mean, StD, median, min-max) by cohort and median average 
daily dose.  
The presumed total number of tablets administered to a subject will be determined by the 
data collected on the drug accountability CRF using the following formula: 
                                    
 (∑                       )  (∑                      ) 
If a bottle is not returned or returned with unknown number of tablets, it is assumed that 
subject did not consume any tablet from this bottle. 
4.3.2.1. 
Average Daily Dose 
The average daily dose in mg will be calculated using the following formula: 


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

Daily Dose in mg
Average Daily Dose (mg)
Total Number of Days on Study Drug


 
 
where Total Number of Days on Study Drug = Last Dosing Date – First Dosing Date + 1 
 
For each cohort, the median value will be calculated for average daily dose. Summaries of 
combined data from parent studies and GS-US-352-1154 will be grouped by cohort and 
median average daily dose (<=median value, > median value) and Total. 
 
4.3.2.2. 
On-Treatment Adherence 
The level of on-treatment adherence to the study drug regimen will be determined by the 
total amount of study drug administered relative to the total amount of study drug expected to 
be administered during a subject‟s actual on-treatment period based on the study drug 
regimen. Investigator-prescribed interruption, reductions and escalations as specified in the 
protocol will be taken into account. 
The level of on-treatment adherence will be expressed as a percentage using the following 
formula:
Total Amount of Study Drug Administered
On-Treatment Adherence (%) = 
 x 100
Study Drug Expected to be Administered on Treatment






 
Descriptive statistics for the level of on-treatment adherence, total number of tablets received 
and average daily dose will be provided by dose level for the Rollover Safety Analysis Set.  
 
A by-subject listing of study drug administration will be provided by subject ID number (in 
ascending order) and visit (in chronological order). 
 
4.4. Protocol Deviations 
Protocol deviations occurring after subjects entered the study are documented during routine 
monitoring. The number and percentage of subjects with important protocol deviations by 
deviation reason (eg, non-adherence to study drug, violation of select inclusion/exclusion 
criteria) will be summarized by dose level for the Rollover Safety Analysis Set. A by-subject 
listing will be provided for those subjects with important protocol deviation. 


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5. 
BASELINE DATA 
5.1. 
Demographics 
Subject demographic variables (ie, age, sex, race, and ethnicity) will be summarized by dose 
level and overall using descriptive statistics for age, and using number and percentage of 
subjects for sex, race, and ethnicity. Age and sex are collected in GS-US-352-1154 study and 
other demographic data were collected in the parent study. The summary of demographic 
data will be provided for the Rollover Safety Analysis Set. 
A by-subject demographic listing will be provided by subject ID number in ascending order. 
5.2. 
Other Baseline Characteristics 
Other baseline characteristics collected in the parent study include body weight (in kg), 
height (in cm), body mass index (BMI; in kg/m2), and Eastern Cooperative Oncology Group 
(ECOG) performance status, transfusion dependence status (Yes, No) at baseline and prior 
treatment for PV/ET/PMF. These baseline characteristics will be summarized by dose level 
and overall using descriptive statistics for continuous variables and using number and 
percentage of subjects for categorical variables. The summary of baseline characteristics will 
be provided for the Rollover Safety Analysis Set.  
A by-subject listing of other baseline characteristics will be provided by subject ID number 
in ascending order. 
5.3. 
Medical History 
Medical history from the parent study will not be reported in the electronic case report form 
(eCRFs) thus will not be listed for this study. Any ongoing AE from the parent study at the 
time of enrollment in this study will be considered medical history on this study and will be 
listed. 
 


