A Phase Ib, Open-label, Dose-finding Study of the JAK Inhibitor INC424 Tablets Administered Orally to Patients With Primary Myelofibrosis (PMF), Post-polycythemia Veramyelofibrosis (PPV-MF) or Post-essentialthrombocythemia-myelofibrosis (PET-MF) and Baseline Platelet Counts ≥50 x109/L and <100 x109/L (EXPAND)
Phase: PHASE1
Conditions: Myelofibrosis
Sponsor: Incyte Corporation



Novartis / Incyte Corp.
Confidential
Page 2
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table of contents
Table of contents .................................................................................................................2
List of Appendices...............................................................................................................6
List of figures ......................................................................................................................6
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 4 ....................................................................................................................12
Amendment 3 ....................................................................................................................15
1
Background........................................................................................................................24
1.1
Overview of myelofibrosis and current treatment options ....................................24
1.2
Overview of INC424 (ruxolitinib).........................................................................25
1.2.1
Preclinical studies..................................................................................26
1.2.2
Clinical pharmacology of INC424........................................................26
1.2.3
INC424 clinical safety in healthy volunteers........................................27
1.2.4
INC424 clinical safety and efficacy in myelofibrosis patients 
(Phase I/II study)...................................................................................27
1.3
Study purpose/rationale .........................................................................................32
2
Objectives and endpoints...................................................................................................33
2.1
Study objectives.....................................................................................................33
2.2
Study endpoints .....................................................................................................33
3
Investigational plan ...........................................................................................................36
3.1
Study design...........................................................................................................36
3.1.1
Investigational treatment, other study treatment, study treatment, 
supportive treatment..............................................................................39
3.1.2
Treatment arms......................................................................................39
3.1.3
Treatment duration................................................................................39
3.1.4
Patient numbering and screening ..........................................................39
3.1.5
Treatment assignment/randomization...................................................40
3.1.6
Treatment blinding................................................................................40
3.2
Rationale for the study design ...............................................................................40
3.3
Purpose and timing of interim analyses/design adaptations..................................40
3.4
Rationale for the dose/regimen selection and treatment duration .........................41
3.4.1
Clinical safety and tolerability..............................................................41
3.4.2
Clinical pharmacodynamics..................................................................42
3.4.3
Clinical pharmacokinetics.....................................................................42
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 3
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
3.4.4
Non-clinical data...................................................................................44
3.4.5
Dose selection .......................................................................................45
3.5
Rationale for choice of combination drugs............................................................46
3.6
Rationale for choice of comparators drugs............................................................46
3.7
Sub-studies.............................................................................................................46
3.8
Definition of end of the study................................................................................46
3.9
Early study termination..........................................................................................47
4
Population..........................................................................................................................47
4.1
Inclusion criteria ....................................................................................................48
4.2
Exclusion criteria...................................................................................................49
5
Treatment...........................................................................................................................50
5.1
Treating the patient................................................................................................50
5.1.1
Administration.......................................................................................50
5.1.2
Dosing and treatment schedule .............................................................51
5.1.3
Dose modification and dose delay ........................................................56
5.1.4
Treatment interruption and treatment discontinuation..........................57
5.1.5
Dose reduction of INC424 for concomitant CYP inhibitor usage ........63
5.1.6
Optional dose tapering strategy for INC424 in the event of 
discontinuation......................................................................................64
5.1.7
Rescue medication ................................................................................64
5.1.8
Permitted concomitant therapy .............................................................64
5.1.9
Permitted concomitant therapy requiring caution and/or action...........64
5.1.10
Prohibited concomitant therapy ............................................................65
5.1.11
Hormonal contraception allowed/excluded...........................................65
5.2
Study drug(s) .........................................................................................................66
5.2.1
Packaging and labeling .........................................................................66
5.2.2
Supply, receipt and storage ...................................................................66
5.2.3
Dispensing and preparation...................................................................66
5.2.4
Drug compliance and accountability.....................................................66
5.2.5
Disposal and destruction .......................................................................67
6
Visit schedule and assessments .........................................................................................67
6.1
Study flow and visit schedule................................................................................67
6.1.1
Screening examination..........................................................................74
6.1.2
Run-in period ........................................................................................75
6.1.3
Treatment period...................................................................................75
6.1.4
Discontinuation of Study Treatment/ Study..........................................76
6.1.5
Follow up for safety evaluations...........................................................78
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 4
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
6.1.6
Lost to follow-up...................................................................................78
6.1.7
Withdrawal of Consent .........................................................................79
6.2
Assessment types...................................................................................................79
6.2.1
Efficacy .................................................................................................79
6.2.2
Safety and tolerability ...........................................................................79
6.2.3
Pharmacokinetics ..................................................................................82
6.2.4
Other assessments .................................................................................83
7
Safety monitoring and reporting........................................................................................85
7.1
Adverse events.......................................................................................................85
7.1.1
Definitions and reporting ......................................................................85
7.1.2
Laboratory test abnormalities................................................................87
7.2
Serious adverse events...........................................................................................87
7.2.1
Definitions.............................................................................................87
7.2.2
Reporting...............................................................................................88
7.2.3
Emergency unblinding of treatment assignment...................................88
7.3
Pregnancies............................................................................................................88
7.4
Warnings and precautions......................................................................................89
7.5
Data Monitoring Committee..................................................................................89
7.6
Steering Committee ...............................................................................................89
8
Data review and management ...........................................................................................89
8.1
Data confidentiality ...............................................................................................89
8.2
Site monitoring ......................................................................................................90
8.3
Data collection.......................................................................................................90
8.4
Database management and quality control............................................................90
9
Statistical methods and data analysis ................................................................................91
9.1
Analysis sets ..........................................................................................................92
9.1.1
Full Analysis Set ...................................................................................92
9.1.2
Safety Set ..............................................................................................92
9.1.3
Dose-determining Set............................................................................92
9.1.4
Pharmacokinetic analysis set.................................................................92
9.2
Patient demographics/other baseline characteristics .............................................93
9.3
Treatments (study drug, concomitant therapies, compliance)...............................93
9.4
Primary objective...................................................................................................93
9.4.1
Variable.................................................................................................93
9.4.2
Statistical hypothesis, model, and method of analysis..........................94
9.4.3
Handling of missing values/censoring/discontinuations.......................98
9.4.4
Supportive analyses...............................................................................99
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 5
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
9.5
Secondary objectives .............................................................................................99
9.5.1
Efficacy objectives................................................................................99
9.5.2
Safety objectives ...................................................................................99
9.5.3
Resource utilization.............................................................................101
9.5.5
Pharmacokinetics, pharmacodynamics and pharmacokinetics-
pharmacodynamics..............................................................................101
9.6
Exploratory objectives.........................................................................................102
9.7
Interim analysis....................................................................................................103
9.8
Sample size calculation........................................................................................103
10 Ethical considerations and administrative procedures ....................................................104
10.1
