Conditions: Myelofibrosis
Keywords: Myelofibrosis Primary myelofibrosis PMF Post polycythemia myelofibrosis PPV MF Post-essential thrombocythemia myelofibrosis PET-MF INC424 Ruxolitinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2233
Healthy volunteers: no

Brief summary:
The primary objective of this study was to collect additional safety of INC424 in patients with Primary Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis, who either received prior treatment with commercially available agents or who have never received treatment.

Detailed description:

Arms:
arm 1: 5 - 25 mg twice a day (BID)

Interventions: intervention 1: INC424
Intervention descriptions: intervention 1: All patients enrolled into the study will receive INC424 (ruxolitinib). Starting dose is based on baseline platelet counts, with doses ranging from 5 to 20 mg twice a day. No INC424 dose will exceed 25 mg BID orally.

Protocol document:
Prot_001.pdf: 
Clinical Development
INC424 (ruxolitinib)
Protocol CINC424A2401 / NCT01493414
An open-label, multicenter, expanded access study of 
INC424 for patients with primary myelofibrosis (PMF) or 
post polycythemia myelofibrosis (PPV MF) or post-
essential thrombocythemia myelofibrosis (PET-MF)
Authors
Document type
Amended Protocol Version 
EUDRACT number
2010-024473-39
Version number
05 (Clean)
Development phase
IIIB
Document status
Final
Release date
21-Mar-2016
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 5 ....................................................................................................................11
Oncology clinical study protocol synopsis........................................................................39
1
Background........................................................................................................................51
1.1
Overview of myelofibrosis and myeloproliferative neoplasms and current 
treatment options ...................................................................................................51
1.2
Inhibition of Janus Kinases (JAK) in MPN...........................................................55
1.3
Overview of INC424 .............................................................................................56
1.3.1
INC424 pharmacokinetics.....................................................................57
1.3.2
INC424 preclinical safety .....................................................................58
1.3.3
INC424 clinical safety in healthy volunteers........................................59
1.3.4
INC424 clinical safety and efficacy in phase I/II trials.........................59
1.3.5
Phase III INC424 clinical trials (controlled MF study with oral 
JAK inhibitor treatment [COMFORT; (INCB 18424-351 and 
CINC424A2352)]) ................................................................................65
2
Rationale............................................................................................................................69
2.1
Study rationale and purpose...................................................................................69
2.2
Rationale for dose and regimen selected ...............................................................70
3
Objectives and endpoints...................................................................................................70
3.1
Primary objectives .................................................................................................70
3.2
Secondary objectives .............................................................................................70
3.3
Study endpoints .....................................................................................................70
3.3.1
Safety.....................................................................................................70
3.3.2
Efficacy .................................................................................................71
3.3.3
Quality of Life.......................................................................................71
3.3.4
Medical resource utilization (MRU).....................................................71
4
Study design ......................................................................................................................71
4.1
Description of study design ...................................................................................71
4.2
Early study termination..........................................................................................73
5
Population..........................................................................................................................74
5.1
Patient population..................................................................................................74
 


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5.2
Inclusion criteria ....................................................................................................74
5.3
Exclusion criteria...................................................................................................75
6
Treatment...........................................................................................................................77
6.1
Investigational treatment, other study treatment, supportive treatment ................77
6.1.1
Study drug dosing .................................................................................77
6.2
Dose modifications................................................................................................78
6.2.1
Dose increases of INC424.....................................................................78
6.2.2
Dose interruption or dose reduction......................................................81
6.2.3
Restarting or reinstituting previous dose...............................................83
6.2.4
Dose reductions for concomitant CYP inhibitor usage.........................84
6.2.5
Optional dose tapering strategy in the event of study drug 
discontinuation......................................................................................84
6.2.6
Dose interruption and discontinuation of study drug............................85
6.2.7
Treatment of investigational drug overdose..........................................86
6.3
Concomitant medications ......................................................................................86
6.3.1
Permitted concomitant therapy .............................................................87
6.3.2
Permitted concomitant therapy requiring caution and/or action...........87
6.3.3
Prohibited concomitant therapy ............................................................88
6.4
Patient numbering, treatment assignment and randomization...............................88
6.4.1
Patient numbering .................................................................................88
6.4.2
Treatment assignment and randomization ............................................89
6.4.3
Treatment blinding................................................................................89
6.5
Study drug supply..................................................................................................89
6.5.1
Study drug preparation and dispensation..............................................89
6.5.2
Study drug packaging and labeling.......................................................89
6.5.3
Drug supply and storage........................................................................89
6.5.4
Study drug compliance and accountability ...........................................90
7
Visit schedule and assessments .........................................................................................91
7.1
Study flow and visit schedule................................................................................91
7.2
Study evaluations...................................................................................................96
7.2.1
Efficacy .................................................................................................96
7.2.2
Safety and tolerability ...........................................................................96
7.3
Screening ...............................................................................................................96
7.3.1
Information to be collected on screening failures.................................98
7.4
Baseline evaluations (Day -7 to Day -1)................................................................98
7.4.1
Combining Screening and Baseline Visits into 1 Visit.........................99
 


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7.5
On treatment evaluations.......................................................................................99
7.5.1
On treatment evaluation requirements ................................................100
7.6
End of treatment visit, including premature withdrawal and study 
discontinuation visit.............................................................................................107
7.6.1
Criteria for premature withdrawal.......................................................107
7.6.2
End of treatment evaluations...............................................................109
7.6.3
Follow-up period.................................................................................109
8
Study assessments ...........................................................................................................110
8.1
Demographic and other pretreatment assessments..............................................110
8.2
Safety assessments...............................................................................................110
8.2.1
Adverse events ....................................................................................110
8.2.2
Safety assessments at investigational therapy withdrawal..................111
8.2.3
Physical examinations.........................................................................111
8.2.4
Vital signs............................................................................................111
8.2.5
Height and weight ...............................................................................111
8.2.6
Full neurologic examination and cardiology assessments ..................111
8.2.7
12-lead ECG........................................................................................112
8.2.8
ECG analysis and reporting ................................................................112
8.2.9
Clinical safety laboratory assessments................................................112
8.3
Symptom and functional response assessments ..................................................113
8.3.1
Response assessments .........................................................................113
8.3.2
Quality of Life assessments ................................................................113
8.3.3
Resource utilization.............................................................................114
9
Safety monitoring and reporting......................................................................................115
9.1
Adverse events.....................................................................................................115
9.1.1
Definition and reporting......................................................................115
9.1.2
Laboratory test abnormalities..............................................................116
9.2
Serious adverse events.........................................................................................117
9.2.1
Definitions...........................................................................................117
9.2.2
Reporting.............................................................................................117
9.3
Pregnancies..........................................................................................................118
9.4
Warning and precautions.....................................................................................119
10 Data collection and management.....................................................................................119
10.1
Data confidentiality .............................................................................................119
10.2
Site monitoring ....................................................................................................120
10.3
Data collection.....................................................................................................121
 


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10.4
Database management and quality control..........................................................121
11 Statistical methods and data analysis ..............................................................................122
11.1
Handling of missing values .................................................................................123
11.2
Populations for analysis.......................................................................................123
11.3
Patient demographics/other baseline characteristics ...........................................123
11.4
Treatments (study drug, concomitant therapies, compliance).............................123
11.5
Primary objective.................................................................................................123
11.5.1
Variables .............................................................................................123
11.5.2
Statistical hypothesis, model, and method of analysis........................124
11.6
Secondary objectives ...........................................................................................124
11.6.1
Efficacy ...............................................................................................124
11.6.2
Laboratory abnormalities ....................................................................125
11.6.3
Other safety data: weight, vital signs, ECG, and death.......................126
11.6.4
Tolerability..........................................................................................126
11.6.5
Quality of Life Assessments ...............................................................127
11.6.6
Pharmacokinetics ................................................................................127
11.6.7
Biomarkers..........................................................................................127
11.7
Interim analysis....................................................................................................127
11.8
Sample size calculation........................................................................................128
11.9
Power for analysis of critical secondary variables ..............................................128
12 Ethical considerations and administrative procedures ....................................................128
12.1
Regulatory and ethical compliance......................................................................128
12.2
Responsibilities of the investigator and IRB/IEC/REB.......................................128
12.3
Informed Consent ................................................................................................128
12.4
Discontinuation of the study................................................................................129
12.5
Publication of study protocol and results.............................................................129
12.6
Study documentation, record keeping and retention of documents.....................129
12.7
Confidentiality of study documents and patient records .....................................130
12.8
Audits and inspections.........................................................................................130
12.9
Financial disclosures............................................................................................130
12.10 Protocol adherence...............................................................................................130
12.11 Amendments to the Protocol ...............................................................................131
13 References (available upon request)................................................................................132
14 Appendices ......................................................................................................................139
14.1
Appendix I - Diagnostic criteria for PMF, PPV MF, and PET-MF ....................139
 


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14.2
Appendix II - Information regarding highly effective contraception methods....142
14.3
Appendix III - Clinical laboratory tests...............................................................142
14.4
Appendix IV - Eastern Cooperative Oncology Group performance status .........143
14.5
Appendix V - Bone marrow biopsy evaluation (when performed, they are not 
mandatory)...........................................................................................................143
14.6
Appendix VI - Restricted/prohibited medications...............................................144
14.7
Appendix VII - FACT-Lym Form, Version 4 .....................................................146
14.8
Appendix VIII - FACIT Fatigue Scale (Version 4).............................................149
14.9
Appendix IX - MRU concomitant medication ....................................................150
List of figures
Figure 1-1
Prognostically detrimental ‘HMR’ mutations and survival in PMF: 
Kaplan Meier Plots................................................................................53
Figure 1-2a
Reduction in palpable spleen length in patients receiving different 
doses of INC424 (Verstovsek 2010b)...................................................60
Figure 1-2b
Reduction in palpable spleen length according to INC424 dose 
when maintained for at least 6 months (Verstovsek 2010b).................61
Figure 1-3
Improvements in combined MFSAF score on INC424 ........................62
Figure 4-1
Study design..........................................................................................72
Figure 6-1
Dose increase strategies for patients starting on INC424 15 – 20 
mg BID with inadequate responses after at least Week 4:....................79
List of tables
Table 6-1
Dose and treatment schedule.................................................................78
Table 6-2
Dose reductions in INC424 for safety in patients with platelet 
count declines (for those starting on INC424 dose of 15 – 20 mg 
p.o. BID)................................................................................................81
Table 6-3
Dose reductions in INC424 for safety in patients with platelet 
count declines (for those starting on INC424 dose of 5 mg PO BID)
...............................................................................................................82
Table 6-4
Restarting or increasing INC424 dose after safety interruptions or 
dose reductions for patients starting on doses of 15 – 20 mg BID .......83
Table 6-5
Supply and storage of study treatments ................................................90
Table 7-1
Visit evaluation schedule ......................................................................92
Table 7-2
Laboratory assessment schedule ...........................................................95
 


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List of abbreviations
AE
Adverse event
hCG
Beta human chorionic gonadotropin
alloHSCT
Allogeneic hematopoietic stem cell transplantation
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the concentration time curve
b.i.d./BID
bis in diem/two times per day
BAT
Best available therapy
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Clinical improvement
Cmax
Maximum concentration
CML
Chronic myeloid leukemia
COMFORT
COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment
CR
Complete response
CRO
Contract Research Organization
CSR
Clinical study report
CSR addendum
An addendum to Clinical Study Report (CSR) that captures all the additional information that 
is not included in the CSR
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYPs
Cytochrome P450 system of metabolizing enzymes, includes isoenzymes designated 
CYP3A4, CYP2C11, CYP2C13
DAR
Dosage Administration Record
dL
Deciliter (100 mL)
DS&E
Drug safety and epidemiology
EAP
Expanded access protocol
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form; the term eCRF can be applied to either EDC or Paper
EDC
Electronic Data Capture
EOT
End of treatment
EPO
Erythropoietin
ESA
Erythropoietic stimulating agent
ET
Essential thrombocythemia
FACIT-Fatigue
Functional Assessment of Chronic Illness Therapy-Fatigue Scale
FACT-lym
Functional Assessment of Cancer Therapy for patients with Lymphoma
FAS
Full analysis set
FDA
Food and Drug Administration
FLT3
Fms-like tyrosine kinase 3
FPFV
First patient first visit
FPLV
First patients last visit
 


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FSH
Follicle stimulating hormone
GCP
Good clinical practice
G-CSF
Granulocyte colony-stimulating factor
GI
Gastrointestinal
HDAC
Histone deacetylase
HDL
High density lipoprotein
HEENT
Head, eyes, ears, nose, throat
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HRQOL
Health-related quality of life
HU
Hydroxyurea
i.v.
intravenous(ly)
IB
Investigator’s brochure
IC
Inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMS
Integrated Medical Safety
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IUD
Intrauterine device
IUS
Intrauterine system
JAK
Janus kinase
JUMP
JAK Inhibitor ruxolitinib in myelofibrosis patients
L
Liter
LFS
Leukemia-free survival
LFTs
Liver function tests
LPFV
Last patient first visit
MAA
Marketing Authorization Application
MedDRA
Medical dictionary for regulatory activities
MF
Myelofibrosis
MFSAF
Modified Myelofibrosis Symptom Assessment Form
Mg
Milligram(s)
MID
Minimally important difference
mL
Mililiter(s)
MPD
Myeloproliferative disorder
MPN
Myeloproliferative neoplasms
MRI
Magnetic resonance imaging
MRU
Medical resource utilization
MSDS
Material Safety Data Sheet
NDA
New Drug Application
NOAEL
No-observed-adverse-effect level
o.d.
omnia die/once a day
ORR
Overall response rate
p.o.
per os/by mouth/orally
 


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p.o.
per os/by mouth/orally
PD
Progressive disease
PE
Physical examination
PET-MF
Post essential thrombocythemia-myelofibrosis
PFS
Progression free survival
PHI
Protected health information
PMF
Primary myelofibrosis
PPV-MF
Post polycythemia vera-myelofibrosis
PS
Performance status
pSTAT3
Phosphorylated signal-transducer and activator of transcription 3
PT
Prothrombin time
PTT
Partial thromboplastin time
PV
Polycythemia vera
QAM
Once in the morning
QoL
Quality of life
QPM
Once in the evening
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RDC
Remote data capture
REB
Research Ethics Board
SAE
Serious Adverse Event
SD
Stable disease
SOP
Standard Operating Procedure
SPA
Special Protocol Assessment
STAT
Signal transducers and activators of transcription
T1/2
Half life
Tmax
Time to maximum concentration
TOI
Trial outcome index
ULN
Upper limit of normal
USA
United States of America
VS
Vital signs
WBC
White blood cell count
 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being testing in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background therapy 
required or allowed by the protocol when used in within approved 
indication/dosage
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Patient number
A number assigned to each patient who enrolls in the study. When combined 
with the center number, a unique identifier is created for each patient in the study 
and will be on the study drug dispensing label
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned completion 
of all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned, unless 
the patient will be followed for progression and/or survival
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation(End 
of treatment)
Point/time at which the patient came in for a final evaluation visit or when study 
drug was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples where it is important to judge study treatment relationship 
relative to a drug component of a combination treatment, study treatment in this 
case can refer to a drug component
Study drug discontinuation
Point/time when patient permanently stops taking study drug for any reason; may 
or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points
 


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Amendment 5
Amendment Rationale
The primary purpose of the amendment is to align this protocol with the latest modified 
Novartis standard language for clinical study protocols:

Updated highly effective contraception method
The “contraception use” wording has been updated to provide clarification and 
implement latest available guidelines as to highly effective contraception. Since all 
patients are enrolled, the clarification does not apply per se to exclusion criteria but may 
be used as needed for female of childbearing potential currently enrolled in the trial.

Updates to concomitant therapy and prohibited concomitant therapy
Clarifications to concomitant therapy and prohibited concomitant therapy is also updated 
in appendix. 

Additional changes:
Reticulocytes count and coagulation parameters determination may or may not be part of 
the standard evaluation performed in clinical practice at different health care centers. As 
this study aims to resemble the use of ruxolitinib in patients with myelofibrosis in the 
clinical practice setting, we will allow optional collection and results reporting in the CRF
when collected and deemed clinically relevant on a patient basis.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, and red and bold for insertions.
1. Updated author list of protocol 
 to reflect the team currently working 
on/managing the protocol.
2. Study synopsis:
a. Background
Newer wording and included the EMA approval date.
b. Study design
Updated end recruitment as 31-Dec-2014
c. Inclusion/ Exclusion - exclusion criteria 
Exclusion criteria #15 as to Childbearing potential updated to reflect latest  
international guidance related to highly effective contraception
d. Dose, Regimen, Treatment
Clerical update: added Table 6-2 reference as in the protocol 
3. Section 1 Background 
Updated wording: approved by the EMA on 31-Aug-2012
4. Section 1.1 Overview of myelofibrosis and myeloproliferative neoplasms and current 
treatment options
Updated newest information and Figure 1-1
5. Section 1.3 Overview of INC 424 
 


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Updated wording to reflect latest information on JAK pathway  and approval of Jakavi in 
90 counties.
6. Section 1.3.1 INC 424 Pharmacokinetics 
Updated section with  recent information as to current study results.
7. Section 1.3.3 INC 424 clinical safety in healthy volunteers 
Included recently updated study information.
8. Section 1.3.4.1 Phase I/II study of INC 424 in patients with primary, post-PV, or post ET 
MF
Figure renumbered to Figure 1-2a and Figure 1-2b.
9. Section 1.3.5 Phase III INC424 clinical trials (controlled MF study with oral JAK 
inhibitor treatment [COMFORT; (INCB 18424-351 and CINC424A2352)])
Clinical update information with COMFORT I and II 
10. Section 4.1 Descrition of Study Design 
Updated to current study status 2238 patients enrolled and enrollment ended 31 Dec 2014.
11. Section 5.1 Patient population 
Updated wording to clarify the understanding of the pharmacokinetics and interactions 
that physicians should be aware that CYP3A4 is an isoenzyme that can catalyze a 
biotransformation of INC424.
12. Section 5.3 exclusion criteria 15. 
Updated wording to new standard Childbearing potential wording.
13. Section 6.2.2.3 Dose modification for Renal Impairment
Clarified wording that no specific dose adjustment is needed in patients with mild or 
moderate renal impairment.
14. Section 6.2.2.4 Dose modification for hepatic impairment
Update wording to monitor and reduce dose to avoid adverse drug reactions
15. Section 6.2.4 Dose Reduction for concomitant CYP Inhibitor Usage 
Update wording to clarify more frequent monitoring to prevent events with strong potent 
CYP3A4 inhibitors.
16. Section 6.2.5 Optional dose tapering strategy in the event of study drug discontinuation 
Wording to clarify possible events symptoms due to abruptly stopping ruxolitnib. 
Wording explaining concomitant use of corticosteroids prior to or during the dose tapering. 
17. Section 6.2.6.1 Dose reduction for non-hematological safety
New section created as to non hematological safety recommendation and dosing 
recommendation for these events. 
18. Section 6.3 Concomitant Medication 
Addition of a general sentence as to timeframe for collection in EDC of concomitant 
medication and general warning about use of concomitant medication during trial. 
19. Section 6.3.1 Permitted Concomitant Therapy 
New standard language added natural and herbal treatments allowed.
20. Section 6.3.2 Permitted Concomitant therapy requiring caution and or action 
 


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Updated wording to explain guidance in the referenced appendix and precision added as to 
use of topical ketoconazole not requiring ruxolitinib dose adjustement.
21. Section 6.3.3 Prohibited Concomitant Therapy 
Update wording in the guidance of the referenced appendix
22. Table 7-2 Laboratory assessment
As not being standard tests performed in clinical setting for patients’s follow up, 
reticulocytes assessment will be optional. Coagulation laboratory assessments are also 
optional after enrollment. The investigator may continue to draw labs if considered 
clinically significant to maintain safety evaluation on patients.
23. Section 7.3 Screening
INR added to the Coagulation to be consistant with the table 7.2
24. Section 7.5.1.3, Section 7.5.1.5, Section 7.5.1.7, Section 7.5.1.9, Section 7.5.1.11, Section 
7.5.1.13, Section 7.5.1.15, Section 7.6.3.1
Coagulation parameters are optional for these follow up visits.
25. Section 8.2.9 Clinical Safety laboratory assessments 
Wording made consistent hematology reticulocytes are optional and coagulation 
laboratory assessments are optional after enrollment.
26. Section 9.1.1 Safety Definitions and reporting  disease progression 
Wording clarified as to reportable and exempted events related to disease progression. All 
events not related to disease progression should be reportedevents. 
27. Section 9.1.1.2 Events related to the disease
Updated wording to clarify to the investigator when reporting worsening of symptoms 
(AE), the causality of an AE may be related to the study drug or related to the disease 
28. Section 9.1.1.2 Surgical procedure
Wording updated to clarify that planned surgical procedures do not have to reported as an 
AE
29. Section 9.1.2 Definitions
Confusing wording was updated to clarify protocol exempted SAE. 
30. Section 11.6.1.1 Full Analysis set will be used for all efficacy analysis
Clarified wording as no cycle of therapy are being done with ruxolitinib. 
Progression free survival, Leukemia free survival and  Overall survival are clarified as to 
period of time until which data will be taken into account. Protocol mandating a 28 to 37
days follow up, data will not be considered if collected and reported after this timeframe. 
31. Section 13 References
Updated references related to the updated sections referenced.
32. Appendix II
Updated with new standard language for highly effective contraception.
33. AppendixIII
Updated: Hematology reticulocytes absolute and % are optional and 
Coagulation parameters are optional after enrollment. 
34. Appendix VI
 


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Updated to the most recent Novartis guidance.
Steroids are allowed for use during trial as described in protocol. Steroids are deleted from 
list of prohibited medication to align with protocol requirements.
35. Appendix X
Enrollment being closed from end 2014, eligibility checklist is no longer used and not 
kept to avoid confusion with updated highly effective contracetion measures update that 
will be implemented from Amendment 05 approval.
IRB/IEC Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Amendment 4
Amendment rationale
Sanofi announced on November 18th 2013 the decision to halt all clinical trials and cancel 
plans for regulatory filings with its investigational JAK2 inhibitor, fedratinib (SAR302503).
Fedratinib is a novel, investigational JAK2 inhibitor that was under development for the 
treatment of myelofibrosis, including those previously treated with ruxolitinib.
The decision follows reports of cases consistent with Wernicke’s encephalopathy in patients 
participating in fedratinib clinical trials. Sanofi requested that study investigators discontinue
fedratinib treatment for patients in all trials and notified health authorities worldwide. 
To date, more than 16,000 patients have been treated with ruxolitinib worldwide as part of the 
clinical trial program and commercial usage. Novartis has conducted a search of the 
ruxolitinib worldwide safety database and have found no reported cases of Wernicke’s 
encephalopathy in patients treated with ruxolitinib. Additionally, based on a search of 
scientific information currently available in the public domain, Novartis considers there is no 
evidence suggesting a relationship between the JAK/STAT pathway and Wernicke’s 
encephalopathy.
Physicians having patients under treatment with fedratininb should determine with them the 
best alternative course of therapy for their myelofibrosis and if deemed appropriate consider a 
switch to ruxolitinib.
Acknowledging the urgent medical need for an active therapy that these patients have after 
discontinuing therapy with fedratinib and for countries where ruxolitinib is not commercially 
available, this amendment is deemed necessary to allow patients discontinued from fedratinib 
to have the opportunity to be treated with ruxolitinib if they wish so and if recommended by 
the treating physician and if inclusion/exclusion criteria are dully fulfilled. 
The major changes to the protocol include:
1.0 Addition of inclusion criteria to allow fedratinib pretreated patients to be included in the 
trial as long as clinical, laboratory and image assessments are properly documented.
2.0 Update of visit schedule and assessments.
Study Status
The trial is currently enrolling. As of December 2nd 2013, there are 1784 patients enrolled in 
the study.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, and red and bold for insertions.
1.
Updated author list of protocol 
 to reflect the team currently 
working on/managing the protocol.
2.
Study Synopsis
 


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a. Study objective:

Primary objective: clarification that patients being previously treated by 
investigational drug may be part of the study population as described per initial and 
current inclusion/exclusion criteria.

Secondary objective: correction of typo, secondary objectives is to assess best overall 
response rate of INC424 in patients with PMF, PPV MF, or PET-MF as evaluated by 
investigator.
b. Study design.

Insertion of transplant as a reason for end of treatment.

Clarification that as based on country assessments and not computed, the maximum 
number of patients expected to be included in the trial is not 2484 but 2500. 
c. Population.

Clarification that patients being previously treated by investigational drug may be 
enrolled as per original and current inclusion/exclusion criteria.
d. Sample size.

Clarification that as based on country assessments and not computed, the maximum 
number of patients expected to be included in the trial is 2500. 
e. Inclusion/exclusion criteria

Addition of Inclusion criteria13 describing assessments and documentation for 
fedratinib pre-treated patients:

“Fedratinib pretreated patients with documented complete physical examination 
including full neurologic examination and cardiology assessment, thiamine level 
testing, and MRI of the brain if indicated based on signs or symptoms. Patients 
pretreated with fedratinib should have completed or be receiving thiamine 
supplementation according to the investigator’s instructions.”

Addition of Eclusion criteria describing assessments and documentation for fedratinib 
pre-treated patients: 

Addition of information to Exclusion criteria 13: insertion of statement that patients 
previously treated by fedratinib within 14 days of screening are not eligible for the 
trial. 

Addition of Exclusion criteria 19 defining exclusion criteria for ruxolitinib pre-treated 
patients if primary resistant to ruxolitinib, primary resistance being defined as:

No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib. 
AND

No reduction in symptoms within the first 12 weeks after first-line treatment with 
ruxolitinib.

Addition of Exclusion criteria 20: in the case of ruxolitinib pretreated patients, 
patients discontinuing ruxolitinib due to a Grade 4 AE related or suspected to be
related to ruxolitinib.
f.
Patient numbering.
 


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
Information about patient numbering for those patients who may have participate in 
CINC424A2401 before being under fedratinib: those patients will receive a new 
patient number as per usual process.
g. Dose, regimen, treatment.

As per previous protocol amendments, low platelet patient are defined as patients 
having from 50,000 to ˂100,000/µL platelet count. A correction is needed to update 
upper limit platelet count for patients starting with a 5mg BID regimen, platelet count 
for this starting dose is corrected from 99,000/µL to ˂100,000/µL.

Insertion of transplant as a reason for end of treatment.
h. Statistical methods and data analysis.

Addition of a Per Protocol set.

 
i.
Interim analysis.

Upper limit platelet count for low platelet set have been updated from 99,000/µL to ˂ 
100,000/µL platelet count as defined for low platelet population.

Clarification that analysis may be performed if needed to fulfill regulatory obligation 
or to comply with post-approval commitments.
3.
Section 2.1 Study rationale and purpose.

While regulatory approval is sought, there are no means available for patients with 
PMF, PPV MF, or PET-MF to receive INC424 outside of a clinical trial. Sentence 
“Patients who received prior treatment with commercially available agents or who 
have never received treatment do not have an access path to this new agent.” is 
describing this same population and is deleted.
4.
Section 2.2 Rationale and dose regimen selected.

Correction of low platelet term used for patient with 100,000 to 200,000 µL platelet 
count, based on additional information on efficacy and safety collected from original 
protocol and integrated in previous protocol amendments. Clarification that patients 
with platelet count from 50,000 to  ˂ 100,000µL are part of low platelet population 
and starting treatment at 5mg BID.
5.
Section 3.1 Primary objective.

Clarification that patients being previously treated by investigational drug may be are 
part of the population as per original and current protocol design.
6.
Section 4.1 Study design.

Insertion of transplant as a reason for end of treatment.

Clarification that recruitment will end once 2500 patients are enrolled or by 
31Dec2014, whichever comes first.
7.
Section 5.1 Patient population

Clarification that patients being previously treated by investigational drug may be 
enrolled as per original and current inclusion/exclusion criteria.
8.
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
Addition of Inclusion Criteria 13: fedratinib pretreated patients need to have a  
documented complete physical examination including full neurologic examination 
and cardiology assessment, thiamine level testing, and MRI of the brain if indicated 
based on signs or symptoms. Patients pretreated with fedratinib should have 
completed or be receiving thiamine supplementation according to the investigator’s 
instructions.
9.
Section 5.3 Exclusion criteria.

Addition of information as to fedratinib as previous investigational treatment in 
Exclusion criteria 13: insertion of statement that patients previously treated by 
fedratinib within 14 days of screening are not eligible for the trial.

Addition of Exclusion criteria 19, defining exclusion criteria for ruxolitinib pre-
treated patients if primary resistant to ruxolitinib, primary resistance being defined as: 

No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib. 
AND

No reduction in symptoms within the first 12 weeks after first-line treatment with 
ruxolitinib.

Addition of Exclusion criteria 20: in the case of ruxolitinib pretreated patients, 
patients discontinuing ruxolitinib due to a Grade 4 AE related or suspected to be 
related to ruxolitinib.
10. Section 6.1.1 Study drug dosing

Insertion of transplant as a reason for end of treatment.

Clarification that patients with a Baseline platelet count from 50,000 to ˂ 100,000/µL
will begin dosing at 5 mg BID (one 5 mg tablet BID):

Deletion of “Patients with a Baseline platelet count of 50,000/ µL – 99,000/µL will 
begin dosing at 5 mg BID (one 5 mg tablet BID)” and insertion of sentence “Patients 
with a Baseline platelet count of 50,000/ µL to <100,000/µL will begin dosing at 5 
mg BID (one 5 mg tablet BID)”
11. 6.2.2.1 Dose reduction for patients starting INC424 at doses 15-50 mg po BID.

Table 6.2: correction added to harmonize way platelet count are referred to in the 
table: 100 to <125,000/µL have been replaced by 100,000/µL to <125,000/µL. The 
correction have been done for all platelet counts displayed in the table.
12. 6.2.3.1 Restarting or reinstituting previous dose for patients who start INC424 15-20mg 
BID. 

Table 6-4: correction added to harmonize way platelet count are referred to in the 
table: 100 to <125,000/µL have been replaced by 100,000/µL to <125,000/µL. The 
correction have been done for all platelet counts displayed in the table.
13. Section 6.4.1 Patient numbering.

Clarification on patient number assignment: no Interactive Response Technology 
system is used, patient number is attributed by site in sequential order and entered into 
RDC.
 


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
Information regarding patient numbering for those patients who may have 
participated in CINC424A2401 before being under fedratinib: those patients will 
receive a new patient number as per usual process.
14. Section 6.5.2 Study drug packaging and labeling.

Clarification as regards to global or local supply of drug..

Insertion of transplant as a reason for end of treatment.
15. Section 7.1 Study flow and visit schedule.

Table 7.1: visit evaluation schedule:

Insertion of additional evaluations at screening:

insertion of full neurologic and cardiology assessments, to identify any signs or 
symptoms of thiamine deficiency or Wernicke’s enchepalopathy.

insertion of MRI to be performed if clinically indicated (i.e. presence of clinical 
neurologic or psychiatric symptoms or physical examination findings or an history of 
established or suspected diagnosis of Wernicke’s encephalopathy while under therapy 
with fedratinib.

Insertion of Eligibility checklist to be kept in source documentation
Table 7.2: Laboratory Assessment Schedule:

Insertion of thiamin blood level assessment at screening.
16. Section 7.3 Screening.

Description of clinical patterns, blood evaluation and, if deemed appropriate based on 
clinical symptoms, MRI assessment for patients with a suspicion of Wernicke’s 
Encephalopathy.

Addition of eligibility checklist to be completed and sent to Sponsor, approval is to be 
received back by Site before patient enrollment. This checklist is implemented as no 
IRT system is used.
17. Section 7.6.1 Criteria for premature withdrawal.

Clarification that patient with low platelet count are including patient with baseline 
platelet count from 50,000 to ˂100,000/µL : deletion of  50,000– 90,000/µL platelet 
count and update to 50,000 to <100,000/µL  platelet count for sections related 
premature withdraw due to hematologic and non-hematologic toxicity.
18. Section 8.2.6 Full neurologic evaluation.

Incorporation of full neurologic examination and cardiology assessments to identify 
any signs and symptoms of thiamine deficiency or Wernicke’s Encephalopathy for 
fedratinib pretreated patients:

For fedratinib pretreated patients there is a need to perform neurologic and cardiology 
examinations will be performed to identify any sign of thiamine deficiency or 
Wernicke’s Encephalopathy which common symptoms or signs at disease 
presentation are: ocular abnormalities, mental status changes, and incoordination of 
gait and trunk ataxia. Uncommon symptoms or signs at presentation have to be also 
assessed: stupor, hypotension and tachycardia, hypothermia, bilateral visual 
disturbances and papilledema, epileptic seizures, hearing loss, hallucinations and 
behavioral disturbances.
 


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19. Section 8.2.9 Clinical safety laboratory assessments.

Addition of thiamine blood level assessment as part of laboratory assessment for 
fedratinib pretreated patients.
20. Section 9.1.1 AE Definition and Reporting.

Clarification that monthly AE reporting to DSE will not be done and that reporting in 
place is corresponding to Good Vigilance Practice.
21. Section 10.3 Data collection.

Data collected will include information about previous fedratinib treatment as well as 
its end date when applicable. For pre-treated fedratinib patients, information 
regarding previous treatment by ruxolitinib will be collected, as well as if patient have 
been previously treated by ruxolitinib within CINC424A2401. If patient previously 
participated in CINC424A2401, his/her initial patient number will be collected.
22. Section 11.2 Populations for analysis.

Addition of a Per Protocol set.
23. Section 11.6.1.

Clarification that FAS will be used for all efficacy analysis.
24. Section 11.6.8.

 
25. Section 11.7 Interim analysis

Correction to include patients with platelet count from 50,000 to <100,000/µL in the 
population defined as low platelet patient: deletion of 99.000/µL and insertion of 
<100,000/µL as upper limit for platelet count for this population.

Clarification that analyses may be performed if needed to fulfill regulatory obligations, 
to comply with post-approval commitments or for publication purposes.
26. Section 11.8 Sample size calculation.

Clarification that as based on country assessments and not computed, the maximum 
number of patients expected to be included in the trial is 2500. Trial recruitment will 
end once 2500 patients included is reached or by 31 Dec 2014, whichever comes first. 
27. Appendix III.

Addition of thiamine blood level assessment as part of laboratory assessment for 
fedratinib pretreated patients.
28. Appendix X.

Eligibility checklist.
 


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Amendment 3
Amendment rationale
Since implementation of amendment version 02, dated 13Aug2012, updates from the 
EXPAND trial has provided additional safety data to allow inclusion of patients with baseline 
platelet counts <75,000/ µl. 
Safety and efficacy data obtained from ongoing clinical trials provide additional information 
regarding the efficacy and safety of INC424 in patients with platelet counts between 50 000 
and 75 000/µl, with a level of efficacy comparable to what is observed in patients with higher 
platelet counts and comparable safety profile (Harrison 2012, Talpaz 2012). In these studies, 
patients with lower baseline platelet counts were initially treated with ruxolitinib 5 mg p.o. 
BID.  Patients with lower platelet counts may be treated as per marketing authorization in 
countries where INC424 is approved by the local Health Authority. In order to address 
treatment needs in this population in countries where INC424 is not yet available, and to 
gather additional safety and efficacy data, the trial recruitment is extended to patients having a 
baseline platelet count between 50,000 and 75,000/ µL.
There continues to be a high level of unmet clinical need among patients with MF in countries 
where the local regulatory approval and commercial availability of INC424 has not yet been 
granted.
Due to previous consideration, an amendment is deemed necessary to extend recruitment 
duration and allow additional patients to be recruited until treatment is deemed available.
The major changes to the protocol include:
1.0 Addition of inclusion criteria for patients having a 50,000 to 75,000/ µL baseline platelet 
count if all other inclusion/exclusion criteria are met, and addition of dosing instructions 
for those patients for an initial dose of 5 mg p.o. BID.
2.0 The sample size is to be increased up to a maximum of 2484. 
3.0 Enrollment to the study will complete when the maximum number of patients has been 
enrolled or December 31, 2014, whichever comes first. 
4.0 The decision regarding end of treatment will now include physician decision.
5.0 Data analysis will no longer be performed annually, but may be performed if needed to 
fulfill regulatory request or publication purpose. 
6.0 Where Country-specific local Health Authority approval is in process, drug supply is 
updated to take into account that drug may be supplied centrally, or locally if deemed 
necessary after local Health Authority approval have been granted.
7.0 Statistical analysis reflecting updates in estimated end of enrollment and end of treatment, 
with inclusion of patients with baseline platelet count of 50,000 to 75,000/µL in the pool of 
patients with low platelet counts.
8.0 Update AE definition and processing.
 


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9.0 Update reference list
Study Status
The trial is currently enrolling and close to reaching the original estimate of 1600 patients. 
Changes to the Protocol
Changes to the specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions and red and bold for insertions. 
a. Study Synopsis

Background

Update on regulatory approvals obtained from 2012 in several countries.

Updated clinical trial data (Expand) (Harrison 2012) and addition of data from a 
Phase II trial in patients with low baseline platelet counts (Talpaz 2012)
b. Endpoints (safety)

Clarification regarding laboratory value analysis.
c. Endpoints (efficacy)

Clarification regarding platelet and WBC analysis.
d. Study design

Deletion of planned 2 year duration of recruitment period and insertion that enrollment 
to the study is estimated to complete when the maximum enrollment of 2484 patients 
is reached or December 31, 2014, whichever comes first. 
e. Sample size

Deletion of 1600 plus a 20% attrition rate as projected number of patients to be treated 
in the study and insertion of a maximum of 2484 patients to be enrolled.
f.
Inclusion, exclusion criteria

Inclusion/exclusion criteria: exclusion criteria 9 is updated to reflect possible inclusion 
of patient with a 50,000/ µL platelet count at minimum based on additional data 
obtained from clinical trial and to allow inclusion of patients having the same health 
state that the ones authorized to receive treatment as per marketing authorization in the 
Europe.
g. Dose, regimen, treatment

Updated starting dose instructions taking into account patients enrolled with a 50,000/ 
µL platelet count. Based on available efficacy and safety data and to reflect 
recommended dose as per marketing authorization, the starting dose for those patients 
will be 5 mg p.o. BID.  Patients with platelet count below 50,000/ µL are ineligible for 
this trial.
For those patients who start INC424 treatment at a dose of 5 mg p.o. BID, dose 
increases can be made, at the discretion of the investigator, as described below. The 
dose of INC424 may be escalated 5 mg once a day starting at week 4, and thereafter, 
no more than once every two weeks ONLY if: 

The patient must not have had a prior safety-related dose reduction.
 


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
Platelet count remains ≥50,000/µL since last lab scheduled visit.

ANC > 1000/µL since last scheduled visit.

No dose reduction or interruption for safety occurred in the preceding weeks after the 
last planned visit.

The dose increase may only be an increase of 5 mg o.d. i.e., from 5 mg PO BID to 5 
mg QAM and 10 mg QPM.

The total dose may never exceed 25 mg BID.
Following a dose increase, platelet count and ANC levels should be assessed 
approximately 2 weeks after the dose adjustment.  If a regularly scheduled Study Visit 
does not coincide with this required blood draw, an unscheduled Interim Visit should 
be held to collect samples for hematology.
Dose interruptions of dose reductions for patients starting INC424 5 mg BID are made 
according to the platelet counts:

If platelets ≤25,000/ µL and/or ANC <500/ µL, treatment is to be held

If platelets >25,000 to <50,000/ µL, INC424 dose will be reduced by 5 mg o.d.

The patient should then be reassessed the following month. If the platelet count 
improves, the patient can restart treatment, and if the platelet count does not improve, 
the patient should be withdrawn from the study.