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6. 
EFFICACY ANALYSES 
6.1. 
Primary Efficacy Endpoint 
The primary objective of this study is safety.  There is no primary efficacy endpoint. 
6.2. Secondary Efficacy Endpoints 
6.2.1. 
Definition of Secondary Efficacy Endpoints 
The secondary efficacy endpoints are all efficacy-related endpoints. All analyses/summaries 
of efficacy endpoints will be performed excluding Cohort 3 subjects.  The secondary efficacy 
endpoints are: 
 Overall survival (OS) - defined as the interval from first dosing date of study drug in 
parent study to death from any cause. Subjects who are lost to follow-up or survived 
until the end of the study will be censored at the last date that they were known to be 
alive.  
 Progression-free survival (PFS) - defined as the interval from the first dose of MMB 
on the previous study until the first documentation of definitive progressive disease as 
defined in Appendix 4 or death due to any cause, ie., PFS(months) = (date of 
censoring or date of earliest of Progressive Disease or death – first dose date + 1) / 
30.125. Subjects who are free of Progression will be censored at the last assessment 
date. 
 Leukemia free survival: defined as the interval from the first dose of MMB on the 
parent study until the first documented leukemic transformation defined by the 
occurrence of an AE listed in Appendix 1 or death from any cause, ie., LFS(months) 
= (date of censoring or date of earliest of leukemic transformation or death – first 
dose date + 1) / 30.125. Subjects who are free of leukemia transformation will be 
censored at the last assessment date. Leukemic transformation was documented in the 
AE eCRF page.  
 Rate of RBC transfusion: defined as the average number of RBC units excluding 
cases due to overt bleeding per subject month from the first dose of MMB on the 
parent study. 
 Duration of splenic response: defined as the interval from the first onset of splenic 
response (in the parent study or this study) to the earliest date of loss of splenic 
response. Splenic response is defined according to the 2006 IWG-MRT criteria as a 
reduction of 50% or more in palpable splenomegaly of a spleen that was ≥ 10 cm 
below the LCM at baseline or a spleen that was palpable at > 5 cm and < 10 cm 
below the LCM at baseline becoming not palpable for at least 56 days.   


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 Duration of anemia response: defined as the interval from the first onset date of 
anemia response (in the parent study or GS-US-352-1154 study) to the earliest date of 
loss anemia response. Anemia evaluable subjects were defined as subjects who were 
transfusion dependent at baseline or who were not transfusion dependent (defined for 
Studies CCL09101 and GS-US-352-1672) or were transfusion independent (defined 
for Study YM387-II-02) but with a hemoglobin level < 10 g/dL at baseline. 
Transfusion dependent was defined as receiving at least 2 units of RBCs within 30 
days prior to Cycle 1 Day 1. Anemia response was a composite endpoint of 
transfusion independence response and hemoglobin response. Transfusion responders 
were defined as subjects who had a ≥ 12-week transfusion independence response and 
who were transfusion dependent at baseline. Hemoglobin responders were defined as 
having ≥ 2 g/dL increase from baseline for ≥ 12 weeks and who were not transfusion 
dependent/transfusion independent at baseline. Loss of anemia response was defined 
as having > 0 units of RBC transfusion after achieving a transfusion independence 
response or hemoglobin response. If a subject had a transfusion date but the number 
of units received was not recorded, the subject was assumed to have loss of response. 
 
 Transfusion Response Rate is defined as becoming not transfusion dependent for ≥ 12 
weeks at any time from the first dose of MMB on the previous study until end of this 
study. 
 
 Overall Response Rate: Treatment response is assessed using the 2006 IWG-MRT 
criteria for treatment response in myelofibrosis. Best overall response is determined 
in the following order: complete remission, partial remission, clinical improvement, 
stable disease, or progressive disease. Overall response rate is defined as the 
proportion of subjects who achieve complete remission or partial remission. 
6.2.2. 
Analysis Methods for Secondary Efficacy Endpoints 
Analysis/summaries for secondary efficacy endpoints will be performed using the Full 
Analysis Set by cohort, unless otherwise specified. 
6.2.2.1. 
Overall Survival  
Incomplete death dates will be imputed by the following algorithm: 
 If day is missing but the month and year are available, then the imputed day will be 
the midpoint of the month or the last assessment date + 1, whichever is later. 
 If day and month are missing but year is available, then the imputed day and month 
will be 01Jan or the last day of the latest month that the subject was known to be alive 
if they have the same year, whichever is later. 
OS will be analyzed using the Kaplan-Meier method. Surviving subjects will be censored at 
the last time that the subject is known to be alive on study (including all the in-person visit 