Regulatory and ethical compliance......................................................................104
10.2
Responsibilities of the Investigator and IRB/IEC/REB.......................................104
10.3
Informed consent procedures...............................................................................104
10.4
Discontinuation of the study................................................................................105
10.5
Publication of study protocol and results.............................................................105
10.6
Study documentation, record keeping and retention of documents.....................105
10.7
Confidentiality of study documents and patient records .....................................106
10.8
Audits and inspections.........................................................................................106
10.9
Financial disclosures............................................................................................106
11 Protocol adherence ..........................................................................................................106
11.1
Amendments to the protocol................................................................................106
12 References (available upon request)................................................................................107
13 Appendices ......................................................................................................................109
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 6
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
List of Appendices
1. Classification and diagnosis of myeloproliferative neoplasms and proposed criteria for the 
diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis
3. Information Regarding Effectiveness of Contraceptive Methods
4. Drugs that interfere with coagulation or inhibit platelet function
5. Hepatic encephalopathy grading according to West Haven Criteria
6. MDRD-eGFR Formula
7. CYP3A4 Inhibitors and Inducers
8. New York Heart Association (NYHA) Functional Classification
11. Eastern Cooperative Oncology Group (ECOG) Performance Status
12. Clinical Laboratory Tests
13. Prior calibration, hypothetical dose escalation scenarios, and operating characteristics of 
the Bayesian logistic regression model
List of figures
Figure 1-1
Kaplan-Meier analysis of time to 1st new or worsening grade 3 or 4 
thrombocytopenia in INCB 18424-251 study.......................................29
Figure 1-2
Median percent change from baseline in platelets by baseline 
platelets quartile in INCB 18424-251 study..........................................30
Figure 3-1
Study design..........................................................................................38
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 7
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
List of tables
Table 1-1
Median survival of MF patients according to risk category .................24
Table 1-2
Incidence of thrombocytopenia in the study INCB 18424-251 ............31
Table 2-1
Objectives and related endpoints ..........................................................35
Table 3-1
Study drugs............................................................................................39
Table 5-1
Treatment and treatment schedule ........................................................50
Table 5-2
Dose levels ............................................................................................51
Table 5-3
Criteria for defining dose-limiting toxicities.........................................55
Table 5-4
Criteria for interruption and re-initiation of INC424 treatment –
Recommended dose modifications .......................................................58
Table 5-5
Dose escalation guidelines and allowed maximum doses for 
patients who have previously decreased dosing for 
thrombocytopenia..................................................................................63
Table 5-6
Dose restart guidelines and allowed maximum doses for patients 
who have previously interrupted dose for grade 4 
thrombocytopenia or grade 4 neutropenia.............................................63
Table 5-7
Packaging and labeling .........................................................................66
Table 5-8
Supply and storage of study drugs ........................................................66
Table 5-9
Dispensing and preparation...................................................................66
Table 6-1
Visit evaluation schedule post amendment 4 - Core study period 
(from screening to Day 168) .................................................................68
Table 6-2
Visit evaluation schedule post amendment 4 - Extension study 
period and End of Treatment.................................................................71
Table 6-3
Laboratory assessment schedule post amendment 4 – Extension 
study period...........................................................................................73
Table 6-4
Sample collection time windows for population pharmacokinetic 
assessments ...........................................................................................83
Table 9-1
Final prior for the current study ............................................................95
Table 9-2
Posterior estimates for BLRM based on study [INCB 18424-251]......96
Table 9-3
Predicted probability of DLT quantiles for stratum 1 and 
distribution of log(alpha), log(beta) after accounting for between 
trial heterogeneity..................................................................................97
Table 9-4
Distributions of model parameters and final prior distribution.............97
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 8
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
List of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/GPT
ANC
Absolute Neutrophyl Count
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/GOT
AUC
Area Under Curve
b.i.d.
bis in diem/twice a day
BUN
Blood Urea Nitrogen
CDP
Clinical Development Plan
CTH
Clinical Trial Head
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
CBC
Complete Blood Count
CML
Chronic Myelogenous Leukemia
CRF
Case Report/Record Form
eCRF
Electronic Case Report/Record Form
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
CTCAE
Common Terminology Criteria for Adverse Events
CTT
Clinical Trial Team
CYP
Cytochrome
DDS
Dose-Determining Set
DLT
Dose Limiting Toxicity
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EOT
End Of Treatment
EPO
Erythropoietin
ET
Essential Thrombocythemia
EWOC
Escalation With Overdose Control
FDP
Fibrinogen Degradation Products
FPFV
First Patient First Visit
GCSF
Granulocyte Colony Stimulating Factor
GI
Gastrointestinal
hCG
human Chorionic Gonadotropin
IB
Investigator Brochure
ICF
Informed Consent Form
i.v.
Intravenous(ly)
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMS
Integrated Medical Safety
IN
Investigator Notification
INR
International Normalized ratio
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 9
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
IRB
Institutional Review Board
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IWG
International Working Group,
LPLV
Last Patient Last Visit
LPFV
Last Patient First Visit
MAP
Master Analysis Plan documents project standards in the statistical methods which will be 
used within the individual clinical trial RAP documentation.
MDRD-eGFR
Modification of Diet in Renal Disease estimated Glomerular Filtration Rate
MedDRA
Medical Dictionary for Regulatory Activities
MF
Myelofibrosis
MPN
Myeloproliferative Neoplasm
MTD
Maximum Tolerated Dose
MSSD
Maximum Safe Starting Dose
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NYHA
New York Heart Association
NONMEM
Non-linear Mixed Effects Modeling
o.d.
omnia die/once a day
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamic
PET-MF
Post Essential Thrombocythemia Myelofibrosis
PHI
Protected Health Information
PK
Pharmacokinetic
PLT
Platelet
PMF
Primary Myelofibrosis
p.o.
per os/by mouth/orally
PPV-MF
Post Polycythemia Vera Myelofibrosis
PTT
Partial Thromboplastin time
PV
Polycythemia Vera
q.AM
Every morning
q.PM
Every afternoon
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SSF
Screening Symptom Form
STAT3
Signal transducer and activator of transcription 3
SUSARs
Suspected Unexpected Serious Adverse Reactions
TPO
Thrombopoetin
ULN
Upper Limit of Normal
WBC
White Blood Cell
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 10
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
WHO
World Health Organization
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 11
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (eg: q28 days)
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
Drugs 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 within approved 
indication/dosage
Medication number
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an Interactive Response Technology
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 investigative site number, a unique identifier is created for each 
patient in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, titration, etc.
Patient withdrawal
Point/time when the patient exits from the study; 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
Randomization number
A unique identifier assigned to each randomized patient, corresponding to a 
specific treatment arm assignment
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.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient come in for a final evaluation visit or when 
study drug is discontinued whichever is later
Study drug
Any drug administered to the patient as part of the required study procedures; 
includes investigational drug and any combination or control drug(s)
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 patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 12
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Amendment 4
Amendment rationale
As of 20 January 2015, which is the data cut off for the planned interim analysis, a total of 58 
patients have been screened.  Of the 58 patients screened, 46 patients started study treatment 
and 12 patients were declared as screen failures.  The study consisted of a dose escalation 
phase and a safety expansion phase, and 2 different Stratums to which patients were assigned 
based on their platelet counts at baseline. In Stratum 1 (for baseline PLT counts of < 100 x 
109/L and ≥ 75 x 109/L), 24 patients were enrolled into the dose escalation phase and 3 
patients were enrolled into the safety expansion phase for a total of 27 patients. Of the 27 
patients in Stratum 1, 9 patients in the dose escalation phase and 3 patients in the safety 
expansion phase were evaluated at the maximum safe starting dose (MSSD) of 15 mg BID. In 
Stratum 2 (for baseline PLT counts of < 75 x 109/L and ≥ 50 x 109/L), 15 patients were 
enrolled into the dose escalation phase and 4 patients were enrolled into the safety expansion 
phase for a total of 19 patients. Of the 19 patients in Stratum 2, 9 patients in the dose 
escalation phase and 4 patients in the safety expansion phase were evaluated at the MSSD of 
10 mg BID.  After the planned interim analysis cut off, as of 28 July 2015, no additional 
patients have been enrolled into the safety expansion in Stratum 1, and 2 additional patients 
have been enrolled into the safety expansion in Stratum 2.
The MSSD declaration of 15 mg BID for Stratum 1 was based on the occurrence of protocol-
defined dose limiting toxicities during the first cycle (28 days) of treatment. However, 
observations from the planned interim analysis indicated that patients who started treatment at 
the 15 mg BID MSSD dose subsequently experienced frequent dose reductions after the first 
cycle of treatment. A majority of the patients who had dose reductions eventually continued 
study treatment at the 10 mg BID dose or lower. Additionally, a relevant clinical benefit was 
observed across all starting dose levels, including those who started treatment at the 10 mg 
BID dose levels. These observations warrant further exploration of the 10 mg BID dose level 
as the starting dose in Stratum 1 for myelofibrosis patients with platelet counts of < 75 x 
109/L and ≥ 50 x 109/L.
Therefore, the purpose of this amendment is to revise the starting dose to 10 mg BID, from 
the current starting dose of 15 mg BID, and is applicable for all new patients entering the 
safety expansion phase of Stratum 1.
Following the approval of Amendment 4, new patients enrolled to Stratum 1’s safety 
expansion phase will begin treatment with ruxolitinib at 10 mg BID.  In line with the original 
sample size specification for the MSSD cohorts, approximately 20 patients in total will be 
enrolled into 10 mg BID, inclusive of those already enrolled at the 10 mg BID dose level in 
Stratum 1. Recruitment into the study will continue until approximately 20 patients are 
enrolled at this dose level into stratum 1 OR the Last Patient’s First Visit (LPFV) will occur 
on 01 September 2017, whichever comes first.  Patients already taking the 15 mg BID dose in 
Stratum 1’s safety expansion phase will continue to take their assigned dose.  
Stratum 2 will remain unchanged and maintain its original enrollment requirement of 10 
patients at the MSSD.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 16
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
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 underlined for insertions.
The following sections have been changed:

Section 3.1 Study design

Section 3.1.3 Treatment duration

Section 3.3 Purpose and timing of interim analyses/design adaptations

Section 3.8 Definition of End of the study

Section 5.1.4 Treatment interruption and treatment discontinuation and Table 5-4Criteria 
for interruption and re-initiation of INC424 treatment – Recommended dose modifications

Section 6.1 Study flow and visit schedule: Table 6-1 : Visit Evaluation Schedule and 
Table 6-2: Laboratory Assessment Schedule

Section 6.1.3 Treatment period

Section 6.1.4. End of treatment and withdrawal visit

Section 6.2.2.7 Cardiac assessments

Section 6.2.3.2 Pharmacokinetic blood sample collection and handling


Section 9: Statistical methods and data analysis


Section 9.7 Interim analysis
IRB/IEC/REB 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.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 17
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Amendment 2 for the United Kingdom only
Amendment rationale
The MHRA has requested a change to the major rationale of Amendment 1 to remove the 
wording ‘until ruxolitinib is commercially available’ as this is not an acceptable treatment 
end-point. A specified length of treatment is an acceptable end-point and this has been 
provided.
The rationale for the length of study treatment for Amendment 1 is as follows:

To extend the treatment period for patients benefiting from the study drug after the Study 
Day 168 visit.

If based on investigator’s judgment patients are benefiting from treatment, these patients 
will be able to continue on the study until 30 June 2013 or until the patients have access to 
study drug through commercial supplies [if applicable by local regulations], whichever 
comes first.

The 30 June 2013 date may be re-evaluated in case the drug is not commercially available 
at that time, and an amendment will be issued to extend the treatment duration.
The above rationale for the length of study treatment for Amendment 2 will read as 
follows for the United Kingdom only:

To extend the treatment period for ongoing patients benefiting from the study drug after 
the Study Day 168 visit.

All patients will be treated until LPFV plus 168 days; the minimum treatment duration for 
any patient will therefore be 168 days if the patient is not permanently discontinued for 
other reasons e.g. adverse event.

The treatment duration may be re-evaluated at that time, and an amendment issued to 
extend the treatment duration.
Study status
Fifteen patients have been screened for this study. Six patients were enrolled and nine patients 
were screen failures. Two of the enrolled patients have discontinued treatment.
Changes to the protocol
The following sections have been changed:
Section 3.1, Section 3.1.3, Section 3.8, Section 6.1.3, and Section 6.1.4: Treatment endpoint 
revised to LPFV plus 168 days
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 underlined for insertions.
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 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 18
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 19
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Amendment 1
Amendment rationale
The rationale for the amendment is as follows:

To extend the treatment period for patients benefiting from the study drug after the Study 
Day 168 visit.

If based on investigator’s judgment patients are benefiting from treatment, these 
patients will be able to continue on the study until 30 June 2013 or until the patients 
have access to study drug through commercial supplies [if applicable by local 
regulations], whichever comes first.

The 30 June 2013 date may be re-evaluated in case the drug is not commercially 
available at that time, and an amendment will be issued to extend the treatment 
duration.

To re-evaluate the inclusion & exclusion criteria to the study:

New safety data from [CINC424A2352] and the [INCB 1824-351] trials provided 
further information on the safety of treating patients with low platelet values with 
INC424. Therefore some inclusion & exclusion criteria are no longer necessary.

Fluctuation in the platelet count inherent to the nature of the disease has precluded 
potential patients’ qualification in the study. Therefore the qualifying platelet criteria 
have been revised.

Inclusion & exclusion criteria were too strict, therefore hampering patients’ accrual.

Definition of disease progression will be amended to be in line with the most current 
[CINC424A2352] trial version.

Other non major changes are included in this amendment.

Extend the patient treatment duration. The following items were reviewed:

Study duration: amended to provide the drug to patients benefiting from the study drug 
until 30 June 2013 or until the patients have access to study drug through commercial 
supplies [if applicable by local regulations], whichever comes first. The 30 June 2013 date 
may be re-evaluated in case the drug is not commercially available at that time, and an 
amendment will be issued to extend the treatment duration.

Conditions to continue in the extension period: all patients who are benefiting from study 
drug will have the option to continue the study treatment unless at least one withdrawal 
criteria is met and only if the treatment with INC424 is considered the patient’s best 
therapeutic option by the Investigator. Patients must have completed the Study Day 168 
visit.

Conditions for maximum intra-patient dose escalation after the Study Day 168 visit. Each 
patient may be treated at the higher of:

the MSSD level established for that stratum or

10 mg bid. 10 mg bid dose has been selected as this is the lowest dose which has shown 
efficacy in the completed Phase III [INCB 1824-351] study and because the safety profile 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 23
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

6.1.3 and 6.2.2.5: Laboratory-only visits.