Add physician decision to reasons for end of treatment
h. Supply, preparation, and administration 

Addition of statement that INC424 may be supplied centrally or locally by Novartis 
and that storage condition can refer to local or study label
i.
Statistical methods and data analysis

Clarification regarding laboratory values analysis
j.
Interim Analysis

Deletion of description of analyses to be performed annually beginning with a data 
cutoff of December 2012 and insertion of statement that analyses may be performed as 
needed to fulfill regulatory request or for publication purposes. 
k. Section 1.3.4 INC424 clinical safety and efficacy in phase I/II trials

Update from data presented at the American Society of Hematology meeting in 
December 2012 (Harrison 2012) 

Additional clinical trial data from a phase II study presented at the American Society 
of Hematology meeting in December 2012 (Talpaz 2012)
l.
Section 2.2 Rationale for dose and regimen selected

Updated with clinical trial data (Harrison 2012, Talpaz 2012)
m. Section 3.3 Study Endpoint

Clarification of laboratory value analysis

Clarification of platelet and WBC analysis
n.
Section 4.1 Description of study design

Insertion of estimation that enrollment will complete when the maximum enrollment 
of 2484 patients is reached or by December 31,2014, whichever comes first
 


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
Insertion of physician decision as a reason for end of treatment 
o. Section 5.3, Exclusion criteria.

Exclusion criteria 9 is updated to reflect possible inclusion of patient with a 50,000/µL
platelet count at minimum based on additional data obtained from clinical trial and to
allow inclusion of patients having the same health state that the ones authorized to 
receive treatment as per marketing authorization in the Europe.
p. Section 6.1.1 Study drug dosing

Update dosing instructions

Dosing instructions are updated to take into account patient enrolled with a 
50 000/µl platelet count. Dosage combination table is also updated accordingly.

Addition of physician decision as a reason for end of treatment
q. Section 6.5.1 Study drug preparation and dispensation

Addition of physician decision as a reason for end of treatment
r.
Section 6.5.2 Study drug packaging and labeling

Addition of physician decision as a reason for end of treatment
s.
Section 6.5.3 Drug supply and storage

Table 5-6: addition of statement that INC424 may be supplied centrally or locally by 
Novartis and that storage condition can refer to local or study label
t.
Section 7.2.1 Efficacy

Updated estimated end of recruitment when the maximum enrollment of 2484 patients 
is reached of December 31, 2014, whichever comes first. 
u.
Section 7.5.1.9 Week 24 (± 7 days)

Deletion of collection of Medical Resource Utilization (MRU) in the past 3 months to 
correct MRU collection in the past month,
v. Section 7.6.1 Criteria for premature withdrawal.

Adjustment to reflect acceptable lower limit for baseline platelet count of 50,000/µL.
w. Section 9.1.1 AE Definition and Reporting

Update on AE definition and processing.
x. Section 11 Statistical methods and data analysis

Timing of analyses

Deletion of description of analyses to be performed annually beginning with a 
data cutoff in December 2012 and insertion of statement that analyses may be 
performed as needed to fulfill regulatory request or for publication purpose. 

Change in analysis to data will be analyzed according to platelet count at baseline 

Statistical reporting and grouping

Update of definition of baseline value to integrate that if a baseline assessment is 
not available prior to the start of first dose, assessment on the day of first dose 
may be used as baseline.
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
Change from analysis based on summary of patients in safety set to summary based on 
FAS
z. Section 11.4 Treatments (study drug, concomitant therapies, compliance)

Deletion of summary of duration of dose interruptions
aa. Section 11.5 Primary objective

Deletion of death for consistency with Section 3.1
bb. Section 11.5.1 Variables

Deletion of analysis of incidence of AEs by patient and statement “(i.e., incidence) 
considering or not certain AE characteristics (e.g., relationship to study medication 
severity)

Clarification of incidence to “ratio of the total number of patients experiencing at least 
one AE (defined by its preferred term) divided by the total number of patients in the 
safety set”
cc. Section 11.5.2 Statistical hypothesis, model, and method of analysis

Removal of analysis of deaths and death rate since death is not part of the primary 
analysis
dd. Section 11.6 Secondary objectives; Section 11.6.1 Variables

Clarification of the definitions of progression free survival, leukemia free survival, and 
overall survival
ee. Section 11.6.1.2 Statistical hypothesis, model, and method of analysis

Clarification of the summary of WBC and platelet count changes as descriptive 
statistics
ff. Section 11.6.3 Other safety data

Descriptive statistics for ECGs have been deleted and replaced by “Notably abnormal 
changes in ECG parameters will be displayed in listings” in amendment 02. Previous 
description which is no longer applicable regarding Descriptive analysis of ECGs 
parameters did nevertheless remain, which is corrected.

Addition of assessments of deaths and death rate (moved from Section 11.5)
gg. Section 11.6.5 Quality of Life Assessments.

CINC424A2414 Quality of Life analyses consist of visits and not of cycle. Wording 
have been corrected regarding Quality of Life data analysis to clarify that analysis will 
be based on visits.
hh. Section 11.7 Interim analysis

Deletion of description of analyses to be performed annually beginning with a data 
cutoff in December 2012 and insertion of statement that analyses may be performed if 
needed to fulfill regulatory request or publication purpose. 

Update IA for patients with low platelet count

Include patients with platelet count between 50,000 and 99,000 / IU in this population
ii. Section 11.8 Sample size calculation

Deletion of 1600 plus 20% attrition rate as projected number of patients to be treated 
in the study and insertion of a maximum of up to 2484 patients. 
 


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jj. Section 13 References

Updated reference list with additional references (Harrison 2012, Talpaz 2012)
Amendment 2
Amendment rationale
Since the FPFV date in the JUMP trial our understanding of INC424 in the treatment of MPN 
has changed and thus revisions to the protocol are necessary to adapt to these new findings.
The major changes to the protocol include:
1. To re-evaluate the inclusion and exclusion criteria to the study:

New safety data from [CINC424A2352], [INCB 1824-351], and the [CINC424A2201] 
trials provided further information on the safety of treating patients with low platelet 
values with INC424. Therefore some inclusion and exclusion criteria are no longer 
necessary.

Modification of the inclusion criteria to include patients with platelet counts between 
75,000 and 99,000/µL
a.
Per epidemiology data (Mesa et al 2007), 16.5% of all MF patients are reported 
to have platelet counts < 100,000/µL at diagnosis; while in the intermediate risk-1, 
-2, or high-risk disease population the incidence of thrombocytopenia is estimated 
by medical experts to be higher
b.
Data from ongoing trials presented at medical congresses in 2012 (Gisslinger 
2012, Talpaz 2012) have revealed that INC424 can be safely administered in 
patients with platelet counts between 50,000/µL and 99,000/µL, producing a level 
of efficacy comparable to what is observed in patients with a higher platelet count.
c.
The protocol has been updated with references to this data, and also to broaden 
the inclusion criteria to include patients with platelet counts between 75,000 and 
99,000/µL. This patient population represents 25% to 30% of total MF patients, 
and by including them, we will increase the possibility to cover the global medical 
need in MF.
d.
The dose of INC424 in patients with platelet counts between 75,000/µL and 
99,000/µL differs from patient with platelet counts ≥100,000/µL. In order to 
provide more clarity on how to administer INC424 in this group of patients, the 
protocol has been amended to provide a detailed description of how to start and 
how to adjust the dose based on response and platelet counts.
e.
Fluctuation in the platelet counts inherent to the nature of the disease has 
precluded potential patients’ qualification in the study. Therefore the qualifying 
platelet criteria have been revised.
2. Increase the enrollment sample size from 950 to 1600 patients plus a 20% attrition rate

In addition to enrolling more patients due to the broader inclusion/exclusion criteria 
(i.e., inclusion of patients with low platelets), there is a need to address the increased 
medical need of patients with MF at the country level. This resulted in a reassessment 
of trial commitments by countries for target patient enrollment, and led to an increased 
 


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estimation of approximately 1600 patients plus a 20% attrition rate enrolled by the end 
of trial.
3. Addition of interim analyses

With the enrollment of a larger sample size and the inclusion of patients with a 
baseline platelet count between 75,000 and 99,000/µL, an interim analysis is 
introduced when 50 patients with a low baseline platelet count have received at least 6 
months of therapy. This analysis is intended to provide preliminary information on 
safety and efficacy on patients with a low platelet count in comparison with the 
patients who started with a higher platelet count (≥100,000/µL),

Analyses will also be performed annually, beginning with a data cutoff in December 
2012. These analyses will include descriptive summaries of demographic and baseline 
characteristics, disposition, spleen length response and adverse events. These analyses 
will primarily be used for publication purposes.
Study Status
The trial is currently enrolling and approaching the original estimated accrual of 950 patients.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike-through red font for deletions, and red and bold for insertions.

Updated author list of protocol 
 to reflect the team currently working 
on/managing the protocol

Updated the table of contents to reflect changes made to the protocol; modified table 
numbers; modified the number of appendices following removal of Appendix II

Updated the glossary of terms: the medication number has been deleted from both the 
glossary of terms and Section 6.5.2, as it is not applicable to this study; the patient number 
will be the only identifier used and included on the drug dispensing label for this particular
study. The glossary of terms for ‘patient number’ has been updated to reflect the inclusion 
of this identifier on the drug dispensing label.

Delete references to overnight fasting of at least 8 hours or since midnight as no 
pharmacokinetic studies are being performed

There is no need to collect fasting blood specimen

Update the list of abbreviations to include all abbreviations used in the protocol as several 
were missing from the original version of the protocol

Delete IRT and any references to it throughout the protocol, as this was not used in this 
protocol

Add INR to coagulation parameters as an option for those institutions who are unable to 
measure PT/PTT (not mandatory for all regions, only those regions who are unable to 
perform PT/PTT estimations)

Not all countries enrolling patients are able to measure a PT/PTT, and can measure 
INRs, and as such INR was added to reflect current methods of assessing coagulation 
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
Ensure consistency of language throughout the protocol where set abbreviations are used 
e.g. FACT-Lym version 4

Change spleen size to spleen length in body of protocol (not changed in the background 
section to ensure consistency with published information): spleen length is a more accurate 
assessment of response to treatment and provides a more uniform assessment across the 
conduct of the study (compared to ultrasound and MRI)

Glossary of terms: changed the definition of medication number as this not a randomized 
trial and does not apply. It is a correction from the original protocol.

Removal of reference throughout to “cycle”. INC424 is administered continuously, thus 
cycle terminology does not apply

Clarified throughout that additional bone marrow biopsies are not mandatory as the 
endpoints of the trial are assessment of best overall response, which is characterized by the 
percentage change in spleen length compared with baseline, observed during the study 
follow-up period

Deleted Appendix II as this pertains to traditional measures of disease response; as a 
consequence renumber Appendix II – X (will not become I – IX in total)

All references to Appendix II – X were updated with new numbering throughout the 
protocol

Change the requirement of bone marrow biopsy to be performed at the discretion of the 
investigator and not as a timed procedure. Bone marrow examinations are performed as a 
tool for diagnostic purposes in MF but are not a standard requirement for the management 
of the disease, which is largely based on physical examination. A bone marrow biopsy may 
also be performed as a routine part of clinical care when determining progression to acute 
leukemia, based on alterations to peripheral blood counts.

Study synopsis

Background updated to include:

Inclusion of the New England Journal of Medicine Phase III data on safety and 
efficacy of INC424 (Verstovsek 2012 and Harrison 2012) as the data were not 
published at the time the protocol was written

FDA approval date as this occurred since the original protocol was released

Detailed description of the COMFORT-I and COMFORT-II trials (safety and 
efficacy) as they are now published in peer reviewed journals

Safety and efficacy data supporting dosing of INC424 in patients with platelet 
counts between 75,000/µL and 99,000/µL as the inclusion criteria have been 
expanded to include this group of patients

Purpose/rationale: added the FDA approval date; added in data cut-off dates for 
COMFORT-I and COMFORT-II as data newly available

Endpoints (safety, quality of life): changed language in medical resource utilization to 
include frequency of general practitioner, specialist, urgent care, and emergency room 
visits (changed throughout protocol)

Endpoints (efficacy): clarified how data will be collected and presented
 


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
Changes in spleen length and WBC/platelet count changes from baseline to each 
visit (no longer per cycle/month). INC424 is administered continuously therefore 
there is no cycle.

Where bone marrow biopsy data are available, changes in fibrosis from baseline 
to the worst value will be reported (NOTE: biopsies are not mandatory) 
(Appendix V)

Study design:
a.
Changed period in which baseline evaluations should be performed from 2 weeks 
to within 1 week of the first dose of INC424: modified to correlate with Table 7-1 
(Day -7 to Day -1); was a typographical error in the original protocol

Population:

Added in danocrine (Danazol®) as a permitted prior treatment
Many countries use danocrine (Danazol®) and the lack of a mention of the agent 
in the protocol resulted in a number of calls to the study monitors and hence 
required clarification

Clarified the time period in which all prior treatment for PMF, PPV MF, or PET-
MF must be discontinued prior to the initiation of INC424
The lack of clarification of the time in which prior therapy should be discontinued 
resulted in a significant number of queries and confusion from study sites; thus 
provided clarification
a.
Specified countries that are participating in the JUMP trial

Sample size:

Increase the enrollment sample size from 950 to at least 1600 patients plus a 20% 
attrition rate

In addition to enrolling more patients due to the broader inclusion/exclusion 
criteria (i.e., inclusion of patients with low platelets), there is a need to address the 
increased medical need of patients with MPN at the country level. This resulted in 
a reassessment of trial commitments by countries for target patient enrollment, 
and led to an increased estimation of approximately 1600 patients plus a 20% 
attrition rate enrolled by the end of trial.

Inclusion criteria:
a.
Clarified the timing of risk assessment to the screening visit as it was not listed in 
the original protocol
b.
Added in direct bilirubin exclusion limits

Added total bilirubin as the initial value to be estimated where direct bilirubin 
assessments are not standard (and exclusion limits).
It is local practice, for some countries, to perform an initial assessment of total 
bilirubin. When elevations in the total bilirubin are documented, separation by 
direct and indirect bilirubin will occur.

Exclusion criteria:
 


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a.
Deleted criteria that excludes patients who are receiving hematopoietic growth 
factors
Data have become available since the original INC424 studies were performed 
that suggest INC424 can be safely coadministered with hematopoietic growth 
factors. Deleting these exclusion criteria has the potential to enable greater 
enrollment.
a.
Deleted “patients currently participating in COMFORT-I and the COMFORT-II 
trial” as the inclusion criteria specifies patients should not be eligible for any other 
INC424 trial so this criterion is addressed; furthermore these trials are closed to 
accrual.
The COMFORT-I and COMFORT-II trials are also fully enrolled at this time, so 
the exclusion criteria no longer applies
a.
Clarified that the definition of inadequate bone marrow reserve pertains to the 
baseline visit and also modified the lower platelet threshold (as the new dosing 
cohort was added)
Modified the requisite baseline platelet count to 75,000/µL, from 100,000/µL, 
based on the inclusion of the new cohort of patients with thrombocytopenia who 
start INC424 dosing at 5 mg BID when platelets are between 75,000/µL and 
99,000/µL
a.
Add in INR > 1.5 x ULN to laboratory parameters
Previous version of the protocol had the incorrect upper limit of normal (0.5); 
modified protocol to include upper limit of > 1.5 and also to include INR as an 
option where PT/PTT estimations cannot be performed

Updated the pregnancy language to be consistent with accepted Novartis 
documentation for highly effective contraception by the Pharmacovigilance 
department. These changes are not due to documentation of teratogenic effects of 
INC424.
a.
Patient numbering: changed the time from 2 weeks to 1 week for starting 
treatment from time of meeting eligibility criteria.
This was to correct the erroneous variable on the original protocol; was supposed 
to be 7 days when the trial was initiated.

Investigational and control drugs: added in that there is no control drug in this 
study as it is an open-label study

Dose, regimen, treatment cycle:
a.
Added in a category of patients with platelet counts between 75,000 and 
99,000/µL to be dosed at 5 mg BID INC424
b.
Added in details for the patient population above regarding dose modifications 
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c.
Clarified the dose escalation requirements that were originally listed in the 
protocol pertain to the 15 – 20 mg BID cohort only

MRU: clarified the visits that will be captured are to include emergency room visits, 
urgent care visits, general practitioner and specialist visits, in addition to 
splenectomy/splenic irradiation, transfusions, and concurrent medications

Efficacy assessments: clarified how patients who are splenectomized will be 
monitored
a.
This group of patients is being enrolled onto the study, and the efficacy endpoint 
of changes in spleen length is not assessable in the splenectomized patients. As 
such efficacy outcomes will be based on patient reported outcomes only in this 
population

Statistical analysis updated to include:
a.
The primary analysis will be performed after all patients have either completed 
24 months of treatment or have been prematurely discontinued from the study. All 
patients should have been followed for 28 days after they have discontinued 
INC424. Data collected during this follow-up period will be included in the 
analysis.
a.
Statistical reporting and grouping
Data will be analyzed according to platelet count and displayed considering the 
following two groups:
(a) Low platelet patients (platelets < 100,000 /µL)
(b) Non-low platelets (platelets ≥ 100,000 /µL)

Interim analysis
a.
The interim analysis planned for this study will take place when 50 patients with 
low platelets have completed 6 months of treatment
b.
Interim analysis will be performed annually, beginning with a data cutoff in 
December 2012.

Section 1 (background): added detail on FDA approval in the USA, including date of 
approval and indication

Section 1.3.4.2: Added data from the Phase 1b study of INC424 in patients with MF and 
baseline platelet counts between 50,000 and ≤ 99,000/µL to justify inclusion of patients 
with lower platelet counts
a.
Resulted in the renumbering of items in this section
a. Section 1.3.5 (phase 3 studies): updated to include data from recently published Phase 3 
trials (COMFORT-I and COMFORT-II); added description of the 2 trials; outline efficacy 
and safety results from the licensing studies; updated safety information from the IB
b. Section 2.1 (study rationale and purpose): updated to include published COMFORT-I and 
COMFORT-II safety and efficacy data
c. Section 2.2 (rationale for dose and regimen): added data to support inclusion of patients 
with platelet counts between 75,000 and 99,000/µL
d. Section 3.3.2 (study endpoints, efficacy): change mention of cycle to visits; change in 
fibrosis to shift in fibrosis; provided clarification that bone marrow biopsies on study are 
 


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not mandatory; added in assessment of efficacy in patients who are splenectomized; 
clarified best overall response (as outlined in synopsis changes)
e. Section 3.3.4 (Study endpoints, MRU): updated to include general practitioner, specialist, 
and urgent care visits in addition to emergency room visits (as outlined in synopsis changes)
f.
Section 4.1 (study design):
a.
Removed description of cycles, as INC424 is administered continuously (provided no 
AEs)
b.
Described the ability to use historical results (if within protocol requirements) during 
the 28 days prior to Day 1 to avoid duplication when the screening and baseline visits 
are combined on the same visit
a.
Clarification that laboratory assessments and other examinations performed 
consistent with protocol requirements within a week of the first dose of INC424 
are able to be used , and that duplication of results in this setting is not necessary
c.
Provided details on the FPFV and the planned recruitment period:
1. The FPFV occurred on 16 August 2011 and the recruitment period is planned to 
last 2 years.
d.
Added patients are able to be rescreened if they fail an initial study screening at the 
discretion of the investigator, but no more often than every 7 days
e.
Clarified that the treatment of patients in the treatment period is contingent of meeting 
study criteria
g. Figure 4-1: remove mention of cycles; change to continuous dosing; replaced figure with a 
more descriptive image to describe what is occurring on study
h. Section 5.2 (Inclusion criteria):
a.
Provided additional references for diagnosis of PMF, PPV MF, and PET-MF as not 
encompassed in original reference (Appendix I)
b. Clarified the need to determine patient risk at the screening visit
c.
Clarified the 5 prognostic factors as defined by Cervantes (old version had merged 
criteria)
d. Added total bilirubin as a determinant of liver function test abnormalities

It is local practice, for some countries, to perform an initial assessment of total 
bilirubin. When elevations in the total bilirubin are documented, separation by 
direct and indirect bilirubin will occur.
i.
Section 5.3 (Exclusion criteria):
3
Delete exclusion of patients participating on the COMFORT-I trial as this trial is now 
completed
4
Delete exclusion criteria of “patients undergoing treatment with hematopoietic growth 
factor receptor agonists” as there are data available demonstrating safety when 
coadministering INC424 with hematopoietic growth factor receptor agonists 
(Gisslinger)

Concomitant ESA and INC424 use does not appear to affect these reductions in 
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
No substantially different AEs were reported in patients receiving INC424 in 
combination with ESAs compared with INC424 alone
5
Update coagulation parameters to also include INR (optional) as not all institutions are 
able to determine PT/PTT. Assessment of coagulation and response to anticoagulants 
can effectively be evaluated using INR where PT/PTT estimations are not able to be 
performed [(PT, PTT, INR) > 1.5 x ULN] i.e., either PT/PTT or INR
6
Updated the definition of inadequate bone marrow reserve to enable patients with 
platelet counts between 75,000/µL and 99,000/µL to be enrolled
7
Updated child-bearing criteria to include “highly effective contraception” according to 
Novartis Standards. These changes are not being made because of teratogenic risk, 
rather to be consistent with the verbiage provided by Novartis Pharmacovigilance.
j.
Section 6.1.1 (study drug dosing):

Moved information on supply of study drug to this section

Removed reference to “cycles” as the study drug is administered continuously

Added in the third cohort of dosing of 5 mg p.o. BID for patients with baseline platelet 
counts of 75,000/µL – 99,000/µL

Standardized units of reporting of platelets to thousand/µL, and not x 109/L
k. Section 6.1.2 (treatment duration): deleted this section from the protocol as there is no 
defined treatment period in this program/study other than it is continues until one of the 
stop marker hit. And these stop markers are already described in 6.1.1.
l.
Section 6.2.1 (dose increases after Week 4 [Month 1]):
a. Modified the section to make reading of dose modifications more clear. Separated 
into dose increases for patients starting at a dose of 15 – 20 mg BID (6.2.1.1) 
addressing dose increases after week 4 and then separately after week 4; then added 
section 6.2.1.2 for patients starting at a dose of 5 mg BID, similarly addressing dose 
increases after week 4 and then separately after week 4
b. Modified the section to include permissible Week 4 (and beyond) dose increases 
for those patients who start the study with platelets between 75,000 – 99,000/µL
c. Modified the section to include permissible dose increases beyond week 4 to 
include modifications for patients with platelet counts between 75,000 – 99,000/µL
m. Figure 6-1: replaced the figure with a clearer image
n. Section 6.2.2 (dose interruption or dose reduction): modified this section to include dose 
interruption/dose reduction schedules to encompass the new cohort of patients with platelet 
counts between 75,000 – 99,000/µL
o. Table 6-2: clarified that this table only applies to patients who start on INC424 doses of 15 
– 20 mg p.o. BID
p. Added Table 6-3 to address the dose reduction strategy for patients with platelet declines in 
patients with platelet counts between 75,000 – 99,000/µL at the start of therapy
q. Section 6.2.2.3: Added dose modifications for renal impairment as data now available in 
the IB and these data were not available at the time the original protocol was written
r.
Section 6.2.2.4: Added dose modifications for hepatic impairment as data now available in
the IB and these data were not available at the time the original protocol was written
 


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s.
Section 6.2.3 (restarting or reinstituting previous dose for patients who start INC424 15- 20 
mg BID)
1.
Clarified that the details contained within this section apply only to patients who 
started INC424 at a dose of 15 – 20 mg BID
2.
Eliminate the requirement for a maximum dose of INC424 to be 5mg BID less than the 
dose which caused a platelet count reduction < 100,000/µL. Restricting the dose to no 
higher than 5 mg BID less than any dose that caused a platelet count < 100,000/µL has 
limited the capacity of physician-investigators to dose patients higher when their 
platelet counts have improved above 100,000/µL, sometimes even to within normal 
range.
t.
Section 6.3.2 (permitted concomitant therapy requiring caution and/or action):
1.
Removed the exclusion of corticosteroid therapy
1. Corticosteroids were not permitted in the phase III trials, because they could induce a 
response in the constitutional symptoms of MF, making it difficult to assess the 
real impact of INC424. As this is not a randomized trial, steroids are permitted.
2.
Added in need for dose modification of INC424 in the presence of dual CYP2C9 and 
CYP3A4 inhibitors such as fluconazole to comply with some counties’ SMPC
3.
Added in detail regarding preferred anticoagulation if needed as follows: If 
anticoagulation is required during INC424 administration, low molecular weight 
heparin is preferred, particularly in patients who are: elderly, history of CHF, diabetic, 
hepatic or renal disease, or atrial fibrillation (first episode).
4.
Removed the limitation on hematopoietic growth factors (see earlier explanation)
u. Section 6.3.3 (Prohibited concomitant therapy):
1.
Clarified the time period in which prior treatment for the management of PMF, PPV 
MF, and PET-MF should be discontinued prior to administration of INC424
2.
Corticosteroid therapy is no longer prohibited
1. Corticosteroids were not permitted in the phase III trials, because they could induce 
response in some of the constitutional symptoms of MF, making it difficult to 
assess the real impact of INC424. As this is not a randomized trial, steroids are 
permitted
v. Section 6.4.1 (patient numbering): remove discussion on randomization as this is an open-
label study and does not apply
w. Section 6.4.2 (treatment assignment and randomization): clarified that this is not a 
randomized trial and as such no randomization will occur
x. Section 6.5.2: The medication number has been deleted from both the glossary of terms 
and Section 6.5.2, as it is not applicable to this study; the patient number will be the only 
identifier used and included on the drug dispensing label for this particular. The glossary of 
terms for ‘patient number’ has been updated to reflect the inclusion of this identifier on the 
drug dispensing label.
y. Table 7-1:
1.
Updated to hyperlink to pertinent sections in the protocol such as end of study 
treatment, to enable easier cross-referencing within the protocol for the end-user
2.
Added in disease status documentation to be performed at baseline
 


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3.
Added in bone marrow biopsy requirement (at baseline only for diagnostic purposes), 
but not mandatory following diagnosis. Additional bone marrow biopsies will only 
performed at the discretion of the treating physician as part of routine care and are not 
required for the protocol.
4.
Added in assessment points for BM fibrosis (not mandatory) but when performed 
needs to be collected in a standardized time point
5.
Added in assessment point for leukemia-free survival
z. Table 7-2:
1.
Updated to hyperlink to pertinent sections in the protocol and added in the ability to 
check the INR for those institutions where PT/PTT measurements are not feasible
aa. Section 7.2.1 (efficacy): clarified that assessments at baseline are for disease status only, 
not response to treatment as patients will not be receiving INC424 at this time; all future 
visits will evaluate response to INC424 treatment
bb. Section 7.3 (screening):
1.
Blood sampling for hepatitis updated to include all requisite tests including Hepatitis A 
(IgM antibody); Hepatitis B (Hepatitis B surface antigen [HBsAg], Hepatitis B surface 
antibody [HBsAb], Hepatitis B IgM core antibody [HBcAb-IgM]; and Hepatitis C 
(Hepatitis C antibodies [HC Ab]) or local health authority requirements
2.
Added the need to specify risk group of patient at screening visit
cc. Section 7.4 (baseline evaluations):
1.
Removed requirement to fast prior to baseline evaluation
2.
Update MRU information collection (see synopsis)
3.
Removed the need to fast prior to baseline evaluations
dd. Section 7.4.1: added to address actions to be taken when the screening and baseline visits 
overlap
ee. Section 7.5.1.3 (week 4), 7.5.1.5 (week 8), 7.5.1.7 (week 12), 7.5.1.9 (week 24), 7.5.1.11
(week 36), 7.5.1.13 (week 48):
1.
Update MRU information collection (see synopsis) throughout
2.
Week 4: modified dose escalation based on starting dose of INC424
ff. Section 7.5.1.16: added in recommendations for management of missed/moved visits
gg. Section 8.1: clarified that the body mass index will be calculated automatically based on 
collected height and weight
hh. Section 8.2.7 (ECG analysis and reporting): delete the requirement for ECGs to be 
reviewed by a cardiologist
1.
The need for cardiologist-read ECGs is not supported based on the results of the 
Healthy Volunteer Study (Incyte study 138), and also to date no cardiac concerns have 
been noted in ongoing trials. Given the importance of monitoring electrocardiographic 
function with new compounds, however, it will be required to continue obtaining 
periodic ECG’s but the readings may be performed by the treating physician
ii. Section 8.2.8 (clinical safety laboratory assessments): remove the requirement for patients 
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1.
Local clinical practices often dictate total bilirubin is evaluated first. If results are 
within acceptable range then no further testing is required. However, if the total 
bilirubin result is out of normal range a determination of direct and indirect bilirubin 
will occur. Modification to include total bilirubin will enable countries to determine if 
there is an elevation first, before performing additional testing.
jj. Section 8.2.8.1 (pregnancy test): clarified the time period in which the pregnancy test 
should be obtained i.e., within 14 days of receiving the first dose of INC424
kk. Section 8.3.2.1 (FACT-Lym): removed all references to the FACT-G scale as this is not 
being used in this study
ll. Section 8.3.2.2 (original protocol): delete all references to FACT-G and section on FACT-
G
mm.
Section 9.1.1.2 (surgical events related to disease under study): added this section 
as a separate item. It was incorrectly listed in original protocol under 9.1.2.1 which did not 
pertain to surgical management.
nn. Section 9.1.2.1 (definition and reporting): deleted references to surgical management 
creating a separate section (see 53 above) that addresses this need
oo. Section 9.2.2 (reporting): clarified that the reporting period of 28 days (not 30 days) to 
ensure consistency throughout the protocol
pp. Section 11:
1.
Updated statistical methods and analysis to include an interim analysis, including 
timing of analyses, and statistical reporting and grouping as previously described
qq. Section 11.1 (handling of missing values): updated per BIOS
rr. Section 11.4 (treatments): updated per BIOS to align with the RAP
ss. Section 11.6.1.1:
1.
Clarified the change in fibrosis to shift in fibrosis
2.
Added in the definition of leukemia-free survival
tt. Section 11.6.1.2 (statistical hypothesis, model, and method of analysis): updated per BIOS
uu. Section 11.6.2.2: added in a subsection for biochemistry estimations and 
presentation/analysis of data
vv. Section 11.6.3: added in verbiage to address reporting of ECG and blood pressure results
ww.
Section 11.6.4.1 (resource utilization): clarified data to be presented in the RAP
xx. Section 11.7: added details surrounding the interim analysis to be performed and consistent 
with the rest of the protocol
yy. Section 11.8: deleted text on INC424 procurement as it does not relate to sample size 
calculation; added in rationale for new sample size calculation (see earlier in rationale)
zz. References: added in new references (Verstovsek NEJM 2012; Harrison 2012, Swerdlow 
2008; Gisslinger 2012; McMullin 2012, Mesa 2007, Talpaz 2012), and deleted non-
pertinent references (Trussell)
aaa.
Appendix I: added in criteria for diagnosis of PPV MF and PET-MF (Barosi) as 
they were not in the protocol previously
bbb.
Appendix II: deleted (see earlier in rationale)
 


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ccc.
Appendix III (now II): deleted old appendix and inserted Novartis standard 
language for highly effective contraception per Pharmacovigilance
ddd.
Appendix IV (now III): added in direct bilirubin, INR (where PT/PTT not feasible); 
alkaline phosphatase (where feasible); outlined hepatitis panel to be evaluated
eee.
Appendix X (now IX): removed agents that are contraindicated in the protocol from 
the concomitant medication list
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 1
Amendment rationale
2. The protocol version 00, dated 25-Jan-2011, contained some inconsistencies that 
required correction, thus Amendment 1 was prepared to address these issues.
3. These inconsistencies included:
a.
Clinical study protocol synopsis: exclusion criteria number 13: patients with 
coagulation parameters (PT, PTT, INR) >5 x ULN should be corrected to read >1.5 x 
ULN which is the correct coagulation parameters and the omission on page 15 is 
considered a typographical error.
b.
Study design: screening window: figure 4-1: -14 to -1 Day of screening and eligibility 
clearly noting it should be up to 28 days before first dose; the typographical error was 
corrected.
c.
The correct days before first dose should be “up to 28 days before first dose” as 
written in the text of the protocol under screening and eligibility.
4. There are strict internal policies that govern the development of a protocol and the 
process in which it undergoes final internal review and approval. Upon final approval 
and sign-off by the appropriate reviewers, the process mandates that version control is 
achieved through one of our specified internal electronic systems. Only the version 
available in the electronic system is the approved protocol and related study documents.
a.
Due to a human error, an unapproved version of the amendment 01 dated 05 May 
2011 was released and submitted to Health Authorities in 12 countries.
b.
This error was discovered and all affected Health Authorities were informed. This 
erroneous amendment 01 version was retrieved. Sites were asked not to use this 
version and informed that an amendment 02 would be prepared to address the above 
mentioned errors.
 


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IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
 


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Oncology clinical study protocol synopsis
Investigational 
drug
INC424 (ruxolitinib)
Protocol no.
CINC424A2401
Study phase
IIIB
Study title
An open-label, multicenter, expanded access study of INC424 for patients with primary 
myelofibrosis (PMF) or post-polycythemia vera myelofibrosis (PPV MF) or post-essential 
thrombocythemia myelofibrosis (PET-MF).
Study population
Male or female patients ≥ 18 years of age who have been diagnosed with PMF, PPV MF, 
or post-essential thrombocythemia myelofibrosis (PET-MF) (Appendix I), who meet 
intermediate-1 criteria and have palpable splenomegaly of at least 5 cm below the costal 
margin, or who meet intermediate-2 criteria, or who meet high-risk prognostic criteria. 
Patients are not required to have received prior therapy for MF.
Study objectives
Primary objective
- To collect additional safety of INC424 in patients with PMF, PPV MF, or PET-MF, who 
have either received prior treatment with commercially available agents, investigational 
drug, or never received treatment.
Secondary objectives
- To assess the best overall response rate of INC424 in patients with PMF, PPV MF, or 
PET-MF as evaluated by the Investigator.
- To collect (QoL) information in patients with PMF, PPV MF, or PET-MF treated with 
INC424.
- To document MRU in patients with PMF, PPV MF, or PET-MF treated with INC424
Background
Myelofibrosis (MF) is a clonal hematologic neoplastic disease characterized by the 
presence of megakaryocyte proliferation and atypia, usually accompanied by either 
reticulin and/or collagen fibrosis (Tefferi A (2008)), splenomegaly, anemia, and debilitating 
constitutional symptoms that include fatigue, weight loss, pruritus, night sweats, fever, and 
bone, muscle, or abdominal pain (Mesa RA, Niblack J, Wadleigh M, et al (2007), Abdel-
Wahab OI, Levine RL (2009)). MF can either be primary in origin (primary myelofibrosis, 
or PMF) or result from progression of polycythemia vera or essential thrombocythemia 
vera (Tefferi A (2008)). The median age at diagnosis of MF is approximately 65 years. 
Patients with myelofibrosis have shortened survival that ranges from a median of 
approximately 2 years to 11 years depending on the presence of certain risk factors that 
define their risk category including age, anemia, leukocytosis, etc
The JAK2V617F mutation has been identified in over 95% of patients with PV and 
approximately 50% of patients with essential ET and PMF. The JAK2V617F mutation 
alters the JAK2 tyrosine kinase making it constitutively active. As a result, polycythemia, 
thrombocythemia and leukocytosis can develop independently from growth factor 
regulation. Even in patients lacking a confirmed JAK2 mutation, the detection of STAT 
activation suggests dysregulated JAK activity. Development of JAK1 and JAK2 targeted 
therapies has the potential to improve the outcome of patients with PMF, PPV MF, and 
PET-MF.
INC424 (ruxolitinib, Jakafi®), is an oral JAK 1/JAK 2 inhibitor, was approved by the FDA on 
November 16, 2011 , and approved by the EMA on 31 August 2012, for the
treatment of intermediate or high-risk myelofibrosis , including PMF, PPV MF and PET-
MF. INC424 is also approved in Canada, Switzerland and other countries. A number of 
clinical trials were performed supporting the approval, including Phase I/II trials -
completed; Phase III COMFORT-I trial (Verstovsek 2012) and COMFORT-II trials 
(Harrison 2012) completed, data cut-off 2 Nov 2010 and 4 Jan 2011, respectively. INC424 
has demonstrated activity at a range of different doses and dosing intervals ranging from 
15 mg - 25 mg BID. The Phase III COMFORT clinical trials evaluated a starting dose of 20 
mg BID for patients with platelet counts > 200,000/µL and 15 mg BID for patients with 
 


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platelet counts between 100,000 and 200,000/µL.
In COMFORT-I (INC424 vs. placebo), significantly more patients in the INC424 arm had 
reductions in spleen volume (≥35%) which were maintained (67% of the patients with a 
response had the response for ≥48 weeks). Similarly, significantly more patients had an 
improvement (≥ 50%) in the total symptom score compared to placebo at 24 weeks 
(45.9% INC424 vs.5.3% placebo, P<0.001). INC424 was well tolerated in COMFORT-I, 
with most Grade 3/4 non-hematologic toxicities occurring in less than 6% patients: fatigue 
5.2%, diarrhea 1.9%, dyspnea 1.3%, dizziness 0.6%, vomiting 0.6%, arthralgia 1.9%, 
pyrexia 0.6%, and abdominal pain 2.6%. Hematologic toxicity consisted primarily of 
anemia and thrombocytopenia. Grade 3/4 anemia occurred in 45.2% patients, and Grade 
3/4 thrombocytopenia occurred in 12.9% patients. Approximately half of the Grade 3/4 
anemia and thrombocytopenia events occurred during the first 8 weeks of therapy. 
Treatment with INC424 enabled 41.2% of patients to become transfusion independent. 
Anemia and thrombocytopenia were manageable, and thrombocytopenia generally 
responded to dose reduction or temporary dosing interruption. Thirteen deaths occurred in 
the INC424 group vs. 24 deaths in the placebo group (HR, 0.50; 95% CI, 0.25 to 0.98; 
P=0.04). The rate of discontinuation of the study drug because of AEs was 11.0% in the 
INC424 group vs. 10.6% in the placebo group.
In the COMFORT-II trial (INC424 vs. best available therapy [BAT], 28% of the patients in 
the INC424 group had ≥35% reduction in spleen volume at week 48 vs. 0% in the BAT 
group (P<0.001); the corresponding percentages at week 24 were 32% and 0% 
(P<0.001). The mean palpable spleen length (48 weeks) had decreased by 56% with 
INC424 but had increased by 4% with BAT. The median duration of response with INC424 
was not reached, with 80% of patients still having a response at a median follow-up of 12 
months. INC424 treatment was associated with an improvement in overall QOL measures 
and a reduction in symptoms associated with MF. The most common hematologic 
abnormalities (≥Grade 3) were thrombocytopenia and anemia. Thrombocytopenia and 
anemia occurred more frequently in the patients receiving INC424 vs. BAT, a finding that 
is consistent with the known mechanism of action of INC424, but these events rarely led 
to treatment discontinuation (one patient in each group discontinued the study owing to 
thrombocytopenia) and were generally manageable with dose modifications, transfusions 
of packed red cells, or both. AEs leading to dose modification with INC424 occurred in 
41% patients. Only 5% of the patients receiving INC424 required dose interruptions or 
reductions due to anemia and 1% due to neutropenia. Non-hematologic AEs were rare 
and mostly grade 1 or 2. Two cases of progression to acute myeloid leukemia were 
reported with the best available therapy. INC424 was also well tolerated in the 
COMFORT-II trial, with most Grade 3/4 non-hematologic toxicities occurring in less than 
3% patients: diarrhea 1%, asthenia 1%, dyspnea 1%, pyrexia 2%, nausea 1%, arthralgia 
1%, fatigue 1%, pain in extremity 1%, abdominal pain 3%, headache 1%, and back pain 
2%).
For a significant population of thrombocytopenic MF patients there are limited data about 
the safety of INC424 or what might be an appropriate dose, since in all studies conducted 
to date with INC424, a baseline platelet count of ≥ 100,000/µL has been an inclusion 
criterion. However, thrombocytopenia is a frequent event in MF; as per epidemiology data 
(Mesa 2007), 16.5% of all MF patients are reported to have platelet counts < 100,000/µL 
at diagnosis, while in the intermediate risk-1, -2 or high-risk disease population the 
incidence of thrombocytopenia is estimated by medical experts to be higher. A previous 
phase I/II study, [INCB 18424-251], has established thrombocytopenia as the dose-limiting 
toxicity of INC424 in MF patients with a maximum tolerated dose of both 25 mg BID and 
100 mg o.d. The incidence of grade ≥ 3 thrombocytopenia in this phase I/II trial was 20% 
at 10 mg BID, 29% at 15 mg BID, and 36% at 25 mg BID. Data from the same trial show 
that patients who entered the study with baseline platelet counts of 100,000/µL -
150,000/µL developed grade ≥ 2 thrombocytopenia more frequently (75% vs. 37%, 
respectively, for the most commonly used doses that will be relevant to this trial, 10 mg 
BID and 15 mg BID) compared with patients with baseline platelet counts > 150,000/µL, 
although with a similar nadir (grade 2 and 3). Thrombocytopenia occurred rapidly, and 
resolved with drug interruptions or dose decreases. In [INCB 18424-251] study, some 
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and 100,000/µL, but no patients with platelet counts below 100,000/µL have initiated 
INC424 therapy, and therefore the maximum tolerated dose for patients with low platelets 
needs to be directly established.
A phase Ib study of INC424 to investigate the safety of INC424 and establish the 
maximum safe starting dose in patients with MF who have baseline platelet counts ≥ 
50,000/µL to 99,000/µL is currently ongoing (Gisslinger 2012). The (Evaluating Ruxolitinib 
in Patients with Low Baseline Platelet Counts Diagnosed With Myelofibrosis) study is a 
single-arm, open-label, dose-finding study in adult patients with PMF, PET MF, or PPV-
MF. This study consists of two periods: (a) core study period (day 1 to week 24), and (b) 
an extension period (beyond week 24). There are two different dosing strata based on 
baseline platelet counts (Stratum 1: 75,000/µL to 99,000/µL; Stratum 2: 50,000/µL to 
74,000/µL). An updated analysis was presented at the American Society of Hematology 
meeting in December 2012. The data (n=20; PMF n=14, PPV=MF n=5, PET-MF n=1) 
demonstrates that in this phase 1b study of INC424 in thrombocytopenic patients with MF, 
no DLT has occurred at the first 2 dose levels in patients with platelet counts of 50,000/µL 
to 99,000/µL. INC424 has been generally well tolerated, similar to the tolerability reported 
in the previous studies, and no patient has discontinued because of thrombocytopenia. No 
patient had platelet counts below 20,000/ µL. No Grade 3/4 hemorrhagic events were 
reported.
A 24-week, open-label phase II study of INC424 to investigate the efficacy, hematologic 
effects and dose of INC424 in patients with MF, PPV-MF, and PET-MF and baseline 
platelet counts of 50,000 to 100,000/ µL is ongoing (INCB018424-258) (Talpaz 2012). The 
starting dose of INC424 is 5 mg p.o. BID with dose escalation with adequate platelet count 
by 5 mg once daily every 4 weeks (i.e. 5 mg p.o.AM and 10 mg p.o. PM) to a maximum of 
10 mg BID. Further dose escalation requires evidence of suboptimal efficacy. An initial 
report with data from 41 evaluable patients was presented at the American Society of 
Hematology meeting in December 2012. Among patients who completed 24 weeks of 
treatment, most were receiving INC424 dose of 10 mg p.o. BID or higher. No patients 
have discontinued treatment due to adverse events. Bleeding related events were 
reported in 7 patients (17.1%). Grade 1 bruising events (contusion n=2 and ecchymosis 
n=3) were reported in 7 patients. Other bleeding events were reported in 4 patients 
(subdural hematoma secondary to fall, hematochezia, hemorrhoidal hemorrhage and 
epistaxis; all grade 1 except grade 2 hematochezia).
Purpose/rationale
There were no commercially available agents with consistently demonstrated efficacy and 
safety in PMF, PPV MF, or PET-MF prior to FDA approval of INC424 (INC424; Jakafi®) on 
16 November 2011. Based on the results of the Phase I/II trial with INC424, two Phase III 
trials were initiated and have completed enrollment (COMFORT-I in the USA, Canada and 
Australia-data cut-off 2 Nov 2010; and COMFORT-II in the European Union). Final results 
for COMFORT-1 (Verstovsek 2012) showed positive results in the decrease of spleen 
length. In addition, symptoms associated with these diseases as weight loss, pruritus or 
fever, were improved with the treatment. This EAP protocol is designed to address an 
unmet medical need by providing INC424 to patients who are without satisfactory 
treatment alternatives for PMF, PPV MF and PET-MF, prior to commercial availability at a 
country level to collect additionally safety data of INC424 in PMF, PPV MF and PET-MF.
Endpoints (safety, 
quality of life)
Safety:
- Safety and tolerability will be collected by monitoring the frequency, duration and severity 
of all grade AEs by the National Cancer Institute CTCAE v. 3 0, performing physical 
exams (PE), and evaluating changes in vital signs (VS), ECOG performance status (PS), 
electrocardiograms (ECGs) and serum chemistry and hematology results.
- Grade 3 and 4 AEs, Serious Adverse Events (SAEs).
- Change in laboratory values from Baseline to End of Treatment (serum chemistry and 
hematology).
- Changes in weight from Baseline to each assessment point and at end of treatment.
- Cardiac function as assessed by electrocardiograms (ECGs).
 