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dates captured in the datasets, ie, BM biopsy, central lab collection, CT scan, physical exam, 
drug administration in clinic, concomitant medication and therapy start date, ECG, safety 
follow up, hospitalization,  pregnancy testing). The number of subjects who died, censored, 
Median with 90% CI, Q1, Q3, and Kaplan-Meier survival curves will be presented. 
6.2.2.2. 
Progression-free Survival 
Progression-free survival (PFS) will be analyzed using the Kaplan-Meier method. The 
number of subjects who died and/or having progressive disease, censored, Median with 90% 
CI, Q1, Q3, and Kaplan-Meier survival curves will be presented. 
6.2.2.3. 
Leukemia-free Survival 
Leukemia-free survival (LFS) will be analyzed using the Kaplan-Meier method. The number 
of subjects who died and/or having leukemia, censored, Median with 90% CI, Q1, Q3, and 
Kaplan-Meier survival curves will be presented. 
6.2.2.4. 
Rate of RBC transfusion 
Rate of RBC transfusion will be calculated as the total number of RBC units across all 
subjects divided by the total exposure time among these subjects in a dose level. Descriptive 
statistic of rate of RBC transfusion will be presented. Transfusions due to clinically overt 
bleeding will be excluded from this analysis. 
6.2.2.5. 
Duration of Splenic/Anemia Responses 
Duration of splenic response and anemia response will be summarized by descriptive 
statistics. They will be also analyzed using Kaplan-Meier method. The number of subjects 
who had event, censored, Median with 90% CI, Q1, Q3, and Kaplan-Meier survival curves 
will be presented. Data from responders who keep the response will be censored at the last 
assessment date. Anemia response rate, hemoglobin response rate, transfusion independence 
response rate, and splenic response rate are presented. 
6.2.2.6. 
Transfusion Response Rate 
Transfusion  response rate will be presented by cohort and the numbers and percentages of 
subjects who have not reached transfusion dependence for ≥ 12 weeks. 
6.2.2.7. 
Overall Response Rate per Physician Assessment  
The overall response rate will be presented by cohort and the numbers and percentages of 
subjects who have best overall response as CR, PR, CI, SD, and PD will also be provided. 


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6.3. Exploratory Efficacy Endpoints 
6.3.1. 
Definition of Exploratory Efficacy Endpoints 
Exploratory endpoints are: 
 Change in hemoglobin level over time 
 Patient global impression of change (PGIC)  
6.3.2. 
Analysis Methods for Exploratory Efficacy Endpoints 
The change in hemoglobin level over time from baseline (parent study) will be summarized 
using descriptive statistics along with number of subjects with at least 1g, 1.5g, and 2g 
change in hemoglobin over the course of the study.  
Summary of Patient global impression of change (PGIC) comparing responses in consecutive 
visits  will be done on all post-dose visits. 


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7. 
SAFETY ANALYSES 
7.1. 
Adverse Events and Deaths 
7.1.1. 
Adverse Event Dictionary 
Clinical and laboratory adverse events (AEs) will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.0. System organ class (SOC), high-level group 
term (HLGT), high-level term (HLT), preferred term (PT), and lower-level term (LLT) will 
be provided in the AE dataset. 
7.1.2. 
Adverse Event Severity 
Adverse events except for anemia are graded by the investigator according to Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03. Anemia (hemoglobin) is 
graded using CTCAE Version 3.0. If a CTCAE criterion does not exist, the investigator 
should use the grade or adjectives: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), 
Grade 4 (lift-threatening), or Grade 5 (fatal) to describe the maximum intensity of the AE. 
The severity grade of events for which the investigator did not record severity will be 
categorized as “missing” for tabular summaries and data listings. The missing category will 
be listed last in summary presentation. 
7.1.3. 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related” on the AE CRF to the 
question of “Related to Study Treatment.” Relatedness will always default to the 
investigator‟s choice, not that of the medical monitor. For CCL09101, CCL09101E, 
YM0387-II-02 studies, relationship recorded as „Possibly‟, „Probably‟ and „Definitely‟ will 
be deemed as related, „Not Related‟ and „Unlikely‟ as unrelated. Events for which the 
investigator did not record relationship to study drug will be considered related to study drug 
for summary purposes. However, by-subject data listings will show the relationship as 
missing. 
7.1.4. 
Serious Adverse Events 
Serious adverse events (SAEs) will be identified and captured as SAEs if the AEs met the 
definitions of SAEs that were specified in the study protocol. SAEs captured and stored in 
the clinical database will be reconciled with the SAE database from the Gilead 
Pharmacovigilance & Epidemiology Department, previously Drug Safety and Public Health 
Department, before data finalization. 
 


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7.1.5. 
Treatment-Emergent Adverse Events  
7.1.5.1. 
Definition of Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as 1 or both of the following: 
 Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug 
 Any AEs leading to premature discontinuation of study drug. 
7.1.5.2. 
Newly Onset Adverse Events 
 Newly onset adverse events are defined as any with an onset date on or after the start 
date of study drug in the GS-US-352-1154 study and no later than 30 days after 
permanent discontinuation of study drug. 
 Any AEs leading to premature discontinuation of study drug in the GS-US-352-1154 
study. 
7.1.5.3. 
Incomplete Dates 
When the AE onset date is incomplete and needs to be imputed, the following algorithm will 
be followed: 
 If the day is missing but the month and year are available, then the imputed day will 
be the first day of the month or the first dosing date if they have the same month and 
year, whichever is later. 
 If the day and month are missing but year is available, then the imputed day and 
month will be 01Jan or the first dosing date if they have the same year, whichever is 
later. 
Incomplete AE stop date will be imputed as follows: 
 If day and month are missing but year is available, then the imputed day and month 
will be 31Dec or 30 days after the last dose of study drug if they have the same year, 
whichever is earlier.   
 If day is missing but the month and year are available, then the imputed day will be 
the last day of the month or 30 days after the last dose of study drug if they have the 
same month and year, whichever is earlier. 
An AE with completely missing onset and stop dates, or with the onset date missing and a 
stop date later than the first dosing date of study drug, will be considered to be treatment 
emergent. 