Table 5-5: dose escalation guidelines following thrombocytopenia different than grade 4 
events.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (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.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 24
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
1
Background
1.1
Overview of myelofibrosis and current treatment options
The four classic myeloproliferative neoplasms (MPNs) include chronic myelogenous 
leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary 
myelofibrosis (PMF). Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve 
secondarily from previous PV or ET (post-PV-MF or post ET-MF). Regardless of whether 
MF is a primary or secondary disorder, it is characterized by a clonal stem cell proliferation 
associated with production of elevated serum levels of multiple inflammatory and 
proangiogenic cytokines, a characteristic bone marrow stromal pattern that includes varying 
degrees of collagen fibrosis, osteosclerosis and angiogenesis and a peripheral blood smear 
showing a leukoerythroblastic pattern with varying degrees of circulating progenitor cells. 
Clinically, MF is characterized by progressive anemia, leukopenia or leukocytosis, 
thrombocytopenia or thrombocythemia and multi-organ extramedullary hematopoiesis most 
prominently involving the liver and spleen. Patients may experience severe constitutional 
symptoms, sequelae of massive splenomegaly (pain, limitations of movement, early satiety 
and shortness of breath, hepatic obstruction, and splenic infarction), a hypermetabolic state 
with cachexia, progressive hematopoietic failure, progression to leukemia, and premature 
death.
The median age at diagnosis is approximately 60 to 65 years. The incidence of PMF has been 
estimated at 1.5 cases per 100,000 people. Survival in MF varies with the presence or absence 
of specific risk factors. (Cervantes et al 2009) have recently published a multi-center analysis 
of risk factors and their impact on prognosis in patients with MF. They identified age of 
greater than 65 years, presence of constitutional symptoms (weight loss > 10% of the baseline 
value in the year preceding PMF diagnosis, unexplained fever, or excessive night sweats
persisting for more than 1 month), anemia (Hgb less than 10 g/dL), leukocytosis (white blood 
cell count (WBC) greater than 25 x109/L), and a circulating blast percentage of 1% or higher 
as individually predictive of outcome. They demonstrated that patients could be distinctly 
grouped into four categories without overlapping median survival curves based upon their 
number of risk factors (Table 1-1).
Table 1-1
Median survival of MF patients according to risk category
No of risk factors
Risk category
Median survival (months)
0
Low
135
1
Intermediate-1
95
2
Intermediate-2
48
3 or more
High
27
For a subset of patients who are younger (generally less than 65 years), otherwise healthy and 
have a histocompatible donor, allogeneic stem cell transplantation may provide a curative 
option, although with substantial (10-20%) risks of mortality, (Deeg et al 2003). Drug 
therapies used, including hydroxyurea, busulfan, 6-mercaptopurine, anagrelide, thalidomide, 
lenalidomide, interferon, corticosteroids, and erythropoiesis stimulating agents or growth 
factors, have not been shown to improve survival. Some can increase the risk of leukemic 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 27
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
requiring dialysis showed prolonged PD activity without a demonstrable effect on INC424 
clearance. In patients with mild, moderate and severe hepatic impairment, the mean total 
AUCs of INC424 were 88%, 29% and 66% higher, respectively, compared to patients with 
normal hepatic function. Terminal half-life of INC424 was increased in patients with hepatic 
impairment by approximately 2-fold compared to healthy controls. The patients with severe 
hepatic impairment showed modestly protracted PD activity compared to the other hepatically 
impaired patients who displayed PD activity similar to the healthy controls.
Additional details as to the clinical pharmacology of INC424 may be found in the IB.
1.2.3
INC424 clinical safety in healthy volunteers
INC424 has been administered in single or multiple doses to over 200 healthy volunteers. In 
single dose studies, INC424 has a well established safety profile and has been well tolerated 
with Adverse Events (AEs) generally mild in intensity, reversible and of similar incidence 
following INC424 treatment compared with placebo or with other control treatments.
In a 10-day multiple dose study, a total of 71 healthy volunteers in 6 cohorts received doses of 
50 mg qd, 100 mg qd, 15 mg b.i.d., 25 mg b.i.d. or 50 mg b.i.d. INC424 or placebo,
[INCB 18424-132] study. INC424 was well tolerated in the study, with most AEs reported 
equally by both INC424-treated and placebo-treated volunteers. Neutropenia was noted in 3 
volunteers receiving the highest dose of INC424, 50 mg b.i.d. Neutropenia at the Grade 4 
level led to study drug discontinuation on Day 5 in one volunteer and was reported as a 
Serious Adverse Event (SAE). There was a decline in mean absolute neutrophil count (ANC) 
and, to a lesser extent, in mean WBC count values with INC424 doses of 15 mg b.i.d. or 
higher. In general ANC or WBC returned to Baseline levels within 1 to 2 days following the 
last dose of study drug. Doses of 25 mg b.i.d. and 100 mg qd were determined to be the 
maximum tolerated doses (MTDs) in this study based on the dose limiting toxicity (DLT) of 
neutropenia.
A definitive QT study was carried out in 50 healthy volunteers, evaluating the effects of single 
doses of 25 mg or 200 mg INC424 compared with placebo and 400 mg moxifloxacin (positive 
control). The overall conclusion was that there appeared to be no adverse impact on ECG 
signaling (little change in heart rate, QRS duration, QTcF interval, and a slight, non-clinically 
significant, increase in PR interval) with the administration of INC424.
For additional details related to studies conducted in healthy volunteers, consult the IB.
1.2.4
INC424 clinical safety and efficacy in myelofibrosis patients (Phase I/II 
study)
Study [INCB 18424-251] is an ongoing Phase I/II open label study of INC424 in patients with 
PMF, PPV-MF or PET-MF in patients with baseline platelet counts of at least 100 x 109/L. A 
total of 154 patients have been enrolled and treated at twice daily dose regimens of 10 mg 
b.i.d. to 50 mg b.i.d., or once daily regimens of 25 mg qd to 200 mg qd. Patients enrolled 
since August 2008 have had individually titrated dose regimens that begin at doses of 10 mg 
b.i.d., for patients with baseline platelets 100 x109/L - 200 x109/L, or 15 mg b.i.d., for patients 
with baseline platelets > 200 x109/L, with intra-patient dose escalation allowed up to doses of 
20 mg b.i.d. or 25 mg b.i.d., respectively.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 31
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
For nearly all patients, thrombocytopenia was rapidly reversible and manageable with dose 
interruption and reduction (Section 3.4.5); low platelet count was the primary reason for study 
discontinuation for few patients.
Table 1-2
Incidence of thrombocytopenia in the study INCB 18424-251
Dose
10 mg 
b.i.d.
15 mg 
b.i.d.
25 mg 
b.i.d.
50 mg 
b.i.d.
25 mg 
qd
50 mg 
qd
100 mg 
qd
200 mg 
qd
No of patients
30
35
47
5
6
22
6
3
Grade 3
6 (20%)
1 (2.9%)
12 (26%)
3 (60%)
1 (17%)
6 (27 %)
2 (33%)
0
Grade 4
0
0
5 (11 %)
1 (20%)
0
2 (9.1%)
0
1 (33%)
Total Gr 3 + 4
6 (20 %)
1 (2.9%)
17 (36%)
4 (80%)
1 (17%)
8 (36%)
2 (33%)
1 (33%)
The risk of spontaneous hemorrhage in any patient as a result of thrombocytopenia generally 
does not become manifest until platelet counts fall below 10 to 20 x109/L (Slichter 2004). In 
[INCB 18424-251] study, the lowest platelet counts observed (grade 4 thrombocytopenia 
events) ranged from 6-22 x109/L. There was one patient with associated petechiae and no 
events of hemorrhage in the 9 patients with grade 4 platelet declines.
There were 2 deaths where the primary cause of death was related to hemorrhage (upper 
gastric and cerebral hemorrhage). In the case of upper gastric hemorrhage, the patient had 
emergency surgical repair of a bleeding duodenal ulcer and died of post-operative 
complications. The PLT count was 447 x109/L and there was a history of antecedent aspirin 
use and epistaxis. The event was considered unrelated to INC424. In the case of cerebral 
hemorrhage, the patient had normal PLT count (201 x109/L), normal coagulation tests, and a 
history of hypertension. The event was assessed as possibly related to INC424.
Other SAEs on study [INCB 18424-251] that involved hemorrhage of any kind have been 
examined. One patient was admitted to the hospital with a PLT count of 65 x109/L and 
ultimately required splenectomy, following which a post-operative hemorrhage was noted in 
the surgical drains. The patient was discharged from the hospital but chose to discontinue 
study drug. Another patient had 2 episodes of lower gastrointestinal hemorrhage that were 
assessed as unrelated to INC424. No information about PLT counts during the course of the 
event is provided. A patient suffered from gastrointestinal hemorrhage of unknown source 
with a PLT count of 510 x109/L. One patient had hematuria due to prostatic surgery; the PLT 
count was 1,636 x109/L. Another patient suffering from splenomegaly developed an intra-
abdominal hematoma adjacent to the spleen, with a PLT count of 99 x109/L. One patient was 
hospitalized for melena with a PLT count of 93 x109/L.
Because of the advanced disease present in many of the participants in study 
[INCB 18424-251], there are a number of SAEs that have been reported that were assessed as 
unrelated to study drug. 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 the IB for complete details on INC424 clinical study 
findings.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 37
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