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- Changes in vital signs.
Quality of Life (See Table 7-1 for assessments).
- Change in ECOG PS from Baseline to each visit where measured.
Change in Functional Assessment of Cancer Therapy for patients with Lymphoma 
(FACT-Lym) version 4 from Baseline to each visit where measured (See Appendix VII).
- Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue from 
baseline to each visit where measured (See Appendix VIII).
Medical resource utilization (MRU)
Medical resource utilization (MRU) will be assessed as follows:
- Frequency and duration of hospitalization from Baseline up to week 48 of therapy
- Frequency of emergency room visits from Baseline up to week 48 of therapy.
- Frequency of general practitioner, specialist, and urgent care visits from Baseline up to 
week 48 of therapy.
- Number of transfusions and transfusion dependency status end of study.
- Splenectomy and use of splenic irradiation.
- Changes in use of concomitant medications for MPN symptom management (Appendix 
IX).
Endpoints 
(efficacy)
Efficacy data will be collected.
- Best overall response to treatment as assessed by spleen palpation (calculated as the 
percentage change in spleen length compared with Baseline).
- Change in spleen length from Baseline to end of each visit.
- Change in WBC and platelet count changes from Baseline to end of each visit/month of 
therapy and at end of treatment.
- Shift in fibrosis in the bone marrow from Baseline to worst/best value on study (where 
bone marrow biopsies are performed – not mandatory).
- Progression free survival, acute myeloid leukemia free survival and overall survival.
- In patients without splenomegaly, patient reported outcomes measure symptoms of the 
disease.
Study design
This is a multicenter, single-arm, open-label expanded access study intended to provide 
additional data on the safety and efficacy of INC424 in patients with PMF, PPV MF, or 
PET-MF who have either previously received treatment or have not received treatment. All 
patients will be screened using inclusion and exclusion criteria (Section 5.2 and Section 
5.3) within 28 days prior to the first dose of INC424. See Table 7-1 for a description of the 
screening evaluations required.
Baseline evaluations should be performed within 7 days of the first dose of INC424, 
however platelets should be performed within a maximum of 4 days of the first dose of 
INC424.
Subsequently, patients will be asked to visit the clinic monthly for the first 3 months, then 
every 3 months thereafter, and at study discontinuation. 
All patients will be treated for PMF, PPV MF, or PET-MF in each participating country with 
 


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oral INC424 at a dose of 5 - 25 mg (dose based on Baseline platelet count) BID until 
either:
- Disease progression;
- Transplant;
- Unacceptable toxicity;
- Death;
- Discontinuation from the study for any other reason;
- Withdrawal of consent;
- Physician decision;
- Until 24-months after LPFV; or
- Until the drug is commercially available, whichever occurs first.
The FPFV occurred on 16 August 2011 and the recruitment period ended on 31 Dec 
2014. The study enrolled a total of 2238 patients. The last patient last visit is expected in 
December 2016.
Population
Male or female patient’s ≥ 18 years of age with a diagnosis of PMF, PPV MF, or PET-MF 
will be enrolled. Eligible patients who have either never received treatment, or who have 
received prior treatment with commercially available agents (e.g., busulfan, danocrine 
[danazol®, hydroxyurea, anagrelide, lenalidomide) or have previously received 
investigational drug may be enrolled. Patients must meet all inclusion and none of the 
exclusion criteria within 4 weeks prior to the first dose of INC424.
All prior treatment for PMF, PPV MF, or PET-MF must be discontinued prior to Day 1 of 
INC424, and all AEs attributed to these treatments must be resolved prior to Day 1 of 
INC424 treatment.
This study will be conducted worldwide, excluding USA.
Sample Size
The projected number of patients that will be treated in this study is a maximum of 2500 
patients.
Inclusion/exclusion 
criteria
Inclusion Criteria
Patients eligible for enrollment in this study have to meet all of the following criteria:
1. Patients must give written informed consent according to local guidelines prior to any 
screening procedures.
2. Patients must not be eligible for another ongoing INC424 clinical trial.
3. Male or female patients aged ≥ 18 years of age.
4. Patients must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 
World Health Organization criteria International Standard Criteria (Appendix I), irrespective 
of JAK2 mutation status.
5. Patients with PMF requiring therapy must be classified as high risk (3 prognostic 
factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk 
level 1 (1 prognostic factor, no more) with an enlarged spleen at the screening visit 
(assessment to occur at the Screening Visit).. The prognostic factors, defined by the 
International Working Group (Cervantes 2009) are described in Section 1.1 and Section 
5.2 and should be evaluated at the Screening Visit.
6. Patients with Intermediate-1 and splenomegaly, must have a palpable spleen 
measuring 5 cm or greater from the costal margin to the point of greatest splenic 
protrusion.
7. Patients with a peripheral blood blast percentage count of < 10%.
8. Patients with adequate liver function defined as total bilirubin or direct bilirubin ≤ 2.0 x 
ULN, and ALT ≤ 2.5 x ULN.
 


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9. Patients with adequate renal function defined as serum creatinine
≤ 2 x ULN.
10. Patients with an ECOG performance status of 0, 1, or 2 (Appendix IV).
11. Women of childbearing potential must have had a negative serum pregnancy test 
within 14 days prior to the administration of study drug.
12. Patients must have recovered or stabilized sufficiently from any adverse drug 
reactions associated with prior treatments before beginning treatment with INC424.
13. Fedratinib pretreated patients with documented complete physical examination 
including full neurologic examination and cardiology assessment, thiamine level testing, 
and MRI of the brain if indicated based on signs or symptoms. Patients pretreated with 
fedratinib should have completed or be receiving thiamine supplementation according to 
the investigator’s instructions.
Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a 
suitable donor is available).
2. Patients with a history of malignancy in the past 3 years, except for treated early stage 
squamous or basal cell carcinoma in situ.
3. Patients receiving any medications listed in the “Prohibited Medications” listing 
(Appendix VI).
4. Impairment of GI function or GI disease that may significantly alter the absorption of 
INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, small bowel resection).
5. Patients with cardiac disease which in the Investigator’s opinion may jeopardize the 
safety of the patient or the compliance with the protocol.
6. Patients with currently uncontrolled or unstable angina, rapid or paroxysmal fibrillation 
or recent (approximately 6 months) myocardial infarction or acute coronary syndrome.
7. Patients with clinically significant bacterial, fungal, parasitic or viral infection that 
requires therapy. Patients with acute bacterial infections requiring antibiotic use should 
delay screening/enrollment until the course of antibiotic therapy has been completed.
8. Patients with known active hepatitis A, B, C or who are HIV-positive.
9. Patients with inadequate bone marrow reserve at baseline visit as demonstrated by:
(a)  ANC that is ≤ 1000/µL.
(b)Platelet count that is <50,000/µL without the assistance of growth factors, 
thrombopoietic factors or platelet transfusions.
10. Patients with any history of platelet counts < 50,000/µL or ANC <500/µL except during 
treatment for a MPD or treatment with cytotoxic therapy for any other reason.
11. Patients with coagulation parameters (PT, PTT, INR) >1.5 x ULN.
12. Patients with known hypersensitivity to INC424 or other JAK1/JAK2 inhibitors, or to 
their excipients.
13. Patients under ongoing treatment with another investigational medication within 30 
days of screening or having been treated with fedratinib within 14 days of screening.
 


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14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until termination of gestation, confirmed by a positive βHCG 
laboratory test (> 5 mIU/mL).
15.Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study duration inclusive of 28 day safety follow up. Highly effective 
contraception methods include:
Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment
Male sterilization (at least 6 months prior to screening).  the vasectomized male partner 
should be the sole partner for that subject.
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, including women whose career, lifestyle, or sexual orientation 
precludes intercourse with a male partner and women whose partners have been 
sterilized by vasectomy or other means, UNLESS they are using highly effective 
contraception methods (see ) defined as:
- Total abstinence and
- Female sterilization
- Combination of any two of the following (a+b or a+c or b+c):
(a) Use of oral, injected or implanted hormonal methods of contraception
(b) Placement of an intrauterine device (IUD) or intrauterine system (IUS)
(c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
- The duration of required highly effective contraception is: during dosing and for 5 times 
the terminal half-life of INC424 (i.e. 29 hours). The mean elimination half-life of INC424 is 
approximately 3 hours and the mean half-life of INC424 and metabolites is approximately 
5.8 hours.
16. Patients who are unable to comprehend or are unwilling to sign an ICF.
17. Patients with active alcohol or drug addiction that would interfere with their ability to 
comply with the study requirements.
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jeopardize the safety of the patient or compliance with the protocol.
19. In the case of ruxolitinib pretreated patients, ruxolitinib primary resistant patients 
defined as: 
● No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib 
AND
● No reduction in symptoms within the first 12 weeks after first-line treatment with 
ruxolitinib.
20. In the case of ruxolitinib pretreated patients, patients discontinuing ruxolitinib due to a 
Grade 4 AE related or suspected to be related to ruxolitinib.
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.) that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for 
the patient throughout their participation in the trial.
The Patient No. consists of the Center Number (Center No.) [as assigned by Novartis to 
the investigative site] with a sequential patient number suffixed to it, so that each patient is 
numbered uniquely across the entire database. Upon signing the ICF, the patient is 
assigned to the next sequential Patient No. available to the investigator through the Oracle 
Clinical RDC interface.
Patient who may have been enrolled in CINC424A2401 before being enrolled in fedratinib 
trial and being screened for CINC424A2401 will be assigned a new patient number as 
described above.
Once assigned, the Patient No. must not be reused for any other patient and the Patient 
No. for that individual must not be changed, even if the patient is re-screened.
Patients will begin protocol treatment with INC424 within 7days of meeting eligibility 
criteria. If a patient does not begin study treatment following enrollment, the reason for 
withdrawal must be determined and the Sponsor’s site monitor will be notified as soon as 
possible.
Investigational and 
control drugs
Investigational drug refers to INC424. There is no control drug in this open-labeled study.
Dose, regimen, 
treatment 
The starting dose of INC424 tablets will be determined based on a patients Baseline 
platelet count as follows:
- Patients with a Baseline platelet count > 200,000/µL will begin dosing at 20 mg BID (See 
Section 6.1.1)
- Patients with a Baseline platelet count of 100,000/µL to 200,000/µL (inclusive) will begin 
dosing at 15 mg BID See Section 6.1.1)
- Patients with a Baseline platelet count of 50,000/ µL – <100,000/µL /µL will begin dosing 
at 5 mg BID. See Section 6.1.1)
Patients with a platelet count <50,000/µL are ineligible for the study.
The oral dose listed above will be administered BID continuously until either:
- Disease progression;
- Transplant;
- Unacceptable toxicity;
- Death;
- Discontinuation from the study for any other reason;
- Withdrawal of consent;
- Physician decision;
- Until 24-months after LPFV; or
- Until the drug is commercially available, whichever occurs first.
The trial may be stopped in any single country at any time ahead of other countries.
Dose escalation is permitted for patients receiving starting doses of 15 – 20 mg BID doses 
of INC424 with inadequate responses following at least 4 weeks of therapy if all of the 
 


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following conditions are met:
- Palpable spleen length below the costal margin that has been reduced by < 40% at the 
Week 4 visit relative to baseline.
- Platelet count at the Week 4 blood draw is > 150,000/µL and platelet count has never 
been < 150,000/µL at a prior laboratory assessment while receiving INC424 (Figure 6-1).
- ANC levels have remained ≥1000/µL since enrollment in the study.
Additional dose increases beyond the week 4 dose escalation for patients who start on 15 
– 20 mg BID of INC424 are permitted, at the discretion of the investigator, as follows:
- The patient must not have had a prior safety-related dose reduction.
- The patient must have had a platelet count ≥ 150,000/µL at every assessment since 
baseline.
- The patient must have had ANC ≥ 1000/µL at every assessment since baseline.
- The dose increase may only be an increase of 5 mg BID.
- The total dose may never exceed 25 mg BID.
For those patients who start INC424 treatment at a dose of 5 mg BID, dose increases can 
be made, at the discretion of the investigator, as described below. The dose can be 
escalated 5 mg once a day starting at week 4, and thereafter no more than every two 
weeks ONLY if:
- The patient must not have had a prior safety-related dose reduction.
- Platelet count remains ≥ 50,000/µL since last lab scheduled visit.
- ANC > 1000/µL since last scheduled visit.
- No dose reduction or interruption for safety occurred in the preceding weeks after the 
last planned visit.
- The dose increase may only be an increase of 5 mg o.d. i.e., from 5 mg PO BID to 5 mg 
QAM and 10 mg QPM.
- The total dose may never exceed 25 mg BID.
Following a dose increase, platelet count and ANC levels should be assessed 
approximately 2 weeks after the dose adjustment. If a regularly scheduled Study Visit 
does not coincide with this required blood draw, an unscheduled Interim Visit should be 
held to collect samples for hematology.
Dose interruption or dose reduction (Section 6.2.2) is mandatory as follows for patients 
who start on dose of 15 – 20 mg BID:
Dosing must be held if platelet counts decline to < 50,000/µL (Grade 3 laboratory 
abnormality by CTCAE v. 3.0, or if ANC falls below 500/µL while receiving INC424.
Doses should be decreased for platelet count values < 125,000/µL as shown in Table 6-2
with optional restarting or resuming prior dose after recovery Section 6.2.3 In order to 
provide sufficient data to make dose adjustment decisions, it is recommended that 
hematology parameters be obtained at least weekly for platelet count <100,000/µL or ANC 
< 1000/µL and at least two times weekly for platelet count < 50,000/µL or ANC <500/µL.
Dose interruptions or dose reductions for patients starting INC424 5 mg BID: dose 
 


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interruptions are made according to the platelet count as follows (see Table 6-2 and Table 
6-3):
- If platelets ≤ 25,000/µL and/or ANC < 500/µL): hold treatment
- If platelets > 25,000 - < 50,000/µL: reduce the INC424 dose by 5 mg o.d. increments
The patients should then be reassessed the following month. If the platelet count 
improves, the patient can restart treatment, and if the platelet count does not improve the 
patient should be withdrawn from the study
Dose, regimen, 
treatment, 
continued
The dose strategy in Table 6-4 covers the starting doses (15 mg BID and 20 mg BID) and 
possible doses after an increase for inadequate efficacy (20 mg BID and 25 mg BID).
Patients are free to withdraw consent and discontinue participation in the study at any 
time, without prejudice to further treatment. A patient’s participation in the study may also 
be discontinued at any time at the discretion of the Investigator or Sponsor. The following 
are reasons the Investigator or Sponsor may remove a patient from the study:
- The patient requests discontinuation.
- The Investigator thinks a change of therapy would be in the best interest of the patient.
- The patient experiences an intolerable AE.
- The patient is found to be not eligible for further study treatment.
- The patient is non-compliant with study requirements.
- The patient becomes pregnant during the study or if a patient fails to use adequate birth 
control (for those patients who are able to conceive).
- The patient requires a medication prohibited by the protocol.
Supply, 
preparation, and 
administration
INC424 is provided as a 5 mg or 10 mg tablet. The bottles are labeled in the local 
language.  Once commercially available, the drug may be provided locally.  The study 
medication is referred to as INC424 5 mg or 10 mg tablet on the label. INC424 is to be 
administered orally, without regard to food, in an outpatient setting in accordance with 
specified dosing schedules. The bottles of tablets should be stored at room temperature, 
15°C to 30°C (59°F to 86°F).
Visit schedule and 
assessments
Refer to Table 7-1 in protocol.
Efficacy 
assessment(s)
Response to treatment and disease progression will be assessed by PE, specifically 
assessing changes in spleen length by palpation. Disease assessment will be performed 
at screening/baseline, month 1, 2 month 3, and every 3 months thereafter; and at 
discontinuation of study drug.
In patients without splenomegaly, efficacy assessments will only be provided by the 
patient reported outcomes that measures symptoms of the disease.
Special safety 
assessment(s)
AEs of all grades, Grade 3/4 AEs, SAEs; laboratory assessments (hematology, serum 
chemistry, coagulation), vital signs (blood pressure, heart rate, respiratory rate, 
temperature); cardiac assessments.
Patient reported 
outcomes
The FACT-Lym (version 4) and the FACIT-Fatigue Scale will be used to document patient 
reported symptoms including physical well-being, social/family well-being, emotional well-
being, functional well-being, constitutional symptoms and fatigue.
Medical Resource 
Utilization
MRU will be collected up to week 48 to document number of hospitalizations, emergency 
room visits, outpatient office visits general practitioner, specialist, urgent care visits; 
transfusions; concomitant medications; and splenectomy/splenic irradiation.
Pharmacokinetics
N/A
Biomarker 
assessments
N/A
 


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Exploratory 
Biomarker 
pharmacodynamic 
studies involving 
tumor samples
N/A
Optional Biomarker 
studies on 
additional or 
remaining samples
N/A
DMC
Not applicable
Statistical methods 
and data analysis
The primary study objective (to collect safety data) and secondary objective being 
descriptive; only descriptive statistics will be provided.
Data from all centers will be combined and analyzed together.
The primary analysis will be performed after all patients have either completed 24 months 
of treatment or have been prematurely discontinued from the study.
Analysis sets:
Full Analysis Set (FAS) consists of all patients who received at least one administration of 
study drug.
Safety set consists of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment.
Per protocol set: consists of all FAS patients without any major protocol deviation. Rules 
for identifying major protocol deviations would be detailed in Report Analysis Plan.
Analysis methods
Primary objective
The analysis will provide the incidence of treatment-emergent AEs (occur during 
treatment, including the 28 safety follow-up days) or AEs that worsen on treatment. Death 
rate (any death) at end of study will be summarized.
Secondary objectives: Efficacy
The proportion of patients by best overall response category will be summarized. 
Proportion of responders will be estimated and its 95% confidence intervals provided.
- Change in spleen length from Baseline to end of each visit/month of therapy and at end 
of treatment will be described using descriptive statistics and by relevant change 
categories.
- Change in WBC and platelet count changes from Baseline to end of each visit and at 
end of treatment.
- Shift in fibrosis in the bone marrow from Baseline to worst/best value on study will be 
described. 
- PFS, LFS, and OS will be estimated with the Kaplan Meier method and 95% confidence 
intervals will be provided for the estimated median.
Secondary objectives: MRU
Frequency of hospitalization, of emergency room visits, general practitioner, specialist, or 
urgent care visits,, and of splenectomy and splenic irradiation will be summarized at end 
of each treatment quarter.
Overall duration of hospitalization at end of study will be summarized 
The proportion of patients who are transfusion dependent as well as the proportion of 
patients whose transfusion status (dependent or independent) changed (from dependent 
 


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to independent or vice versa) will be tabulated with summary statistics.
Quality of Life Assessments
ECOG score will be summarized descriptively by visit. A shift summary including number 
and % of patients will be produced by visit for baseline vs. post-baseline scores.
Data from FACT-Lymphoma (version 4) Scores will be analyzed in the sum scores. 
Change and % change from baseline to each scheduled visit will be calculated. The 
treatment effect on FACT-Lymphoma Scores over time will be estimated using repeated 
measurements analysis.
Data from FACIT Scores will be analyzed in the sum scores. Change and % of change 
from baseline to each scheduled visit.
Time to first improvement will be estimated for ECOG performance score and for selected 
scales for FACT-Lymphoma (version 4) and FACIT scale according to minimally important 
difference (MID).
 
Interim analysis 
(IA)
An interim analysis will be performed to closely monitor safety, and ensure an appropriate 
risk/benefit ratio in the patient population with low platelet counts, between 50,000 and 
<100,000/µL /µL. In order to adequately assess the risk/benefit ratio, this analysis will also 
be performed on a non-low platelet population (patients with baseline platelet count 
≥100,000/µL), which will be further detailed in analysis plan, who will serve as an internal 
reference population. This interim analysis will take place when 50 patients with low 
platelets have completed 6 months of treatment
Analyses will also be performed if needed to fulfill regulatory obligation, to comply with 
post-approval commitments or for publication purpose.
 


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1
Background
INC424 phosphate is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) 
that is currently under development for treatment of primary myelofibrosis (PMF), post 
polycythemia vera myelofibrosis (PPV MF) and post essential thrombocythemia 
myelofibrosis (PET-MF). INC424 (ruxolitinib, Jakafi®) was approved by the FDA on 16 
November 2011, and approved by the EMA on 31 August 2012, for the treatment of 
intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia 
vera myelofibrosis and post–essential thrombocythemia myelofibrosis.
1.1
Overview of myelofibrosis and myeloproliferative neoplasms and 
current treatment options
Myelofibrosis (MF) is a clonal hematologic neoplastic disease characterized by the presence 
of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or 
collagen fibrosis (Tefferi A (2008)), splenomegaly, anemia, and debilitating constitutional 
symptoms that include fatigue, weight loss, pruritus, night sweats, fever, and bone, muscle, or 
abdominal pain (Mesa RA, Niblack J, Wadleigh M, et al (2007), Abdel-Wahab OI, Levine RL 
(2009)). MF can either be primary in origin (primary myelofibrosis, or PMF) or result from 
progression of polycythemia vera or essential thrombocythemia vera (Tefferi A (2008)). The 
median age at diagnosis of MF is approximately 65 years. Patients with myelofibrosis have 
shortened survival that ranges from a median of approximately 2 years to 11 years depending 
on the presence of certain risk factors that define their risk category including age, anemia, 
leukocytosis, etc.
Several prognostic risk scores that are based on survival outcomes have been developed in 
MF to better define treatment choices for physicians and therefore improve patient 
management. The International Prognostic Scoring System (IPSS) was developed by the 
International Working Group for Myeloproliferative Neoplasms Research and Treatment 
(IWG-MRT) (Cervantes F, Dupriez B, Pereira A, et al (2009)). The IPSS is used at diagnosis 
and employs five hematologic and clinical variables (age, leukocytosis, anemia, peripheral 
blood blasts and constitutional symptoms) to stratify patients in a low, intermediate-1, 
intermediate-2 and high-risk category. The dynamic IPSS (DIPSS) was subsequently 
developed to be used for patients evaluated after MF diagnosis (Gangat et al 2011). The 
DIPSS relies upon the same five variables as IPSS but utilizes the predictive value of selected 
cytogenetic abnormalities. These scoring systems are expected to facilitate categorizing 
patients to different risk groups, and thus assist physicians in recommending optimal 
treatment management plans.
All currently available pharmacologic treatments are either directed towards the management 
of MF-originated anemia or the treatment of MF-symptoms including splenomegaly. As these 
treatments do not cure or modify the disease progression of MF, they are mostly used to treat 
patients in the higher risk categories. MF patients in the lower risk categories (IPSS Low and 
Int-1), by virtue of a relatively asymptomatic disease and an indolent disease course, are 
managed through active surveillance or a ‘watch and wait’ approach until appearance of 
bothersome symptoms or the definitive progression to the higher risk groups. Allogeneic stem 
 


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cell transplantation is the only curative option, but it is often associated with a high rate of 
mortality and morbidity (Kroger 2008). Other available treatments include splenectomy, 
involved field radiotherapy, erythropoiesis stimulating agents, androgen preparations, 
thalidomide and its analogs, hydroxyurea. More recent advancements in MF treatment include 
the discovery of ruxolitinib, a Janus Kinase (JAK)1 and JAK2 inhibitor. Ruxolitinib is one of 
the first treatments in MF that has demonstrated rapid and durable reductions in MF- related 
splenomegaly, improvement in disease-related symptoms and offers a distinct survival benefit 
(Vannucchi et al 2015).
The recent years have witnessed major advances in the molecular understanding of MF, first 
with the identification of JAK2 and MPL mutations (Kilpivaara, Levine 2008) and more 
recently the calreticulin (CALR) gene (Klampfl T et al 2013), all of which are associated with 
an activation of the Janus Kinase-Signal Transducer & Activator of Transcription (JAK-
STAT) pathway. In addition, as also shown in other myeloid malignancies, mutations in a
multiplicity of other genes involved in the epigenetic and spliceosome regulatory machineries 
have been reported in MF across IPSS risk categories and shown to have a negative 
prognostic impact.
A recent study evaluated 879 PMF patients to determine the individual and combinatorial 
prognostic relevance of somatic mutations. Analysis was performed in 483 European patients 
and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the 
European cohort, collected at the time of diagnosis, were analyzed for mutations in ASXL1, 
SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2 (Vannucchi et al 
2013a). A specific sub-group of mutations were identified (ASXL1, EZH2, SRSF2 and IDH)
that may be predictive of PMF patients who are at risk for premature death or leukemic 
transformation. These mutations are classified as the ‘high molecular risk’ category (HMR) in 
PMF based on the presence of at least one of the five prognostically detrimental mutated 
genes.
[Guglielmelli et al.] further evaluated the additional prognostic value of the number of 
mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo 
Clinic (n=260). In the European cohort, 167 (31%) patients were categorized as HMR: 127 
(23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more 
mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% 
confidence interval (CI) 2.6– 5.7) vs 7.0 years (HR 1.9, 95% CI 1.4– 2.6) for one mutation 
vs 12.3 years for no mutations (Figure 1-1, Guglielmelli et al 2014a). The presence of two or 
more mutations was also associated with shortened leukemia-free survival (HR 6.2, 95% CI 
3.5 – 10.7). Overall, the recent studies demonstrate that patients with PMF harboring 
mutations in any one of the five prognostically detrimental genes (ASXL1, EZH2, SRSF2 and 
IDH1/2) constitute an IPSS/DIPSS-plus independent HMR category with shorter survival and 
greater risk of acute myeloid leukemia (AML) progression compared with the low molecular 
risk (LMR) patients. These findings therefore identify a clinically relevant subgroup of MF 
patients with HMR mutations, who despite being minimally symptomatic (including less 
severe splenomegaly) and thus categorized to harbor a lower risk disease through the IPSS or 
DIPSS scoring systems, may require earlier intervention with treatments that would prevent or 
delay their disease progression and leukemic transformation and potentially improve their 
survival. The majority of HMR positive patients with minimally symptomatic disease (Early 
 


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MF) are currently not treated until symptoms present more aggressively. These HMR positive 
early MF (HMR+ EMF) patients are in need of therapy that can delay progression and 
therefore have an unmet medical need.
Currently, ruxolitinib is the only treatment that has shown evidence through prospective 
randomized trials to not only reduce symptom burden and splenomegaly but also confer a 
longer 
term 
survival 
advantage 
and 
delay 
time 
to 
leukemia 
transformation 
(Vannucchi et al 2015). A retrospective analysis conducted by Guglielmelli et al in the 
COMFORT II study, showed that HMR status did not affect the likelihood of obtaining a 
treatment benefit with ruxolitinib, suggesting that the clinical efficacy and survival 
improvement observed with ruxolitinib in MF patients may occur independently of the 
underlying molecular pattern. These observations were however confined to patients in the 
higher risk categories (IPSS Int-2 and High) and therefore currently not established in the 
lower risk categories. This study will investigate the effect of JAK inhibition with ruxolitinib 
in a patient population with earlier MF disease harboring HMR mutations. It is to be noted 
that the selection of patients with HMR mutations is solely intended to identify a subset of 
patients with an intrinsically aggressive MF disease, with poor prognosis and hence an unmet 
medical need for appropriate therapeutic intervention. The HMR test in the study is not 
intended for preselecting patients who are more likely to respond to ruxolitinib or tolerate the 
treatment.
Figure 1-1
Prognostically detrimental ‘HMR’ mutations and survival in PMF: 
Kaplan Meier Plots
 


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a – Overall survival stratified by zero, one and two/more prognostically detrimental mutations (HMR).
b – Overall survival for IPSS low risk categories (Low and intermediate-1) stratified by number of HMR 
mutations.
c - Overall survival for IPSS high risk categories (intermediate-2 and high) stratified by number of HMR 
mutations.
 


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1.2
Inhibition of Janus Kinases (JAK) in MPN 
A key feature of MPNs is the dysregulation of JAK/STAT signaling. The JAK/STAT pathway 
is involved in normal hematopoiesis, inflammation, and immune function (Ghoreschi 2009). 
The 4 members of the JAK family - JAK1, JAK2, JAK3, and TYK2 - are non-receptor 
tyrosine kinases that play a central role in signal transduction initiated by cytokines (e.g., 
interleukin and interferon signaling), growth factors, and hormones (Ghoreschi 2009). 
Specifically:

JAK1 - role in lymphopoiesis and cytokine response; ubiquitously expressed

JAK2 - role in erythropoiesis; ubiquitously expressed

JAK3 - role in lymphocyte development and proliferation and immune response; expressed 
primarily in hematopoietic cells

TYK2 - role in mediation of cytokine signals; ubiquitously expressed
Upon ligand binding, the receptor undergoes conformational changes that allow JAK 
activation and result in receptor homodimerization (i.e., JAK2/JAK2) or heterodimerization 
(ie, JAK1/JAK2) (Vainchenker 2008). The activated JAKs create docking sites on the 
receptor for STAT (signal transducers and activators of transcription) proteins. STAT proteins, 
once activated, dissociate from the receptor, dimerize, and translocate into the nucleus to 
initiate transcription of target genes (Ghoreschi 2009). Given the importance of this 
interaction, this pathway is also known as the JAK/STAT pathway.
Dysregulation of the JAK pathway can occur in a number of ways. Ligand-independent 
activation of the pathway can occur due to mutations in the JAK receptor. In addition, 
mutations in or activation of other modulators of the signaling pathway can result in pathway 
overactivation. Regardless of a particular mutation’s presence or absence, dysregulation of the 
JAK pathway is a hallmark of MPNs. The majority of patients with MF, PV, and ET bear a 
somatic activating mutation in JAK2 whereby a G>T nucleotide exchange in exon 14 at 
position 1849 results in a substitution of valine by phenylalanine at amino acid 617 (JAK2 
V617F) (Tefferi 2009a).
Recent genome-wide association studies suggest that individuals can have a genetic 
predisposition to the development of JAK2 V617F-positive MPNs. Specific haplotypes have 
been identified that preferentially acquire the JAK2 V617F mutation and confer susceptibility 
to MPNs, which may partially explain the phenotypic diversity observed in carriers of the 
mutation (Tefferi 2009a, Olcaydu 2009).
With frequencies of greater than 95% in PV and approximately 50% in MF and ET (Tefferi 
2009a), the presence of this mutation is a major criterion in the diagnosis of these diseases. 
Although the JAK2 V617F-activating mutation is the most commonly observed mutation in 
MPNs, it is not the only JAK pathway-activating mutation noted in MPN patients. Mutations 
in exon 12 have also been noted, mostly in PV patients (Scott 2007). Indeed, virtually all 
JAK2 V617F-negative PV patients bear JAK2 exon 12 mutations (Schnittger 2009). Of note, 
these mutations affect the pseudokinase domain or a proximal region (“exon 12” mutations) 
but not the kinase domain.
Abnormal activation of JAK1 has also been noted in MF patients (Quintas-Cardama 2010). In 
addition to alterations in JAK1 and JAK2, alterations in other members of the JAK pathway 
 


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have been detected in MPN patients. These alterations include a somatic activating mutation 
in the JAK2-associated thrombopoietin receptor gene MPL at codon 515 (MPL W515L/K) and 
various mutations in LNK, a negative regulator of JAK/STAT signaling (Oh 2010, 
Patnaik 2010). Clearly, JAK pathway dysregulation, regardless of mutational status, is a key 
pathophysiological feature of MPNs. As the most prevalent mutation in MPNs, the prognostic 
impact of the JAK2 V617F mutation has been well-characterized. In both PV and ET, the 
presence of JAK2 V617F is associated with a higher risk of thrombosis and thrombotic effects, 
and its presence indicates a higher risk of transformation to post-PV/ET MF (Barosi 2007, 
Tefferi 2007c, Vannucchi 2007, Basquiera 2009). PMF patients with the JAK2 V617F 
mutation have higher leukocyte counts and a history of thrombosis (Barosi 2007).The V617F 
mutation also predicts large splenomegaly, need for splenectomy, and an increased risk of 
leukemic transformation in PMF patients (Barosi 2007). The clinical course of PV patients 
with JAK2 exon 12 mutations appears to be similar to that of patients with the JAK2 V617F 
mutation (Tefferi 2010b).
1.3
Overview of INC424
INC424 represents a novel, potent, and selective inhibitor of JAK1 and JAK2.
INC424 potently inhibits JAK1 and JAK2 [half maximal inhibitory concentration (IC) 0.4 to 
1.7 nM], yet it does not significantly inhibit (< 30% inhibition) a broad panel of 26 kinases 
when tested at 200 nM (approximately 100 x the average IC50 value for JAK enzyme 
inhibition) and does not inhibit JAK3 at clinically relevant concentrations. Pharmacological 
data obtained in in vivo model systems support the potential utility of orally administered 
INC424 in the treatment of malignancies, including MPDs such as PMF, PPV-MF, and PET-
MF. INC424 retains activity against the JAK2V617F mutant and is effective in reducing 
splenomegaly in mice inoculated with cells carrying this mutation. Additional details as to the 
in vivo pharmacology of INC424 may be found in the [Investigator’s Brochure] (IB).
Dysregulated JAK-STAT signaling, via upregulation of JAK1 and JAK2 or gain of function 
mutations such as JAK2V617F, has been implicated as drivers of BCR-ABL-negative 
myeloproliferative neoplasms (MPN), namely myelofibrosis (MF), polycythemia vera (PV) 
and essential thrombocythemia (ET). Ruxolitinib, which is jointly developed in hematology 
and oncology indications by Novartis Pharma AG (Switzerland) and Incyte Corporation 
(USA), specifically binds to and inhibits JAK1, JAK2 and mutated JAK2V617F, leading to 
inhibition of growth factor-mediated cell signaling and tumor cell proliferation. Given this
mechanism of action of ruxolitinib as a JAK inhibitor and the role played by dysregulation of 
the JAK pathway in the pathogenesis of MPNs, the primary clinical development plan for 
ruxolitinib focused on studies to support regulatory approval in these disorders.
Ruxolitinib is currently approved under the trade name of ‘Jakavi’ in over 90 countries for the
treatment of disease-related splenomegaly or symptoms in adult patients with (primary 
myelofibrosis) PMF, post-polycythemia vera myelofibrosis (PPV-MF) and post-essential 
thrombocythemia myelofibrosis (PET-MF). The use of ruxolitinib to treat polycythemia vera 
(PV) patients who are resistant to or intolerant of hydroxyurea is currently under regulatory 
review worldwide based on the results from the RESPONSE study. So far approval in this 
second indication was granted in more than 45 countries including EU and Switzerland. 
Ruxolitinib is also approved in the USA under the trade name of ‘Jakafi’ and is indicated for 
 


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the treatment of patients with intermediate or high risk myelofibrosis, including PMF, PPV-
MF and PET-MF and for the treatment of PV patients who have had an inadequate response 
to or are intolerant of hydroxyurea.
1.3.1
INC424 pharmacokinetics
Fifteen Phase I , nine Phase II and three Phase III clinical studies (two in MF, one in PV) 
provided clinical pharmacology data on ruxolitinib in healthy volunteers and in patients with 
MF, ET, PV, subjects with renal or hepatic impairment, prostate cancer, pancreatic cancer, 
multiple myeloma (MM) or rheumatoid arthritis (RA). 
Oral absorption of ruxolitinib is rapid and nearly complete, with ≥95% absorption indicating 
high in vivo
permeability in the human gastrointestinal tract, consistent with a 
Biopharmaceutical Classification System (BCS) Class I compound. Mean peak plasma 
concentration (Cmax) is achieved 1-2 h post-dose. The effect of food on ruxolitinib exposure 
is minimal and is not expected to be clinically significant; as a result, the drug may be 
administered either with or without food.
Dose proportional exposure is observed between 5 and 200 mg dose range with linear 
pharmacokinetics (PK). Plasma protein binding is approximately 97% in vitro. There is 
moderate distribution to organs and tissues with no long-term retention of drug-related 
material in preclinical species and limited drug penetration into the central nervous system 
(CNS) or across the blood-brain barrier. There was >95% [14C] drug recovery in a mass 
balance study with 74% and 22% of the dose excreted in urine and feces of healthy subjects, 
respectively. Less than 1% of the administered dose is recovered in urine and feces as 
unchanged parent drug. The mean terminal elimination half-life (T1/2) is ~3 h with no 
appreciable accumulation of either parent or metabolites with twice daily dosing.
Metabolism is predominantly via the cytochrome P450 isozyme CYP3A4 to yield oxygenated 
and subsequent conjugated metabolites. Oxidative metabolites of ruxolitinib retain 
pharmacological activity albeit with one half to one fifth of the activity of the parent 
compound. Ex vivo pharmacokinetic/pharmacodynamic (PK/PD) analysis indicates that the 
total of 8 active metabolites contribute to 18% of the overall PD activity of ruxolitinib.
When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose should be 
reduced by approximately 50%.
No dose adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 
inducers. No dose adjustment is necessary when co-administering ruxolitinib with CYP3A4 
substrates. Ruxolitinib did not decrease the exposure of a fixed dose oral contraceptive 
metabolized via the CYP3A4 pathway, thus demonstrating lack of CYP3A4 induction 
potential.
In patients with severe (creatinine clearance (Clcr) <30 mL/min) and moderate renal 
impairment (Clcr = 30-59 mL/min), the recommended starting dose based on platelet count 
should be reduced by approximately 50% to be administered twice a day. Patients on 
hemodialysis should initiate ruxolitinib with a single dose of 15 mg or 20 mg based on platelet 
counts on day of hemodialysis with subsequent doses only on hemodialysis days and 
following each hemodialysis session. Ruxolitinib doses should be titrated based on individual 
safety and efficacy.
 