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7.1.6. 
Summaries of Adverse Events and Deaths 
Treatment-emergent AEs will be summarized based on the Rollover Safety Analysis Set. 
7.1.6.1. 
Summaries of AE Incidence  
The number and percentage of subjects who experienced at least 1 TEAE will be provided 
and summarized by SOC, HLT, PT, and dose level. For other AEs described below, 
summaries will be provided by SOC, PT, and dose level: 
 TEAEs 
 TEAEs of Grade 3 or higher 
 Drug-related TEAEs 
 Drug-related TEAEs of Grade 3 or higher 
 TE SAEs 
 TE drug-related SAEs 
 TEAEs leading to discontinuation of study drug 
 TEAEs leading to death 
 TEAEs leading to change in dose or temporary interruption of study drug 
 AE of interest for 
o  Peripheral Neuropathy Standardized MedDRA Queries (SMQ) (narrow and 
broad terms; defined as AEs listed in Appendix 2. 
Peripheral Neuropathy 
SMQ AEs) 
o Peripheral Neuropathy SMQ (narrow and broad terms) leading to study drug 
discontinuation 
o Cataract MedDRA Search Terms (MST) (defined as AEs listed in 
Appendix 3. 
Cataract MST AEs) 
 Newly Onset AE for 
o Peripheral Neuropathy Standardized MedDRA Queries (SMQ) (narrow and 
broad terms; defined as AEs listed in Appendix 2. 
Peripheral Neuropathy 
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o Cataract MedDRA Search Terms (MST) (defined as AEs listed in 
Appendix 3. 
Cataract MST AEs) 
A brief, high-level summary of AEs described above will be provided by dose level and by 
the number and percentage of subjects who experienced the above AEs. The number and 
percentage of subjects who experienced at least 1 TEAE will be summarized by SOC, PT, 
maximum severity, and dose level. 
Multiple events will be counted only once per subject in each summary. Adverse events will 
be summarized and listed first in alphabetic order of SOC and HLT within each SOC (if 
applicable) and then by PT in descending order of total frequency within each SOC for the 
overall column. For summaries by severity grade, the most severe grade will be used for 
those AEs that occurred more than once in a given subject during the study. 
For TEAE during parent and GS-US-352-1154 studies described below, summaries will be 
provided by cohort and median average daily dose: 
 Overall summary of AEs 
 TEAEs by SOC, PT 
 TE SAEs by SOC, PT 
 TEAEs by SOC, PT, and maximum severity 
In addition, data listings will be provided for the following: 
 All AEs, indicating whether the event is treatment emergent 
 AEs with Severity of Grade 3 or Higher 
 SAEs 
 Deaths 
 AEs leading to death 
 AEs leading to discontinuation of study drug 
 AEs leading to change in dose or temporary interruption of study drug 
 AE of interest for  
 Peripheral Neuropathy SMQ (narrow and broad terms) 


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 Peripheral Neuropathy SMQ (narrow and broad terms) leading to study drug 
discontinuation  
 Cataract MST 
7.1.6.2. 
Summaries of Exposure-Adjusted AE Incidence  
Exposure-adjusted TEAEs during parent and GS-US-352-1154 studies will be provided. The 
number of subjects with a TEAE, total person years, incidence rate per person year and 95% 
confidence intervals will be presented by PT, cohort and median average daily dose. Total 
person year (exposure at risk) is the sum of (AE onset date minus first dosing date in parent 
study plus 1) divided by 365.25. Incidence rate per person year is calculated as the number of 
subjects with a TEAE divided by total person year. The following summaries will be 
provided: 
 TEAEs by PT 
 TEAEs of Grade 3 or higher by PT 
 TE SAEs by PT 
7.2. 
Laboratory Evaluations 
Laboratory data collected during the study will be analyzed and summarized using both 
quantitative and qualitative methods. Summaries of laboratory data will be based on 
observed data and will be reported using SI units. The focus of laboratory data 
summarization will be on treatment-emergent laboratory abnormalities for the Rollover 
Safety Analysis Set and Combined Safety Analysis Set. 
A by-subject listing for laboratory test results will be provided by subject ID number and 
time point in chronological order for hematology, serum chemistry, and urinalysis separately. 
Values falling outside of the relevant reference range and/or having a CTCAE version 4.03 
severity grade of 1 or higher will be flagged in the data listings, as appropriate. 