grade ≥3 febrile neutropenia*

grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥0.5 mg/dL

grade 3 non-hematologic toxicity for ≥ 7 consecutive days

grade 4 non-hematologic toxicity
* At the discretion of the Investigator, laboratory values can be confirmed with a second 
assessment. In this case, only the result of the second assessment will be considered valid 
and final.
Adverse events occurring after Study Day 28 will not be considered DLTs, however, they 
may be considered in further decisions regarding the number of patients to enroll in a given 
dosing cohort. If a patient is not followed for the 28-day period following Study Day 1 due to 
discontinuation, for reasons other than DLTs, or if, from Study Day 1 through Study Day 28,
a patient misses > 6 consecutive doses of treatment or > 20% of the planned study drug doses,
another patient will be enrolled into that dose level and stratum. For toxicities which, by 
definition, require a time-window for them to be defined as DLTs (grade 3 non-hematologic 
toxicity for ≥ 7 consecutive days) a subsequent visit(s) and/or laboratory assessment(s) must
be scheduled accordingly, in order for this toxicity to qualify as a DLT. A minimum of 9 
evaluable patients from each stratum (stratum 1 consists of patients with baseline PLT counts 
75-99 x109/L and stratum 2 consists of patients with baseline PLT counts 50-74 x109/L) must 
be treated at the dose declared to be the MSSD.
Enrollment of patients and dose escalation will be performed as described in Section 5.1.2.1, 
Section 5.1.2.2, Section 5.1.2.3 and Section 5.1.2.4.
Intra-patient escalation during the dose escalation phase of the study will be allowed 
according to the rules described in the Section 5.1.2.6.
Following determination of the MSSD, a safety expansion phase will be conducted. Patients 
from both strata can be enrolled simultaneously during the safety expansion phase, allocated 
to a dose equal to the respective MSSD for their stratum. If the MSSD is the same in both 
strata, all patients in the safety expansion phase will be treated with the same dose, regardless 
of the baseline PLT counts.
In the safety expansion phase, the safety and tolerability of the MSSD will be further 
evaluated with the purpose of establishing that this dose is suitable for use in the low-platelet 
population of patients with MF. The Bayesian logistic regression model (BLRM) with 
escalation with overdose control (EWOC) will continue to be updated with data from patients 
participating in the safety expansion phase.
With the approval of Amendment 4, all new patients enrolled to Stratum 1’s safety expansion 
phase will be given the 10 mg BID dose, instead of the 15 mg BID dose level previously 
evaluated as the MSSD.  This will allow 10 mg BID to be evaluated as the starting dose.  
Approximately 20 patients will be evaluated at this dose level in Stratum 1, inclusive of the 
patients already enrolled into this dose during the dose escalation phase, OR the Last Patient’s 
First Visit (LPFV) will occur on 01 September 2017, whichever comes first.  
Patients already taking the 15 mg BID dose in Stratum 1’s safety expansion phase will 
continue to take their assigned dose.  Stratum 2 will maintain its original enrollment 
requirement of 10 patients at the MSSD.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 39
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
3.1.1
Investigational treatment, other study treatment, study treatment, 
supportive treatment
During the study all patients will receive INC424 tablets (see Section 5.1.1). INC424 tablets 
will be the only investigational drug in this study (Table 3-1).
Table 3-1
Study drugs
Study drugs
Investigational drug
INC424 tablets (5 mg)
3.1.2
Treatment arms
All patients will receive INC424 tablets. See Figure 3-1 for details regarding dose escalation.
3.1.3
Treatment duration
The study will consist of 2 periods: the initial 24 weeks core treatment period from Study Day 
1 to Study Day 168 and the extension treatment period from Study Day 168 (Week 24) until 3 
years (Week 156). The core study period consists of a dose escalation phase and a safety 
expansion phase (Figure 3-1).
[For patients in the United Kingdom only:
After 3 years of study treatment, if the patient continues to benefit in the opinion of the 
Investigator and does not have access to study drug outside of this clinical trial, the patient 
may continue on study treatment until LPFV plus 3 years. After LPFV plus 3 years, if the 
study treatment is not commercially available and reimbursable in the UK, an alternative UK-
specific free of charge (FOC) program exists to provide continued access for patients 
benefitting from the study treatment]
3.1.4
Patient numbering and screening
Each patient is identified in the study by a patient ID number with a maximum length of 9 
digits, which is a combination of his/her site ID (the first 4 digits (maximum) of the patient 
ID) and patient number (the last 5 digits (maximum) of the patient ID) when the patient is first 
enrolled. The site ID is assigned by the Sponsors to the investigative site. (Novartis 
Pharmaceuticals and Incyte Corporation are co-sponsors in this study. Novartis is the Sponsor 
for the European sites only and Incyte is the Sponsor for the US sites only). Upon signing the 
informed consent form (ICF), the patient number is assigned by the Investigator. In stratum 1, 
patient numbers will be assigned sequentially per investigative site, beginning with 101. In 
stratum 2, patient numbers will be assigned sequentially per investigative site, beginning with 
201. In the safety expansion phase, patient numbers will be assigned sequentially per 
investigative site, beginning with 301 in stratum 1 and 401 in stratum 2. Subsequent patients 
enrolled in each phase of the study will be assigned consecutive patient ID numbers per phase 
and per site (e.g. the second patient at a site in a specific phase will be assigned patient
number 102/202/302/402, the third patient will be assigned patient number 103/203/303/403, 
etc).
Only the assigned patient ID number should be entered in the field labeled as “patient
number” on the EDC data entry screen. Once assigned, the patient number must not be re-
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 40
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
used for any other patient and the patient number for that individual must not be changed, 
even if the patient is re-screened.
If the patient fails to be started on treatment for any reason, the reason and the patient’s 
demography information should be collected. No other data will be entered into the clinical 
data base for screen failure patients.
3.1.5
Treatment assignment/randomization
Prior to patient signing of the informed consent form (ICF), the Investigators must contact the 
Sponsors in order to be informed that the respective cohort and stratum is open to enrollment.
The assignment of a patient will be coordinated by the Sponsors in agreement with the 
Investigators.
3.1.6
Treatment blinding
Not applicable. This is an open label study.
3.2
Rationale for the study design
For a significant population of thrombocytopenic MF patients there are limited data about the 
safety of INC424 or what might be an appropriate dose. In all studies conducted to date with 
INC424, baseline PLT count of ≥ 100 x109/L has been an inclusion criterion. However, 
thrombocytopenia is a frequent event in MF; as per epidemiology data (Mesa et al 2007), 
16.5% of all MF patients are reported to have PLT counts < 100 x109/L 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. As noted in Section 1.2.4, thrombocytopenia was 
established as the DLT of INC424 in MF patients with a MTD of both 25 mg b.i.d. and 100 
mg qd. In that study, some patients continued to receive INC424 while their platelet count 
ranged between 50 and 100 x109/L (for details, see Section 3.4.5), but no patients with platelet 
counts below 100 x109/L have initiated INC424 therapy, and therefore the MSSD for patients 
with low platelets needs to be directly established.
This clinical trial will be a single arm, safety and dose-finding phase Ib study. It will evaluate 
the safety of INC424 in the low-PLT MF population and will establish the MSSD. Gradually 
increasing doses of INC424, ranging from 5 mg b.i.d. to 15 mg b.i.d., will be used in the dose 
escalation part of the study. Initially, only patients with PLT counts 75-99 x109/L (first 
stratum) will allow to be enrolled. Once safety in patients in the first stratum is established at 
the first two dose cohorts (5 mg b.i.d. and 5 mg q.AM / 10 mg q.PM) the eligible population 
will be further expanded to patients with PLT counts 50-74 x109/L (second stratum).
Following determination of the MSSD, the safety expansion phase will be conducted. In the 
safety expansion phase, the safety and tolerability of the MSSD will be further evaluated, with 
the purpose of establishing that this dose is suitable for use in the low-platelet population of 
patients with MF. Moreover, estimates of efficacy will be obtained.
3.3
Purpose and timing of interim analyses/design adaptations
A Bayesian logistic regression model will be used to assist patients’ assignment to treatment 
dose levels and to guide dose escalation decisions. The dose-finding part of the study requires 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 41
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
data to be reviewed after each cohort is completed in order to determine the best dose for the 
next cohort of patients.
An interim analysis is planned at the time the MSSD is declared and all patients in the dose 
escalation phase have completed the core study period. The interim analysis will include 
primary and secondary endpoints of safety and efficacy. Full PK data will be available at the 
time of the interim analysis and the results will be reported in a separate PK report.
3.4
Rationale for the dose/regimen selection and treatment duration
3.4.1
Clinical safety and tolerability
3.4.1.1
Healthy volunteers
INC424 has been administered in single or multiple doses to over 200 healthy volunteers. In 
single dose studies, INC424 has a well established safety profile and has been well tolerated 
with AEs generally mild in intensity, reversible and of similar incidence following INC424 
treatment compared with placebo or with other control treatments. INC424 was examined in a 
10-day multiple dose study in a total of 71 healthy volunteers in 6 cohorts who received doses 
of 50 mg qd, 100 mg qd, 15 mg b.i.d., 25 mg b.i.d. or 50 mg b.i.d. of INC424 or placebo
(study [INCB 18424-132]). INC424 was well tolerated in the study, with most Adverse 
Events reported equally by both INC424-treated and placebo-treated volunteers. Neutropenia, 
as an AE, was noted in 3 volunteers receiving the highest dose of INC424, 50 mg bid. 
Neutropenia at the grade 4 level led to study drug discontinuation on Day 5 in one volunteer, 
and was reported as a SAE. There was a decline in mean ANC and to a lesser extent, mean 
WBC values with INC424 doses of 15 mg b.i.d. or higher. In general, these declines in ANC 
or WBC were observed early during the 10-day dosing period with b.i.d. regimens; did not 
worsen with continued dosing, and returned to baseline levels within 1 to 2 days following the 
last dose of study drug, suggestive of a neutrophil margination effect. Doses of 25 mg b.i.d.
and 100 mg qd were determined to be the maximum tolerated doses in this study. For 
additional details related to these studies, consult the IB.
A definitive QT study: An Assessment of Heart Rate Corrected QT Intervals in Healthy 
Subjects 
Dosed 
with 
Single 
Doses 
of 
INC424
Compared 
with 
Moxifloxacin 
([INCB 18424-138]) was carried out in 50 healthy volunteers, evaluating the effects of single 
doses of 25 mg or 200 mg INC424 compared with placebo and 400 mg moxifloxacin (positive 
control). The results showed little change in the mean heart rate, QRS duration, or QTcF 
duration indicating a lack of a drug effect. 
 