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In patients with mild, moderate or severe hepatic impairment, the recommended starting dose 
based on platelet count should be reduced by approximately 50% with subsequent dose 
titration based on individual safety and efficacy.
Ruxolitinib PK in healthy volunteers was largely comparable between Japanese, Chinese and 
Western subjects and did not lead to a conclusion of meaningful ethnic differences.
Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in patients with MF were associated 
with constitutional symptoms such as fatigue, pruritus, and night sweats. Decreases were 
observed in these markers over the 24 weeks of treatment with ruxolitinib, with no evidence 
that patients became refractory to the effects of ruxolitinib treatment
1.3.2
INC424 preclinical safety
The toxicologic and toxicokinetic profiles of INC424 were characterized in single and repeat 
oral dose studies of up to 6 months in duration in rats and dogs. Genetic toxicology, safety 
pharmacology, and embryo-fetal toxicology studies have also been conducted. In a 6 -month 
study in rats, doses up to 60 mg/kg/day were evaluated. An adverse decrease in body weight 
gain was noted in male, but not in female rats. A dose related decrease in lymphocytes was 
noted. Minimal-to-mild lymphoid depletion in spleens and in mandibular lymph nodes was 
noted at the 60 mg/kg/day dose level; at lower doses, lymphoid tissues were within normal 
histologic limits. The no-observed-adverse-effect level (NOAEL) for oral administration of 
INC424 for 26 weeks was 30 mg/kg/day for the males (unbound AUC 0.119 µM*h), due to 
adverse effects on body weight at 60 mg/kg/day, and 60 mg/kg/day for female rats (unbound 
AUC 4.64 µM*h). (Lower parent drug levels in male rats are due to male rat specific 
isoenzymes 2C11, 2C13 and CYP3A2 which metabolize INC424 to active metabolites). 
Additional details on rat toxicology studies are available in the [Investigator Brochure].
In the 6-month dog study, doses studied included 0.5, 2.5, 5, and 10 mg/kg/day. Demodectic 
mange, lymphopenia, eosinopenia, decreases in erythron parameters, moderate to severe 
cellular depletion of lymphoid tissues, bacterial pneumonia, viral induced papillomas, 
microscopic invasive demodectic mange, and prostate hypoplasia/atrophy were seen in dogs 
receiving high dose. Deaths attributed to bacterial pneumonia occurred in 3 of 14 dogs given 
10 mg/kg/day. Demodectic mange was observed in several animals given 5 mg/kg/day and, 
microscopically, in one animal given 2.5 mg/kg/day. These events most likely reflect a 
response to the immunosuppressive effects of INC424. All tissues were normal in the 0.5 
mg/kg/day group. The NOAEL dose was defined at 2.5 mg/kg/day (unbound AUC 0.76 µ
M*h) due to minimal findings which were not present in recovery animals. The low dose, 0.5 
mg/kg/day, was defined as the no-observed effect-level (NOEL). Additional details regarding 
dog toxicology studies are available in the [Investigator Brochure].
INC424 was not genotoxic in the bacterial mutagenicity assay, the in-vitro chromosome 
aberration assay, or the in-vivo micronucleus assay in rats.
In embryo-fetal assessments in rat and rabbit, maternal toxicity and minimal embryo-fetal 
toxicity were noted at the highest doses evaluated. INC424 was not teratogenic in either the 
rat or the rabbit. The NOAEL dose for the rat and rabbit study was 30 mg/kg/day. Additional 
toxicology and safety pharmacology information is available in the [Investigator Brochure].
 


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1.3.3
INC424 clinical safety in healthy volunteers
The safety profile for ruxolitinib in the Phase I development program was assessed in over 
370 subjects for single or repeat doses. Ruxolitinib has been administered to 40 subjects with 
various degrees of renal impairment and 32 subjects with various degrees of hepatic 
impairment. Additionally, a DDI study with methotrexate was completed in 18 RA patients. 
AEs were, in general, mild and resolved without interventions. In the first-in-human study one 
subject had hyponatremia after receiving 5 mg ruxolitinib. The hyponatremia was assessed as 
severe in intensity, unrelated to study medication, reversed within 5 days, and was reported as 
serious adverse event (SAE).
In the repeat-dose study in healthy subjects, the dose-limiting AE was neutropenia, which 
occurred at a dose of 50 mg b.i.d. Neutropenia as an AE was noted in three subjects, all 
receiving the highest dose of ruxolitinib, 50 mg b.i.d. Neutropenia at the Grade 4 level, 
assessed as severe, led to study drug discontinuation on Day 5 in one subject, and was 
reported as an SAE. Neutrophil count returned to a normal level 12 days after the final dose of 
study medication. In two other subjects, neutropenia was Grade 1 or 2, and resolved with dose 
interruption or during continued dosing. The AE profile was similar for single- and multiple-
dose studies, and no differences were observed between males and females. The most 
frequent (≥2 subjects) treatment-emergent AEs (TEAEs) occurring in the Phase I multiple-
dose study were: neutropenia (4.2%), dizziness (2.8%), headache (2.8%) and nausea (2.8%). 
Overall, in healthy volunteer studies where frequent sampling of the neutrophil count was 
performed, a transient, reversible decrease in neutrophil count was frequently seen following 
dosing, which reversed after 12-24 h off drug.
The AE profile of ruxolitinib has also been assessed in 198 healthy volunteers, subjects with 
various degrees of renal (n=32) or hepatic (n=24) impairment, and in patients with RA (n=59) 
receiving ruxolitinib: AEs were, in general, mild and resolved without interventions.
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supra-therapeutic dose of 200 
mg indicating that ruxolitinib has no effect on cardiac repolarization.
Please refer to the [Investigator Brochure] for further information.
1.3.4
INC424 clinical safety and efficacy in phase I/II trials
1.3.4.1
Phase I/II study of INC 424 in patients with primary, post-PV, or 
post-ET MF
Study INCB 18424-251 is a completed Phase I/ II open-label study of orally administered 
INC424 in patients with PMF, PPV MF and PET MF. A total of 153 patients were enrolled at 
the following oral dosing levels/regimens: starting dose of 25 mg BID followed by escalation 
up to 50 mg BID; once daily (QD) dosing ranging from 25 mg QD to 200 mg QD. The 
maximum tolerated doses were identified as 25 mg BID or 100 mg QD, based on dose-
limiting thrombocytopenia. In the Phase II component of the trial additional dosing schedules 
were also evaluated including 25 mg BID (with a reduction to 10 mg BID after 2 cycles 
[months] of therapy); 10 mg BID, with dose escalation permitted after 3 cycles (months) of 
therapy; 10 mg BID (in patients with a baseline platelet count of 100 - 200 x 109/L); and 15 
 


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mg BID (in patients with a baseline platelet count of > 200 x 109/L) with dose increases to 25 
mg BID (in 5 mg increments). Data from the completed Study INCB 18424-251 demonstrate 
marked and durable reductions in spleen size. In this study spleen size was measured as 
palpable length below the left costal margin. Figure 1-2a illustrates the mean reduction in 
absolute spleen size (measured by palpation) for patients receiving 15 mg BID and 25 mg 
BID, and Figure 1-2b mean reduction in absolute spleen size (measured by palpation) for 
patients receiving their originally assigned dose for at least 6 months (Verstovsek 2010b).
Figure 1-2a
Reduction in palpable spleen length in patients receiving different 
doses of INC424 (Verstovsek 2010b)
 


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Figure 1-2b
Reduction in palpable spleen length according to INC424 dose when 
maintained for at least 6 months (Verstovsek 2010b)
As noted in Figure 1-2a, BID regimens are associated with a prompt decrease in spleen size. 
Response rates have been demonstrated to be greatest in the BID dosing cohort, with reduced 
responses in the 50 mg PO QD dosing cohort, and lowest in the 10 mg PO BID dosing cohort 
(Verstovsek 2010b). The majority of patients had a ≥ 25% reduction in spleen size on therapy 
(70% in 10 mg BID cohort; 82% in 15 mg BID dosing cohort; 77% in the 25 mg BID cohort). 
Responses occurred quickly, within 1-2 months of therapy and appear durable (> 1 year in 16 
patients for whom data were available at 1.5 years and all 8 patients for whom data were 
available at 2 years). Best responses were greatest in the 25 mg BID dosing cohort (among 
patients starting at 25 mg BID and maintaining that dosing schedule), although dose 
interruptions were common (60%) primarily due to thrombocytopenia. Based on this profile 
an initial dose of 15 mg INC424 BID is recommended. Spleen reduction occurred regardless 
of presence/absence of the JAK2V617F mutation (data not shown). Progressive MPN are 
associated with weight loss and cachexia. Dysregulation and abnormal elevation of a variety 
of pro-inflammatory cytokines may produce a hypercatabolic state which contributes to the 
weight loss and wasting seen in patients with MF. After an initial weight loss (presumably due 
to the rapid decrease in splenomegaly and hepatomegaly and loss of ascites and/or pleural 
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are present in most patients, including those with body mass index at baseline in the lowest 
quartile (body mass index below ~ 22).
Improvements in QoL were rapidly demonstrated, typically within 1 month of therapy. The 
Modified Myelofibrosis Symptom Assessment Form (MFSAF) developed by Mesa et al, and 
based on an international internet-based survey of over 1000 patients with MPD, was used to 
probe a range of constitutional symptoms related to splenomegaly (including impaired ability 
to move around and early satiety) and elevated cytokines (including fatigue, night sweats and 
pruritus) (Mesa 2007; Appendix VIII). Most patients in the 10 to 25 mg BID dose groups 
demonstrated a ≥ 50% improvement in total or individual symptom scores per the MF-SAF, 
which assesses constitutional symptoms including fatigue, night sweats, and pruritus (Figure 
1-3). These responses were durable through 6 months of therapy. Symptomatic improvements 
were similar among the 10, 15, and 25 mg BID dose groups, with improvements in abdominal 
discomfort and pain accompanying the reduction in spleen size. Additionally, patients started 
to gain weight as early as after 2 cycles of therapy, with patients in the lowest quartile for 
body mass index at baseline gaining more weight than those in the highest quartile. Functional 
improvements in the ability to walk were observed; patients improved their walking ability by 
34, 57, and 71 m after 1, 3, and 6 months, respectively (Verstovsek 2010b).
Figure 1-3
Improvements in combined MFSAF score on INC424
In summary, INC424 is associated with prompt and marked reduction in spleen size, gains in 
total body weight, improvement in ECOG status PS and improvement in constitutional 
symptoms that can be debilitating in this patient population. Refer to the IB and Verstovsek 
(2010b) for more complete information. INC424 has been well tolerated by this aged 
population with advanced disease. Nonhematologic adverse events were uncommon and 
 


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included diarrhea (5.9%), fatigue (4.3%), headache (3.3%), peripheral edema (2.6%), pain in 
extremities (2.6%), urinary tract infections (2.6%), dizziness (2.6%), dyspnea (2.6%), asthenia 
(2%), fever (2%), cardiac murmur (2%), musculoskeletal pain (2%), peripheral neuropathy 
(2%), edema (2%), anxiety (2%), insomnia (2%), epistaxis (2%), flatulence (2%), and nausea 
(2%). The majority of these were Grade 1/ 2 CTCAE toxicity. Grade 3/ 4 nonhematologic 
toxicity included fatigue (1.3%), asthenia (2%), fever (0.7%), anxiety (1.3%) and insomnia 
(1.3%). Hematologic toxicity consisted primarily of anemia and thrombocytopenia. 
Thrombocytopenia appeared to be dose related occurring less frequently in the 15 mg BID 
group (3% Grade 3) than the 25 mg BID group (23% Grade 3; 6% Grade 4). 
Thrombocytopenia was not related to JAK V617F mutational status. Grade 3 
thrombocytopenia occurred in 10% of patients receiving 10 mg BID of INC424, 3% of 
patients receiving 15 mg BID of INC424, 23% of patients receiving 25 mg BID of INC424, 
60% of patients receiving 50 mg BID of INC424, 0% of patients receiving 25 mg QD of 
INC424, 27% of patients receiving 50 mg QD of INC424; 33% of patients receiving 100 mg 
QD; and 0% of patients receiving 200 mg QD of INC424. Thrombocytopenia of Grade 4 
severity occurred in 0% of patients receiving 10 mg BID of INC424, 0% of patients receiving 
15 mg BID of INC424, 6% of patients receiving 25 mg BID of INC424, 20% of patients 
receiving 50 mg BID of INC424, 0% of patients receiving 25 mg QD of INC424, 9% of 
patients receiving 50 mg QD of INC424, 0% of patients receiving 100 mg QD of INC424, and 
33% of patients receiving 200 mg QD of INC424. Thrombocytopenia occurred more 
frequently in patients with lower baseline platelet counts (< 200 x 109/L), and was reversible 
within 1 to 3 weeks after dose interruption and/or reduction. New onset anemia occurring in 
patients who were not transfusion dependent at baseline occurred in 23% of patients across all 
dosing intervals, and was most common in the 25 mg BID dosing cohort (27%) and least 
common in the 15 mg BID dosing cohort (8%). Anemia, though dose dependent, largely 
reflects the low Hgb status at baseline in this disease population.
SAEs occurred in 59 (39%) patients, of which 12 were assessed as at least possible related to 
study drug, including bone marrow suppression, febrile neutropenia, syncope, progression to 
CMMoL, B-cell lymphoma, pharyngotonsilitis, pharyngitis, myalgia, sinusitis, and cerebral 
hemorrhage. Of related SAEs reported in the study to date, the most frequent are those 
reflecting inhibition of bone marrow function(s) (i.e., thrombocytopenia) and activation of 
inflammatory cytokines when the inhibitory influence of INC424 is removed due to drug 
interruption or discontinuation. See Verstovsek (2010b) for complete details on INC424 
clinical study findings.
Fourteen patients discontinued study drug participation due to death, disease progression, 
unacceptable toxicity, or intercurrent illness. Four of 14 discontinuations were thought to be 
“possibly related to study drug, and included the following: (a) a 69 year-old male patient 
suffering from intracerebral hemorrhage without thrombocytopenia and associated death on 
day 374 of study drug dosed at 25 mg PO BID; (b) 71 year-old male with disease progression 
to CMMoL (evidence of CMMoL at screening) on day 147 of 25 mg p.o. BID; (c) 56 year old 
female developed grade 3 thrombocytopenia on day 278 on 50 mg p.o. BID; and (d) a 74 
year-old male developed grade 3 thrombocytopenia on day 57 on 50 mg p.o. BID.
During 2 or more years of follow-up, a number of patients discontinued study drug treatment 
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treatment, or other reasons (n = 24); progressive disease (n = 4); toxic effects (n = 2); 
intercurrent illness (n = 3), and death (n = 5). A total of 17 patients died during the follow-up 
period of which 5 died on treatment, and 3 died within 30 days of study treatment 
discontinuation.
1.3.4.2
Phase 1b study of INC424 in patients with MF and baseline platelet 
counts between 50 x 109L and less than or equal to 99 x 109/L
A phase Ib study of INC424 to investigate the safety of INC424 and establish the maximum 
safe starting dose in patients with MF who have baseline platelet counts ≥ 50,000/µL to 
99,000/µL is currently ongoing (Gisslinger 2012). The (Evaluating Ruxolitinib in Patients 
with Low Baseline Platelet Counts Diagnosed With Myelofibrosis) study is a single-arm, 
open-label, dose-finding study in adult patients with PMF, PET-MF, or PPV MF. This study 
consists of two periods: (a) core study period (day 1 to week 24), and (b) an extension period 
(beyond week 24). There are two different dosing strata based on baseline platelet counts 
(Stratum 1: 75,000/µL to 99,000/µL starting dose is 5 mg BID; Stratum 2: 50,000/µL to 
74,000/µL). A preliminary analysis based on an unplanned data cutoff date of May 16, 2012 
was presented at the European Hematology Association meeting in June 2012. An updated 
analysis was presented at the American Society of Hematology meeting in December 2012 
(Harrison 2012). The data (n=20; PMF n=14, PPV=MF n=5, PET-MF n=1) demonstrates that 
in this phase 1b study of INC424 in thrombocytopenic patients with MF, no DLT has 
occurred at the first 2 dose levels in patients with platelet counts of 50,000/µL to 99,000/µL. 
INC424 has been generally well tolerated, similar to the tolerability reported in the previous 
studies, and no patient has discontinued because of thrombocytopenia. No patient has had 
platelet counts below 20,000/ µL. No Grade 3/4 hemorrhagic events were reported. Treatment 
with INC424 led to spleen length reductions from baseline in 17 of 20 patients and three 
patients have experienced complete resolution of palpable splenomegaly as best response on 
study.
1.3.4.3
Phase II study of INC424 in patients with low baseline platelet counts 
(50 x 109/L to 100 x 109/L)
A 24-week, open-label phase II study of INC424 to investigate the efficacy, hematologic 
effects and dose of INC424 in patients with MF, PPV-MF, and PET-MF and baseline platelet 
counts of 50,000 to 100,000/ µL is ongoing (INCB018424-258) (Talpaz 2012).  The starting 
dose of INC424 is 5 mg p.o. BID with dose escalation with adequate platelet count by 5 mg 
once daily (i.e. 5 mg p.o. AM and 10 mg p.o.PM) every 4 weeks to a maximum of 10 mg BID. 
Further dose escalation requires evidence of suboptimal efficacy. An initial report with data 
from 41 evaluable patients was presented at the American Society of Hematology meeting in 
December 2012. Among patients who completed 24 weeks of treatment, most were receiving 
INC424 dose of 10 mg p.o. BID or higher. No patients have discontinued treatment due to 
adverse events. Bleeding related events were reported in 7 patients (17.1%).  Grade 1 bruising 
events (contusion n=2 and ecchymosis n=3) were reported in 7 patients. Other bleeding events 
were reported in 4 patients (subdural hematoma secondary to fall, hematochezia, 
hemorrhoidal hemorrhage and epistaxis; all grade 1 except grade 2 hematochezia).
 


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1.3.4.4
Phase II study of INC 424 in PV and ET patients refractory to 
hydroxyurea
A two-part phase 2 study was initiated to study INC424 in PV and ET patient’s refractory to 
hydroxyurea. The first part of the study randomized patients to various doses of INC424 for 
determination of the optimum dose level, and the second part of the study expanded the best 
cohort, with allowance for dose modification to normal counts (Verstovsek 2009a).The dose 
levels chosen for expansion were 10 mg BID in PV patients and 25 mg BID in ET patients. A 
total of 34 PV and 39 ET patients were enrolled and remained on treatment for ≥ 6 months. 
INC424 was well tolerated in these patient populations. The most common AEs possibly 
related to INC424 treatment in PV patients were anemia (grade 2, 12%; no grade 3), 
leukopenia (grade 2, 9%; no grade 3), and thrombocytopenia (grade 2, 3%; grade 3, 3%), with 
ET patients most frequently demonstrating anemia (grade 2, 18%; no grade 3) and leukopenia 
(no grade 2; grade 3, 5%). No grade 4 toxicities were observed in this study 
(Verstovsek 2009a).
Rapid and sustained responses were observed in PV patients treated with INC424 
(Verstovsek 2009b).Two response criteria were used to evaluate the activity of INC424 in PV 
patients (Table 4), both of which evaluate hematocrit, WBC counts, platelet counts, spleen 
size, and other symptoms (Quintas-Cardama 2009, Barosi 2009b).
The first response criteria were defined by the Department of Leukemia at the University of 
Texas MD Anderson Cancer Center, whereas the second was outlined by the European 
LeukemiaNet (Quintas-Cardama 2009, Barosi 2009b). Per criteria 1, 100% (34/34) of PV 
patients achieved an overall response (62% [21/34] complete response [CR], 38% [13/34] 
partial response [PR]), and 97% (33/34) of patients achieved normalization of hematocrit 
without phlebotomy. The primary reasons for not achieving CR per criteria 1 were an elevated 
WBC count and a palpable spleen. Per criteria 2, a 97% (33/34) overall response was 
observed in PV patients (45% CR, 52% PR), and 68% of patients achieved normalization of 
hematocrit without phlebotomy. In addition to normalization of hematocrit, WBC counts, and 
platelet counts and reductions in palpable spleen, reductions in constitutional symptoms, 
including pruritus, bone pain, and night sweats, were frequently observed (Verstovsek 2009b). 
Encouraging results were also noted in the ET patient population. The response criteria used 
were those outlined by the European LeukemiaNet (Barosi 2009b)). CR was defined as a 
platelet count < 400 109/L, a WBC count < 10 109/L, a normal spleen, and no disease-
related symptoms, and PR was defined as a platelet count < 600 109/L or a > 50% decrease 
from baseline. Per these response criteria, 90% (35/39) of ET patients achieved an overall 
response (13% [5/39] CR, 77% [30/39] PR). Additionally, reductions in pruritus, bone pain, 
night sweats, and peripheral numbness or tingling were observed (Verstovsek 2009b).
1.3.5
Phase III INC424 clinical trials (controlled MF study with oral JAK 
inhibitor treatment [COMFORT; (INCB 18424-351 and CINC424A2352)])
The results from two Phase III studies in myelofibrosis (COMFORT-I, COMFORT-II) 
demonstrate the effectiveness of ruxolitinib in patients with PMF, PPV-MF and PET-MF. The 
results of these two studies were consistent, demonstrating statistically significant (p < 0.0001) 
differences in rates of ≥35% spleen volume reduction compared with either placebo or an 
investigator’s selection of best available therapy (BAT). Although, the time point for the 
 


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primary endpoint  (spleen volume reductions) were different in COMFORT-I (at Week 24) 
and COMFORT-II (at Week 28) the mean reduction in spleen volume is similar at Week 24 
(31.6% vs. 29.2%, COMFORT-I and COMFORT-II, respectively).
The COMFORT-I trial is a randomized, double-blind, placebo-controlled Phase III study of 
the oral JAK1/JAK2 inhibitor INC424 in 309 patients with PMF, PPV MF, or PET-MF. 
Patients from 89 sites in the USA, Canada and Australia were randomized 1:1 to receive 
either INC424 (15 mg PO BID or 20 mg PO BID depending on baseline platelet count) or 
placebo. The primary endpoint of the study was the proportion of patients achieving ≥35% 
reduction in spleen volume from baseline to Week 24 as measured by MRI (or CT scan in 
applicable patients) and the secondary endpoints included: duration of maintenance of a ≥35% 
reduction from baseline in spleen volume among patients initially randomized to receive 
INC424, and the proportion of patients with ≥50% reduction in total symptom score from 
baseline to Week 24 as measured by the modified MFSAF v2.0 diary.
A total of 309 patients were enrolled in the study, with 155 randomized to INC424 and 154 to 
placebo. The groups were matched for baseline characteristics; the majority of patients had 
high-risk disease (61.2%). Patients were eligible to cross-over in this study, and 36 patients in 
the placebo group (23.4%) crossed over to INC424. The data cutoff date was 2-Nov-2010, the 
date of last patient last visit.
Significantly more patients in the INC424 group had a reduction in spleen volume (≥35%) at 
week 24 (41.9% vs. 0.7%; P<.0001). A reduction in spleen volume for ≥48 weeks was 
maintained in 67% patients who achieved a response on INC424. More patients receiving 
INC424 had an improvement of ≥50% in the total symptom score at 24 weeks compared to 
placebo (45.9% vs. 5.3%, P<0.001). Patient’s receiving INC424 also had improvements in 
each symptom assessed on the MF-SAF. Overall survival was a secondary endpoint of 
COMFORT-I. Ten deaths occurred in the INC424 group vs. 14 deaths in the placebo group 
(hazard ratio, 0.67; 95% CI, 0.30 to 1.50; P = 0.33). A survival analysis based on a planned 
data cutoff with 4 additional months of follow-up (median follow-up, 51 weeks) revealed a 
significant survival advantage for patients who received INC424 (13 deaths in the INC424 
group (8.4%) vs. 24 deaths in the placebo group (15.6%) (Hazard ratio, 0.50; 95% confidence 
interval, 0.25 to 0.98; P = 0.04).
INC424 was well tolerated in COMFORT-I, with most Grade 3/4 nonhematologic toxicities 
occurring in less than 6% patients: fatigue 5.2%, diarrhea 1.9%, dyspnea 1.3%, dizziness 
0.6%, vomiting 0.6%, arthralgia 1.9%, pyrexia 0.6%, and abdominal pain 2.6% (Verstovsek 
2012). Hematologic toxicity consisted primarily of anemia and thrombocytopenia. Grade 3/4 
anemia occurred in 45.2% patients, Grade 3/4 thrombocytopenia occurred in 12.9% patients, 
and Grade 3/4 neutropenia occurred less frequently in 7.1% of patients. Approximately half of 
the Grade 3/4 anemia and thrombocytopenia events occur during the first 8 weeks of therapy. 
Treatment with INC424 enabled 41.2% to become transfusion independent. Anemia and 
thrombocytopenia was manageable, and thrombocytopenia generally responded to dose 
reduction or temporary dosing interruption. Thirteen deaths occurred in the INC424 group vs. 
24 deaths in the placebo group (HR, 0.50; 95% confidence interval, 0.25 to 0.98; P = 0.04). 
The rate of discontinuation of the study drug because of AEs was 11.0% in the INC424 group 
vs. 10.6% in the placebo group.
 


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The COMFORT-II study (Study INCB 18424-352) is an open-label, randomized, active-
comparator trial that compared INC424 therapy to best currently available therapy (BAT) [as 
determined by the investigator for each individual patient randomized to the control group] in 
219 adult patients with PMF, PPV-MF or PET-MF. The control group therapy could also 
consist of no therapy (i.e., “watchful waiting”), or a combination of agents. COMFORT-II
assessed the impact of therapy on spleen length; evaluated durability of response; and gave 
additional data on the long-term safety of INC424 use. Patients were randomized in a 2:1 ratio 
of INC424:BAT. At randomization, patients were stratified by IPSS prognostic category as 
having either two prognostic risk factors (intermediate-2 risk), or three or more prognostic 
risk factors (high risk). In COMFORT-II, the randomized treatment phase started on Study 
Day 1 and continued until the patient met defined criteria for disease progression. During this 
phase, all patients in both arms underwent an objective evaluation of spleen length using MRI 
or CT. The percentage of patients achieving a 35% reduction in spleen volume at 48 weeks 
was the primary endpoint for efficacy. MRI was the primary modality of spleen length
(volume) measurement. Patients who were not candidates for MRI (including at sites where 
MRI is unavailable) were evaluated with sequential CT. Spleen volume was assessed by a 
central reader. While investigators were able to follow spleen length by palpation, results of 
MRI (or CT) spleen volume assessments were only to be made known to the investigator if a 
patient had reached a protocol-defined criterion for disease progression based upon increase in 
spleen volume. Patients having reached this endpoint were eligible to continue study 
participation in the extension phase, and if originally randomized to the control group, could
cross over to receive INC424 if they met safety requirements.
The rates of leukemic-free survival, progression-free survival, overall survival, and durability 
of response will be determined and compared between the randomized treatment groups, 
using data from both the randomized treatment phase and extension phase. Additional 
assessments will include analysis of JAK mutation status, cytokine levels, and change in 
symptoms as assessed by the EORTC QLQ-C30 and MFSAF v 2.0 questionnaires.
In the COMFORT-II trial (Harrison 2012), 28% of the patients in the INC424 group had 
≥35% reduction in spleen volume at week 48 vs. 0% in the BAT group (P < 0.0001); the 
corresponding percentages at week 24 were 32% and 0% (P < 0.001). The mean palpable 
spleen length (48 weeks) had decreased by 56% with INC424 but had increased by 4% with 
BAT. The median duration of response with INC424 was not reached, with 80% of patients 
still having a response at a median follow-up of 12 months. INC424 treatment was associated 
with an improvement in overall quality-of-life measures and a reduction in symptoms 
associated with MF. The most common hematologic abnormalities (≥Grade 3) were 
thrombocytopenia and anemia, which were managed with a dose reduction, interruption of 
treatment, or transfusion. One patient in each group discontinued treatment due to 
thrombocytopenia, and none discontinued due to anemia. Non-hematologic AEs were rare and 
mostly grade 1 or 2. Two cases of AML were reported with the best available therapy. 
INC424 was also well tolerated in the COMFORT-II trial, with most Grade 3/4 non-
hematologic toxicities occurring in < 3% patients: diarrhea 1%, asthenia 1%, dyspnea 1%, 
pyrexia 2%, nausea 1%, arthralgia 1%, fatigue 1%, pain in extremity 1%, abdominal pain 3%, 
headache 1%, and back pain 2%. Thrombocytopenia and anemia occurred more frequently in 
the patients receiving INC424 vs. BAT, although these events rarely led to treatment 
discontinuation (1 patient in each group discontinued the study due to thrombocytopenia) and 
 


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were generally manageable with dose modifications, transfusions of packed red cells, or both. 
AEs leading to dose modification with INC424 occurred in 41% patients. Only 5% of the 
patients receiving INC424 required dose interruptions or reductions due to anemia and 1% 
due to neutropenia.
When pooling the results of COMFORT-I and COMFORT-II to examine safety of INC424, 
the incidence of headache was more frequent in INC424-treated patients (13.6% vs. 6.0% on 
placebo and 5.5% on BAT). Most AEs of headache were Grade 1 or 2. Similarly, dizziness 
(12.0% vs. 6.6% on placebo and 6.8% on BAT) was more frequent in INC424-treated patients, 
again mostly Grade 1 or 2. When adjusted for patient-year exposure, the differences were still 
present for headache and dizziness. Weight increase was also more frequent in INC424-
treated patients than in the control groups (9.6% vs. 1.3% on placebo and 1.4% on BAT). 
Although some of these patients had co-reported AEs of edema, many had a past medical 
history of weight loss and the weight gain usually gradually accumulated over the course of 
one year of treatment. The majority of weight gain AEs were Grade 1 and 2. It is worth noting 
that weight gain may be a beneficial effect in patients with MF, given the catabolic nature of 
the disease and the frequency of weight loss reported as a constitutional symptom.
Other “preferred terms” with increased frequency in the INC424 arms included bruising 
(2.6% vs. 1.3% on placebo in [COMFORT-I, INCB 18424-351] only), contusion (8.6% vs. 
5.3% on placebo and 1.4% on BAT), urinary tract infection (7.3% vs. 4.6% on placebo and 
2.7% on BAT), herpes zoster (4.0% vs. 0.7% on placebo and 0% on BAT) and flatulence 
(3.3% vs. 1.3% on placebo and 0% on BAT). Abdominal pain was more frequent in the 
control groups than in the INC424 group (43% on placebo and 13.7% on BAT vs. 12% on 
INC424), as were weight decrease (8.6% on placebo and 8.2% on BAT vs. 1% on INC424), 
early satiety (8.6% on placebo and 0% on BAT vs. 0.3% on INC424) and splenic infarction 
(6.0% on placebo and 0% on BAT vs. 1.0% on INC424).
The most frequently occurring Grade 3 and 4 AEs regardless of study drug relationship were 
hematologic including anemia (14%) and thrombocytopenia (8%) (Source: [120 day safety 
update-Table 2.1-1.4 in Investigator Brochure]). Non-hematologic Grade 3-4 AEs were 
infrequent and rarely reported more frequently than in the control arms. Two patients (0.7%) 
had febrile neutropenia. In general, the pattern of AEs was similar between the two INC424 
arms in both studies, although there were some differences in frequency for specific AEs.
In the INC424-treated Phase III population, the overall frequency of AEs leading to study 
drug discontinuation was 11%. This frequency was similar across both studies. None of the 
AEs leading to discontinuation was reported in more than two patients in any group. In the 
INC424-treated Phase III population, the overall frequency of AEs requiring dose reduction or 
interruption was 59.8%. This frequency was higher than in the control groups (placebo: 27.2%, 
BAT: 15.1%). The most frequently reported AEs requiring dose reduction or interruption in 
INC424 treated patients were thrombocytopenia (36.9%), platelet count decrease (7.6%) and 
anemia (5.6%). The high frequency for thrombocytopenia is due to protocol-mandated dose 
reductions and interruptions. Although there were no protocol specified guidelines for dose 
reductions secondary to anemia, some investigators chose to reduce a patient’s dose in the 
setting of anemia to minimize this particular cytopenia. The frequency of these AEs was 
higher than in the control groups. All other AEs requiring dose reduction or interruption 
occurred with a frequency of 1.3% or less in the INC424 treated patients. There are no data 
 


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from the use of INC424 in pregnant women. Animal studies have shown that INC424 is 
embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits; however, the 
exposure margins compared to the highest clinical dose were low and the results are therefore 
of limited relevance for humans.The potential risk for humans is unknown. As a precautionary 
measure, the use of INC424 during pregnancy is contraindicated. Women of child-bearing 
potential should use effective contraception.
In the randomized period of the two pivotal studies in MF, COMFORT-I and COMFORT-II 
discontinuation due to adverse events, regardless of causality was observed in 11.3% of 
patients. The most frequently reported adverse drug reactions were thrombocytopenia and 
anemia. Hematological adverse reactions (any Common Terminology Criteria for Adverse 
Events [CTCAE] Grade) included anemia (82.4%), thrombocytopenia (69.8%) and 
neutropenia (16.6 %). Anemia, thrombocytopenia and neutropenia are dose related effects. 
The three most frequent non-hematological adverse reactions were bruising (21.6%), 
dizziness (15.3%) and headache (14.0%). The three most frequent non-hematological 
laboratory abnormalities were raised alanine aminotransferase (27.2%), raised aspartate 
aminotransferase (18.6%) and hypercholesterolemia (16.9%).
Long-term follow-up in patients with MF in the phase I/II study INCB 18424-251 and the 
COMFORT studies has shown that as expected, the numbers and proportions of adverse 
events (AEs) and serious adverse events (SAEs) have increased; however, no new safety 
signals have emerged. Additionally in patients with MF, the dose optimization strategy of 
dose reduction and occasional dose interruption for thrombocytopenia was successful in 
maintaining patients on therapy with only one patient on the ruxolitinib arm of each study 
discontinuing for thrombocytopenia; platelet transfusions occurred with low frequency, 
comparable to the control arms in the Phase III studies.
2
Rationale
2.1
Study rationale and purpose
The two pivotal Phase III clinical trials (COMFORT-I and COMFORT-II) evaluating INC424 
are fully enrolled and published (Verstovsek 2012, Harrison 2012). Results from the 
COMFORT-I study (Verstovsek 2012) published in March 2012 showed a decrease in the 
spleen size. In addition, symptoms associated with the disease such as weight loss, pruritus, 
and fever were improved with the treatment. Results from the COMFORT II clinical trial also 
published in March 2012 (Harrison 2012), similarly demonstrated a prolonged reduction in 
spleen volume as well as improvement in overall QOL measures and a reduction in symptoms 
associated with MF. The NDA filing for INC424 with the FDA occurred on August 3rd, 2011, 
and FDA approval was granted on November 16th 2011.
While regulatory approval and reimbursement approval are sought, there are no means 
available for patients with PMF, PPV MF, or PET-MF to receive INC424 outside of a clinical 
trial. Implementation of an Expanded Access Program will provide an access path to INC424 
for patients with PMF, PPV MF, and PET-MF, and enable collection of additional safety and 
efficacy data until approval by the regulatory agencies or until drug reimbursement is 
obtained at a country level.
 


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2.2
Rationale for dose and regimen selected
Phase I/II trials evaluated a number of different doses and schedules of INC424. The dose that 
provided the best clinical outcomes coupled with the optimum safety profile was 20 mg orally
BID. Among patients with baseline platelet counts from 100,000 to 200,000/ µL, a lower 
starting dose of 15 mg orally p.o. BID should be initiated, and in patients with platelet counts 
of (75,000 – <100,000/µL /µL) a starting dose of 5 mg p.o. BID should be initiated.
A more recent Phase Ib study (EXPAND) evaluating the safety and MTD of INC424 in 
patients with lower baseline platelet counts (75,000– 99,000/µL) was presented at the 
American Society of Hematology meeting in December 2012. Enrollment to date suggests 
that INC424 can be safely administered to patients with lower baseline platelet counts and as 
such patients with platelet counts of 50,000 – 99,000/µL are to be enrolled starting at a dose 
of INC424 of 5 mg p.o BID. A Phase II study evaluating open-label INC424 in patients with 
lower baseline platelet counts (50,000 – 100,000/ µL), presented at the American Society of 
Hematology meeting in December 2012, supports use of a starting dose of 5 mg p.o. BID 
(Talpaz 2012).
3
Objectives and endpoints
3.1
Primary objectives
To collect additional safety of INC424 in patients with PMF, PPV MF, or PET-MF who have 
either received prior treatment with commercially available agents, investigational drug or 
who have never received treatment.
3.2
Secondary objectives

To assess the best overall response rate of INC424 in patients with PMF, PPV MF, or PET-
MF, as evaluated by the investigator.

To collect QoL information in patients with PMF, PPV MF, or PET-MF treated with 
INC424.

To document MRU in patients with PMF, PPV MF, or PET-MF treated with INC424.
3.3
Study endpoints
3.3.1
Safety

Safety and tolerability will be collected by monitoring the frequency, duration and severity 
of all grade AEs by the National Cancer Institute CTCAE v. 3 0, performing physical 
exams (PE), and evaluating changes in vital signs (VS), ECOG performance status (PS), 
electrocardiograms (ECGs) and serum chemistry, hematology results.

Grade 3 and 4 AEs, Serious Adverse Events (SAEs).

Change in laboratory values from Baseline to End of Treatment (serum chemistry and 
hematology).

Changes in weight from Baseline to each assessment point and at end of treatment.

Cardiac function as assessed by electrocardiograms (ECGs).
 


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
Changes in vital signs.
3.3.2
Efficacy

Best overall response to treatment as assessed by spleen palpation (calculated as the 
percentage change in spleen length compared with baseline).

Change in spleen length from Baseline to end of each visit.

Change in WBC and platelet count from Baseline will be summarized to end of treatment.

Shift in fibrosis in the bone marrow from Baseline to worst/best value on study (where 
bone marrow biopsies are performed - not mandatory).

Progression free survival (PFS), acute myeloid leukemia free survival (LFS) and overall 
survival (OS).