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7.2.1. 
Summaries of Numeric Laboratory Results 
Descriptive statistics will be provided by dose level for Hgb, Platelets, ANC, Uric Acid, 
Creatinine and Thiamine as follows: 
 Baseline values  
 Values at each postbaseline visit 
 Postbaseline maximum value 
 Postbaseline minimum value 
 Change and percentage change from baseline at each postbaseline visit 
 Change and percentage change from baseline to postbaseline maximum value 
 Change and percentage change from baseline to postbaseline minimum value 
The baseline laboratory values for combined data and GS-US-352-1154 study data will be 
defined as the last measurement obtained on or prior to the date/time of first dose of study 
drug in parent study and this study, respectively. Change from baseline to a postbaseline visit 
will be defined as the visit value minus the baseline value. The mean, median, Q1, Q3, 
minimum, and maximum values will be displayed to the reported number of digits; StD 
values will be displayed to the reported number of digits plus 1. 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3. 
7.2.2. 
Graded Laboratory Values 
CTCAE Version 4.03 will be used to assign toxicity grades (0 to 4) to laboratory results for 
analysis except for anemia (hemoglobin) which will be graded using the CTCAE Version 
3.0. Grade 0 includes all values that do not meet the criteria for an abnormality of at least 
Grade 1. For laboratory tests with criteria for both increased and decreased levels, analyses 
for each direction (ie, increased, decreased) will be presented separately.  
7.2.2.1. 
Treatment-Emergent Laboratory Abnormalities 
Treatment-emergent laboratory abnormalities are defined as values that increase at least 
1 toxicity grade from baseline at any postbaseline time point, up to and including the date of 
last dose of study drug plus 30 days for subjects who permanently discontinued study drug. If 
the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 
observed within the time frame specified above will be considered treatment emergent. 


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7.2.2.2. 
Summaries of Laboratory Abnormalities 
The following summaries (number and percentage of subjects) for treatment-emergent 
laboratory abnormalities will be provided by lab test and dose level; subjects will be 
categorized according to the most severe postbaseline abnormality grade for a given lab test: 
 Graded Treatment-emergent laboratory abnormalities 
 Grade 3 or 4 laboratory abnormalities 
For all summaries of laboratory abnormalities, the denominator is the number of subjects 
with nonmissing postbaseline values up to 30 days after last dosing date. 
A by-subject listing of treatment-emergent Grade 3 or 4 laboratory abnormalities will be 
provided by subject ID number and visit in chronological order. This listing will include all 
test results that were collected throughout the study for the lab test of interest, with all 
applicable severity grades displayed. 
7.3. 
Body Weight and Vital Signs 
Descriptive statistics will be provided by dose level for body weight as follows: 
 Baseline value 
 Values at each postbaseline visit 
 Postbaseline maximum value 
 Postbaseline minimum value 
 Change from baseline at each postbaseline visit 
 Change and percentage change from baseline to postbaseline maximum value 
 Change and percentage change from baseline to postbaseline minimum value 
In the case of multiple values in an analysis window, data will be selected for analysis as 
described in Section 3.8.3.  
A by-subject listing of body weight and other vital sign parameters will be provided by 
subject ID number and visit in chronological order.  
7.4. 
Prior and Concomitant Medications 
Medications collected at screening and during the study will be coded using the current 
version of the World Health Organization (WHO) Drug dictionary. 