 A slight increase in PR interval the first hour after dosing was noted, but 
unlikely to be clinically significant in the opinion of the expert cardiologist. The overall 
conclusion is that there appears to be no adverse impact on ECG signaling with the 
administration of INC424.
3.4.1.2
Myelofibrosis patients
INC424, in the context of the [INCB 18424-251] study (refer to Section 1.2.4), has been well 
tolerated by this aged population with advanced disease. Most adverse events were mild to 
moderate in severity, considered unrelated to study drug administration and not dose 
dependent. Related adverse events occurring in at least 8 patients (5%) included in the safety 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 43
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
CYP3A4 based on in vitro studies. Nearly 100% of INC424 is metabolized by the liver, while 
nearly zero metabolism occurs in the kidney. The kidney is an organ of INC424 excretion and 
does not metabolize INC424
Elimination: Following a single oral dose of 25 mg [14C]-labeled INC424 in healthy adult 
volunteers, the recovery of the administered radioactivity was 95.53 ± 4.93%, with 73.61 ± 
10.18% and 21.92 ± 5.95% in urine and feces, respectively; indicating that urine was the 
major route of excretion for INC424-related radioactivity. Parent compound was the 
predominant entity in circulation, representing 57% of total radioactivity. The mean 
elimination half-life of INC424 is approximately 3 hours.
3.4.3.1
Healthy volunteers
In healthy volunteers INC424 absorption is rapid, mean peak plasma concentrations are 
achieved 1-2 hours post dose. Single dose exposure (Cmax and AUC) increased proportionately 
with dose (range 5 mg to 200 mg). The mean terminal phase elimination half-life was 
approximately 3 hours and explains minimal accumulation observed upon repeat dosing. A 
high fat breakfast slowed the absorption (mean Tmax increased from 1.3 to 2.7 h), and reduced 
the mean Cmax by 24% without significant effect on area under the curve, of a 25 mg INC424 
tablet.
In healthy volunteers dosed orally with 14C-INC424, unchanged INC424 was the predominant 
circulating drug-related entity with two major circulating metabolites observed, both of which 
are mono-oxidation products. 75% of total radioactivity was recovered in urine, while 
recovery of parent was minimal. The metabolites of INC424 are pharmacologically active 
with varying degrees of activity on JAK kinases. The two metabolites with the highest 
exposure as a fraction of the parent, 30% and 14%, exhibit IC50 values for inhibition of IL6 
stimulated pSTAT3 in human whole blood that is ≥ 3-4 fold higher than the parent (280 nM). 
This in vitro estimate for INC424 is in good agreement with the IC50 (225 nM) estimated ex 
vivo with data collected in a multiple dose volunteer study.
3.4.3.2
Special population
Elderly: No overall differences in safety, effectiveness, or pharmacokinetics of INC424 were 
observed between elderly and younger patients.
Renal Insufficiency: Following a single INC424 dose of 25 mg, the pharmacokinetics were 
similar in patients with various degrees of renal impairment and in those with normal renal 
function. INC424 is not removed by dialysis. Patients with end stage renal disease on dialysis 
had prolonged pharmacodynamic activity (inhibition of IL-6 stimulated STAT3 
phosphorylation in whole blood). Patients with severe kidney disease (MDRD-eGFR < 30 
mL/min/1.73m2) or on dialysis will be excluded from this study.
Hepatic Insufficiency: Following a single INC424 dose of 25 mg in patients with varying 
degrees of hepatic impairment (8 patients per group), the pharmacokinetics and 
pharmacodynamics of INC424 were assessed. There was no rank order correlation between 
exposure and degree of hepatic impairment assessed by Child-Pugh scores. The mean AUC 
for INC424 was increased in patients with hepatic impairment by about 88%, 29% and 66% 
respectively, in patients with mild, moderate and severe hepatic impairment compared to 
patients with normal hepatic function. INC424 pharmacodynamic activity (inhibition of IL-6 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 46
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
During the dose escalation phase, the following dose levels are planned to be tested with 
regards to safety, particularly:

5 mg q.AM / 5 mg q.PM

5 mg q.AM / 10 mg q.PM

10 mg q.AM / 10 mg q.PM

10 mg q.AM / 15 mg q.PM, and

15 mg q.AM / 15 mg q.PM.
Twice daily schedule is preferred to once daily posology for this study, because the phase II 
data from [INC18424-251] study demonstrated better efficacy with this schedule. The phase 
III trials, [INC18424-351] and [INC18424-352], also use twice daily schedules for the same 
reason.
The highest INC424 dose allowed in the study will be 15 mg b.i.d. Further dose escalation 
beyond the MSSD, for additional clinical benefit, although will not be tested in this study, 
may be feasible in selected MF patients presenting with thrombocytopenia and could be 
explored in another clinical trial.
3.5
Rationale for choice of combination drugs
Not applicable.
3.6
Rationale for choice of comparators drugs
Not applicable.
3.7
Sub-studies
Not applicable.
3.8
Definition of end of the study
The End of the Study (Last Patient Last Visit, LPLV) will occur after all patients in the study 
have completed their last assessment as per protocol. Patients who are benefiting from study 
drug may continue study treatment for the duration of 3 years unless one or more withdrawal 
criteria (Section 6.1.4.1) are met and if the treatment with INC424 is considered the patient’s 
best therapeutic option by the Investigator.
[The above paragraph will read as follows for the United Kingdom only:
The End of the Study (Last Patient Last Visit, LPLV) will occur after all patients in the study 
have completed their last assessment as per protocol. Patients who are benefiting from study 
drug may continue study treatment for 3 years if the treatment with INC424 is considered the 
patient’s best therapeutic option by the Investigator. 
After 3 years of study treatment, if the patient continues to benefit in the opinion of the 
Investigator and does not have access to study drug outside of this clinical trial, the patient 
may continue on study treatment until LPFV plus 3 years. After LPFV plus 3 years, if the 
study treatment is not commercially available and reimbursable in the UK, an alternative UK-
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 48
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Patients enrolled in the study cannot participate in any concurrent clinical study investigating 
other investigational agents or devices. Patients who have completed or discontinued the 
study may not be re-enrolled in the study for a second course of treatment.
The Investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered enrollment in the study. All data for 
selection criteria must be verifiable in the patient’s source documents.
A written Informed Consent Form (ICF) must be obtained before the start of any screening 
procedure. For screening procedures refer to Section 6.1.1.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patients 18 years of age or older
2. Patients must be diagnosed with PMF, PPV-MF or PET-MF irrespective of 
, guided by the criteria outlined in the 2008 World Health Organization 
(WHO) criteria for PMF (Table 2 in Tefferi and Vardiman, 2008, Appendix 1a), and the 
proposed criteria for PPV-MF and PET-MF outlined by the International Working Group 
for Myelofibrosis Research and Treatment (IWG-MRT) (Table 1 in Barosi et al, 2008, 
Appendix 1b).
3. Patients with myelofibrosis requiring therapy must be classified at least as intermediate 
risk level 1 (1 or more prognostic factors). The prognostic factors, defined by the 
International Working Group (Cervantes et al 2009) are:

age > 65 yrs

presence of constitutional symptoms (weight loss > 10% in the year preceding the 
Screening Visit, unexplained fever, or excessive night sweats persisting for more than 
1 month)

marked anemia (Hgb < 10g/dL)*

leukocytosis (history of WBC > 25 x109/L)

circulating blasts ≥ 1%

A hemoglobin value < 10 g/dL must be demonstrated during the Screening for 
patients who are not transfusion dependent. Patients receiving regular transfusions of 
packed red blood cells will be considered to have hemoglobin < 10 g/dL for the 
purpose of evaluation of risk factors
4. Patients must have palpable spleen of at least 5 cm from the costal margin to the point of 
greatest splenic protrusion
5. Patients must have active symptoms of MF as demonstrated by one symptom score of at 
least 5 (0-10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the 
Screening Symptom Form, SSF (Appendix 2)
6. Patients must fulfill all the following criteria at Screening or at Study Day 1:

PLT counts < 100 x 109/L and ≥ 75 x 109/L for the first stratum of the trial or PLT 
counts < 75 x 109/L and ≥ 50 x 109/L for the second stratum

coagulation parameters as follows: INR and PTT < 1.5 x ULN
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 49
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
7. Patients with ANC > 1 x 109/L at Screening
8. Patients with peripheral blood blast count of < 5% at Screening
9. Patients with an ECOG performance status of 0, 1, or 2 at Screening (Appendix 11)
10. Patients must have discontinued all drugs used to treat underlying MF disease no later 
than 7 days prior to Screening evaluations visit
11. Patients who have not previously received treatment with a JAK inhibitor
4.2
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Pregnant or nursing (lactating) women
2. Women of childbearing potential who are unwilling to take appropriate precautions (from 
Screening through Follow-up) to avoid becoming pregnant

Females of non-childbearing potential are defined as women who (a) are ≥ 55 years of 
age with history of amenorrhea for 1 year with serum FSH levels > 40 mIU/mL, OR
(b) are surgically sterile for at least 12 weeks

For females of childbearing potential, appropriate precautions (at least two highly 
effective contraception methods) are those that are at least 99% effective in 
preventing the occurrence of pregnancy. These methods should be communicated to 
the patients and their understanding confirmed (Appendix 3)
3. Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e. 
erythropoietin (EPO), granulocyte colony stimulating factor (GCSF), romiplostim, 
eltrombopag) for at least 30 days prior to receiving the first dose of study drug
4. Patients with any history of PLT counts < 45 x 109/L within 30 days prior to Screening,
except during treatment for a myeloproliferative neoplasm or treatment with cytotoxic 
therapy for any other reason. Patients who have received PLT transfusion within 14 days
prior to Screening evaluations.
5. Any history or predisposition to clinically significant bleeding
6. Any history of platelet dysfunction and/or bleeding diathesis
7. Any regular use of drugs that interferes with coagulation or inhibits PLT function
(Appendix 4).
NOTE: low doses of aspirin ≤ 125 mg/day are allowed.
8. Patients with inadequate liver or renal function as demonstrated by:

encephalopathy grade 1 or more, as per West Haven Criteria (Appendix 5)

known hepatocellular disease (e.g. active hepatitis or cirrhosis)

total bilirubin ≥2 x ULN and subsequent determination of direct bilirubin ≥ 2 x ULN