In patients without splenomegaly, patient reported outcomes measure symptoms of the 
disease.
3.3.3
Quality of Life
(See Table 7-1 for assessments)

Change in ECOG performance status from Baseline to each visit where the variable is 
measured.

Changes in Functional Assessment of Cancer Therapy for patients with Lymphoma
(FACT-Lym) version 4 from Baseline to each visit where measured (Appendix VII).

Change in the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale 
from Baseline to each visit where measured (See Appendix VIII).
3.3.4
Medical resource utilization (MRU)
Medical resource utilization (MRU) will be assessed as follows:

Frequency and duration of hospitalization from Baseline up to week 48 of therapy

Frequency of emergency room visits from Baseline up to week 48 of therapy.

Frequency of general practitioner, specialist, and urgent care visits from Baseline up to 
week 48 of therapy.

Number of transfusions and transfusion dependency status end of study.

Splenectomy and use of splenic irradiation.

Changes in use of concomitant medications for MPN symptom management (Appendix 
IX).
4
Study design
4.1
Description of study design
This is a multicenter, single-arm, open-label expanded access study intended to provide 
additional data on the safety and efficacy of INC424 in patients with PMF, PPV MF, or PET-
MF who have either previously received treatment or have not received treatment.
 


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All patients will be treated for PMF, PPV MF, or PET-MF in each participating country with 
oral INC424 at a dose of 5 - 25 mg (dose based on Baseline platelet count) BID until either:

Disease progression;

Transplant;

Unacceptable toxicity;

Death;

Discontinuation from the study for any other reason;

Physician decision;

Withdrawal of consent;

Until 24-months after LPFV; or

Until the drug is commercially available, whichever occurs first.
The FPFV occurred on 16 August 2011 and the recruitment period ended on December 31, 
2014. The study enrolled a total of 2238 patients. The last patient last visit is planned for Dec 
2016.
Figure 4-1
Study design
* Baseline evaluations should be performed within 7 days of the first dose of INC424, however 
platelets should be performed within a maximum of 4 days of the first dose of INC424
All patients should be screened for inclusion and exclusion criteria (Section 5.2 and 
Section 5.3) within 28 days prior to the first dose of INC424. See Section 7.3 for a description 
of the required screening evaluations. Baseline evaluations should be performed within 7 days 
of the first dose of INC424, however platelets should be performed within a maximum of 4 
days of the first dose of INC424. See Section 7.4 for a description of the baseline evaluations 
required.
Screening and eligibility: Eligibility assessment may take place up to 28 days before the first 
dose of INC424 (Day -28 to Day -1). See Section 7.3 for required assessments.
 


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To avoid duplication of laboratory assessments and other examinations during the 28 days 
before Day 1, it is permissible to use historical results provided the examinations were 
performed consistent with protocol requirements 7 days prior to date of first dose, however 
platelets should be performed within a maximum of 4 days of the first dose of INC424.
Rescreening of patients is permissible at the discretion of the investigator i.e., a patient is 
screened and is found to be ineligible, they may be rescreened at a later date and entered onto 
the study provided all inclusion and no exclusion criteria are met. Rescreening should not 
occur more often than every 7 days.
Treatment period (open): All patients who consent to study participation will start treatment 
with INC424 upon meeting all study eligibility criteria. The study period commences on Day 
1 (day of first dose of study drug) and continues until either:
a. Disease progression;
b. Transplant;
c. Unacceptable toxicity;
d. Death;
e. Discontinuation from the study for any other reason;
f.
Physician decision
g. Withdrawal of consent;
h. Until 24-months after LPFV; or
i.
Until the drug becomes commercially available, whichever occurs first
Should INC424 not be available to patients after the drug is commercialized or 24-months 
after LPFV, Novartis will have a local transition plan in place to ensure that patients have 
access to INC424 without delays to treatment. Once the last dose of INC424 open label study 
drug is taken, or it becomes commercially available in each participating country or 24-
months after LPFV, no further AEs/SAEs will be collected after the required Study 
Completion (see Section 7.6.3).
End of study / treatment: Day of last dose of open-label INC424.
Follow-up period: 28 days following the last dose of open-label INC424.
4.2
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.6 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be 
responsible for informing the IRB and/or EC of the early termination of the trial.
 


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5
Population
5.1
Patient population
Adult male or female patients ≥ 18 years of age diagnosed with PMF, PPV MF, or PET-MF 
who have either received prior treatment with commercially available agents, investigational
drug or never received treatment are eligible for this Expanded Access Study.
All relevant medical and other considerations should be taken into account when deciding 
whether this protocol is appropriate for a particular patient. To maximize patient safety, 
patients should be treated on this protocol only at centers having ready and adequate staff to 
care for the thrombocytopenic patient. Physicians should consider the risks and benefits of 
any therapy and, therefore, only enroll patients for whom the agents administered are 
appropriate. Although they will not be considered as formal eligibility criteria, as part of this 
decision-making process physicians should recognize that the following may increase the risk 
to the patient entering this protocol: physicians should be aware that studies show CYP3A4 is 
the major human CYP450 isoenzyme catalyzing biotransformation of INC424. A clinical 
study where a strong CYP3A4 inhibitor (ketoconazole) and INC424 was co-administered 
resulted in a 90% increase in AUC of INC424. Thus, INC424 dose should be adjusted when 
co-administration with a strong CYP3A4 inhibitor (see Section 6.2.4). Other CYP3A4 
inhibitors or inducers are to be dosed with caution.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patients must give written informed consent according to local guidelines prior to any 
screening procedures.
2. Patients must not be eligible for another ongoing INC424 clinical trial.
3. Male or female patients aged ≥ 18 years of age.
4. Patients must be diagnosed with PMF, PPV MF or PET-MF, according to the 2008 revised 
International Standard Criteria Appendix I, Swerdlow 2008, Vardiman 2009, Barosi 2008), 
irrespective of JAK2 mutation status.
5. Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) 
OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 
(1 prognostic factor, no more) with an enlarged spleen (assessment to occur at the 
Screening Visit).
The prognostic factors, defined by the International Working Group (Cervantes 2009) are:

Age > 65 years;

Presence of constitutional symptoms (weight loss, fever, night sweats);

Marked anemia (Hgb < 10g/dL)*;

Leukocytosis (history of WBC > 25 x109/L);

Circulating blasts > 1% (in the peripheral blood).
*A Hgb value < 10 g/dL must be demonstrated during the Screening Visit for patients 
who are not transfusion dependent. Patients receiving regular transfusions of packed 
 


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red blood cells will be considered to have Hgb < 10 g/dL for the purpose of evaluation 
of risk factors.
6. Patients with Intermediate-1 disease and splenomegaly must have a palpable spleen 
measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.
7. Patients must have a peripheral blood blast count percentage of < 10%.
8. Patients with adequate liver function defined as total bilirubin or direct bilirubin ≤ 2.0 x 
ULN and ALT ≤ 2.5 x ULN.
9. Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN.
10. Patients with an ECOG PS of 0, 1, or 2 (Appendix IV).
11. Women of childbearing potential must have had a negative serum pregnancy test within 14 
days prior to the administration of study drug.
12. Patients must have recovered or stabilized sufficiently from any adverse drug reactions 
associated with prior treatment before beginning treatment with INC424.
13. Fedratinib pretreated patients with documented complete physical examination including 
full neurologic examination and cardiology assessment, thiamine level testing, and MRI of 
the brain if indicated based on signs or symptoms. Patients pretreated with fedratinib 
should have completed or be receiving thiamine supplementation according to the 
investigator’s instructions.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a 
suitable donor is available).
2. Patients with history of malignancy in past 3 years except for treated, early-stage 
squamous or basal cell carcinoma in situ.
3. Patients receiving any medication listed in the “Prohibited Medications” listing 
(Section 6.3.3 and Appendix VI).
4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection).
5. Patients with cardiac disease which in the investigator’s opinion may jeopardize the safety 
of the patient or the compliance with the protocol.
6. Patients with currently uncontrolled or unstable angina, rapid or paroxysmal atrial 
fibrillation or recent (approximately 6 months) myocardial infarction or acute coronary 
syndrome.
7. Patients with clinically significant bacterial, fungal, parasitic or viral infection which 
require therapy. Patients with acute bacterial infections requiring antibiotic use should 
delay screening/enrollment until the course of antibiotic therapy has been completed.
8. Patients with known active hepatitis A, B, C or who are HIV-positive.
9. Patients with inadequate bone marrow reserve at the Baseline visit as demonstrated by:

ANC ≤ 1000/µL.
 


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
Platelet count <50,000/µL without the assistance of growth factors, thrombopoietic 
factors or platelet transfusions.
10. Patients with any history of platelet counts < 50,000/µL or ANC < 500/µL except during 
treatment for a MPD or treatment with cytotoxic therapy for any other reason.
11. Patients with coagulation parameters (PT, PTT, or INR) >1.5 x ULN.
12. Patients with known hypersensitivity to INC424 or other JAK1/2 inhibitors, or to their 
excipients.
13. Patients under ongoing treatment with another investigational medication or having been 
treated with  an investigational medication within 30 days of screening or with fedratinib 
within 14 days of screening. 
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test (> 5 mIU/mL).
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study duration inclusive of 28 day safety follow up. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
16. Patients who are unable to comprehend or are unwilling to sign an ICF
17. Patients with active alcohol or drug addiction that would interfere with their ability to 
comply with the study requirements
18. Patients with any concurrent condition that, in the Investigator’s opinion would jeopardize 
the safety of the patient or compliance with the protocol.
 


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19. In the case of ruxolitinib pretreated patients, ruxolitinib primary resistant patients defined 
as: 

No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib. 
AND

No reduction in symptoms within the first 12 weeks after first-line treatment with 
ruxolitinib.
20. In the case of ruxolitinib pretreated patients, patients discontinuing ruxolitinib due to a 
Grade 4 AE related or suspected to be related to ruxolitinib.
6
Treatment
6.1
Investigational treatment, other study treatment, supportive 
treatment
6.1.1
Study drug dosing
All eligible patients with PMF, PPV MF, or PET MF who consent to participate in this study 
will receive INC424 open-label investigational drug provided free of charge by Novartis 
Pharmaceuticals at a dose of 5 – 25 mg BID [dose based on Baseline platelet count] until 
either:

Disease progression;

Transplant;

Unacceptable toxicity;

Death;

Discontinuation from the study for any other reason;

Physician decision

Withdrawal of informed consent;

Until 24-months after LPFV; or

Until the drug is commercially available, whichever occurs first.
The starting dose of INC424 will be determined based on baseline platelet counts as follows:

Patients with a baseline platelet count of > 200,000/µL will begin dosing at 20 mg PO 
BID.

Patients with a baseline platelet count of between 100,000/µL – 200,000/µL (inclusive) 
will begin dosing at 15 mg PO BID.

Patients with a Baseline platelet count of 50,000/ µL – <100,000/µL /µL will begin dosing 
at 5 mg BID (one 5 mg tablet BID)

Patients with platelet counts less than 50,000/µL are ineligible for the study (see Section 
5.2 and Section 5.3).
Dosage Tablet Combinations for Patients
For 25 mg PO BID
For 20 mg PO BID
For 15 mg PO BID
For 10 mg PO BID
For 5 mg PO BID
Two 10 mg tablets 
Four 5 mg tablets
One 10 mg tablet and 
One 10 mg tablet
One 5 mg tablet
 


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For 25 mg PO BID
For 20 mg PO BID
For 15 mg PO BID
For 10 mg PO BID
For 5 mg PO BID
and one 5mg tablet
one 5 mg tablet
One 10 mg tablet 
and three 5 mg
tablets
Two 10 mg tablets
Three 5mg tablets
Two 5 mg tablets
Five 5 mg tablets
Two 5 mg tablets and 
one 10 mg tablet
INC424 tablets will be administered orally without regards to food in an outpatient setting in 
accordance with the specified dosing schedules. The dosage strength is 5 mg or 10 mg per 
tablet INC424. INC424 tablets are to be taken orally BID, approximately 12 hours apart 
(morning and night). INC424 will be self-administered by the patient, and each investigator 
should instruct the patient to take the study drug as per protocol (if applicable). All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record (DAR) eCRF.
A standardized approach is to be taken for dosing adjustments and for safety and efficacy so 
that each patient is titrated to their most appropriate doses (see Section 6.2). Doses of INC424 
are not to exceed 25 mg PO BID
Table 6-1
Dose and treatment schedule
Study drugs
Pharmaceutical form and route of administration
Dose
Frequency
INC424
Tablet for oral use
See Section 6.1.1.
BID continuously
6.2
Dose modifications
6.2.1
Dose increases of INC424
6.2.1.1
Dose modification for patients starting INC424 at a dose of 15 – 20 mg
BID
6.2.1.1.1 Dose increases of INC424 at week 4
As indicated in Section 6.1.1 Study Drug Dosing, the initial dose of INC424 will be 
determined by the Baseline platelet count. In order to optimize each patient’s dosage, after the 
first 4 weeks of therapy, doses may be increased by 5 mg BID for patients who meet all of the 
following conditions:

Palpable spleen length below the costal margin that has been reduced by LESS THAN 
40% at Week 4 visit relative to Baseline.

Platelet count at the Week 4 blood draw is > 150,000/µL and platelet count has never been 
below 150,000/µL at a prior laboratory evaluation while receiving INC424. (See Figure 6-
1).
Absolute neutrophil count (ANC) levels have remained at or above 1000/µL since enrollment 
in the study.
 


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Figure 6-1
Dose increase strategies for patients starting on INC424 15 – 20 mg 
BID with inadequate responses after at least Week 4:
Patients with Inadequate Response at Week 4
Starting Dose
20 mg BID
Starting Dose
15 mg BID
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
New Dose
25 mg BID
No Increase 
In Dose
New Dose
20 mg BID
No Increase
In Dose
Patients with Inadequate Response at Week 4
Starting Dose
20 mg BID
Starting Dose
15 mg BID
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
New Dose
25 mg BID
No Increase 
In Dose
New Dose
20 mg BID
No Increase
In Dose
>
>
>
>
Patients with Inadequate Response at Week 4
Starting Dose
20 mg BID
Starting Dose
15 mg BID
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
New Dose
25 mg BID
No Increase 
In Dose
New Dose
20 mg BID
No Increase
In Dose
Patients with Inadequate Response at Week 4
Starting Dose
20 mg BID
Starting Dose
15 mg BID
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
PC always 150 K /µL 
And
ANC  always 
1000/µL
PC <150 K/µL
Or
PC was <150 K/µL
Or 
ANC is/was <1000/µL
New Dose
25 mg BID
No Increase 
In Dose
New Dose
20 mg BID
No Increase
In Dose
>
>
>
>
6.2.1.1.2 Dose increases beyond week 4
After Week 4 (month 1), dose increases of INC424 are allowed for those patients who exhibit 
an INCREASE in palpable spleen length. The rules for these optional dose increases are as 
follows:

The dose increases may only occur if the platelet count and ANC data for that visit are 
available.

The palpable spleen length for that Study Visit must show a 2 cm or greater INCREASE 
in length compared to the on-study nadir (lowest palpable spleen measurement during the 
study, including Baseline).

The patient must NOT have had a prior safety-related dose reduction.

The following platelet threshold have been met:

The patient must have had a platelet count ≥150,000/µL at every assessment since 
Baseline for those starting INC424 at a starting dose of 15 – 20 mg BID.

The patient must have had ANC ≥1000/µL at every assessment since baseline.

The dose increase may only be an increase of 5 mg BID.

The total dose may never exceed 25 mg BID.

Following a dose increase, platelet count and ANC levels should be assessed 
approximately 2 weeks after the dose adjustment. If a regularly scheduled Study Visit 
does not coincide with this required blood draw, an unscheduled Interim Visit should be 
held to collect samples for hematology.
Dose adjustments for safety (Section 6.2.2), and reinstitution of doses (Section 6.2.3) will 
apply whether the patient is on the original dose, or a dose that was increased for lack of 
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6.2.1.2
Dose modification for patients starting INC424 at a dose of 5 mg BID
6.2.1.2.1 Dose increases at week 4
For those patients who start INC424 treatment at a dose of 5 mg BID, dose increases can be 
made as described below. The dose can be escalated 5 mg once a day starting at week 4, and 
thereafter no more than every two weeks ONLY if:

Inadequate efficacy is seen with the current dose level (See Section 6.2.1.1.1)

No treatment-related toxicity has occurred with the current dose level, resulting in 
treatment reduction or interruption or discontinuation in the previous 28 days

The minimum platelet count at the time of the escalation is ≥ 50,000/µL

ANC > 1000/µL since last scheduled visit

The total dose may never exceed 25 mg BID
If the above criteria are met, then the INC424 dose can be increased by 5 mg o.d. e.g., from 5 
mg BID to 5 mg QAM and 10 mg QPM.
6.2.1.2.2 Dose increases beyond week 4
After Week 4, dose increases of INC424 are allowed for those patients who exhibit an 
INCREASE in palpable spleen length. The rules for these optional dose increases are as 
follows:

The dose increases may only occur if the platelet count and ANC data for that visit are 
available.

The palpable spleen length for that Study Visit must show a 2 cm or greater INCREASE 
in length compared to the on-study nadir (lowest palpable spleen measurement during the 
study, including Baseline).

The patient must NOT have had a prior safety-related dose reduction.

The following platelet threshold have been met:

The patient must have had a platelet count ≥50,000/µL at every assessment since 
Baseline for those starting INC424 at a starting dose of 5 mg BID

The patient must have had ANC ≥1000/µL at every assessment since baseline.

The dose increase may only be an increase of 5 mg once daily for those starting on an 
INC424 dose of 5 mg BID.

The total dose may never exceed 25 mg BID.

Following a dose increase, platelet count and ANC levels should be assessed 
approximately 2 weeks after the dose adjustment. If a regularly scheduled Study Visit 
does not coincide with this required blood draw, an unscheduled Interim Visit should be 
held to collect samples for hematology.
Dose adjustments for safety (Section 6.2.2), and reinstitution of doses (Section 6.2.3) will 
apply whether the patient is on the original dose, or a dose that was increased for lack of 
efficacy.
 


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6.2.2
Dose interruption or dose reduction
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following 
guidelines need to be applied: for all patients who are receiving INC424, there are mandatory 
dose decreases or dose interruptions for declining platelet counts or ANC levels that might be 
observed while on INC424 therapy. In addition to mandatory dose interruption or decrease for 
hematologic toxicities, there are mandatory criteria for permanent discontinuation of INC424 
(See Section 6.2.6).
Dosing must be held if platelet counts decline below 50,000/µL (Grade 3 laboratory 
abnormality by CTCAE v. 3.0, or if ANC falls below 500/µL while receiving INC424.
6.2.2.1
Dose interruption or dose reduction for patients starting INC424 at
doses of 15 – 20 mg p.o. BID
Doses should be decreased for platelet count values < 125,000/µL as shown in Table 6-2 with 
optional restarting or resuming prior dose after recovery (Section 6.2.3). In order to provide 
sufficient data to make the dose adjustment decisions, it is recommended that hematology 
parameters be obtained at least weekly for platelet count <100,000/µL or ANC < 1000/µL and 
at least two times weekly for platelet count < 50,000/µL or ANC < 500/µL.
These changes must be recorded on the Dosage Administration Record eCRF.
Table 6-2
Dose reductions in INC424 for safety in patients with platelet count 
declines (for those starting on INC424 dose of 15 – 20 mg p.o. BID)
Platelet Count at 
Time of Decline
Dose at the Time of Platelet Decline
25 mg BID
20 mg BID
15 mg BID
10 mg BID
5 mg BID
Dose that MUST be Instituted
≥ 125,000/µL
No dose reduction required
100,000/µL to < 
125,000/µL
20 mg BID
20 mg BID
15 mg BID
10 mg BID
5 mg BID
75,000/µL to < 
100,000/µL
10 mg BID
10 mg BID
10 mg BID
10 mg BID
5 mg BID
50,000/µL to < 
75,000/µL
5 mg BID
5 mg BID
5 mg BID
5 mg BID
5 mg BID
< 50,000/µL
Stop Dosing
6.2.2.2
Dose interruption or dose reduction for patients starting INC424 at 
doses of 5 mg p.o. BID
Dose modifications are made according to the platelet count as follows (see Table 6-3):

If platelets > 25,000 - < 50,000/µL: reduce the INC424 dose by 5 mg o.d.

If platelets ≤ 25,000/µL: hold treatment. Treatment can be restarted at a later date if 
platelets increase to ≥50,000/µL.
The patients should then be reassessed the following month. If the platelet count improves, the 
patient can restart treatment, and if the platelet count does not improve the patient should be 
withdrawn from the study.
 


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These changes must be recorded on the DAR eCRF.
Table 6-3
Dose reductions in INC424 for safety in patients with platelet count 
declines (for those starting on INC424 dose of 5 mg PO BID)
Platelet count at time of decline
Dose reduction/hold
≥50,000/µL
No dose reduction required
< 50,000/µL and > 25,000/µL
Decrease dose by 5 mg OD
≤25,000/µL
Hold treatment; treatment may be restarted once the 
platelet count increases to >50,000/µL as outlined in
Section 6.2.3.2
Study drug MAY be permanently discontinued for a Grade 4 clinical event that has NOT been 
confirmed upon rechallenge with the study drug, at the option of the Investigator.
6.2.2.3
Dose modification for renal impairment
No specific dose adjustment is needed in patients with mild or moderate renal impairment.
In patients with severe renal impairment (creatinine clearance less than 30 mL/min) the 
recommended starting dose based on platelet count should be reduced by approximately 50% 
BID (15mg BID or 25mg BID should have the higher dosage taken in the morning). Patients 
diagnosed with severe renal impairment while receiving ruxolitinib should be carefully 
monitored and need to have their doses reduced to avoid adverse drug reactions. 
There are limited data to determine the best dosing options for patients with end-stage renal 
disease on hemodialysis. Available data in this population suggest that the starting dose for 
patients with end-stage renal disease on hemodialysis is 15 mg INC424 for patients with 
platelet count between 100,000-200,000/µL or 20 mg for patients with platelet count 
of >200,000/µL. Subsequent doses (single administration) should be administered on 
hemodialysis days following each dialysis session. Additional dose modification should be 
made with careful monitoring of safety and efficacy. No data is available for dosing patients 
who are undergoing peritoneal dialysis or continuous venovenous hemofiltration. No data is 
available for patients who have lower platelet counts and renal failure.
6.2.2.4
Dose modification for hepatic impairment
Patients diagnosed
with hepatic impairment while receiving
ruxolitinib
should be
carefully monitored and may need to have their dose reduced to avoid adverse drug
reactions.
In patients with any hepatic impairment the recommended starting dose based on platelet
count should be reduced by approximately 50% BID (15mg BID or 25mg BID should have 
the higher dosage taken in the morning). Subsequent doses should be adjusted based on 
careful monitoring of safety and efficacy. Patients diagnosed with hepatic impairment while 
receiving INC424 should have complete blood counts, including a white blood cell count 
differential (neutrophils, lymphocytes, eosinophils, basophils, monocytes, and blast cells), 
monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with 
INC424 and as clinically indicated thereafter once their liver function and blood counts have 
been stabilized. INC424 dose can be titrated to reduce the risk of cytopenia.
 


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6.2.3
Restarting or reinstituting previous dose
6.2.3.1
Restarting or reinstituting previous dose for patients who start INC424 
15 – 20 mg BID
Dosing of INC424 may be restarted or increased following recovery of platelet counts and/or 
ANC to acceptable levels as illustrated in Table 6-4 for those patients who start on INC424 15 
– 20 mg BID. The objective for restarting or escalating after a reduction for safety is to find 
the highest safe dose of INC424 for each patient, with increases in dose generally not more 
than in increments of 5 mg BID and not more often than every 2 weeks. Patients who are 
restarting after a reduction for thrombocytopenia may not receive doses above 20 mg BID 
maximum. Similarly, ANC levels that decline to < 500/µL necessitate immediate dose 
interruption (Section 6.2.6). ANC level recovery to 500 /µL and above but less than 750/µL 
will allow dosing to be restarted at 5 mg BID, and ANC levels between 750/µL, but < 
1000/µL may restart at 10 mg BID. Absolute neutrophil count level increases to above 
1000/µL will allow a further dose increase to a maximum of 20mg BID.
The maximum dose used should never exceed 5mg BID LESS than any dose that resulted in 
platelets falling below 100,000/µL or ANC falling below 500/µL. After restarting using the 
guidelines in Table 6-4, if it is found that a patient cannot tolerate the lowest allowed dose 
(5mg BID, or 5mg QD with concomitant CYP3A4 inhibitor, see Section 6.2.4) without 
platelets falling below 50,000/µL, neutrophils falling below 500/µL, or Hgb falling below 
6.5g/dL despite the use of transfusion therapy, drug must be permanently discontinued 
(Section 6.2.6, and Section 7.6.1).
Table 6-4
Restarting or increasing INC424 dose after safety interruptions or 
dose reductions for patients starting on doses of 15 – 20 mg BID
Current Platelet Count 
Dose Restart or Dose Increase Guidelines
< 50,000/µL
Continue hold
50,000/µL to < 75,000/µL
5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID
75,000/µL to < 100,000/µL
10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID
100,000/µL to < 125,000/µL
15 mg BID
≥125,000/µL
20 mg BID 
Current ANC Level
Dose Restart or Dose Increase Guidelines
< 500/µL
Continue hold
500 to < 750/µL
5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID
750 to < 1000/µL
10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID
1000 to < 1500/µL
15 mg BID for at least 2 weeks; if stable may increase to 20 mg BID
≥1500/µL
20 mg BID 
NOTE: Whether the dose interruption occurred because of neutropenia, thrombocytopenia or 
both, when restarting, both the platelet count and ANC must be considered to determine the
restart dose, with the lower calculated dose being used. 
 


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6.2.3.2
Restarting or reinstituting previous dose for patients who start INC424 
at 5 mg BID
Dosing of INC424 may be restarted or increased following recovery of the platelet count to 
≥50,000/µL. Reinitiate treatment at a dose of 5 mg o.d. The dose may be increased by 5 mg 
o.d. every two weeks based on platelet counts and the absence of other adverse events.
When the ANC is < 500/µL, hold INC424 dosing. INC424 can be reinitiated in this 
population once the ANC is ≥500/µL, at a dose of 5 mg o.d. The dose may be increased by 5 
mg o.d. every two weeks based on platelet counts and the absence of other adverse events.
6.2.4
Dose reductions for concomitant CYP inhibitor usage
INC424 is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the 3A4 isoenzymes. With concomitant dosing of strong (potent)
CYP inhibitors such as oral ketoconazole, plasma exposure of INC424 increases 
approximately 2-fold. Thus, a dose reduction of ~ 50% for INC424 is appropriate for patients 
who take ketoconazole or other potent CYP3A4 inhibitors as concomitant medication. Twice 
daily (BID) doses will be decreased to the corresponding once daily dose as follows:

If dose is 25 mg BID, change dose to 25 mg QD

If dose is 20 mg BID, change dose to 20 mg QD

If dose is 15 mg BID, change dose to 15 mg QD

If dose is 10 mg BID, change dose to 10 mg QD

If dose is 5 mg BID, change dose to 5 mg QD
If a patient is already on a once daily dose of INC424, and a potent CYP3A4 inhibitor is 
added as a concomitant medication, the dose should be reduced to 5 mg every other day.
More frequent monitoring of hematology parameters and clinical signs and symptoms of 
ruxolitinib related adverse reactions is recommended upon initiation of a strong (potent) 
CYP3A4 inhibitor.
Potent inhibitors of CYP3A4 include oral ketoconazole, clarithromycin, itraconazole, 
voriconazole, nefazodone, telithromycin (Flockhart 2007). Based on the very low overall 
bioavailability of topical ketoconazole, no dosage adjustment is needed for use with topical 
ketoconazole. NOTE: once the course of therapy using a CYP 3A4 inhibitor has been 
completed, the patient should resume their prior BID dose regimen of INC424 beginning the 
next day.
6.2.5
Optional dose tapering strategy in the event of study drug 
discontinuation
Following interruption or discontinuation of ruxolitinib, symptoms of myelofibrosis may 
return over a period of approximately one week. There have been cases of patients 
discontinuing ruxolitinib who sustained more severe events, particularly in the presence of 
acute intercurrent illness. It has not been established whether abrupt discontinuation of 
ruxolitinib contributed to these events. Unless abrupt discontinuation is required, gradual 
tapering of the dose of ruxolitinib may be considered, although the utility of the tapering is 
unproven.
 


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When a decision is made to permanently discontinue INC424 therapy for reasons other than
low platelet counts or ANC levels, a dose tapering strategy may be considered, based on 
evaluation of the condition of the patient, current dosing regimen, and the clinical judgment of 
the investigator. If considered to be medically necessary, the investigator may use any 
treatment to manage withdrawal from INC424 including a gradual tapering of the study drug 
dosage or use of other medications to manage adverse drug reactions of discontinuation. 
Short-term courses of corticosteroids have been used to moderate the withdrawal of INC424 
and may be considered as part of a tapering strategy. Corticosteroids may be started prior to, 
or concurrent with, INC424 tapering. When a decision has been made to discontinue the 
patient with utilization of a tapering strategy, regardless of the use of concomitant medications, 
safety data will continue to be assessed in accordance with the protocol until the end of 
INC424 administration and in the event of an AE through resolution of the AE.
6.2.6
Dose interruption and discontinuation of study drug
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
adverse drug reaction that may have an unclear relationship to study drug. Except in cases of 
emergency or for protocol mandated holds for ANC or platelet count, it is recommended that 
the investigator consult with the Sponsor medical monitor (or other representative of the 
Sponsor) before temporarily interrupting therapy. Study drug may be held by the investigator 
at any time if there is concern about patient safety, and for all aspects of the conduct of the 
protocol the safety of the individual patient is paramount. Treating investigators may employ 
any means necessary to ensure patient safety, particularly in medical circumstances not 
anticipated by this protocol. Additionally, the investigator must obtain approval from the 
Sponsor before restarting study drugs that were temporarily discontinued for an adverse 
experience.
Dosing must be halted immediately if any of the following occur for patients starting with 15 
& 20 mg BID:

Platelet counts fall below 50,000/µL

ANC levels fall below 500/µL

Hemoglobin cannot be maintained ≥6.5 g/dL despite the use of transfusion therapy
Dosing may be reinstated following dose holding using the re-start schema detailed in 
Section 6.2.3. In order to provide sufficient data to make the dose adjustment decisions, it is 
recommended that hematology parameters be obtained at least weekly for platelet count < 
100,000/µL or ANC < 1000/µL and at least two times weekly for platelet count < 50,000/µL 
or ANC < 500/µL. (Note: patients with platelet counts of < 10,000/µL should be hospitalized, 
unless local or national practice does not permit it).
If a patient on a dose-hold requires frequent testing for safety parameters, these tests may be 
performed at a local laboratory. If the study drug is interrupted for any reason for more than 8 
weeks, dosing may not be restarted, except in the case of splenectomy, for which a maximum 
12 week period of study drug interruption is permitted. Although study guidelines provide for 
dose reduction/interruption for the management of hematologic or non-hematologic toxicities 
that occur during the course of the study, the following guidelines should be used to determine 
whether permanent discontinuation of study drug is necessary.
 


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Discontinuation of study drug for hematologic toxicity:
Study drug MUST be permanently discontinued if the lowest allowed dose (5 mg BID or 5 
mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following:

Platelets cannot be maintained ≥ 50,000/µL.

Absolute neutrophil count cannot be maintained ≥500/µL.

Hemoglobin cannot be maintained ≥6.5 g/dL despite the use of transfusion therapy.
In the event that any patient permanently discontinues the study drug, regardless of reason, 
reasonable efforts should be made to have the patient return for an early termination visit and 
have the End of Treatment evaluations completed as described in Section 7.6 and 
Section 7.6.2. The site is requested to provide voluntary follow-up of all withdrawn patients, 
with regard to incidence of leukemia or death.
The date the patient discontinued the study drug and the specific reason for discontinuation 
will be recorded in the eCRF. This will include reasons such as discontinued due to disease 
worsening or withdrawn due to adverse event. This information will be used to summarize the 
reasons for study withdrawal.
6.2.6.1
Dose reduction for non-hematological safety
Study drug MUST be permanently discontinued upon the occurrence of a clinically significant 
Grade 3 or Grade 4 laboratory or non-laboratory abnormality attributed to ruxolitinib if fails 
to resolve to Grade 2 or better within 8 weeks or if a lower re-start dose or administration 
schedule is either not available or likely to be clinically ineffective. 
Although study guidelines provide for dose reduction/interruption for the management of 
hematologic or non-hematologic toxicities that occur during the course of the study, the 
investigator should determine whether permanent discontinuation of study drug is necessary.
6.2.7
Treatment of investigational drug overdose
There is no known antidote for INC424 overdose. Overdose will be defined as the use of 
INC424 in doses in excess of that specified in the protocol. . Patients overdosed should be 
treated with appropriate supportive care until recovery. Use of INC424 in doses in excess of 
that specified in the protocol should not be recorded in the eCRFs as an AE of ‘Overdose’. An 
overdose with associated SAEs should be recorded as the SAE diagnosis/symptoms on the 
relevant AE and SAE forms in the eCRFs. An overdose with associated non-serious AEs 
should be recorded as the AE diagnosis/symptoms on the relevant AE forms in the eCRFs. An 
overdose without associated symptoms should not be recorded as an AE in the eCRFs.
6.3
Concomitant medications
All concomitant medications and treatments must be recorded on the appropriate eCRF. Any 
prior medication received up to 30 days prior to the first dose of study drug will be recorded 
in the CRF. All prior medications used to treat (record applicable indication) disease will be 
recorded. Patients will be instructed not to take any additional medications (including over-
the-counter products) during the course of the study without consultation with the investigator.
 


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6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies eCRF, respectively.
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without consultation with the investigator. At each 
visit, the patient must be asked about any new medications he/she is or has taken.
All medications taken ≤ 30 days prior to study entry should be recorded on the Concomitant 
Medications Prior to Start of Study Drug Case Report Form (eCRF). All prior medications 
used to treat PMF, PPV MF, or PET-MF will be recorded. All concomitant treatments during 
the trial will also be recorded in the eCRF.
The following restrictions apply during the study:

No other investigational therapy should be given to patients.

No anticancer agents other than the study medication (INC424) should be given to patients 
until disease progression or withdrawal from the study. If such agents are required for a 
patient then the patient must first be withdrawn from the study.
6.3.2
Permitted concomitant therapy requiring caution and/or action
The following medications have restrictions on use or doses or require changes to the way in 
which INC424 is administered during the study:

In patients for whom warfarin or heparin use will be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored, and dose of 
anticoagulant adjusted accordingly. If anticoagulation is required during INC424 
administration, low molecular weight heparin is preferred, particularly in patients who are: 
elderly, history of CHF, diabetic, hepatic or renal disease, or atrial fibrillation (first 
episode).

Low dose aspirin (≤150 mg/day) and non-steroidal anti-inflammatory agents 
(acetaminophen, ibuprofen) may be used. Aspirin doses > 150 mg are prohibited.

Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Appendix VI):

When concomitant administration of a strong (potent) inhibitor of CYP3A4 metabolizing 
enzymes or dual CYP2C9/CYP3A4 inhibitors (Appendix VI) is required for patient 
management, the dose of INC424 tablets must be reduced by approximately 50% to be 
administered twice daily by decreasing the twice daily dose or by decreasing the 
frequency of dosing to the corresponding once daily dose when twice daily dose is not 
practical.” (See Section 6.2.4).

Note: No dose adjustment of ruxolitinib is needed for use with topical ketoconazole.  
Note: More frequent monitoring of hematology parameters and clinical signs and 
symptoms of ruxolitinib realted adverse reacstions is recommended upon initiation of 
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
No dose adjustment will be made when moderate systemic CYP3A4 inducers (Appendix 
VI) are co-administered with study treatment.

Granulocyte growth factors are not allowed while study treatment is being administered 
but may be used for severe neutropenia at the Investigator’s discretion while study 
medication is being withheld.

Certain herbal supplements see Appendix VI are prohibited. Because the composition, 
pharmacokinetics and metabolism of many herbal supplements are unknown, the 
concurrent use of all herbal supplements is strongly discouraged during the study however 
if used during the trial please ensure the treatment is entered on the proper eCRF page (see 
Section 6.3.1).
6.3.3
Prohibited concomitant therapy
The following medications are prohibited during the study until treatment discontinuation:

Concomitant use of another JAK inhibitor.

Any investigational medication other than INC424 that is not approved for any indication. 
Use of such medications within 30 days or 5 half-lives, whichever is longer, prior to the 
first dose of study drug and until treatment discontinuation is prohibited.

Use of hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide is not 
permitted at any time during participation in the study. These medications should be 
discontinued prior to Day 1 of INC424 therapy. All adverse events attributed to these 
medications should be resolved prior to Day 1 of INC424 treatment.

Potent inducers of CYP3A4 Appendix VI are not permitted.

Aspirin in doses exceeding 150 mg per day is prohibited.
6.4
Patient numbering, treatment assignment and randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each patient is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. available to the investigator through the Oracle Clinical RDC interface.. 
Once assigned, the Patient No. must not be reused for any other patient and the Patient No. for 
that individual must not be changed, even if the patient is re-screened.
If the patient fails to be enrolled for any reason, the reason will be entered into the Screening 
Disposition page.
Patient numbering for those patients who may have participate in CINC424A2401 before 
being under fedratinib: those patients will receive a new patient number as per process 
described above.
 


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6.4.2
Treatment assignment and randomization
The investigational treatment (INC424) will be provided to all participants and no 
randomization processes will apply.
6.4.3
Treatment blinding
All study participants will receive active medication, therefore blinding is not applicable.
6.5
Study drug supply
6.5.1
Study drug preparation and dispensation
Study drug refers to open label INC424 (ruxolitinib). All dosages prescribed to the patient and 
all dose changes during the study must be recorded on the DAR form.
6.5.2
Study drug packaging and labeling
INC424 investigational drug is provided as 5 mg and 10mg tablets. INC424 5 mg and 10mg 
tablets are packaged in bottles or in blisters according to local Heath Authority requirements. 
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include the patient number, but no information about the patient.
Patients will initially receive a 4-week supply of INC424 each month for the first 3 months of 
the study. Once the study visits expand to every 3 months, patients will have a 3-month 
supply of INC424 dispensed. Immediately before dispensing the study drug to the patient, the 
investigator or his/her designee will detach the outer part of the label from the packaging and 
affix it to the source document containing the patients’ unique patient number (identifier).
INC424 treatment will be administered until either:

Disease progression;

Transplant;

Unacceptable toxicity;

Death;

Discontinuation from the study for any other reason;

Physician decision

Withdrawal of consent;

Until 24-months after LPFV; or

Until the drug is commercially available, whichever occurs first
Should INC424 not be available to patients after the drug is commercialized or 24-months 
after LPFV, Novartis will have a local transition plan in place to ensure that patients have 
access to INC424 without delays to treatment.
6.5.3
Drug supply and storage
Study treatments must be received by a designated person at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
 


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designated assistants have access. Upon receipt, INC424 should be stored according to the 
instructions specified on the drug labels. Details are listed in Table 6-5.
Table 6-5
Supply and storage of study treatments
Study treatments
Supply
Storage
INC424
Centrally and/or locally supplied 
by Novartis
Refer to study treatment label and/or to local 
treatment label
Under normal conditions of handling and administration, INC424 is not expected to pose 
significant safety risks to site staff. A Material Safety Data Sheet (MSDS) describing the 
occupational hazards and recommended handling precautions will be provided to site staff if 
required by local laws or will otherwise be available from Novartis Pharmaceuticals upon 
request.
Investigational product must be kept in an appropriate, secure area and stored in accordance 
with the physical conditions specified on the INC424 label. Patients should be carefully 
instructed regarding INC424 storage conditions when they receive their 4-week or 12-week 
supplies of investigational product. All drug supplies are to be used only for this protocol and 
not for any other purpose. Patients should be advised to keep the INC424 in a locked 
cupboard away from children where possible.
Access to, and administration of, the investigational product will be limited to the investigator 
and authorized staff. Investigational product must be dispensed or administered only to 
patients enrolled in the study in accordance with the protocol and not for any other purpose.
6.5.4
Study drug compliance and accountability
6.5.4.1
Study drug compliance
Patients will be requested to bring any unused medication (if applicable), including empty 
packaging to the clinic at each visit. Compliance will be assessed by the investigator and/or 
study personnel at each patient visit and information provided by the patient and/or caregiver 
will be captured in the Drug Accountability Form. This information must be captured in the 
source document at each patient visit.