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7.4.1. 
Prior Medications 
Prior medications are defined as any medications taken before a subject took the first dose of 
study drug in the parent study. 
Prior medications will be listed for the Rollover Safety Analysis Set.  
7.4.2. 
Concomitant Medications 
Concomitant medications are defined as any medications meeting the following criteria: 
Starting on or after the first dose of study drug in the parent study up to 30 days post 
the last dose 
Starting before and continuing after the first dose of study drug in the parent study up 
to 30 days post the last dose 
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (Section 7.1.5.3). 
Concomitant medications will be summarized by preferred name using the number and 
percentage of subjects for each dose level and overall. A subject reporting the same 
medication more than once will be counted only once within each ATC drug class when 
calculating the number and percentage of subjects who received that medication. Medication 
may appear under multiple ATC drug classes. The summary will be ordered alphabetically 
by ATC Drug class and then by preferred term in order of descending overall frequency 
within each ATC Drug class. For drugs with the same frequency, sorting will be done 
alphabetically. 
Concomitant medications will be summarized and listed for the Rollover Safety Analysis Set. 
7.5. 
Electrocardiogram Results 
Electrocardiogram (ECG) data will be listed only. No summary table will be provided for 
ECG data. 
7.6. 
Changes From Protocol-Specified Safety Analyses 
Any changes to protocol-specified safety analyses after finalization of this document will be 
outline in the clinical study report. 


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8. 
REFERENCES 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guideline for Industry: E3 Structure and Content of 
Clinical Study Reports Federal Register. July 17, 1996 (61 FR 37320). 
U.S. Department of Health and Human Services, Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: E9 Statistical Principles for 
Clinical Trials. Federal Register. September 16, 1998 (63 FR 49583). 


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9. 
SOFTWARE 
SAS Software Version 9.2. SAS Institute Inc., Cary, NC, USA. 
nQuery Advisor(R) Version 7.0. Statistical Solutions, Cork, Ireland. 


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10. 
SAP REVISION 
Revision Date 
(dd month, yyyy) 
Section 
Summary of Revision 
Reason for Revision 
 
 
 
 
 
 
 
 
 


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11.
APPENDICES
Appendix 1. 
Leukemic Transformation MST AEs 
Appendix 2. 
Peripheral Neuropathy SMQ AEs 
Appendix 3. 
Cataract MST AEs 
Appendix 4. 
International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT) consensus criteria for treatment response in myelofibrosis with myeloid 
metaplasia 


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Appendix 1.  Leukemic Transformation MST AEs 
MEDDRA Term Name  
MEDDRA Code  
MEDDRA Level 
Acute megakaryocytic leukaemia 
10000860 
PT 
Acute megakaryocytic leukaemia (in 
remission)  
10057194 
PT 
Acute monocytic leukaemia  
10000871 
PT 
Acute monocytic leukaemia (in remission)  
10000872 
PT 
Acute myeloid leukaemia  
10000880 
PT 
Acute myeloid leukaemia (in remission)  
10000881 
PT 
Acute myeloid leukaemia recurrent  
10059034 
PT 
Acute myelomonocytic leukaemia  
10000890 
PT 
Acute promyelocytic leukaemia  
10001019 
PT 
Erythraemic myelosis (in remission)  
10015246 
PT 
Erythroleukaemia  
10015281 
PT 
Acute biphenotypic leukaemia  
10067399 
PT 
Acute leukaemia 
10000830 
PT 
Acute leukaemia in remission  
10060930 
PT 
Acute undifferentiated leukaemia  
10073479 
PT 
Blast cell crisis  
10053747 
PT 
Blast crisis in myelogenous leukaemia  
10050282 
PT 
Chloroma  
10008583 
PT 
Chloroma (in remission)  
10008584 
PT 
Eosinophilic leukaemia  
10014958 
PT 
Leukaemia basophilic  
10024293 
PT 
Leukaemia granulocytic  
10024299 
PT 
Leukaemia monocytic 
10024305 
PT 
Monocytic leukaemia in remission  
10061295 
PT 
Myeloid leukaemia  
10028549 
PT 
Myeloid leukaemia in remission  
10061301 
PT 
Aleukaemic leukaemia  
10001660 
PT 
Central nervous system leukaemia  
10066231 
PT 
Leukaemia  
10024288 
PT 
Leukaemia cutis  
10053180 
PT 
Leukaemia in remission  
10061220 
PT 
Leukaemia recurrent  
10062489 
PT 
Leukaemic cardiac infiltration  
10077563 
PT 
Leukaemic infiltration  
10069360 
PT 
Leukaemic infiltration extramedullary  
10067117 
PT 
Leukaemic infiltration gingiva  
10067431 
PT 
Leukaemic infiltration hepatic  
10058671 
PT 
Leukaemic infiltration ovary  
10075853 
PT 
Leukaemic infiltration pulmonary  
10052368 
PT 