All doses taken by the patient and all dose changes or interruptions during the study must 
be recorded on the DAR eCRF.

The investigator or his/her designee must keep documentation (overall drug accountability 
for the study as well as individual study drug accountability for each patient) of tablets 
administered, tablets used, dose changes, and dates dispensed.

Drug accountability will be monitored by the field monitor during site visits and at the 
completion of the study.
In the absence of safety concerns, the patient may be dispensed up to an 84-day supply of 
medication at the investigator’s discretion
6.5.4.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability ledger. Drug accountability will be noted by the 
 


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field monitor during site visits and at the completion of the study. Patients will be asked to 
return all unused study treatment and packaging on a regular basis, at the end of the study or 
at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability ledger to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
6.5.4.3
Disposal and destruction
The drug supply can be destroyed at the local Novartis facility, Drug Supply group or third 
party, as appropriate.
The drug supply may be destroyed at the site only if permitted by local regulations and 
authorized by Novartis.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments except for laboratory assessments and indicates with an 
“X” the visits when they are performed. Table 7-2 lists all laboratory assessments. All data 
obtained from these assessments must be supported in the patient’s source documentation. 
The table indicates which data are entered into the database (D) or remain in source 
documents only (S). Assessments that generate data for database entry and which are recorded 
in eCRFs are listed using the eCRF name. Assessments that are transferred to the database 
electronically (e.g., laboratory data) are listed by test name.
Study assessments and procedures are outlined in Section 7.4. Baseline assessments, and in 
Section 7.5 (On treatment assessment). Please refer to Table 7-1. Visit Evaluation Schedule, 
for timing of assessment.
 


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Table 7-1
Visit evaluation schedule
Evaluation
Reference 
to Section
Screening
Baseline
Day 
1
Week 
4#
Week 
8#
Week 
12#
Week 
24#
Week 
36
Week 
48
Week 60 
& q12w 
onwards
End of 
Study/End 
of 
Treatment
Section 
7.6.2
Follow-up / 
Study 
Completion 
Evaluation
Section 
7.6.3
Visit name
1
2
3
4
5
6
7
8
9
Day of visit
-28 to -1
-7 to -1
Day 
1
Day 
28
Day 
56
Day 
84
Day 
168
Day 
252
Day 
336
Eligibility checklist(s)
7.3
Written Informed Consent (D)
12.3
X
Patient Demographics (D)
11.3
X
Inclusion / exclusion criteria 
(D)
5.2/5.3
X
X
Relevant medical history/
current conditions (D)
7.3
X
MRI if clinically indicated (S)
7.3
X
Diagnosis of PMF, PPV MF, 
and PET-MF(D) includes bone 
marrow biopsy with grading of 
fibrosis (if available)
Appendix I
X
Prior and current concomitant 
medications/significant non-
drug therapies (D)
7.3
X
X
X
X
X
X
X
X
X
X
X
X
History of disease (D)
7.3
X
X
Treatment History (D)
7.3
X
X
Disease status documentation 
(low, intermediate-1, 
intermediate-2, high risk) (D)
7.3
X
Transfusion history (S)(D)
7.4
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination (S)
7.4/8.2.3
X
X
X
X
X
X
X
X
X
X
X
 


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Evaluation
Reference 
to Section
Screening
Baseline
Day 
1
Week 
4#
Week 
8#
Week 
12#
Week 
24#
Week 
36
Week 
48
Week 60 
& q12w 
onwards
End of 
Study/End 
of 
Treatment
Section 
7.6.2
Follow-up / 
Study 
Completion 
Evaluation
Section 
7.6.3
Visit name
1
2
3
4
5
6
7
8
9
Day of visit
-28 to -1
-7 to -1
Day 
1
Day 
28
Day 
56
Day 
84
Day 
168
Day 
252
Day 
336
Vital signs (D)
7.4/8.2.4
X
X
X
X
X
X
X
X
X
X
X
Height (D)
7.3/8.2.5
X
Weight (D)
7.4/8.2.5
X
X
X
X
X
X
X
X
X
X
X
Full neurologic and cardiac 
assessment for fedratinib 
pretreated patients (S)
7.3/8.2.6
X
Measurement of spleen by 
palpation (D)
(See Section 8.3.1.1)
7.4
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status (D)
7.4
X
X
X
X
X
X
X
X
X
X
12-lead ECG (D)
(See Section 7)
7.4
X
X
X
X
X
Adverse events (D)
7.4/8.2.1
X
X
X
X
X
X
X
X
X
X
X
X
Quality of Life
7.4/8.3.2
FACT-Lym version 4 (D)
7.4/8.3.2
X
X
X
X
X
FACIT-Fatigue Subscale (D)
7.4/8.3.2
X
X
X
X
X
Medical resource utilization (D)
3.3.4/7.4
X
X
X
X
X
X
X
Dispense Investigational 
Product (D)
7.4
X
X
X
X
X
X
X
X
Drug Accountability 
Assessment (D)
6.5.4/7.4
X
X
X
X
X
X
X
X
Assess Investigational Product 
Compliance (D)
7.4/11.4
X
X
X
X
X
X
X
INC424 Dose Administration 
6.1/7.4
X
X
X
X
X
X
X
X
X
 


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Evaluation
Reference 
to Section
Screening
Baseline
Day 
1
Week 
4#
Week 
8#
Week 
12#
Week 
24#
Week 
36
Week 
48
Week 60 
& q12w 
onwards
End of 
Study/End 
of 
Treatment
Section 
7.6.2
Follow-up / 
Study 
Completion 
Evaluation
Section 
7.6.3
Visit name
1
2
3
4
5
6
7
8
9
Day of visit
-28 to -1
-7 to -1
Day 
1
Day 
28
Day 
56
Day 
84
Day 
168
Day 
252
Day 
336
Record (D)
Survival (D)
7.6.3.1
X
Leukemia-free survival (D)
11.6.1.1
X
Bone marrow biopsy (optional) 
including percentage blasts (D)
7.3/8.3.1.2
X
 


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Table 7-2
Laboratory assessment schedule
Evaluation
Screening
Baseline
Day 
1
Week 
4
Week 
8
Week 
12
Week 
24
Week 
36
Week 
48
Week 60 & 
q12 wk 
onwards
See Section 
7.5.1.15
End of 
Study/
End of 
Treatment
See 
Section 
7.6.2
Follow-up / 
Study 
Completion 
Evaluation
See Section 
7.6.3
Visit number
1
2
3
4
5
6
7
8
9
Day of visit
-28 to -1
-7 to -1
Day 
1
Day 
28
Day 
56
Day 
84
Day 
168
Day 
252
Day 
336
Hematology (See Appendix III; Section 
8.2.8) (D) Reticulocyte count 
(absolute, %) are optional 
X
X
X
X
X
X
X
X
X
X
X
Serum Chemistry (See Appendix III; 
Section 8.2.8) (D)
X
X
X
X
X
X
X
X
X
X
X
Coagulation (PT, PTT,or INR) See
Appendix III; Section 8.2.8. (D)
Required for Screening / Baseline, 
optional after enrollment 
X
X
X
X
X
X
X
X
X
X
Pregnancy Test (for women of 
childbearing potential). See Section 
7.3 and Section 8.2.9.1. (D)
X
Human immunodeficiency virus 
antibody test Section 7.3 (S)
X
Hepatitis A, B, and C (S) (See Section 
7.3 and Appendix III )
X
Thiamine level testing for fedratinib 
pretreated patients. Section 7.3 (S)
X
 


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7.2
Study evaluations
7.2.1
Efficacy
Documentation of disease status will be performed at Screening/Baseline and assessment of 
spleen response will be repeated at week 4, week 8, week 12, and then every 3 months 
thereafter, until early discontinuation of the study drug (disease progression; unacceptable 
toxicity; discontinuation from the study for any other reason; withdrawal of consent; until 24-
months after LPFV; or until the drug becomes commercially available in each participating 
country or, whichever occurs first). Documentation of the Investigator’s Assessment of Best 
Overall Response will be captured. Efficacy will be assessed as outlined in Section 3.3.2.
7.2.2
Safety and tolerability
Safety will be monitored by collection of laboratory values (hematology, serum chemistry, 
coagulation parameters), and patient clinical signs and symptoms as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8.2
and Section 9.
7.3
Screening
Prospective participants will be scheduled for a screening visit by study site staff. The 
required procedures will be scheduled over a -28- to -1-day period. The following procedures 
will be performed:

Obtain informed consent before any study specific procedures are conducted.

Determine if patient meets the inclusion/exclusion criteria (Section 5.2 and Section 5.3).

A repeat bone marrow biopsy is not required if the diagnostic bone marrow biopsy result 
is available documenting disease status

Discussion of methods known to be at least 99% effective in preventing pregnancy 
(Appendix II). Patients must agree to take appropriate precautions to avoid fathering a 
child or becoming pregnant while on the study. Additionally, because the effects on male 
fertility have not been determined, males should not father children for at least 6 months 
after completing therapy with INC424. Male patients should be informed that if they plan 
to father children in the future, they may wish to seek counseling on the option of sperm 
cryopreservation prior to starting study medication.

Review of medical history and prior medication history (see Section 6.3.1, Permitted 
Concomitant Therapy). Record the identity and dose of all medications used to treat 
underlying PMF, PPV MF, or PET-MF. These therapies should not be added, 
discontinued, or dose-adjusted during the Screening period; patients should continue this 
stable regimen through the first day of INC424 treatment (Day 1), where applicable.

Document the risk group of the patient (low, intermediate-1, intermediate-2, high risk).

Review of transfusion history.

Comprehensive (complete) physical examination including height, body weight and 
spleen length. See Section 8.2.3.
 


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
The edge of the spleen shall be determined by palpation, measured in centimeters, using a 
soft ruler, from the costal margin to the point of greatest splenic protrusion. The spleen 
should be measured in the same manner at all subsequent visits.

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

ECOG status must be 0, 1, or 2 (Appendix IV).

12-lead electrocardiogram (ECG) performed in the recumbent position after 5 minutes of 
rest.

Blood sampling for the following (Appendix III):

Serum chemistry tests, hematology, coagulation (PT, PTT,or INR). Serum pregnancy 
test (females of childbearing potential only).

Serology tests for HIV.

Hepatitis A, B, and C. Hepatitis A (IgM antibody); Hepatitis B (Hepatitis B surface 
antigen [HBsAg], Hepatitis surface antibody [HBsAb], Hepatitis B IgM core antibody 
[HBcAb-IgM]); and Hepatitis C (Hepatitis C antibodies [HC Ab], or local health 
authority requirements.

Thiamine level testing for fedratinib pretreated patients as per guidance below.

For fedratinib pretreated patients there is a need to perform a complete neurologic 
examination and cardiology assessments to identify any signs or symptoms of thiamine 
deficiency or Wernicke’s Encephalopathy. Thiamine level testing must be documented. 
MRI of the brain if clinically indicated based on signs and symptoms must be documented 
as well.

In case the patient has any positive signs or symptoms in the neurologic and 
cardiology assessments before starting ruxolitinib treatment, please ensure a complete 
description of these in the medical chart.

For thiamine level testing, please also ensure that the value is documented in the 
medical chart.

In case of an existing normal thiamine level done in the context of the fedratinib 
trial follow up there is no need to repeat the test unless clinically indicated based 
on signs and symptoms.

In case of an existing abnormal thiamine level done more than 7 days prior to 
baseline in the context of the fedratinib trial follow up there is a need to repeat 
the test and document the value in the medical chart prior to start ruxolitinib 
treatment. Management of thiamine deficiency should be done as per local usual 
clinical practice.

Patients should have completed or should being receiving thiamine 
supplementation as per previous investigator’s instructions.

For MRI of the brain, please also ensure that a complete report is documented in the 
medical chart.

In case of an existing normal MRI done in the context of the fedratinib trial 
follow up there is no need to repeat the procedure unless clinically indicated 
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In case of existing MRI done more than 7 days prior to baseline in the context of the 
fedratinib trial follow up showing lesions in the brain there is a need to repeat the procedure 
and document the description of the actual status of those lesions in the medical chart prior to 
start ruxolitinib treatment. The management of any findings should be done as per usual 
clinical practice. All inclusion/exclusion criteria (Section 5.2 and 5.3) are to be fulfilled and 
documented before proceeding to patient enrollment.
An eligibility checklist (Appendix X) has to be completed once all screening procedures are 
completed. The eligibility checklist will be sent from the site to the Sponsor either by fax or 
email for evaluation. Upon confirmation of eligibility, the Sponsor will return the signed 
eligibility checklist to the site by fax or email. The investigator site will then be allowed to 
enroll patient.
7.3.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason 
will be considered a screen failure. The reason for not being started on INC424 will be 
entered on the Screening Log eCRFs and includes one of the following reasons: unacceptable 
or past medical history/concomitant diagnosis; intercurrent medical event; unacceptable 
laboratory value(s); unacceptable test procedure result(s); did not meet diagnostic/severity 
criteria; unacceptable use or excluded medication(s)/therapies; subject withdrew consent; 
unknown; other. In addition, Demography data, Informed Consent information and 
Inclusion/Exclusion eCRFs must be collected.
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a SAE during the Screening Phase (see Section 9 for SAE 
reporting details).
7.4
Baseline evaluations (Day -7 to Day -1)
The results from the Screening visit evaluations will be reviewed to determine if the patient 
continues to meet the eligibility requirements as specified in the protocol. Patients who have 
signed the informed consent form and meet all the entry criteria (see Inclusion/Exclusion 
Criteria Section 5.2 and Section 5.3) will be enrolled in the study. Procedures for the Baseline 
visit may be conducted over 1 to 7 days as needed. Blood samples for hematology and serum 
chemistry should be performed at least 4 days prior to the intended Study Day 1, in order to 
allow ample time for results to be returned before administration of INC424. All evaluations 
should be recorded in the source documents and promptly entered in the eCRF.
The following procedures will be performed at the Baseline visit and prior to enrollment for 
all patients:

Confirm that the patient continues to meet all relevant inclusion and exclusion criteria, 
considering evaluations occurring at screening and baseline.

Update medication history; confirm all drugs used to treat underlying PMF, PPV MF, or 
PET-MF.

Record any concomitant medications.

Update transfusion history status.
 


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
Blood sampling for serum chemistry tests, hematology, and coagulation (PT, PTT, or INR) 
(see Appendix III).ECOG status must be 0, 1, or 2 (Appendix IV).

FACT-Lym version 4 (Appendix VII) and FACIT-Fatigue Subscale (Appendix VIII).

Medical resource utilization:

Number and duration of hospitalization in the past 3 month

Number of emergency room visits in the past 3 months

Number of general practitioner, specialist, urgent care visits in the past 3 months.

Number of transfusions in the past 3 months and baseline transfusion dependency 
status

Number of splenic irradiation treatments in the past 3 months.

Targeted physical examination including body weight and measurement of spleen by 
palpation (Section 8.2.3).

Record adverse events.

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

12-lead ECG performed in the recumbent position after 5 min of rest, ONLY if not 
conducted during the Screening Visit, or if conducted and found to include an abnormality 
deemed clinically significant.

Patients will be instructed to discontinue all drugs to treat PMF, PPV MF, or PET-MF on 
the morning of the Day 1 Visit.
7.4.1
Combining Screening and Baseline Visits into 1 Visit
It is permissible to combine the Screening and Baseline visits if necessary, provided all results 
are available prior to the first dose of INC424
If Screening visit and Baseline visits overlap (-7 to -1)
a. Enter information as required
b. Information requested at both Screening visit and Baseline visit should be entered only 
once in Screening visit pages
7.5
On treatment evaluations
On-treatment evaluations are scheduled for Study Visits at Day 1, and at the end of Weeks 4, 
8, 12, and every 12 weeks thereafter. If it is determined at any Study Visit that the patient will 
discontinue study drug that day, then that study visit will be the End of Study Visit, and the 
End of Study Visit procedures will be followed.
After 4 weeks of treatment (Week 4 Visit), patients may have the dose of INC424 increased 
because of inadequate responses. At this visit or anytime during the study, the dose may be 
adjusted for safety, following the guidelines described in Section 6.2, Dose Modifications. 
The individual study visit descriptions describe activities that must occur to support and 
document these dose changes.
This study schedule is designed to closely monitor any drug related adverse events associated 
with INC424. If, at any time during the study, a patient experiences unexpected signs or 
 


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symptoms, additional safety evaluations should be conducted at a regular Study Visit or 
unscheduled visit. For example, weekly monitoring is advised for patients with platelet counts 
< 100,000/μL or neutrophils < 1000/μL, and at least twice -weekly for platelets < 50,000/μL 
or neutrophils < 500/μL. Additionally, x-ray examination of the thorax, echocardiography, 
and pulmonary function testing and/or arterial blood gas analysis should be considered in 
patients developing new or worsening cardiopulmonary symptoms including cough, shortness 
of breath, exercise intolerance or peripheral edema.
Women of childbearing potential will be assessed for pregnancy status, either by serum or 
urine pregnancy tests, prior to starting treatment with INC424 only (see Section 5.2). If local 
requirements mandate more frequent testing, applicable sites will conduct monthly testing.
See Section 6.2.2 and Section 6.2.6 for criteria for mandatory reduction, interruption, or 
discontinuation of study drug based upon results of safety monitoring.
7.5.1
On treatment evaluation requirements
7.5.1.1
Day 1
The Day 1 visit may occur as soon all Baseline evaluations have been completed, and the 
laboratory data (including platelet count) from the Baseline Visit are available. The following 
procedures will be performed and all observations will be recorded in the eCRF:

Record any concomitant medications.

Determine the date and time of last administration of prior therapy (if any) for treatment of 
PMF, PPV MF, or PET-MF.

Update transfusion history status.

Administer the morning dose of INC424, and monitor the patient for adverse 
events/tolerability.

Dispense study drug for the first 28 days (plus overage) along with dosing instructions.

The importance of compliance will be reviewed with the patient.

The patient will be educated on medications and food that should be avoided while 
taking INC424.

The patient and/or family members are to be instructed to telephone the study site 
with any changes in mental or physical status or questions about INC424, and also to 
return all unused INC424.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. These adverse events 
will be recorded on the eCRF.
7.5.1.2
Week 1 through Week 4
Patients will self-administer INC424 BID as instructed, morning and evening (at 
approximately 12-hour intervals), in an outpatient setting. Patients will call the investigator or 
designated research staff if they experience any unexpected and unfavorable signs and/or 
symptoms.
 


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Patient may attend the study clinic up to 3 days prior to week 4 to provide blood samples for 
serum chemistry tests and hematology (Appendix III). The laboratory results should be 
available for interpretation and potential dose modification on the Week 4 Study Visit.
7.5.1.3
Week 4 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

A targeted physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

provided all requirements for dose at week 4 according to starting INC424 dose as follows:

By 5 mg BID if palpable spleen length reduced by less than 40% relative to Baseline, 
provided all requirements for dose increase are met (see Section 6.2.1.1).

The dose increase may only be an increase of 5 mg o.d. (e.g., for those patients 
starting INC 424 at 5 mg PO BID to 5 mg QAM and 10 mg QPM).

All changes in dose, including rationale for dose increase, should be recorded in the eCRF.

The dose of INC424 may need to be decreased or interrupted because of low platelet 
counts or ANC levels (see Section 6.2.2).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Determination of ECOG performance status (see Appendix IV).

Complete FACT-Lym version 4 (Appendix VII).and FACIT-Fatigue Subscale (prior to 
examination) (Appendix VIII).

Medical Resource Utilization in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

12-lead ECG performed in the recumbent position after 5 minutes of rest.

Drug accountability assessment (see Section 6.5.4).

Assessment of patient compliance.

Record adverse events.

Study drug for the next 28 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms.
 


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7.5.1.4
Week 4 through Week 8
Patients will self-administer INC424 BID as instructed, morning and evening in an outpatient 
setting. Patients will call the investigator or designated research staff if they experience any 
unexpected and unfavorable signs and/or symptoms.
7.5.1.5
Week 8 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

A targeted physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

Determination of ECOG performance status (see Appendix IV).

MRU in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

Document new (changed) or ongoing dose information for INC424. Dose changes that are 
necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

Drug accountability assessment (see Section 6.5.4).

Assess patient compliance.

Record adverse events.

Study drug for the next 28 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any signs and/or symptoms. These adverse events will be recorded on the 
eCRF. Patients will be reminded to bring the study drug to the clinic with them.
7.5.1.6
Week 8 through Week 12
Patients will self-administer INC424 BID as instructed, morning and evening in an outpatient 
setting. Patients will call the investigator or designated research staff if they experience any 
unexpected and unfavorable signs and/or symptoms.
 


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7.5.1.7
Week 12 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

A targeted physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

12-lead ECG performed in the recumbent position after 5 minutes of rest.

Determination of ECOG performance status (see Appendix IV).

Complete FACT-Lym version 4 (Appendix VII) and FACIT-Fatigue Subscale (prior to 
examination) (Appendix VIII)

MRU in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

Document new (changed) or ongoing dose information for INC424. Dose changes that are 
necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

Drug accountability assessment (see Section 6.5.4).

Assess patient compliance

Record adverse events.

Study drug for the next 84 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. These adverse events 
will be recorded on the eCRF. Patients will be reminded to bring the study drug to the 
clinic with them.
7.5.1.8
Week 12 through Week 24
Patients will self-administer INC424 twice daily as instructed, morning and evening, in an 
outpatient setting. Patients will call the Investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms.
Those patients who underwent dose modifications at the Week 12 (Month 3) visit must return 
to the clinic as follows:
 


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
Patients experiencing hematologic adverse events - following laboratory draws as outlined 
in Section 6.2.2.

Patients who underwent dose escalation at week 12 (Month 3) should return to the clinic 
for serum chemistries and hematology assessments.
7.5.1.9
Week 24 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

A complete physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

Determination of ECOG performance status (see Appendix IV).

Complete FACT-Lym version (Appendix VII) and FACIT-Fatigue Subscale (prior to 
examination) (Appendix VIII).

Medical resource utilization in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

Drug accountability assessment (see Section 6.5.4).

Record adverse events.

Assess patient compliance.

Document new (changed) OR ongoing dose information for INC424. Dose changes that 
are necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

INC424 for the next 84 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. Patients will be 
reminded to bring the study drug to the clinic with them.
7.5.1.10 Week 24 through Week 36
Patients will self-administer INC424 BID as instructed, morning and evening in an outpatient 
setting. Patients will call the investigator or designated research staff if they experience any 
unexpected and unfavorable signs and/or symptoms.
 


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7.5.1.11 Week 36 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

A complete physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

Determination of ECOG performance status (see Appendix IV).

MRU in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

Drug accountability assessment (see Section 6.5.4).

Record adverse events.

Assess patient compliance.

Document new (changed) OR ongoing dose information for INC424. Dose changes that 
are necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

INC424 for the next 84 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. Patients will be 
reminded to bring the study drug to the clinic with them.
7.5.1.12 Week 36 through Week 48
Patients will self-administer INC424 BID as instructed, morning and evening, in an outpatient 
setting. Patients will call the investigator or designated research staff if they experience any 
unexpected and unfavorable signs and/or symptoms.
7.5.1.13 Week 48 (± 7 days)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.
 


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
A complete physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

12-lead ECG performed in the recumbent position after 5 minutes of rest.

Determination of ECOG performance status (see Appendix IV).

Complete FACT-Lym version 4 (Appendix VII) and FACIT-Fatigue Subscale (prior to 
examination) (Appendix VIII).

Medical resource utilization in the past month:

Number and duration of each hospitalization.

Number of emergency room visits.

Number of urgent care visits.

Number of additional general practitioner and specialist office visits.

Number of transfusions and transfusion dependency status.

Splenectomy or splenic irradiation.

Drug accountability assessment (see Section 6.5.4).

Assess patient compliance.

Record adverse events.

Document new (changed) OR ongoing dose information for INC424. Dose changes that 
are necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

INC424 for the next 84 days (plus overage) will be dispensed along with dosing 
instructions.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. Patients will be 
reminded to bring the study drug to the clinic with them.
7.5.1.14 Weeks 49 and afterwards
Patients will self-administer INC424 BID as instructed, morning and evening (at 
approximately 12-hour intervals), in an outpatient setting. Patients will call the investigator or 
designated research staff if they experience any unexpected and unfavorable signs and/or 
symptoms.
7.5.1.15 Weeks 60 (± 7 days) and each 12 Weeks thereafter (Week 72, 84, 96, 
etc)
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.
 


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
A targeted physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

Determination of ECOG performance status (see Appendix IV).

Record adverse events.

Document new (changed) OR ongoing dose information for INC424. Dose changes that 
are necessary between study visits will be communicated immediately and directly to the 
patient by telephone; the communication will be documented in the source documents.

INC424 for the next 84 days (plus overage) will be dispensed along with dosing 
instructions.

Drug accountability assessment (see Section 6.5.4)

Assess patient compliance.

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms. Patients will be 
reminded to bring the study drug to the clinic with them.
7.5.1.16 Missed/moved visit
If a visit is moved or missed, the next scheduled visit should comply as much as possible with 
the original schedule.
7.6
End of treatment visit, including premature withdrawal and study 
discontinuation visit
Patients who discontinue study treatment before the end of the study should be scheduled for 
a visit as soon as possible, at which time all of the assessments listed for the End of Treatment 
(EOT) visit will be performed. The appropriate eCRF page should be completed, giving the 
date and reason for stopping the study treatment. At a minimum, all patients who discontinue 
study treatment, including those who refuse to return for a final visit, will be contacted for 
safety evaluations during the 28 days following the last dose of study treatment.
7.6.1
Criteria for premature withdrawal
Patients may voluntarily withdraw from the study at any time without penalty of jeopardizing 
their health care or loss of benefits to which the patient is otherwise entitled or be dropped 
from it at the discretion of the investigator at any time. Every reasonable effort should be 
made to determine the reason a patient withdraws prematurely and this information should be 
recorded in the eCRF. A patient may be withdrawn from the study if, in the investigator’s 
medical judgment, the patient is non-compliant with the study requirements. A patient MUST 
be withdrawn from the study if she becomes pregnant, or if he intends to father a child during 
the anticipated duration of study participation. The investigator MUST discontinue a patient 
from the study if the following occurs:
 


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
Consent is withdrawn.

Further participation would be injurious to the patient’s health or well-being in the 
investigator’s medical judgment.

The study is terminated.

If the study drug has been interrupted for 8 weeks or more for any reason, except in the 
case of splenectomy where a maximum of 12 weeks of drug interruption is permitted.

The study drug has been permanently discontinued for safety according to the criteria 
specified in Section 6.2.6. Specifically:

Hematologic toxicity. The lowest allowed dose (5 mg BID or 5 mg QD with concomitant 
CYP3A4 inhibitor or those patients with low platelet counts [50,000 – <100,000/µL ]) is 
not tolerated due to the following:

Platelets cannot be maintained ≥50,000/µL.

Absolute neutrophil count cannot be maintained ≥500/µL.

Hemoglobin cannot be maintained ≥6.5g/dL despite the use of transfusion therapy (or 
if the patient will not accept blood transfusions).

Non-hematologic toxicity. The lowest allowed dose (5 mg BID or 5 mg QD with 
concomitant CYP3A4 inhibitor or those patients with low platelet counts [50,000 –
<100,000/µL ]) is not tolerated due to the following:

The occurrence of a Grade 4 laboratory abnormality that is considered at least 
possibly related to the study drug, and is clinically significant in the view of the 
investigator. Exceptions NOT requiring study withdrawal are serum iron, total 
bilirubin not accompanied by direct bilirubin of 2 x ULN, triglycerides, total 
cholesterol, HDL cholesterol, not accompanied by at least a Grade 3 elevation of 
serum creatinine.

Recurrence of a Grade 4 clinical event (non-laboratory based) after re-challenge with 
the study drug. Exceptions NOT requiring study withdrawal are fatigue, insomnia, 
obesity, constitutional symptoms (disabling but not life threatening), salivary gland 
changes, arthritis, and joint effusion.
Study drug MAY be permanently discontinued for a Grade 4 clinical event that has NOT been 
confirmed upon rechallenge with the study drug, at the option of the investigator.
If a patient is withdrawn from the study:

The study Medical Monitors (Sponsor and CRO) must be notified.

The reasons for discontinuation must be documented in the patient’s medical record and 
eCRF.

The End of Treatment Visit procedures should be completed at the last study visit while 
patient is receiving INC424 study drug.

The Follow-up Visit should be performed 28 to 37 days after the last dose of study drug 
was taken (i.e., 28 - 37 days after the End of Study Visit).
 


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7.6.2
End of treatment evaluations
7.6.2.1
End of study or early termination visit
The End of Study or Early Termination Visit constitutes the final study visit where study drug 
has been taken. An End of Study Visit may occur with a planned discontinuation for any 
reason (e.g., at Week 20, it is determined that patient will participate in the study only 1 more 
month; therefore, the Week 24 Visit will become the End of Study Visit).
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Update transfusion history status.

A targeted physical examination will be performed, including body weight and 
measurement of spleen by palpation (Section 8.2.3).

Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology (see Appendix III).

Determination of ECOG performance status (see Appendix IV).

Drug accountability assessment (see Section 6.5.4).

Record adverse events.

Document the dose the patient was on at the time of study discontinuation.

Patients will be asked to return to the clinic between 28 and 37 days later for a final 
Follow-up Visit.

The sponsor (Novartis Pharmaceuticals) will be notified of the patient withdrawal.
7.6.3
Follow-up period
All patients must have safety evaluations for 28 days after the last dose of study treatment.
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc.
7.6.3.1
Follow-up evaluations
The following evaluations will be performed 28 to 37 days after the completion of the End of 
Study or Early Termination Visit or approximately 1 month post-dosing for a patient who is 
discontinuing from the study:
The following procedures will be performed and all observations will be recorded in the eCRF:

Review of concomitant medications.

Review of transfusion history.

A complete physical examination will be performed, including body weight and 
measurement of spleen by palpation.
 


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
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) to be 
performed in a sitting position after 5 minutes of rest.

Blood sampling for serum chemistry tests, hematology, and optional coagulation (PT, PTT, 
or INR) (see Appendix III).

Record adverse events.

Survival assessments (Overall, LFS, PFS).
8
Study assessments
8.1
Demographic and other pretreatment assessments
After written informed consent is obtained, demographic data and a complete medical and 
medication history will be collected at Screening. Height and body weight measurements will 
be done and body mass index will be calculated in the database
8.2
Safety assessments
8.2.1
Adverse events
AEs will be monitored continuously during the study. Patients will be instructed to report all 
AEs during the study and patients will be assessed for the occurrence of AEs throughout the 
study. In order to avoid bias in eliciting AEs, patients will be asked general, non-leading 
questions such as "How are you feeling?” All AEs (serious and non-serious) must be recorded 
on the source documents and case report forms regardless of the assumption of a causal 
relationship with the study drug. The definition, reporting, and recording requirements for 
AEs are described in Section 9.
8.2.1.1
Assessment of causality
Every effort should be made by the investigator to explain each adverse event and assess its 
relationship, if any, to study drug treatment. Causality should be assessed using the following 
categories: no (not related), or yes (reasonable possibility).
The degree of certainty with which an adverse experience is attributed to drug treatment (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the experience can be understood in terms of the following:
1. Known pharmacology of the drug
2. Reaction of a similar nature being previously observed with this drug or class of drug.
3. The event having often been reported in the literature for similar drugs as drug related (e.g. 
skin rashes, blood dyscrasias).
4. The event being related by time to drug administration terminating with drug withdrawal 
(dechallenge) or reproduced on rechallenge.
The investigator may change his/her opinion of causality in light of follow-up information, 
amending the SAE form. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements.
 


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8.2.2
Safety assessments at investigational therapy withdrawal
All the safety assessments performed at the every 4 or 12-week visit should be performed at 
the time of investigational therapy conclusion or withdrawal.
8.2.3
Physical examinations
A comprehensive physical examination will be performed as noted in the Description of 
Study Visits (Table 7-1 and Table 7-2). The comprehensive physical examination will include 
the following organ/body system assessments: general appearance, skin; HEENT (head, eyes, 
ears, nose and throat); thyroid; lungs; cardiovascular; abdomen (liver, spleen); lymph nodes; 
neurological examination, assessment of edema and extremities. A targeted physical 
examination will be performed as indicated in Section 7.5 (On-Treatment Evaluations) and 
will always include liver and spleen, and assessment of edema. In addition, the targeted 
physical examination will include body systems as indicated by patient symptoms, AEs, prior 
physical examinations, or other findings as determined by the investigator. Both complete and 
targeted physicals will include a measurement of spleen length, assessed by palpation, and 
measured in centimeters, using a soft ruler, from the costal margin to the point of greatest 
splenic protrusion.
Significant findings that were present prior to the signing of informed consent must be 
included in the Relevant Medical History/Current Medical Conditions page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the patient’s eCRF.
8.2.4
Vital signs
Vital sign measurements including blood pressure, heart rate, respiratory rate, and body 
temperature will be collected on the days noted in the Description of Study Visits 
(Section 7.1). After the patient has been sitting for five minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be measured three times 
using an automated validated device, e.g. OMRON, with an appropriately sized cuff. The 
repeat sitting measurements will be made at 1 - 2 minute intervals and the mean of the three 
measurements will be used. In case the cuff sizes available are not large enough for the 
patient's arm circumference, a sphygmomanometer with an appropriately sized cuff may be 
used.
8.2.5
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.
8.2.6
Full neurologic examination and cardiology assessments
For fedratinib pretreated patients there is a need to perform neurologic and cardiology 
examinations to identify any sign of thiamine deficiency or Wernicke’s Encephalopathy
which common symptoms or signs at disease presentation are: ocular abnormalities, mental 
status changes, and incoordination of gait and trunk ataxia. Uncommon symptoms or signs at 
presentation have to be also assessed: stupor, hypotension and tachycardia, hypothermia, 
 


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bilateral visual disturbances and papilledema, epileptic seizures, hearing loss, hallucinations 
and behavioral disturbances.
8.2.7
12-lead ECG
Twelve-lead ECGs will be obtained for each patient during the study as per the Description of 
Study Visits (Table 7-1). Baseline ECGs will be obtained at Screening. All 12-lead ECGs 
obtained at subsequent time points during the study will be compared with this pre-study 
treatment 12-lead ECG as follows:

For ECG morphology, all post-dose ECG recordings will be compared to the 
Screening/Baseline ECG tracing.

For the calculation of changes in cardiac intervals (QT interval), the intervals from the 
Screening will be used as the Baseline for comparison of all post dose intervals.
Interpretation of the tracing must be made by a qualified physician and documented on the 
ECG eCRF page. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the 
study site. Clinically significant abnormalities present when the patient signed informed 
consent should be reported on the Medical History eCRF page. Clinically significant findings 
must be discussed with the Novartis Medical Monitor prior to enrolling the patient in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded on the Adverse Events eCRF page.
8.2.8
ECG analysis and reporting
The investigator or another appropriately trained individual will perform the initial ECG 
analysis of the data collected for each patient. All ECGs will be analyzed according to ECG 
abnormality criteria defined in cooperation with the Sponsor and taking into account the 
protocol requirements.
8.2.9
Clinical safety laboratory assessments
Clinical laboratory tests [hematology, serum chemistry, and coagulation (PT, PTT, or INR)] 
will be performed at the center where the patient is enrolled. All patients will have samples of 
blood collected on the days noted in the Description of Study Visits (Table 7-2) for analysis of 
serum chemistry, hematology, and coagulation (PT, PTT, or INR). Coagulation tests are 
required for screening and or baseline, and are optional after enrollment. Appendix III
provides a complete list of blood chemistry and hematology tests that will be performed.
Hemoglobin, hematocrit, WBC count with differential (neutrophils. lymphocytes, eosinophils, 
basophils, monocytes, and blast cells) and platelet count will be measured. RBC sediment rate
(where available) will also be measured.
Recticulocyte count (absolute and % reticulocytes) is optional.
Serum creatinine, total or direct bilirubin, AST, ALT, alkaline phosphatase (where available).
Thiamine blood level testing for fedratinib pretreated patients as per guidance described in 
Section 7.3.
 


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8.2.9.1
Pregnancy test
Patients who are older than age 55 and have a history of amenorrhea for 1 year, or patients 
who have been surgically sterile for at least 3 months, will not be considered to be of 
childbearing potential. All other female patients will have pregnancy test within 14 days prior 
to Day 1 of INC424.
A positive urine pregnancy test requires immediate interruption of study treatment until serum 
B-hCG is performed and found to be negative. If positive, the patient must be discontinued 
from the study.
8.2.9.2
Serology
A complete list of serology tests to be performed at the Screening Visit is provided in 
Appendix III.
8.3
Symptom and functional response assessments
8.3.1
Response assessments
8.3.1.1
Primary response assessments
Spleen length: Spleen length will be assessed by manual palpation at every study visit, and 
will be used to determine if dose increases for lack of efficacy should be considered. 
investigators will be provided with a soft centimeter ruler so that palpable spleen length is 
measured in centimeters and not in finger breadths. The edge of the spleen shall be 
determined by palpation, and measured in centimeters, using a soft ruler, from the costal 
margin to the point of greatest splenic protrusion.
8.3.1.2
Additional response assessments
A bone marrow biopsy will be collected only if it is a normal routine of the attending 
physician, and is not mandatory.
8.3.2
Quality of Life assessments
Patients with MPNs often present with significant constitutional symptoms that interfere with 
their QoL including splenomegaly, pruritus, weight loss, weakness, night sweats. The effect 
of INC424 on patient QoL will be measured using several assessment tools including ECOG 
performance status (See Appendix IV) and the FACT-Lym version 4 (See Appendix VII) and
FACIT-Fatigue Subscale tools (See Appendix VIII).
8.3.2.1
FACT-Lym Scale (version 4)
The FACT measurement system is a collection of self-report scales of health reported quality 
of life (HRQOL) for people with cancer (Cella 1993) See Appendix VII. 
8.3.2.2
FACIT-Fatigue Scale
The FACIT Fatigue (FACIT-F) questionnaire was developed to assess fatigue associated with 
anemia and includes 13 fatigue-related questions (FACIT fatigue). The responses to the 13 
 


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items in the questionnaire are each measured on a 4-point Likert scale (Cella et al 1993). Thus, 
the total score ranges from 0 to 52. High scores represent less fatigue. The FACIT Fatigue 
Scale has been validated in the general population, in patients with cancer and in patients with 
RA. In patients with cancer, the FACIT Fatigue Scale showed excellent internal consistency 
and reliability and differentiated patients by hemoglobin level and patient-related performance 
status (Chandran 2007).
Cella et al (2002) determined the minimally important difference (MID) of the FACIT-
Fatigue scale to be 3 points.
Subjects will complete this assessment at Baseline and at each visit as indicated in Table 7-1.
8.3.3
Resource utilization
Medical resource utilization will be captured at each visit out to 48 weeks. Data collection 
will include medical resources utilized since the last visit. MRU includes office visits (general 
practitioner and specialist visits), procedures/treatments, emergency room visits, urgent care 
visits,
hospitalizations, transfusions, splenectomy, splenic radiation and changes in 
concomitant medications.
 


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9
Safety monitoring and reporting
9.1
Adverse events
9.1.1
Definition and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test results occurring 
after informed consent constitute adverse events only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic 
abnormality that requires transfusion or hematological stem cell support), or require changes 
in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History eCRF. Adverse event monitoring should be continued for at 
least 28 days following the last dose of study treatment. Adverse events (including lab 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible, 
rather than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate Adverse Event.
Adverse events will be assessed according to the CTCAE version 3.0. If CTCAE grading does 
not exist for an adverse event, the severity of mild, moderate, severe, and life-threatening, 
corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this 
study; rather, information about deaths will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
 


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
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 9.2.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome.
Progression of myelofibrosis, including leukemic transformation (including fatal outcomes), if 
documented by use of appropriate method, should not be reported as a serious adverse event.
Adverse events separate from the progression/ transformation of myelofibrosis (example, 
pneumonia at the time of progression or septic shock concurrent with finding of AML) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
All AEs occurring from the first dose of investigational product until 28 days after the last 
dose must be recorded regardless of whether or not they are considered drug related.
All subjects who have AEs, whether considered associated with the use of the investigational 
product or not, must be monitored to determine the outcome. The clinical course of the AE 
will be followed up according to accepted standards of medical practice, even after the end of 
the period of observation, until a satisfactory explanation is found or the investigator 
considers it medically justifiable to terminate follow-up. Should the AE result in death, a full 
pathologist’s report should be supplied if and when available.
SAEs must be reported as outlined in Section 9.2.2. In addition, any SAEs which occur as a 
result of protocol specific diagnostic procedures or interventions must also be reported. 
9.1.1.1
Events related to disease under study
Worsening of a pre-existing illness other than disease under study will be assessed as an AE. 
Worsening of a sign or symptom of the disease under treatment will normally be measured by 
efficacy parameters and not considered an AE unless the Sponsor or the reporting physician 
considers that the study drug contributed to the worsening.
9.1.1.2
Surgical procedures related to disease under study
Surgical procedures themselves are not AEs; they are therapeutic measures for conditions that 
require surgery. The condition for which the surgery is required may be an adverse event, if it 
occurs or is detected during the study period. 
9.1.2
Laboratory test abnormalities
9.1.2.1
Definition and reporting
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
significant, induce clinical signs or symptoms, require concomitant therapy or require changes 
in study treatment), should be recorded on the Adverse Events eCRF. Whenever possible, a 
 


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diagnosis, rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event, 
it is not necessary to separately record the lab/test result as an additional event.
Laboratory abnormalities, that do not meet the definition of an AE, should not be reported as 
adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a 
SAE unless it meets the definition of serious as defined below and/or as per investigator’s 
discretion. A dose hold or medication for the lab abnormality may be required by the protocol 
and is still, by definition, an adverse event.
9.2
Serious adverse events
9.2.1
Definitions
A serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
Progression of myelofibrosis, including leukemic transformation (including fatal outcomes) 
are exempted from SAE reporting.
This information is collected in the study as part of study endpoints: progression free survival 
(PFS) and acute myeloid leukemia free survival (LFS).
9.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 28 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 28 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
 


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episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The investigator must assess and record the relationship of each SAE to each specific 
study treatment (if there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to the oncology Novartis 
DS&E department.
The telephone and telefax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
9.3
Pregnancies
Pregnancy, in and of itself, is not regarded as an AE, unless there is suspicion that study drug 
may have interfered with the effectiveness of a contraceptive medication or method.
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. Pregnancy outcomes must be collected for the female partners of any 
males who took study treatment in this study. Consent to report information regarding these 
pregnancy outcomes should be obtained from the mother.
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form.
The procedures that will be followed based on whether a pregnancy is confirmed by a positive 
serum or urine test result are listed below:

Investigator and subject must notify each other immediately.

Investigator must notify the Sponsor immediately.

Discontinue study drug immediately.

Perform the required End-of-treatment visit study evaluations.
 


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
Investigator must complete and submit the Pregnancy Initial and Follow-up report forms 
to the Sponsor.

A serum pregnancy test must be performed to confirm the urine test result. (The serum test 
should be performed at the investigative site to ensure the test will be performed promptly 
and the result available immediately for review.)

Withdraw the patient from the study.
If a negative serum test does not confirm the urine test result, then:

The investigator will use his/her expert judgment, based on an assessment of the potential 
benefit/risk to the subject, to determine if it is in the patients best interest to resume study 
drug and continue participation in the study.
Any pregnancy diagnosed during the study, or that occurs within 28 days after stopping study 
drug, must be reported immediately to the investigator. The investigator will notify the 
Sponsor or designee by following the procedures described in Section 9.2.2. The outcome of 
all such pregnancies (i.e., spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be documented and followed-up on a form that will be provided 
by the Sponsor. The pregnancy will be followed to term and the outcome, including any 
premature termination, must be reported to the Sponsor. All live births must be followed for a 
minimum of 30 days or to the first well-baby visit. All reports of congenital 
abnormalities/birth defects and spontaneous abortions/miscarriages should be reported as an 
SAE for this study. Elective abortion procedures, without complications, should not be 
considered as AEs.
9.4
Warning and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
10
Data collection and management
10.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study.

Who will have access to that information and why.

Who will use or disclose that information.

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
 


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authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who 
have completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements 
and to enable appropriate age-related normal ranges to be used in assessing laboratory test 
results.
10.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative or authorized designee will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the site regularly to 
check the completeness of patient records, the accuracy of entries on eCRFs, the adherence to 
the protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that 
study drug is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
patient's file. Data not requiring a separate written record will be defined before study start 
and will be recorded directly on the eCRFs, which will be documented as being the source 
data (see items listed as Category “D” in Table 7-1 and Table 7-2). The investigator must also 
keep the original informed consent form signed by the patient (a signed copy is given to the 
patient).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the patients will be disclosed.
 


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10.3
Data collection
The designated investigator staff will enter the data required by the protocol into the eCRF 
using fully validated software that conforms to 21 CFR Part 11 requirements. Designated 
investigator site staff will not be given access to the EDC system until they have been trained. 
The Principal Investigator is responsible for assuring that the data entered into the eCRF is 
complete, accurate, and that entry is performed in a timely manner. Automatic validation 
programs check for data discrepancies in the eCRFs and, by generating appropriate error 
messages, allow modification or verification of the entered data by the investigator staff 
before transfer to Novartis (or designated CRO) via a secure network. After database lock, the 
investigator will receive a CD-ROM or paper copies of the patient data for archiving at the 
investigational site.
In addition, data collected will include:

information about previous fedratinib treatment and the end date, 

for those patients with fedratinib treatment:

information about ruxolitinib received or not, 

and if ruxolitinib received, information on receipt when participating to 
CINC424A2401 or not will be collected. For patient enrolled previously in 
CINC424A2401, previous patient number will be collected.
10.4
Database management and quality control
Data will be entered into the study database by Investigator/Study Coordinator for electronic 
data capture (EDC) studies.
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Detected discrepancies for which the resolution is 
obvious/self-evident will be corrected by Novartis Data Management personnel (or designated 
CRO). Electronic data queries are stating the nature of the problem and requesting 
clarification will be created for all other discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff is required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
At the conclusion of the study the occurrence of any protocol deviations will be determined.
After these actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Global Head 
of Biostatistics and Statistical Reporting and the Global Therapeutic Area Head.
 


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11
Statistical methods and data analysis
The primary objective of this study is to collect safety data on patients with PMF, PPV MF, or 
PET-MF treated by INC424, while secondary objectives are on collecting some efficacy data 
and medical resource use.
This section is describing all analyses to be performed, the primary and secondary objective 
being descriptive; no hypotheses testing will be performed.
The data will be analyzed by Novartis. All data from all centers that participate in this 
protocol will be combined and analyzed together.
Timing of analyses
The primary analysis will be performed after all patients have either completed 24 months of 
treatment or have been prematurely discontinued from the study. All patients should have 
been followed for 28 days after they have discontinued INC424, data collected during this 
follow-up period will be included in the analysis. An interim analysis planned for this study 
will take place when 50 patients with low platelets will have completed 6 months of treatment. 
Additional analyses may also be performed if needed to fulfill regulatory obligation or 
publication purpose.
Statistical reporting and grouping
Data will be analyzed according to platelet count at baseline and displayed considering the 
following two groups:

Low platelet patients (platelets < 100, 000 /µL)

and non-low platelets (platelets ≥100, 000 /µL).
All analyses for categorical data will be presented as frequencies and percentages (% based on 
number of patients from the considered population unless specified otherwise).
For all continuous data, except time related ones, the following descriptive statistics will be 
presented: n, mean, standard deviation, median, minimum and maximum. Time related data 
(i.e. durations such as overall survival) will be summarized using n, median, minimum and 
maximum.
For all analyses, baseline value will be defined as the latest available assessment obtained 
prior to the date of first dose of study drug administration. If assessment prior to first dose of 
study drug administration is not available, then assessment on the day of first dose of study 
drug administration will be used at baseline.
All data considered in the analysis will be listed individually.
Please note: due to the trial design and intent, it is not possible to ensure that a sufficient 
number of patients will be available to conduct the analyses as planned. Therefore, it is 
important to consider that certain analyses described in the subsequent section may not be 
relevant if study population is too small.
 


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11.1
Handling of missing values
No imputation for missing data will be performed, unless otherwise specified
11.2
Populations for analysis
Full Analysis Set (FAS) consists of all patients who received at least one administration of 
study drug.
Safety set consists of all patients who received at least one dose of study drug and had at least 
one post-baseline safety assessment.
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment. Patients who have received at least one dose of study drug but 
who have no post-treatment safety data of any kind would be excluded from the safety 
population.
Per protocol set:  Consists of all FAS patients without any major protocol deviation. Rules 
for identifying major protocol deviations will be detailed in RAP.
11.3
Patient demographics/other baseline characteristics
Demographic (gender, age, weight, height, BMI) and other baseline data (disease 
characteristics, medical history, medication history, and serology) will be summarized 
descriptively for all patients of the FAS.
11.4
Treatments (study drug, concomitant therapies, compliance)
All analyses from this section will be performed on all patients from the safety set.
Duration of INC424 administration will be summarized using descriptive statistics. Also, 
proportion of patients by dose intensity range will be presented.
Frequency of dose reductions and interruptions will be summarized by reason, if available. 
The duration of the dose interruptions will also be summarized.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized by ATC code.
11.5
Primary objective
The primary objective of this study is to collect safety data on patients with PMF, PPV MF, or 
PET-MF treated by INC424. This will be assessed considering incidence of treatment-
emergent AEs.
The safety set will be used for the analysis of clinical safety data.
11.5.1
Variables
Primary analysis will be performed on the incidence of treatment-emergent AEs.
Incidence of a given AE is defined as the ratio of total number of patients experiencing at 
least once this AE (defined by its preferred term) divided by the total number of patients in 
the safety set.
 


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A treatment-emergent AE is an AE that starts during treatment (including the 28 days 
following last treatment administration) or worsen on treatment.
11.5.2
Statistical hypothesis, model, and method of analysis
No hypotheses or models will be considered for these analyses, descriptive statistics will be 
provided.
The treatment-emergent AEs only will be summarized, while all reported AEs will be 
included in listing.
In this section the term adverse event or AE refers only to treatment-emergent AEs unless 
specified otherwise.
The incidence of AEs will be tabulated by MedDRA® (Medical Dictionary for Regulatory 
Activities) preferred term and by system organ class (SOC).
Incidence of AEs will also be summarized by system organ class, severity (based on CTCAE 
grades).
The same analysis will be repeated for SAEs regardless of drug relationship, drug related 
SAEs, AEs which CTCAE grade is 3 or 4 and for drug related AEs.
AEs that will not have relationship to study drug specified will be considered to be treatment-
related.
11.6
Secondary objectives
11.6.1
Efficacy
This study provides an opportunity to collect further data on INC424 efficacy, resource use 
and patient’s quality of life in patients with PMF, PPV MF, or PET-MF. For this reason, the 
following exploratory analysis will be conducted.
11.6.1.1 Full analysis set will be used for all efficacy analyses
The following endpoints are considered in assessing efficacy of INC424 in the study 
population.
Best overall response to treatment as assessed by spleen palpation, is defined by the 
investigator.
Change of spleen length from Baseline to end of each visit and at end of treatment. This 
parameter is computed by dividing the difference of spleen length at assessment time and at 
baseline by the length at baseline multiplied by one hundred.
WBC and platelet count changes from Baseline at end of each visit  and at end of 
treatment. For each parameter, the percent of change will be computed by dividing the 
difference of value at assessment time and at baseline by the value at baseline, and 
multiplying by one hundred.
 


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Shift in fibrosis in the bone marrow from Baseline, is defined as the status change of 
fibrosis at time of worst/best response (whenever it occur) compared to fibrosis status at 
baseline. Assessment of fibrosis in the bone marrow after enrollment is not mandatory.
Progression free survival (PFS) is the time from first study drug administration to date of 
documented progression (based on International Working Group for Myelofibrosis Research 
and Treatment Response Criteria, IWG-MRT) (Tefferi A, Barosi G, Mesa RA, et al (2006) or 
deaths. Time will be censored at the last date the patient is known to be free of disease
progression for patients without event. 
Leukemia free survival (LFS) is the time from the first study drug administration date to: the 
date of the bone marrow blast count ≥20% OR the date of the first peripheral blood blast 
count ≥20% that is subsequently confirmed to have been sustained for at least 8 weeks or the 
date of death, whichever occurs first. LFS will be computed whenever data of bone marrow 
blast and/or peripheral blood blast counts is/are available. Time will be censored at the last 
date the patient is known to be free of leukemia for patients without event.
Overall survival (OS) is the time from first study drug administration to date of deaths 
(whatever the cause). Time will be censored at the last date the patient is known to be alive 
for patients without event.
11.6.1.2 Statistical hypothesis, model, and method of analysis
The proportion of patients by best overall response category will be summarized. Proportion 
of responders will be estimated and its 95% confidence intervals provided.
Change in spleen length from Baseline to end of each visit/month of therapy and at end of 
treatment will be described using descriptive statistics and by relevant change categories (e.g.
(≤50%, (-50%, -25%], (-25%, -5%], (-5%, 5%], (5%, 25%], (25%, 50%] and >50%).
WBC and platelet count changes from baseline will be summarized using descriptive statistics 
at the end of each visit and at the end of treatment.
Number and proportion of patients by fibrosis status change from Baseline will provided for 
each possible combination.
PFS, LFS, and OS will be estimated with the Kaplan Meier method and 95% confidence 
intervals will be provided for the estimated median.
11.6.2
Laboratory abnormalities
All laboratory values will be converted into SI units and the severity grade calculated using 
appropriate common toxicity criteria (CTCAE).
11.6.2.1 Hematology
A listing of laboratory values will be provided by laboratory parameter. A separate listing will 
display notable laboratory abnormalities (i.e. newly occurring CTCAE grade 3 or 4 laboratory 
toxicities).
The frequency of laboratory abnormalities will be displayed by parameter.
Laboratory data will be summarized by presenting shift tables.
 


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11.6.2.2 Biochemistry
A listing of laboratory values will be provided by laboratory parameter. A separate listing will 
display notable laboratory abnormalities (i.e. newly occurring CTCAE grade 3 or 4 laboratory 
toxicities).
The frequency of laboratory abnormalities will be displayed by parameter.
Laboratory data will be summarized by presenting shift tables.
11.6.3
Other safety data: weight, vital signs, ECG, and death
Weight change from Baseline will be described at each assessment time. Frequency of weight 
relative change by more than 20% will be summarized. Patients exhibiting clinically notable 
abnormalities will be listed.
Descriptive statistics and mean change from Baseline will be determined for vital signs (oral 
temperature, blood pressure and pulse) at each assessment time. Frequency of clinically 
notable abnormalities will be summarized. Patients exhibiting clinically notable abnormalities 
will be listed.
Notably abnormal changes in ECG parameters will be displayed in listings.
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of AE.
Death rate (any death) at end of study will be summarized, if sufficient number, rate by cause, 
SOC, and preferred term will also be tabulated, else death and cause will only be listed.
11.6.4
Tolerability
11.6.4.1 Resource utilization
Frequency of hospitalization, of emergency room visits, urgent care visits, additional general 
practitioner and specialist office visits, and splenic irradiation will be summarized at end of 
each quarter (i.e. every three months after start of study medications).
Overall duration of hospitalization at end of study will be summarized.
The proportion of patients who are transfusion dependent as well as the proportion of patients 
whose transfusion status (dependent or independent) changed (from dependent to independent 
or vice versa) (Gale 2011) at each visit will be tabulated with summary statistics.

Transfusion dependence at Baseline will be defined as patient who received 2 or more 
units of red blood cell product(s) during the 12 weeks prior to first study treatment 
administration.

New onset of transfusion dependence will be defined as the use of 2 or more units of red 
blood cell product(s) during the last 12 weeks prior to end of study for patients who were 
not transfusion dependent at Baseline.

New transfusion independency will be defined as no (0) use of red blood cell product(s) 
during the last 12 weeks prior to end of study for patients who met the definition of 
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
Prior and concomitant mediations, as listed in protocol (Appendix IX) will be 
summarized. Concomitant medications at week 24, as listed in protocol (Appendix IX), 
will be summarized.
11.6.5
Quality of Life Assessments
The ECOG performance score will be summarized descriptively by visit. The summary will 
include the number and percent of patients at each reported value. A shift summary including 
the number and percent of patients will also be produced by visit for baseline vs. post-baseline 
scores.
Data from FACT-Lymphoma version 4 Scores will be analyzed in the sum scores. Change 
and percent change from baseline to each scheduled visit when the FACT-Lymphoma version 
4 scores were collected will be calculated with the data collect from the last visit prior to and 
at Day 1 as the baseline. The scores will be summarized descriptively by visit.
The treatment effect on FACT-Lymphoma version Scores over time will be estimated using 
repeated measurements analysis including all patients with at least one post-baseline scale 
score. Patients without baseline value will not be considered in the analysis.
Data from FACIT Fatigue Scores will be analyzed in the sum scores. Change and percent 
change from baseline to each scheduled visit when the FACIT Fatigue scores were collected 
will be calculated with the data collect from the last cycle prior to and at Day 1 as the baseline. 
The scores will be summarized descriptively by visit.
Time to improvement and proportion of patients showing improvement will be estimated for 
ECOG performance score and for selected scales for FACT-Lymphoma version 4 and FACIT 
scale according to minimally important difference (MID) specified for each instrument.
11.6.6
Pharmacokinetics
Not applicable.
11.6.7
Biomarkers
Not applicable.
 
11.7
Interim analysis
An interim analysis will be performed to closely monitor safety, and ensure an appropriate 
risk/benefit ratio in the patient population with low platelet counts, between 50,000 and 
100,000/µL. In order to adequately assess the risk/benefit ratio, this analysis will also be 
performed on non-low platelet patients (≥100,000/µL), which will be further detailed in 
analysis plan, who will serve as an internal reference population. This interim analysis will 
take place when 50 patients with low platelets have completed 6 months of treatment.
 


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Analyses may be performed if needed to fulfill regulatory obligations, to comply with post-
approval commitments or for publication purposes.
11.8
Sample size calculation
This is an expanded access study and thus no sample size and no power computation was 
performed. The maximum number of patients that will be treated in this study is up to 2500  
and is based on country assessments of the number of potential patients.
11.9
Power for analysis of critical secondary variables
Not applicable.
12
Ethical considerations and administrative procedures
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC and US Code of 
Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of 
Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required.
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents to request approval of a 
protocol deviation, as no authorized deviations are permitted. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
12.3
Informed Consent
Eligible patients may only be included in the study after providing written (witnessed, where
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
 


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patient. Informed consent must be obtained before conducting any study-specific procedures 
(i.e., all of the procedures described in the protocol). In cases where the patient’s legally 
acceptable representative gives consent, the patient (e.g., minors, patients with severe 
dementia), should be informed about the trial to the extent compatible with the patient’s 
understanding and if capable, the patient should assent, sign and personally date the written 
informed consent. The process of obtaining informed consent should be documented in the 
patient source documents. In emergency situations when prior consent of the patient is not 
possible and the patient’s legally acceptable representative is not available, enrollment of the 
patient should require measures described in the protocol with documented favorable opinion 
of the IRB/IEC/REB. The patient or the patient’s legally appointed representative should be 
informed about the trial as soon as possible and consent to continue and other consent as 
appropriate should be requested.
A proposed informed consent form that complies with the ICH GCP guideline and regulatory 
requirements and is considered appropriate for this study will be provided to all centers 
participating in the study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC/REB and a copy 
of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval.
12.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.2.
12.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
12.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
 


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evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, and subject files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. For electronic eCRFs an audit trail will be maintained by the system. The 
investigator should retain records of the changes and corrections to paper eCRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
12.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
12.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
12.9
Financial disclosures
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12.10
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
 


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Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.11
Amendments to the Protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days.
 


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13
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WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles 
for Medical Research Involving Human Subjects. Adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, 
Tokyo, Japan, October 1975, 35th WMA General Assembly, Venice, Italy, October 1983, 
41st WMA General Assembly, Hong Kong, September 1989, 48th WMA General Assembly, 
Somerset West, Republic of South Africa, October 1996, and the 52nd WMA General 
Assembly, Edinburgh, Scotland, October 2000. Note of Clarification on Paragraph 29 added 
by the WMA General Assembly, Washington 2002. Note of Clarification on Paragraph 30 
added by the WMA General Assembly, Tokyo 2004. Available at 
http://wma.net/en/30publications/10policies/b3/index.html.
 


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14
Appendices
14.1
Appendix I - Diagnostic criteria for PMF, PPV MF, and PET-MF
Criteria for post-polycythemia vera myelofibrosis (Barosi 2008)
Required criteria:
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria (Tefferi 2007d)
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a
Additional criteria (two are required):
1. Anemiab or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or 
cytoreductive treatment for erythrocytosis
2. A leukoerythroblastic peripheral blood picture
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of the tip 
of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
4. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained 
fever (>37.5oC)
aGrade 2–3 according to the European classification:
3 diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, 
coarse fiber network with areas of collagenization (positive trichrome stain).
Grade 3–4 according to the standard classification:
4 diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis.
bBelow the reference range for appropriate age, sex, gender and altitude considerations.
Criteria for post-essential thrombocythemia myelofibrosis (Barosi 2008)
Required criteria:
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria (Tefferi 
2007d)
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a
Additional criteria (two are required):
1. Anemiab and a ≥2mg ml-1 decrease from baseline hemoglobin level
2. A leukoerythroblastic peripheral blood picture
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of the tip 
of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly
4. Increased LDH (above reference level)
5. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained 
fever (> 37.5oC)
aGrade 2–3 according to the European classification:
3 diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, 
coarse fiber network with areas of collagenization (positive trichrome stain).
Grade 3–4 according to the standard classification:
4 diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis. 
bBelow the reference range for appropriate age, sex, gender and altitude considerations.
 


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Diagnostic criteria for polycythemia vera essential thrombocythemia, and 
primary myelofibrosis (Swerdlow 2008, Vardiman 2009)
Criteria for the diagnosis of polycythemia vera (PV)
Diagnosis requires the presence of both major criteria and one minor criterion or the presence of the first 
major criterion together with two minor criteria
Major Criteria
Hemoglobin > 18.5 g/dL in men; 16.5 g/dL in women or other evidence of increased red cell volume*
Presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation
Minor Criteria
Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) with prominent 
erythroid, granulocytic, and megakaryocytic proliferation
Serum erythropoietin level below the reference range for normal
Endogenous erythroid colony formation in vivo
* Hemoglobin or hematocrit > 99th percentile of method-specific reference range for age, sex, altitude of residence 
or hemoglobin > 17g/dL in men, 15 g/dL in women if associated with a documented and sustained increase of at 
least 2 g/dL from a person’s baseline value that cannot be attributed to correction of iron deficiency or elevated red 
cell mass > 25% above mean normal predicted value.
Criteria for the diagnosis of essential thrombocythemia (ET)
Diagnosis requires meeting all four criteria
1. Sustained platelet count ≥ 450 x 109/L*
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased 
numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of neutrophil granulopoiesis or 
erythropoiesis.
3. Not meeting WHO criteria for polycythemia vera,
primary myelofibrosis,
BCR-ABL1-positive CML,
or 
myelodysplastic syndrome,|| or other myeloid neoplasm.
4. Demonstration of JAK2 V617F or other clonal marker, or in the absence of JAK2 V617F, no evidence of 
reactive thrombocytosis¶.
ET indicates essential thrombocythemia; BM, bone marrow; WHO, World Health Organization; and CML, chronic 
myelogenous leukemia.
*
Sustained during the work-up process.
Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range 
in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and 
hematocrit levels, and red cell mass measurement is not required.
Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral blood leukoerythroblastosis, or 
markedly hypercellular marrow accompanied by megakaryocyte morphology that is typical for primary 
myelofibrosis-small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, 
bulbous, or irregularly folded nuclei and dense clustering.
Requires the absence of BCR-ABL1.
||
Requires the absence of dyserythropoiesis and dysgranulopoiesis.
¶
Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, 
connective tissue disease, metastatic cancer, and lymphoproliferative disorders. However, the presence of a 
condition associated with reactive thrombocytosis does not exclude the possibility of ET if other criteria are met.
 


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Criteria for the diagnosis of primary myelofibrosis (PMF)
Diagnosis requires meeting all 3 major criteria and 2 minor criteria
Major Criteria
1. Presence of megakaryocyte proliferation and atypia,* usually accompanied by either reticulin or collagen 
fibrosis or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an 
increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis 
(i.e., prefibrotic cellular-phase disease)
2. Not meeting WHO criteria for polycythemia vera,
BCR-ABL1-positive chronic myelogenous leukemia,
myelodysplastic syndrome,
or other myeloid disorders
3. Demonstration of JAK2 V617F or other clonal marker (e.g., MPLW515K/L) or, in the absence of the above 
clonal markers, no evidence that bone marrow fibrosis is secondary to infection, autoimmune disorder or other 
chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic 
(chronic) myelopathies||
Minor Criteria
1. Leukoerythroblastosis¶
2. Increase in serum lactate dehydrogenase level¶
3. Anemia¶
4. Palpable splenomegaly¶
*
Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous, or 
irregularly folded nuclei and dense clustering.
Requires the failure of iron replacement therapy to increase hemoglobin level to the polycythemia vera range 
in the presence of decreased serum ferritin. Exclusion of polycythemia vera is based on hemoglobin and 
hematocrit levels. Red cell mass measurement is not required.
Requires the absence of BCR-ABL1.
Requires the absence of dyserythropoiesis and dysgranulopoiesis.
||
It should be noted that patients with conditions associated with reactive myelofibrosis are not immune to 
primary myelofibrosis, and the diagnosis should be considered in such cases if other criteria are met.
¶
Degree of abnormality could be borderline or marked.
 


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14.2
Appendix II - Information regarding highly effective
contraception methods
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening).  The vasectomized male partner 
should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception you 
should have been using the same pill on a stable dose for a minimum of 3 months before 
screening)
14.3
Appendix III - Clinical laboratory tests
Serum chemistry
Hematology
Other
ALT
AST
Bilirubin - Total and Direct 
Alkaline phosphatase
Serum Creatinine
Complete Blood Count (CBC) 
Differential (neutrophils, lymphocytes, 
eosinophils, basophils, monocytes), 
including reporting of % blasts
Platelets
Reticulocyte count (absolute and % 
reticulocytes) optional
Serology: hepatitis A, B, and C
HIV Antibody
Pregnancy Test: Female patients of 
childbearing potential only. Serum 
test at Screening
(Section 7).
Thiamine blood level (Section 7)
Coagulation (Required for 
screening / baseline , optional after 
enrollment)
PT (or INR)
PTT
ALT = alanine aminotransferase, AST = aspartate aminotransferase, PT = prothrombin time, PTT = partial 
thromboplastin time.
 


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14.4
Appendix IV - Eastern Cooperative Oncology Group performance 
status
Grade
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
14.5
Appendix V - Bone marrow biopsy evaluation (when performed, 
they are not mandatory)
Fibrosis density should be assessed in hematopoietic areas
Fibrosis Grade
Description
0
Scattered linear reticulin with no intersections corresponding to normal bone marrow
1
Loose network of reticulin with many intersections, especially in perivascular areas
2
Diffuse and dense increase in reticulin with extensive intersections, occasionally with only 
focal bundles of collagen and/or focal osteosclerosis
3
Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of 
collagen, often associated with significant
Note: Fibrosis density should be assessed in hematopoietic areas. Source: Tefferi (2006).
 


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14.6
Appendix VI - Restricted/prohibited medications
These medications are restricted or prohibited in combination with INC424:
Prohibited medications

Aspirin > 150 mg/day

Any other investigational medication

Any other medication for myelofibrosis (these medications must be discontinued prior to 
Day 1 of INC424 treatment, and all adverse events associated with these medications must 
be resolved prior to Day 1 of INC424 therapy).

Anagrelide

Busulfan

Hydroxyurea

Interferon

Lenalidomide

Thalidomide
Restricted medications
Use of all CYP3A4 inhibitors is discouraged as they may have effects on plasma levels of
INC424; alternative therapies should be considered, if available
Category
Drug Names
Strong inhibitorsa of 
CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, eltegravir/ritonavir, 
grapefruit juice1, idelalisib, indinavir, itraconazole, ketoconazole,  lopinavir/ritonavir, 
LCL161, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
sequinavir/ritonavir,  telaprevir, telithromycin, voriconazole, indinavir/ritonavir, 
tipranoavir/ritonavir, troleandomycin,  
Moderate 
inhibitorsb of 
CYP3A
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir,, casopitant, cimetidine, 
ciprofloxacin, crizotinib, cyclosporin, duranavir, darunavir/ritonavir, diltiazem, dronedarone, 
erythromycin, faldaprevilr, fluconazole2, fosamprenavir, grapefruit juice1, imatinib, 
lomitapide, netupitant,nilotinib, schisandra sphenanthera3, tofisopam, verapamil
Strong inducersc of 
CYP3A
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, rifampin, St. John’s wort3, 
rifabutin, phenobarbital, 
Moderate inducersd
of CYP3A
bosentan, efavirenz, etravirine, genistein3, lersivirine, lopinavir, modafinil, nafcillin, ritonavir, 
semagacestat4, talviraline4, thioridazine, tipranavir, , 
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction 
Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table and from the University of 
Washington’s Drug Interaction Database. Note that this may not an exhaustive list.  Please refer to footnotes.
 


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1. Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol.
2. Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor. Fluconazole is a strong CYP2C9 inhibitor based on the 
AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A inhibitor. 
3. Herbal product.
4. Drugs not available in the US Market.
aA strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold. 
bA moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold
c A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%.
d A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%.
Dual CYP2C9 and CYP3A4 inhibitors:
Fluconazole avoid the concomitant use of ruxolitinib with fluconazole doses ≥ 200 mg daily; 
If clinically necessary to use doses ≥ 200 mg daily consultation with Sponsor is required.  
Please refer to Section 6.4.2.
 


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14.7
Appendix VII - FACT-Lym Form, Version 4
 


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14.8
Appendix VIII - FACIT Fatigue Scale (Version 4)
 


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14.9
Appendix IX - MRU concomitant medication
Listed below are the concomitant medications for MPN symptom management that will be 
recorded for MRU.
GENERIC NAME
INDICATION
ACECLOFENAC
pain
ACETAMINOPHEN
fever, pain
ACETYLSALICYLIC ACID
thrombosis prophylaxis
ACICLOVIR
herpes zoster
ALLOPURINOL
hyperuricemia
AMIKACIN SULFATE
bacterial infection
AMITRIPTYLINE
postherpetic neuralgia
AMOXICILLIN
bacterial infection
AMOXICILLIN W/CLAVULANATE
bacterial infection
AMPHOTERICIN B
fungal infection
ANAGRELIDE
thrombosis prophylaxis
AZTREONAM
bacterial infection
BIOFLAVONOIDS
thrombosis prophylaxis
CARBASALATE CALCIUM
thrombosis prophylaxis
CASPOFUNGIN
fungal infection
CEFEPIME
bacterial infection
CEFOTAXIME SODIUM
bacterial infection
CEFTAZIDIME
bacterial infection
CEFTRIAXONE
bacterial infection
CEFUROXIME
bacterial infection
CELECOXIB
pain
CETIRIZINE
pruritus
CIPROFLOXACIN
bacterial infection
CLARITHROMYCIN
bacterial infection
CLAVULANIC ACID
bacterial infection
CLINDAMYCIN
bacterial infection
CLOPIDOGREL
thrombosis prophylaxis
CLOTRIMAZOLE
fungal infection
CODEINE PHOSPHATE
pain
CO-TRIMOXAZOLE
bacterial infection
DALTEPARIN
thrombosis prophylaxis
DANOCRINE (Danazol®)
myelofibrosis
DARBEPOETIN ALFA
anemia
DEFERASIROX
iron overload
DEFEROXAMINE MESILATE
iron overload
DEXIBUPROFEN
pain
DICLOFENAC
pain
DIHYDROCODEINE
pain
DIMENHYDRINATE
nausea
DIMETINDENE
pruritus
 


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GENERIC NAME
INDICATION
DIPHENHYDRAMINE
pruritus
DIPYRIDAMOLE
thrombosis prophylaxis
DOXYCYCLINE
bacterial infection
ENOXAPARIN
thrombosis prophylaxis
EPOETIN ALFA
anemia
EPOETIN BETA
anemia
ERYTHROMYCIN
bacterial infection
ESOMEPRAZOLE
gastritis-reflux
ETOFENAMATE
pain
ETORICOXIB
pain
FENTANYL
pain
FILGRASTIM
leukopenia
FLUCLOXACILLIN
bacterial infection
FLUCONAZOLE
fungal infection
FUROSEMIDE
edema
FUSIDIC ACID
bacterial infection
GABAPENTIN
postherpetic neuralgia
GENTAMICIN
bacterial infection
HEPARIN
thrombosis prophylaxis
HYDROCHLOROTHIAZIDE
edema
HYDROMORPHONE HYDROCHLORIDE
pain
IBUPROFEN
pain
IMIPENEM
bacterial infection
INDOBUFEN
thrombosis prophylaxis
KETOPROFEN
pain
LEVOFLOXACIN
bacterial infection
LIDOCAINE HYDROCHLORIDE
pain
LINEZOLID
bacterial infection
LORATADINE
pruritus
MEFENAMIC ACID
pain
MEROPENEM
bacterial infection
METAMIZOLE
fever, pain
METOCLOPRAMIDE HYDROCHLORIDE
nausea
MINOCYCLINE HYDROCHLORIDE
bacterial infection
MORPHINE
pain
MOXIFLOXACIN
bacterial infection
NADROPARIN
thrombosis prophylaxis
NAPROXEN
pain
NIMESULIDE
fever, pain
NITROFURANTOIN
bacterial infection
NORFLOXACIN
bacterial infection
OFLOXACIN
bacterial infection
OMEPRAZOLE
gastritis-reflux
ONDANSETRON
nausea
 


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GENERIC NAME
INDICATION
OXYCODONE
pain
PALONOSETRON HYDROCHLORIDE
nausea
PANTOPRAZOLE
gastritis-reflux
PARACETAMOL
fever, pain
PARACETAMOL W/TRAMADOL
pain
PETHIDINE HYDROCHLORIDE
pain
PHENPROCOUMON
thrombosis prophylaxis
PIPERACILLIN
bacterial infection
PIPERACILLIN/TAZOBACTAM
bacterial infection
PIROXICAM
pain
PLATELETS, CONCENTRATED
thrombocytopenia
PREDNISOLONE
fever prophylaxis
PRIMAXIN
bacterial infection
PRISTINAMYCIN
bacterial infection
PROPRANOLOL
prophylaxis of variceal bleeding
RANITIDINE
gastritis-reflux
RED BLOOD CELLS, CONCENTRATED
anemia
ROXITHROMYCIN
bacterial infection
SPIRONOLACTONE
edema
TICLOPIDINE
thrombosis prophylaxis
TOBRAMYCIN SULFATE
bacterial infection
TORASEMIDE
edema
TRAMADOL
pain
TRIMETHOPRIM
bacterial infection
VALACYCLOVIR
herpes zoster
VALORON N
pain
VANCOMYCIN HYDROCHLORIDE
bacterial infection
VORICONAZOLE
fungal infection
WARFARIN
thrombosis prophylaxis
XIPAMIDE
edema
 

SAP_000.pdf: 
Clinical Development
INC424/ruxolitinib/Jakavi®
CINC424A2401 / NCT01493414
An open-label, multicenter, expanded access study of 
INC424 for patients with primary myelofibrosis (PMF) or 
post polycythemia myelofibrosis (PPV MF) or post-
essential thrombocythemia myelofibrosis (PET-MF)
Statistical Analysis Plan (SAP)
Amendment 2
Author:
 
Document type:
SAP Documentation
Document status:
Final; Amendment 2
Release date:
26-Apr-2017
Number of pages:
28
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment 2
CINC424A2401
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and 
title impacted 
(Current)
08-Mar-
2012
Prior to 
DB lock
Creation of final 
version
N/A - First version
NA
04-Jul-
2016
Creation of 
amendment 1
This SAP is developed based on the 
already approved study RAP M3 
(approved on 08-Mar-2012). The changes 
in the SAP reflect changes in the study 
protocol amendment  version 5. The 
language of the SAP has been updated to 
be aligned with the protocol amendment 
version 5.
Key changes:
1.
Included the definition of the per 
protocol set (PPS) and 
2.
Imputation rule for
missing/partial dates of study
drug
3.
Data handling rules for death
4.
Updated 
definitions 
for 
transfusion dependency
5.
Spleen Response and Loss of 
Response Criteria by IWG MRT 
criteria
Section 1: 
Introduction
-
Section 1.1
-
Section 1.2
Section 2: Patients 
and treatments
-
Section 2.3: 
Section 3: 
Statistical 
analysis
-
Section 3.1.2
-
Section 3.2
-
Section 3.3
-
Section 
3.4.1.2
-
Section 3.4.2
-
Section 3.4.4
-
Section 3.5
-
Section 3.6
-
Section 3.11 
Section 4
27-Sep-
2016
Creation of final 
version of
amendment 1
13-Feb-
2017
Creation of 
amendment 2
Key changes:
1.
Modified per-protocol set 
definition
2.
Included a listing on non-serious 
adverse event
3.
Included text for tables required 
to meet leagal requirements of 
posting safety data on EudraCT 
and CT.gov sites.
4.
Removed section on AEs of 
interest and relative details from 
section 16.1.9
Section 2:
-
Section 2.1
Section 3:
-
Section 3.5.1
-
Section 3.5.2
Section 16.1.9


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SAP Amendment 2
CINC424A2401
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
1.2.1
Primary Objective ...................................................................................7
1.2.2
Secondary Objectives:.............................................................................7
2
Patients and Treatments:......................................................................................................7
2.1
Analysis sets ............................................................................................................7
2.2
Subgroup definitions................................................................................................8
2.3
Assessment windows, baseline and post baseline definitions, missing data 
handling ...................................................................................................................8
3
Statistical analysis ...............................................................................................................8
3.1
Patient disposition, background and demographic characteristics ..........................9
3.1.1
Patient disposition...................................................................................9
3.1.2
Background and demographic characteristics.........................................9
3.1.3
Medical history........................................................................................9
3.2
Study medication .....................................................................................................9
3.3
Concomitant medication:.......................................................................................11
3.4
Primary and secondary endpoints analyses ...........................................................12
3.4.1
Primary endpoints .................................................................................12
3.4.2
Secondary endpoints: ............................................................................13
3.4.3
Analysis of secondary endpoints...........................................................13
3.4.4
Analysis of patient reported outcomes..................................................15
3.5
Safety evaluation ...................................................................................................17
3.5.1
Adverse events ......................................................................................18
3.5.2
Clinical laboratory values .....................................................................19
3.5.3
Vital signs..............................................................................................20
3.5.4
Electrocardiogram (ECG) .....................................................................20
3.6
Resource Utilization ..............................................................................................21
3.7
Interim analyses .....................................................................................................21
3.8
Data monitoring committee (DMC) ......................................................................22
3.9
Sample size and power considerations ..................................................................22
3.10
Pharmacokinetic analyses......................................................................................22


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SAP Amendment 2
CINC424A2401
3.11
Other topics............................................................................................................22
4
Change to protocol specified analyses ..............................................................................23


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SAP Amendment 2
CINC424A2401
List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
INC424
Ruxolitinib
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRU
Medical Resource Utilization
o.d.
Once Daily
OS
Overall Survival
PET-MF
Post essential thrombocytopenia-myelofibrosis
PFS
Progression-Free Survival
PMF
Primary Myelofibrosis
PPS
Per-Protocol Set
PPV
Polycythemia vera
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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SAP Amendment 2
CINC424A2401
1
Introduction
This document is describing the analyses and conventions planned for reporting the 
INC424A2401 study. 
INC424A2401 is a phase IIIB study designed to collect additional safety of INC424 
(Ruxolitinib) in patients with primary myelofibrosis (PMF) or post polycythemia vera-
myelofibrosis (PPV MF), or post essential thrombocytopenia-myelofibrosis (PET-MF), who 
have either received prior treatment with commercially available agents or never received 
treatment.
1.1
Study design
This is a phase IIIB, multicenter, single-arm, open-label expanded access study intended to 
provide additional data on the safety and efficacy of INC424 in patients with PMF or PPV MF, 
or PET-MF who have either received prior treatment or who have never received treatment.  
Patients will be screened within four weeks prior to the first dose of INC424.  
Baseline evaluations will be performed within a week of the first dose of INC424. 
Visits will occur on a monthly basis for the first 3 months, then every 3 months thereafter and 
at study discontinuation.
In this document, study drug refers to INC424.
For this study, study drug will be administered continuously. All patients will be treated with 
oral INC424 at a dose of 5 - 25 mg (dose based on baseline platelet count) BID until one of 
the following occurs:
disease progression;
transplant;
unacceptable
toxicity; death; 
discontinuation from the study for any other reason; withdrawal of consent; physician 
decision; until the study drug becomes commercially available in each participating country or 
until 24- months after last patient first visit (LPFV), or the project is discontinued, whichever 
occurs first.
If it is determined at any study visit that the patient will discontinue study drug that day, then 
that study visit will be the end-of-study visit, and the end-of-study visit procedures will be 
followed. (Refer to protocol section 7.6.2)
An interim analysis planned for this study will take place when 50 patients with low platelets 
will have completed 6 months of treatment. Additional analyses may also be performed if 
needed to fulfill regulatory obligation or publication purpose. 
The final analysis will be performed after all patients have either completed the study or have 
been prematurely discontinued from the study.
1.2
Study objectives and endpoints
This study is intended to collect additional safety of INC424 in patients with PMF or PPV MF, 
or PET-MF.