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Leukaemic infiltration renal  
10069359 
PT 
Leukaemic retinopathy  
10059239 
PT 
Mastocytic leukaemia  
10056450 
PT 
Neonatal leukaemia  
10028958 
PT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2. Peripheral Neuropathy SMQ AEs 
Name 
Code 
Level 
Scope 
Acute painful neuropathy of rapid glycaemic control 
10072909 
PT 
Narrow 
Acute polyneuropathy 
10066699 
PT 
Narrow 
Amyotrophy 
10002027 
PT 
Narrow 
Autoimmune neuropathy 
10070439 
PT 
Narrow 
Axonal neuropathy 
10003882 
PT 
Narrow 
Biopsy peripheral nerve abnormal 
10004846 
PT 
Narrow 
Decreased vibratory sense 
10067502 
PT 
Narrow 
Demyelinating polyneuropathy 
10061811 
PT 
Narrow 
Guillain-Barre syndrome 
10018767 
PT 
Narrow 
Ischaemic neuropathy 
10051307 
PT 
Narrow 
Loss of proprioception 
10057332 
PT 
Narrow 
Miller Fisher syndrome 
10049567 
PT 
Narrow 
Multifocal motor neuropathy 
10065579 
PT 
Narrow 
Myelopathy 
10028570 
PT 
Narrow 
Nerve conduction studies abnormal 
10029175 
PT 
Narrow 
Neuralgia 
10029223 
PT 
Narrow 
Neuritis 
10029240 
PT 
Narrow 
Neuronal neuropathy 
10071579 
PT 
Narrow 
Neuropathic muscular atrophy 
10075469 
PT 
Narrow 
Neuropathy peripheral 
10029331 
PT 
Narrow 
Notalgia paraesthetica 
10072643 
PT 
Narrow 
Peripheral motor neuropathy 
10034580 
PT 
Narrow 
Peripheral nervous system function test abnormal 
10034591 
PT 
Narrow 
Peripheral sensorimotor neuropathy 
10056673 
PT 
Narrow 
Peripheral sensory neuropathy 
10034620 
PT 
Narrow 
Polyneuropathy 
10036105 
PT 
Narrow 
Polyneuropathy chronic 
10064135 
PT 
Narrow 
Polyneuropathy idiopathic progressive 
10036111 
PT 
Narrow 
Radiation neuropathy 
10068886 
PT 
Narrow 


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Name 
Code 
Level 
Scope 
Sensorimotor disorder 
10062162 
PT 
Narrow 
Sensory disturbance 
10040026 
PT 
Narrow 
Sensory loss 
10040030 
PT 
Narrow 
Small fibre neuropathy 
10073928 
PT 
Narrow 
Tick paralysis 
10077336 
PT 
Narrow 
Toxic neuropathy 
10067722 
PT 
Narrow 
Anti-ganglioside antibody positive 
10072516 
PT 
Broad 
Areflexia 
10003084 
PT 
Broad 
Autonomic failure syndrome 
10056339 
PT 
Broad 
Autonomic neuropathy 
10061666 
PT 
Broad 
Burning feet syndrome 
10070237 
PT 
Broad 
Burning sensation 
10006784 
PT 
Broad 
Decreased nasolabial fold 
10076861 
PT 
Broad 
Dysaesthesia 
10013886 
PT 
Broad 
Electromyogram abnormal 
10014431 
PT 
Broad 
Formication 
10017062 
PT 
Broad 
Gait disturbance 
10017577 
PT 
Broad 
Genital hypoaesthesia 
10068912 
PT 
Broad 
Hereditary motor and sensory neuropathy 
10077306 
PT 
Broad 
Hypoaesthesia 
10020937 
PT 
Broad 
Hyporeflexia 
10021089 
PT 
Broad 
Hypotonia 
10021118 
PT 
Broad 
Mononeuritis 
10027910 
PT 
Broad 
Mononeuropathy 
10062203 
PT 
Broad 
Mononeuropathy multiplex 
10027918 
PT 
Broad 
Motor dysfunction 
10061296 
PT 
Broad 
Muscle atrophy 
10028289 
PT 
Broad 
Muscular weakness 
10028372 
PT 
Broad 
Nerve degeneration 
10056677 
PT 
Broad 
Neuromuscular pain 
10074313 
PT 
Broad 
Neuromuscular toxicity 
10062284 
PT 
Broad 
Neuromyopathy 
10029323 
PT 
Broad 