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1.2.1
Primary Objective

To collect additional safety of INC424 in patients with PMF, PPV MF, or PET-MF, 
who have either received prior treatment with commercially available agents or who 
have never received treatment.
1.2.2
Secondary Objectives:

To document the best overall response rate to INC424 in patients with PMF, PPV MF, 
or PET-MF as evaluated by the Investigator.

To collect quality of life (QoL) endpoints in patients with PMF, PPV MF, or PET-
MF treated with INC424.

To document medical resource utilization (MRU) in patients with PMF, PPV MF, or 
PET-MF treated with INC424.
2
Patients and Treatments:
Eligible patients for this Expanded Access study are male or female aged ≥ 18 years who are
diagnosed with PMF or PPV MF or PET-MF and who have either never received treatment, 
or who have received prior treatment with commercially available agents or have previously 
received INC424, patients with high risk OR intermediate risk level 2 OR intermediate risk 
level 1 with an enlarged spleen.
Patients who are not eligible for this Expanded Access study are patients with active hepatitis 
A, B, C or who are HIV-positive, and patients with coagulation parameters (PT, PTT, or 
INR) >=1.5 x ULN.
2.1
Analysis sets
Full Analysis Set (FAS) consists of all patients who received at least one administration of 
study drug.
Safety Set (SS) consists of all patients who received at least one dose of study drug and had at 
least one post-baseline safety assessment.
Please note: the statement that a patient had no adverse events (on the Adverse Event CRF) 
constitutes a safety assessment. Patients who have received at least one dose of study drug but 
who have no post-treatment safety data of any kind would be excluded from the safety 
population.
Per protocol set (PPS) consists of all FAS patients without any major protocol deviation. 
The following major protocol deviations will lead to exclusion from the PPS:.

Male or female patients aged < 18 years of age at screening (Deviation code: I03)

Unconfirmed diagnosis of PMF, PPV-MF or PETMF at screening (Deviation code: I04).

Secondary MF (PPV-MF or PETMF) grade 0 and 1 for Fibrosis on scale 0-3. or grade 0, 1 
and 2 on scale 0-4 at screening (Deviation code: I13).
The Full analysis set will be used for all population and efficacy analyses, while Safety set 
will be used for treatment administration description and safety analyses.


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2.2
Subgroup definitions
No sub-group analyses are planned for this study.
2.3
Assessment windows, baseline and post baseline definitions, 
missing data handling
Assessment windows: 
On-treatment, evaluations are scheduled for study visits at Day 1, and at the end of Weeks 4, 8, 
12, and every 12 weeks thereafter with time window of +/-7 days. 
Baseline definition: 
Baseline is the latest available assessment obtained prior to the date of first dose of study drug 
administration. If assessment prior to first dose of study drug administration is not available, 
then assessment on the day of first dose of study drug administration will be used at baseline. 
Otherwise baseline will be considered missing.
Post baseline definition: 
All assessments obtained after the baseline assessment (see definition above) are considered 
as post-baseline.
Study day calculation:
In this study, we will use study day instead of actual event date. 
Study day will be calculated as 

event date - start date of study drug + 1 , if the event date is on or after the start date of 
study drug or

event date - start date of study drug, if the event date is prior to the start date of study drug
Month for this study will be considered as 4 weeks, so that Month 1 is at Week 4 and so on.
Similarly, quarter would be considered as 12 weeks, so that Quarter 1 is at Week 12 and so on.
Data Handling:
All patients will be followed-up for 28 days after they have discontinued INC424, data 
collected during this follow-up period will be included in the analysis.
Unless otherwise specified, no imputation for missing data will be performed.
3
Statistical analysis
This section describes the planned statistical analyses for Sections 10-12, 14, and 16 of the 
clinical study report.
The final analysis for this study will be performed after all patients have either c ompleted or 
have been prematurely discontinued from the study. 


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Unless otherwise specified, qualitative data (e.g., gender) will be described using frequency 
and percentages, while quantitative data, will be described using descriptive statistics: n, mean,
standard deviation, median, minimum, and maximum. 
3.1
Patient disposition, background and demographic 
characteristics
3.1.1
Patient disposition
The number of patients included in the Full analysis set will be presented.  The number and 
percentage of patients in the Full analysis set who completed the study, who discontinued the 
study and the reason for discontinuation, will be presented.
3.1.2
Background and demographic characteristics
The FAS will be used for all baseline and demographic summaries and listings.  
Demographic characteristics include age, gender, race, and ethnicity. Baseline characteristics 
include weight at baseline, height at screening, body mass index and ECOG scores. 
Disease history and disease characteristics include type of MF, time since initial diagnosis, 
hemoglobin, platelets, neutrophils, blast cells, prior splenectomy, hydroxurea, prior 
radiotherapy, transfusion history, splenic irradiation history and palpable spleen length.
Qualitative data (e.g., gender, race, ECOG performance status) will be summarized by means 
of contingency tables and quantitative data (e.g., age, body weight) will be summarized by 
appropriate descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum).
3.1.3
Medical history
Any condition entered on the relevant medical history / current medical conditions CRF will 
be coded using the latest version of MedDRA dictionary at the time of database lock. The 
number and percentage of patients with each medical condition will be provided for the FAS.
Medical history will be tabulated with the number and percent of patients with significant 
medical history for each system/organ class.
3.2
Study medication
The duration of study drug administration is defined as the time interval from first (non -zero) 
dose of study drug administration to last study drug administration date (i.e. last known study 
drug administration date). 
Duration of exposure 
The following algorithm will be used to calculate the duration of study drug exposure for 
patients who took at least 1 dose of study drug: 
Duration of exposure (days) = [(date of last administration of study drug) – (date of 
first non-zero dose administration of study drug) + 1 day].


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For patients who discontinued the study drug, last dose date is the last dose date in the EOT 
page.
For ongoing patients, that is, when they do not have information on EOT page, last dose date 
will be imputed by the date of interim analysis data cutoff.
Summary statistics on exposure of study drug will be provided. Cumulative dose, average 
daily dose, actual dose intensity will be summarized by description statistics (n, mean, 
standard deviation, median, minimum, and maximum) using safety set.
Cumulative dose is defined as the total sum of all doses given during the study drug exposure.
Actual dose intensity (DI) = Cumulative dose (mg) / Duration of exposure (days)
Average daily dose = Total dose / Number of dosing days (drug free day(s) are not counted).
The duration includes the periods of temporary study drug interruption. For patients who did 
not take any study drug, the duration of exposure is defined as zero. The duration of exposure 
and duration of follow-up will be summarized by length of exposure, median, as well as by 
duration category (> 0 - ≤4 months, >4 – ≤8 months, >8 – ≤12 months….)
Duration of on-study follow-up 
The duration of on-study follow-up is defined as the time interval from first (non-zero) dose 
of study drug administration to the last date of contact. Date of last contact will be the last 
available assessment date on or before the end of study visit.  
Duration of follow-up (days) = [(last contact date – (date of first non-zero dose 
administration of study drug) +1 day]
Dose reduction and dose interruption
A record with a total daily dose of 0 (zero) mg will be considered a dose interruption, if

the immediate prior total daily dose is non-zero (>0) and

the immediate following record has a non-zero (> 0) total daily dose.
A dose reduction occurs when a non-missing total daily dose record is followed by a record 
with a smaller total daily dose. A dose reduction may or may not have a dose interruption in 
between.
For details see protocol section 6.2.2.   Some hypothetical examples are provided here:
If an investigator advices a patient to go from (say) 
a. 20 mg to a halt/stop and then go to 15 mg, that would be considered a dose 
interruption and also a dose reduction
b. 20 mg to 15 mg without a halt/stop in between – there is a dose reduction here, 
but no dose interruption
c.
20 mg to 15 mg after a halt/stop, but the patient never returns to the study, this 
will be considered a permanent study drug discontinuation 
In the case of a dose escalation, say, from 10 mg to 15 mg, there should not be any 
dose interruption in between.


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Imputation rule for missing/partial dates of study drug
The following rule should be used for the imputation of the dose end date:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death date, 
the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the last dosing date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 
Case 1: The dose end date is completely missing, and the EOT completion date is complete (date 
of death is available in the EOT page), then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date or only 
year of EOT date is available:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year of 
EOT date and mm <= the month of EOT date: 
Use last day of the Month (mm)
Case 5: Both dose end date and EOT date are completely missing:
Use the last contact data across all panels in the database.
After imputation, compare the imputed date with start date of treatment, if the imputed date is less 
than the start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing and no imputation will be made. If 
start date is missing then end-date should not be imputed.
3.3
Concomitant medication:
Prior medications are defined as drugs taken and stopped prior to first dose of study 
medication.  Any medication given at least once between the day of first dose of study 
medication and the last day of study visit will be a concomitant medication, including those 
which were started pre-baseline and continued into the treatment period.
Prior and concomitant medications will be summarized in two separate tables.
Missing and incomplete start date for concomitant medications will be imputed according to 
Novartis conventions described in [RAP Module 8].
No imputation algorithm will be applied to any missing stop date. 
Table 1-1
Allocation of concomitant medications
If
Concomitant 
medication
Start date ≤  study drug start date AND Stop > study 
drug start date OR Stop=missing OR ongoing
X
Start > study drug start date 
X


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Prior medications to treat MF
Prior medications to treat PMF, PPV MF, or PET-MF will be recorded including regimens 
discontinued up to 30 days prior to the study entry. This information will be summarized by 
ATC class and preferred term, and best response on last therapy will be summarized 
seperately.
3.4
Primary and secondary endpoints analyses
This section describes the planned statistical analyses for Section 11 of the clinical study 
report. Full analysis set will be used for efficacy data.
3.4.1
Primary endpoints
3.4.1.1
Variables
The analysis of the primary endpoint will be performed on the incidence by patients of 
treatment-emergent AEs considering or not certain AEs characteristics (e.g. relationship to 
study medication, severity). 
Incidence of a given AE is defined as the ratio of total number of patients experiencing the 
given AE at least once (defined by its preferred term [PT]) divided by the total number of 
patients at risk (i.e. part of the safety set).
A treatment-emergent AE is an AE that first occurs or worsens during treatment (including 
the 28 days following last treatment administration).
3.4.1.2
Analysis
No hypotheses or models will be considered for these analyses, descriptive statistics will be 
provided. 
In this section the term adverse event or AE refers only to treatment-emergent AEs unless 
specified otherwise. 
The treatment-emergent AEs will be summarized, while all reported AEs will be included in 
listings. 
The incidence of AEs will be tabulated using MedDRA (Medical Dictionary for Regulatory 
Activities) preferred term and system organ class (SOC).
Incidence of AEs will also be summarized by system organ class, severity (based on CTC AE 
grades version 3.0). 
The same analysis will be repeated for SAEs regardless of drug relationship, drug related 
SAEs, AEs which CTCAE grade is 3 or 4 and for drug related AEs.
The following AEs will be summarized –

AEs by primary system organ class (SOC), preferred term and maximum grade

AEs suspected to be study drug related by primary system organ class, preferred term and 
maximum grade


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
AEs leading to study drug discontinuation by primary system organ class, preferred term 
and maximum grade

Serious adverse events will be analyzed, by primary system organ class, preferred term 
and maximum grade
Separate summaries for on-treatment and all on-study deaths (on-treatment and post-treatment) 
will be produced by system organ class and preferred term. All deaths collected in the 
database will be listed and post treatment and post-follow-up deaths will be flagged.
Note: The death summaries cover subjects from the Safety Set. The count of deaths in safety 
analyses could be different from the number of deaths in the efficacy analyses.
Data handling rules for death:
The following rule will be used for the analysis of deaths:
1. On-treatment deaths: If date of death is within 28 days following last treatment 
administration or study evaluation completion visit  i.e.
date of death ≤ min (last dose date + 28 days; study evaluation completion visit date)
2. Post-treatment deaths: If date of death is greater than 28 days after treatment end date 
but before the study evaluation completion visit i.e.
(Last dose date +28 days) < date of death ≤ study evaluation completion visit date
3. Post-follow up deaths: If date of death is after the end of study evaluation completion 
visit i.e. date of death > study evaluation completion visit date
3.4.2
Secondary endpoints:
3.4.3
Analysis of secondary endpoints
In this section the term ‘percent of change from baseline’ at a time T is defined as per 
following definition:
% change at time T =    − 
 
 100
At least 50% reduction in spleen length from baseline at any time: The proportion of 
patients who achieved at least 50% reduction in spleen length at any time will be displayed 
along with the 95% CI for proportion of reduction.
If a patient is palpable at Baseline and becomes non-palpable at post-baseline, then this post-
baseline value will be imputed as 0 (zero).
The proportion of responders (achieving at least 50% reduction in spleen length at any time 
from baseline) will be estimated for patients whose spleen were palpable at baseline and 
remained palpable or became non palpable at the post-baseline visit. In addition to the FAS, 
this analysis will also be done by the PPS.
Time to response is defined as the time between date of start of treatment to the date of first 
response. Response is defined by the 50% reduction in spleen length from baseline. Summary 
statistics for those responders will be provided.


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Duration of response is defined as the time between date of first response (≥50% reduction in 
spleen length from baseline) to date of loss of response or death due to MF. Loss of response
is defined as going back to baseline level after first time ≥50% reduction in spleen length from 
baseline. In case a patient does not have loss of response or death due to myelofibrosis by t he 
data cutoff date, DOR will be censored at the date of the last adequate assessment of spleen 
length OR cut-off date whichever occurs first.
Best overall response to treatment as assessed by spleen palpation is defined by the 
investigator.
Best overall response is defined as the best response observed during the study follow-up 
period. The proportion of patients in the best overall response category will be summarized.
In addition, best overall response will be evaluated and summarized by the IWG MRT criteria 
given in Section 3.11.2.
Change of spleen length from Baseline to end of each visit/month of therapy and at end 
of treatment. The change in spleen length from Baseline to end of each visit/month of 
therapy and at end of treatment will be described using descriptive statistics and by relevant 
change categories: 
≤-50%, (-50%, -25%], (-25%, -5%], (-5%, 5%], (5%, 25%], (25%, 50%] and ≥50%
The descriptive summary will include the mean, standard deviation, median, minimum, 
maximum and 95% CI of the mean over time and at EOT visit for patients who were palpable 
at baseline and remained palpable or non-palpable at the post-baseline visit considered. In 
addition, number (n) of patients who remain non palpable, or became palpable from non-
palpable at baseline will also be displayed.
WBC and platelet count changes from Baseline at end of each visit/month of therapy 
and at end of treatment. For each parameter, the percent of change will be computed by 
dividing the difference of value at assessment time and at baseline by the value at baseline, 
and multiplying by one hundred. WBC and platelet count changes from baseline will be 
summarized at end of each visit of therapy and at end of treatment.
Shift in fibrosis in the bone marrow from Baseline, is defined as the status change of 
fibrosis at time of worst/best response (whenever it occur) compared to fibrosis status at 
baseline. 
Assessment of fibrosis in the bone marrow after enrollment is not mandatory and a listing will 
be provided with the results of the bone marrow biopsy (if performed).
Progression free survival (PFS) is the time from first study drug administration to date of 
documented progression (based on International Working Group for Myelofibrosis Research 
and Treatment Response Criteria) or deaths. Time will be censored at the last date the patient 
is known to be free of disease progression for patients without event. Deaths on or before the 
follow up/study completion evaluation visit (on-treatment and post-treatment deaths – Section 
3.4.1.2) will be considered in the analyses.
Leukemia free survival (LFS) is the duration from first study drug administration to date of 
documented leukemia. Observation will be censored, if leukemia is not observed before the 


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end-of-study, death or lost to follow-up, at last date the patient is known to be free of 
leukemia. Deaths on or before the follow up/study completion evaluation visit (on-treatment 
and post-treatment deaths – Section 3.4.1.2) will be considered in the analyses.
Overall survival (OS) is the duration from first dose of study drug administration to the date 
of death due to any cause. If a patient is alive at the time of data cutoff, OS time will be 
censored at the time of last contact that is no later than the follow up/study completion 
evaluation visit. In case of early termination due to any reason, OS observation will be 
censored at the last contact date. Deaths on or before the follow up/study completion 
evaluation visit (on-treatment and post-treatment deaths – Section 3.4.1.2) will be considered
in the analyses.
Method of analysis of secondary endpoints
The proportion of patients by best overall response category will be summarized. Proportion 
of responders will be estimated and its 95% confidence intervals provided. 
Change in spleen length from Baseline to end of each visit/month of therapy and at end of 
treatment will be described using descriptive statistics and by relevant change categories (e.g. 
(≤50%, (-50%, -25%], (-25%, -5%], (-5%, 5%], (5%, 25%], (25%, 50%] and >50%). 
WBC and platelet count changes from baseline will be summarized using descriptive statistics 
at the end of each visit and at the end of treatment.
Listing of patients with bone marrow biopsy will be provided with fibrosis status.
PFS, LFS, and OS will be estimated with the Kaplan Meier method and 95% confidence 
intervals will be provided for the estimated median.
3.4.4
Analysis of patient reported outcomes
For the analysis of quality of life assessments/patient reported outcomes (PRO), the scoring of 
the questionnaires will be handled as specified by the instrument developers. 
To assess rate of missing data, a table of completion rates for each questionnaire at each 
scheduled assessment will be created. The table will include number of patients eligible for 
PRO assessment and number of patients with complete PRO assessment data, completion will 
be defined by each instruments scoring guidelines.
Change in individual scores/scales from baseline will be summarized descriptively at each 
visit.  For FACT-Lymphoma scores, repeated measures analysis will also be used.  
Change in ECOG Performance Status
The ECOG performance score will be summarized descriptively by visit.  The summary will 
include the number and percent of patients at each reported value.  A shift table including the 
number and percent of patients will also be produced by visit of baseline vs. post-baseline 
scores.
Change in FACT-Lym scores
The FACT-Lym questionnaire consists of a total of 42 questions contributing to 5 subscales 
(i.e., physical well-being, social/family well-being, emotional well-being, functional well-
being and lymphoma subscale) which in turn contribute to three total sum scores, namely 


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FACT-Lym Trial Outcome Index (TOI), FACT-General (FACT-G) total score and FACT-
Lym total score. More details on the questionnaire and derivation of the score can been found 
in Section 16.1.9.
Data from FACT-Lymphoma scores will be analyzed in the three sum scores and one subscale 
LymS. Change and percent change from baseline to each scheduled visit when the FACT-
Lymphoma scores were collected will be calculated.  The scores will be summarized 
descriptively by visit. The change from baseline score at each time point will be estimated by 
using repeated measurement analysis for patients with at least one post-baseline scale score.
Patients without baseline value will not be considered in the analysis and baseline is the data 
collected from the last visit prior to or at Day1. 
Time on treatment time will be treated as a discrete variable to allow for a nonlinear 
relationship between PRO scores and time. Time, DIPSS status and baseline score (as a 
covariate) will be included in the model as fixed effects, while the patient-specific intercept 
will be included as a random effect. 
DIPSS status will be calculated as per the criteria given in section 3.11.3
Change in FACIT Fatigue scores:
Data from FACIT-Fatigue scores will be analyzed in the sum scores. Change and percent
change from baseline to each scheduled visit when the FACIT Fatigue scores were collected
will be calculated with the data collect from the last visit prior to and at Day 1 as the
baseline. The scores will be summarized descriptively by visit.
Responder Analysis and Time to first improvement:
The proportion of patients showing improvement will be estimated for ECOG performance 
score, the three FACT Lym sum scores and one subscale LymS and FACIT Fatigue scale.
The improvement (i.e. the responder) will be defined by the upper limit of the MID. Patients 
with the best possible score at baseline will be excluded from this analysis because their 
HRQoL cannot be further improved. 
Additionally, the proportion of patients achieving response (HRQoL) by the lower limit of 
MID will be presented by visit.
Responders and non-responders for a PRO endpoint will be defined based on change from 
baseline scores using pre specified cutoff points. Patients with an improved PRO score 
compared to baseline, for which the magnitude of the change was at least the cutoff value, 
will be classified as responder; otherwise, non-responder. 
To define PRO responder, the cutoff points are chosen based on minimum important 
difference from literature as listed in the following table.
PRO Score
Range
MID
Responder Cutoff
FACT –G total
0-108
3-7c
7
ECOG performance status
0-5
NA
1
FACT-Lym subscale
0-60
2.9-5.4d
5.4
FACT-Lym TOI
0-116
5.5-11d
11


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PRO Score
Range
MID
Responder Cutoff
FACT-Lym Total
0-168
6.5-11.2d
11.2
FACIT - Fatigue
0-52
3
3
a Kvam et al., 2010; b Osaba et al., 1998; c Webster et al., 2003; d Carter et al., 2008. 
The median time to first improvement will be estimated using Kaplan Meier method for 
ECOG performance score, the three FACT Lym sum scores and one subscale LymS and 
FACIT Fatigue scale. The time to improvement event will be determined based on upper 
bound of the MID. The time to improvement is calculated from the date of first study drug 
administration.
Patients, who prematurely discontinued the study drug, will be censored at the date of their 
last assessment before study discontinuation.
Patients with no baseline score will be censored at study day 1.
3.4.4.1
Handling of missing values/discontinuations in efficacy analyses
No imputation for missing data will be performed.
Patients with missing baseline assessments will be excluded from analysis where baseline 
value is required to compute the corresponding endpoint.
3.4.4.2
Center pooling
All data from all centers participating in this trial will be combined and analyzed together.
Unless specified otherwise, all assessments (scheduled and unscheduled) will be used for 
every patient in the analysis.
3.5
Safety evaluation
This section describes the planned statistical analyses for Sections 10, 12, 14, and 16 of the 
clinical study report.
Safety analysis will be based on safety population and will use the data collected during the 
study. Cut off for the safety reporting is end-of-treatment date + 28 days.
The following safety endpoints will be analyzed:

Treatment-emergent AEs and serious adverse events (SAEs).

AEs leading to study drug discontinuation.

Adverse events of interest.

Clinical laboratory values.

Vital signs.

Targeted physical examinations.

12-lead electrocardiograms (ECGs).


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3.5.1
Adverse events
In this section the term adverse event or AE refers only to treatment-emergent AEs unless
specified otherwise.
Only treatment emergent AEs will be summarized, i.e. events started after the first dose of 
study medication or events present prior to the first dose of study medication but increased in 
severity during study treatment based on PT, while all reported AEs will be included in listing.
The incidence of AEs will be tabulated by MedDRA (Medical Dictionary for Regulatory
Activities) PT and SOC. Incidence of AEs will also be summarized by system organ class, 
severity (based on CTCAE grades version 3.0).
The same analysis will be repeated for SAEs regardless of drug relationship, drug related 
SAEs, AEs which CTCAE grade is 3 or 4 and for drug related AEs.
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type
of AE. 
Separate summaries for on-treatment and all on-study deaths (on-treatment and post-treatment) 
will be produced by system organ class and preferred term. All deaths will be listed and post 
treatment deaths will be flagged.
The most up to date MedDRA will be used for reporting AEs in the study. If a patient
reported more than one AE with the same PT, the AE with the greatest severity will be 
presented. If a patient reported more than one AE within the same primary SOC, the patient
will be counted only once with the greatest severity at the SOC level, where applicable. 
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant adverse events leading to discontinuation and AEs leading to dose adjustment.
Non-serious adverse events will be listed separately.
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 
5% and on on-treatment serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set 
population.`
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.


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The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT
The relationship or association of the AE to a study drug will be characterized as Suspected 
or Not suspected. 
Any missing onset date, causality, or severity must be queried for resolution.  Un resolved 
missing values will be imputed according to the following:

An unresolved missing causality will be imputed by being suspected.

An unresolved missing severity will be left as missing in the AE tables. 

An unresolved missing onset date will be imputed by the Study Day 1, which will force 
the AE to be treatment emergent, with the following exceptions:

If the stop/resolution date is prior to Study Day 1, the AE will then be considered as 
not being treatment-emergent.

If both the month and day are missing, and the last day of the year is prior to Study 
Day 1, the AE will then be considered as not being treatment-emergent. 

If only the day is missing, and the last day of the month is prior to Study Day 1, then 
the AE will be considered as not being treatment-emergent.
Date imputation for AEs will be imputed according to Novartis conventions described in 
[RAP Module 8].
3.5.2
Clinical laboratory values 
The summary of laboratory evaluations will be presented for three groups of laboratory tests 
(Hematology, Serum chemistry and coagulation).
All laboratory values will be converted into SI units and the severity grade calculated using 
the appropriate common toxicity criteria (CTC).
Descriptive summary statistics (mean, median, standard deviation, minimum and maximum) 
for the change from baseline to each study visit will be presented. These descriptive 
summaries will be presented by laboratory test. Change from baseline will only be 
summarized for patients with both baseline and post baseline values and will be calculated as:
change from baseline = post baseline value – baseline value
The following summaries will be produced for the laboratory data (by laboratory parameter):

Number and percentage of patients with worst post-baseline CTC grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed post-
baseline.

Shift tables using CTC grades to compare baseline to the worst post-baseline value will be 
produced for hematology biochemistry laboratory parameters and coagulation with CTC 
grades.


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
For laboratory parameters where CTC grades are not defined, shift tables to the worst 
post-baseline value will be produced using the low/normal/high classifications based on 
laboratory reference ranges.  

A listing of laboratory values will be provided by laboratory parameter. A separate listing 
will display notable laboratory abnormalities (i.e. newly occurring CTCAE grade 3 or 4 
laboratory toxicities)
3.5.3
Vital signs
Analysis of vital sign measurement using descriptive summary statistics (mean, median, 
standard deviation, min, max) for the change from baseline to worst post-baseline value will 
be performed. These descriptive summaries will be presented by vital sign. Change from 
baseline will only be summarized for patients with both baseline and post-baseline values and 
will be calculated as:
% of change from baseline = [(post-baseline value – baseline value)/ baseline value] x 100;
The change and percent change in body weight from baseline to each assessment time when 
body weight was measured will be summarized descriptively.  Summary will include the 
mean, standard deviation, median, minimum, and maximum.
Frequency of weight relative change by at least 20% will be summarized.
The number and percentage of patients with clinically notable vital signs changes from 
baseline will be presented. Clinically notable vital sign results are provided in Table 1-2
below.
Table 1-2
Criteria for clinically notable vital sign abnormalities
Vital sign (unit)
Clinically notable criteria
Weight (kg)
decrease >= 20% from Baseline
increase >= 20% from Baseline
Systolic blood pressure (mmHg)
<=90 and decrease from baseline of >=20
>=180 and increase from baseline of >=20
Diastolic blood pressure (mmHg)
<=50 and decrease from baseline of >=15
>=105 and increase from baseline of >=15
Pulse (bpm)
<=50 and decrease from baseline of >= 15
>=120 and increase from baseline of >=15
Respiratory rate (bpm)
>=30 bpm  
<=10 bpm
Body temperature
>=37.5°C 
<=35°C 
bpm = beats per minute.
3.5.4
Electrocardiogram (ECG)
A listing of all newly occurring or worsening abnormalities will be provided, as well as a by -
patient listing of all ECG parameters.  


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3.6
Resource Utilization 
Frequency of hospitalization, of emergency room visits, general practitioner, Specialist, 
urgent care, splenectomy and splenic irradiation will be summarized at end of each quarter (i.e.
every three months after start of study medications).
Overall duration and number of hospitalization at the end-of-study will be summarized.
Change in blood transfusion dependency
The proportion of patients who are transfusion dependent as well as the proportion of patients,
whose transfusion status (dependent or independent) changed (from dependent to independent 
or vice versa) , will be tabulated with summary statistics.  For the purposes of this assessment 

Transfusion dependence at baseline will be defined as patient who received 6 or 
more units of red blood cell product(s) during the 12 weeks prior to first study drug 
administration.

New onset of transfusion dependence will be defined as the use of 6 or more units of 
red blood cell product(s) during any consecutive 12 weeks prior to end of study for 
patients who were not transfusion dependent at baseline.

New transfusion independency will be defined as no (0) use of red blood cell 
product(s) during any consecutive 12 weeks prior to end of study for patients who met 
the definition of transfusion dependence at baseline.

Transfusion dependence response: will be defined as the use of 5 or less units of red 
blood cell product(s) during any consecutive 12 weeks prior to end of study for 
patients who were transfusion dependent at baseline.
Patients who were not transfusion-dependent at baseline and who required transfusions during 
the study, but not during the last 12 weeks of observation, will be considered transfusion 
independent.
The number and percent of patients who received any blood component transfusions will be 
summarized by blood component (PRBC (Packed Red Blood Cells), platelets), and visit when 
the transfusion data were collected. 
Prior and concomitant medications, as listed in protocol Appendix IX will be summarized.
Concomitant medication at week 24, as listed in protocol Appendix IX, will be summarized.
3.7
Interim analyses
An interim analysis will be performed to closely monitor safety, and ensure an appropriate 
risk/benefit ratio in the patient population with low platelet counts, between 50,000 and 
100,000/μL. In order to adequately assess the risk/benefit ratio, this analysis will also be 
performed on non-low platelet patients (≥100,000/μL), which will be further detailed in 
analysis plan, who will serve as an internal reference population. This interim analysis will 
take place when 50 patients with low platelets have completed 6 months of treatment.
Analyses may be performed if needed to fulfill regulatory obligations, to comply with post -
approval commitments or for publication purposes.


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3.8
Data monitoring committee (DMC)
No DMC are planned for this study.
3.9
Sample size and power considerations
This is an expanded access study and thus no sample size and no power computation was
performed. Patient will be enrolled until INC424 is commercially available at their sites of 24 
months after LPFV. The maximum number of patients that will be treated in this study is up 
to 2500 and is based on country assessments of the number of potential patients. Actual 
number of enrolled patients may vary and reflect individual site conditions, which may lead to 
imbalance between centers, or countries. 
3.10
Pharmacokinetic analyses
Not applicable.
3.11
Other topics 
3.11.1
Handling of missing data
Patients with missing baseline values where a change from baseline is calculated or when the 
baseline is used as a covariate will be excluded from the analysis of that variable. Missing 
values in the QoL will be handled following the instruction of the instruments.
3.11.2
Table of Spleen Response and Loss of Response Criteria by IWG MRT 
criteria 
Patients with spleen 
length at baseline
Response criteria
Loss of response criteria 1
Less than 5 cm
Non evaluable for response
Non evaluable for loss of 
response
Between 5 and 10 cm
Responder: achieve non palpable 
spleen
Splenomegaly 5 cm or more
Stable disease: does not meet 
criteria for response NOR for 
disease progression
Meet criteria of progressive 
disease
Progressive disease: increase of 
100% from baseline
-
More than 10 cm
Responder: reduction of 50%
Loss of the 50% reduction
Stable disease: does not meet 
criteria for response NOR for 
Meet criteria of progressive 
disease


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disease progression
Progressive disease: increase of 
50% from baseline
-
3.11.3
Dynamic International Prognostic Scoring System (DIPSS)
The DIPSS can be used to assess a patient’s progrnosis as conditions change over time.
The risk level is assigned by the total score:
4
Change to protocol specified analyses
The definitions for the transfusion dependence at baseline, new onset of transfusion 
dependence and new transfusion independency (protocol v05 section 11.6.4.1) are not current. 
For the final analysis these definition have been updated as per IWG MRT 2013 ( section 3.6
of this SAP). 
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Clinical Study Report
Appendix 16.1.9 Documentation of statistical methods
FACIT-Fatigue Scale questionnaire:
FACIT-Fatigue scale consists of a total of 13 items (an item is equivalent to a question); each 
item is scored on a scale of 0 to 4. For some questions, a reversal of the raw item score is 
required to make all item scores in the same direction: higher the score is, better the QOL is. 
For each raw item score where reversal is required, the reversal will always be calculated by:
Based on the 13 individual item scores, the total score will be derived:
FACIT- Fatigue total score = sum of all the individual scores
FACIT-Fatigue scoring guidelines
Instructions:
1. Record answers in "item response" column. If missing, mark with an X.
2. Perform reversals as indicated, and sum individual items to obtain a score.
3. Derive total score. 
4. The higher the score, the better the QOL.
The FACIT-Fatigue Scale questionnaire consists of the following 13 questions.
1. I feel fatigued
2. I feel weak all over
3. I feel listless (“washed out”)
4. I feel tired
5. I have trouble starting things because I am tired
6. I have trouble finishing things because I am tired
7. I have energy
8. I am able to do my usual activities
9. I need to sleep during the day
10. I am too tired to eat
11. I need help doing  my usual activities
12. I am frustrated by being too tired to do the things I want to do
13. I have to limit my social activity because I am tired
Score
Item
Raw
Score
Item
New

4


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FACT-Lymphoma questionnaire
FACT-Lymphoma questionnaire consists of a total of 42 questions; each question takes an 
item score of 0 to 4. For some questions, a reversal of the raw item score is required to make 
all item scores in the same direction: higher the score is, better the QOL is. For each raw item 
score that the reversal is required, the reversal will always be calculated by
Based on the 42 individual item scores, the following 5 subscales will be derived:
1. Physical Well-Being (PWB): it is the mean of non-missing individual item scores from 
Questions GP1, GP2, GP3, GP4, GP5, GP6, and GP7 multiplied by 7, where each item 
score is the reverse of the raw item score. 
2. Social/Family Well-Being (SWB): it is the mean of non-missing individual item scores 
from Questions GS1, GS2, GS3, GS4, GS5, GS6, and GS7 multiplied by 7.
3. Emotional Well-Being (EWB): it is the mean of non-missing  individual item scores 
from Questions GE1, GE2, GE3, GE4, GE5, and GE6 multiplied by 6, where each item 
score is the reverse of the raw item score except for the 2nd item score from Question GE2.
4. Functional Well-Being (FWB): it is the mean of non-missing individual item scores from 
Questions GF1, GF2, GF3, GF4, GF5, GF6 and GF7 multiplied by 7.
5. Lymphoma Subscale (LymS): it is the mean of non-missing  individual item scores from 
Questions P2, LEU1, BRM3, ES3, LYM1, LYM2, BMT6, C2, GA1, H18, N3, LEU6, 
LEU7, BRM9, and LEU4 multiplied by 15, where each item score is the reverse of the 
raw item score.
A subscale will be missing if the corresponding item scores are all missing. Based on the 5 
subscale scores, the following 3 total scores will be calculated:

FACT-Lymphoma Trial Outcome Index (TOI) = PWB + FWB + LymS

FACT-G total score 
= PWB + SWB + EWB + FWB

FACT-Lymphoma total score 
= PWB + SWB + EWB + FWB + LymS
A total score will be missing if any of the corresponding subscales is missing.
FACT-Lymphoma scoring guidelines
Instructions:
5. Record answers in "item response" column. If missing, mark with an X.
6. Perform reversals as indicated, and sum individual items to obtain a score.
7. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered. This produces the subscale score.
8. Add subscale scores to derive total scores (TOI, FACT-G & FACT-Lymphoma). 
9. The higher the score, the better the QOL.
Score
Item
Raw
Score
Item
New

4


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Subscale
Item 
code
Reverse 
item?
Item response
Item score
PHYSICAL 
WELL-BEING 
(PWB)
Score range: 0-28
GP1
4
–
___________
=___________
GP2
4
–
___________
=___________
GP3
4
–
___________
=___________
GP4
4
–
___________
=___________
GP5
4
–
___________
=___________
GP6
4
–
___________
=___________
GP7
4
–
___________
=___________
Sum individual item scores: ________
Multiply by 7: ________
Divide by number of items answered: ________=PWB subscale score
SOCIAL/FAMILY 
WELL-BEING 
(SWB)
Score range: 0-28
GS1
0
+
___________
=___________
GS2
0
+
___________
=___________
GS3
0
+
___________
=___________
GS4
0
+
___________
=___________
GS5
0
+
___________
=___________
GS6
0
+
___________
=___________
GS7
0
+
___________
=___________
Sum individual item scores: ________
Multiply by 7: ________
Divide by number of items answered: ________=SWB subscale score
EMOTIONAL 
WELL-BEING 
(EWB)
Score range: 0-24
GE1
4
–
___________
=___________
GE2
0
+
___________
=___________
GE3
4
–
___________
=___________
GE4
4
–
___________
=___________
GE5
4
–
___________
=___________
GE6
4
–
___________
=___________
Sum individual item scores: ________
Multiply by 6: ________
Divide by number of items answered: ________=EWB subscale score


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FUNCTIONAL 
WELL-BEING 
(FWB)
Score range: 0-28
GF1
0
+
___________
=___________
GF2
0
+
___________
=___________
GF3
0
+
___________
=___________
GF4
0
+
___________
=___________
GF5
0
+
___________
=___________
GF6
0
+
___________
=___________
GF7
0
+
___________
=___________
Sum individual item scores: ________
Multiply by 7: ________
Divide by number of items answered: ________=FWB subscale score
FACT-Lymphoma scoring guidelines (Version 4) – Page 2
Subscale
Item 
code
Reverse 
item?
Item response
Item score
LYMPHOMA 
SUBSCALE 
(LYMS)
Score range: 0-60
P2
4
–
___________
=___________
LEU1
4
–
___________
=___________
BRM3
4
–
___________
=___________
ES3
4
–
___________
=___________
LYM1
4
–
___________
=___________
LYM2
4
–
___________
=___________
BMT6
4
–
___________
=___________
C2
4
–
___________
=___________
GA1
4
–
___________
=___________
HI8
4
–
___________
=___________
N3
4
–
___________
=___________
LEU6
4
–
___________
=___________
LEU7
4
–
___________
=___________
BRM9
4
–
___________
=___________
LEU4
4
–
___________
=___________
Sum individual item scores: ________
Multiply by 15: ________
Divide by number of items answered: ________=LYM subscale score


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To derive a FACT-Lymphoma Trial Outcome Index (TOI):
Score range: 0-116
__________ + __________ + __________ =________=FACT-Lymphoma TOI
(PWB score)   (FWB score)   (LymS score)  
To derive a FACT-G total score:
Score range: 0-108
__________ + __________ + __________ + __________=________=FACT-G Total 
score
(PWB score)    (SWB score)   (EWB score)  (FWB score)
To derive a FACT-Lymphoma total score:
Score range: 0-168
(PWB score) + (SWB score) + (EWB score) + (FWB score) + (LymS score) = FACT-
Lymphoma Total score