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Name 
Code 
Level 
Scope 
Neuropathy vitamin B6 deficiency 
10029332 
PT 
Broad 
Neurotoxicity 
10029350 
PT 
Broad 
Paraesthesia 
10033775 
PT 
Broad 
Paraesthesia ear 
10052433 
PT 
Broad 
Peripheral nerve lesion 
10067633 
PT 
Broad 
Peripheral nerve palsy 
10058530 
PT 
Broad 
Peripheral nerve paresis 
10071663 
PT 
Broad 
Peroneal nerve palsy 
10034701 
PT 
Broad 
Phrenic nerve paralysis 
10064964 
PT 
Broad 
Skin burning sensation 
10054786 
PT 
Broad 
Temperature perception test decreased 
10068015 
PT 
Broad 
Tinel's sign 
10052492 
PT 
Broad 
Ulnar neuritis 
10045380 
PT 
Broad 
Vulvovaginal hypoaesthesia 
10075520 
PT 
Broad 
 
 
 
 


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Appendix 3. Cataract MST AEs 
MEDDRA Term Name 
MEDDRA Code 
MEDDRA Level 
Atopic cataract 
10069649 
PT 
Cataract 
10007739 
PT 
Cataract congenital 
10007747 
PT 
Cataract cortical 
10007748 
PT 
Cataract diabetic 
10007749 
PT 
Cataract nuclear 
10007759 
PT 
Cataract operation 
10063797 
PT 
Cataract subcapsular 
10007764 
PT 
Cataract traumatic 
10007766 
PT 
Lens discolouration 
10070549 
PT 
Lenticular opacities 
10024214 
PT 
Radiation cataract 
10037756 
PT 
Toxic cataract 
10044135 
PT 
Bioptic surgery 
10078003 
PT 
Cornea verticillata 
10077604 
PT 
 
 
 


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Appendix 4. International Working Group for Myelofibrosis Research and Treatment 
(IWG-MRT) consensus criteria for treatment response in myelofibrosis with 
myeloid metaplasia 
Complete remission (CR) 
I. 
Complete resolution of disease-related symptoms and 
signs including palpable hepatosplenomegaly. 
II. 
Peripheral blood count remission defined as 
hemoglobin level at least 110 g/L, platelet count at 
least 100 x 109/L, and absolute neutrophil count 
(ANC) at least 1.0 x 109/L. In addition, all 3 blood 
counts should be no higher than the upper normal 
limit. a 
III. 
Normal leukocyte differential including disappearance 
of nucleated red blood cells, blasts, and immature 
myeloid cells in the peripheral smear, in the absence of 
splenectomy. 
IV. 
Bone marrow histologic remission defined as the 
presence of age-adjusted normocellularity, no more 
than 5% myeloblasts, and an osteomyelofibrosis grade 
no higher than 1.b 
Partial remission (PR) 
Requires all of the above criteria for CR except the 
requirement for bone marrow histologic remission. However, 
a repeat bone marrow biopsy is required in the assessment of 
PR and may or may not show favorable changes that do not 
however fulfill criteria for CR. 
Clinical improvement (CI) 
Requires one of the following in the absence of both disease 
progression (as outlined below) and CR/PR assignment (CI 
response is validated only if it lasts for no fewer than 8 
weeks): 
i. 
A minimum 20-g/L increase in hemoglobin level or 
becoming transfusion independent (applicable only for 
subjects with baseline hemoglobin level of less than 
100 g/L). 
ii. 
Either a minimum 50% reduction in palpable 
splenomegaly of a spleen that is at least 10 cm at 
baseline or a spleen that is palpable at more than 5 cm 
at baseline becomes not palpable. c 


Momelotinib (MMB) 
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iii. 
A minimum 100% increase in platelet count and an 
absolute platelet count of at least 50 000 x 109/L 
(applicable only for subjects with baseline platelet 
count below 50 x 109/L). 
iv. 
A minimum 100% increase in ANC and an ANC of at 
least 0.5 x 109/L (applicable only for subjects with 
baseline ANC below 1 x109/L). 
Progressive disease (PD) 
Requires 1 of the following: d 
i. 
Progressive splenomegaly that is defined by the 
appearance of a previously absent splenomegaly that is 
palpable at greater than 5 cm below the left costal 
margin or a minimum 100% increase in palpable 
distance for baseline splenomegaly of 5-10 cm or a 
minimum 50% increase in palpable distance for 
baseline splenomegaly of greater than 10 cm. 
ii. 
Leukemic transformation confirmed by a bone marrow 
blast count of at least 20%. 
iii. 
An increase in peripheral blood blast percentage of at 
least 20% that lasts for at least 8 weeks. 
Stable disease (SD) 
None of the above. 
Relapse (Loss of CR, PR, or 
CI) 
Subject with CR or PR is considered to have undergone 
relapse when he or she no longer fulfills the criteria for even 
CI.