alanine aminotransferase (ALT) > 2.5 x ULN

MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis (Appendix 6)
9. 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
10. Patients with known active hepatitis A, B or C at Screening or with known HIV positivity
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 50
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
11. Patients being treated concurrently with a potent systemic inhibitor or a potent systemic 
inducer of CYP3A4 at the time of Screening (see Appendix 7)
12. Patients with impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of oral INC424 (e.g., uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection)
13. Patients who currently are candidates for a stem cell transplantation at the time of the 
screening assessments
14. Patients with an active malignancy over the previous 5 years, except treated cervical 
intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of 
the skin, with no evidence for recurrence in the past 3 years
15. Patients with currently rapid or paroxysmal atrial fibrillation, currently uncontrolled or 
unstable angina, recent (approximately 6 months) myocardial infarction or acute coronary 
syndrome or any clinically significant cardiac disease (NYHA Class III or IV; 
Appendix 8)
16. Patients under ongoing treatment with another investigational medication or having been 
treated with an investigational medication within 30 days or 5 half-lives (whichever is 
longer) prior to enrollment
17. Patients who have had splenic irradiation within 12 months prior to Screening
18. Patients who are unable to comprehend or are unwilling to sign an informed consent form
19. Patients with active alcohol or drug addiction that, in the investigator’s expert judgment,
would interfere with their ability to comply with the study requirements
20. Patients with any concurrent condition that, in the Investigator’s opinion, would 
jeopardize the safety of the patient or compliance with the protocol
21. Patients who cannot operate electronic diary equipment, or who cannot read the screen or 
who cannot speak or read and understand the languages provided with the diary (as per e-
diary vendor manual)
22. Subject with a life expectancy of less than 6 months.
5
Treatment
5.1
Treating the patient
The Investigator needs to instruct the patient to take the study drug as per protocol. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
5.1.1
Administration
Table 5-1
Treatment and treatment schedule
Study 
treatment
Pharmaceutical form and 
route of administration
Dose
Frequency
INC424
Tablets for oral use
Starting dose 5 mg to be increased 
or decreased (5 mg steps) per 
Bayesian design (see Section 5.1.2)
b.i.d. (approximately 12 
hours apart: morning 
and night)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 51
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Patients will self-administer INC424 tablets as instructed (see Table 5-1 and Section 5.1.2). If 
the patient forgets to take a dose, then he/she should take INC424 within 3 hours after the 
missed dose. If more than 3 hours have passed, then that missed dose should be omitted and 
the patient should continue treatment with the next scheduled dose. Patients will be given a 
paper treatment-compliance diary and will be asked to complete it on a daily basis. Patients 
must carry the diary with them at each Study Visit so as the data to be captured by the site 
investigative staff (Table 6-1 and Table 6-3).
Patients will not take the morning dose of INC424 on the Study Days 1 and 15 for their timed 
PK assessment (see Table 6-4); study drug will be administered in the clinic in order to obtain 
post-dose plasma levels of INC424 (Section 6.2.3). On all other days corresponding to Study 
Visits, patients will take the morning dose of study drugs prior to the visit.
5.1.2
Dosing and treatment schedule
INC424 tablets will be administered b.i.d. (approximately 12 hours apart: morning and night) 
orally, with at least 240 mL of any liquid, apart from alcohol, without regard to food, in an 
outpatient setting.
The dosage strength is 5 mg/tablet INC424 phosphate (free base equivalent). Patients will 
begin dosing on a b.i.d. schedule.
In the dose escalation phase, the starting dose will be 5 mg b.i.d. and the maximum dose will 
be 15 mg b.i.d., if MSSD is not reached at a lower dose. An adaptive Bayesian logistic 
regression model guided by escalation with overdose control will be used to allocate patients 
into each cohort. The dose-escalation cohorts will be: 5 mg q.AM / 5 mg q.PM, 5 mg q.AM / 
10 mg q.PM, 10 mg q.AM / 10 mg q.PM, 10 mg q.AM / 15 mg q.PM, and 15 mg q.AM / 15
mg q.PM (see Table 5-2).
Following determination of the MSSD, a safety expansion phase will be conducted. Patients 
from both strata can be enrolled simultaneously during the safety expansion phase. If the 
MSSD is the same in both strata, all patients in the safety expansion phase will be treated with 
the same dose, regardless of the baseline PLT counts (see Section 5.1.3).
5.1.2.1
Starting dose level for cycle 1
INC424 will be dosed on a flat scale of mg/day (b.i.d.) and not individually adjusted by 
weight or body surface area. In the dose escalation phase of the study, the starting dose, for 
both strata, will be 5 mg q.AM / 5 mg q.PM. INC424 tablets of 5 mg are available.
5.1.2.2
Dose escalation levels
Table 5-2
Dose levels
Dose levels
Dose level 1
5 mg q.AM / 5 mg q.PM
Dose level 2
5 mg q.AM / 10 mg q.PM
Dose level 3
10 mg q.AM / 10 mg q.PM
Dose level 4
10 mg q.AM / 15 mg q.PM
Dose level 5
15 mg q.AM / 15 mg q.PM
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 52
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Doses will be administered according to the dose escalation schedule listed in Table 5-2. Dose 
escalation will continue until MSSD is reached.
5.1.2.3
Criteria for dose escalation and determination of MSSD
The primary analysis method is an adaptive Bayesian logistic regression model guided by 
escalation with overdose control (Babb 1998). To make decisions about escalation to the next 
dose level, the Investigators and the Sponsors study personnel (including the study physician, 
a safety physician and a statistician) will evaluate the available clinical and laboratory data (of 
all patients participating in the study, in all dose levels regardless duration), the toxicity 
information (including adverse events that are not DLTs) and the recommendations from the 
BLRM at a dose-escalation decision meeting or teleconference
(T/C).
Regarding 
thrombocytopenia, not only absolute PLT values, but also the speed at which the PLT counts 
decline will be taken into account for dose-escalation or dose-modification decisions. PK 
analysis data will not be a factor considered during this dose escalation decision process. The 
meetings should be conducted according to Sponsors’ Standard Operating Procedures and 
further details will be provided in the Study Manual. Both Sponsors’ study personnel 
(Novartis Pharmaceuticals and Incyte Corporation) must be in agreement for dose-escalation 
decisions and/or MSSD declaration. Drug administration at the next dose level may not 
proceed until the Investigators receive written confirmation from the Sponsors that the results 
of the previous dose levels were evaluated and it is safe to proceed to a higher dose level.
Criteria for dose escalation are provided in the Section 3.1 and Section 9.4.2. The MSSD will 
be the dose level most closely associated with a posterior DLT probability of between 16% 
and 33% that does not also have a greater than 25% probability of excessive toxicity.
In case the MSSD cannot be established due to lack of toxicity at the dose levels tested, the 15 
mg b.i.d. dose will be the proposed dose for the patients in the safety expansion phase.
5.1.2.4
Dose escalation
A prior distribution for the model parameters is derived based on experience with INC424 in 
adult patients in clinical study [INCB 18424-251], which was the dose-finding study in 
patients with myelofibrosis that preceded the pivotal phase III studies, [INCB 18424-351] and 
[INCB 18424-352] (see Section 1.2.4). The model will then be updated after each cohort of 
patients in each stratum with the DLT data from the current study. A detailed description of 
the methodology can be found in Section 9.4.2.
The first 3 patients enrolled in the study must be enrolled from stratum 1 (patients with 
baseline PLT counts 75-99 x109/L). These 3 patients will be enrolled at the first dose level
(dose level 1, Table 5-2). At least 3 evaluable patients are needed per dose level to make dose 
escalation decisions. The previously mentioned (see Section 5.1.2.3) BLRM with EWOC will 
be updated after all patients in a cohort become evaluable (for the dose-determining analysis 
set) or discontinue therapy. The dose-determining set (DDS), as defined in Section 9.1.3,
consists of all patients from the safety set who either (a) meet the minimum exposure criterion 
and have sufficient safety evaluations or (b) discontinue due to DLT. Decisions to escalate 
will be in accordance with satisfying the overdose control criterion based on the results of this 
modeling, and will be implemented after a joint teleconference or meeting between 
Investigators and Sponsors, as described in Section 5.1.2.3. As an exception, if the first 2 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 53
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
patients in the cohort experience DLT before the enrollment of the 3rd patient, the model will
be re-evaluated before enrollment of any additional patients to the cohort.
Enrollment will begin in stratum 1 at dose level 1. Once at least 6 patients from stratum 1 are 
confirmed to be in the dose-determining set (DDS) and dose level 3 is allowed for enrolment 
in stratum 1, then patients from stratum 2 (patients with baseline PLT counts 50-74 x109/L) 
may be enrolled at the first dose level. For the subsequent dose levels, patients in stratum 2 
cannot be enrolled unless patients from stratum 1 have been allowed to be enrolled at 2 dose 
levels higher. Once the MSSD criteria have been met for stratum 1, stratum 2 can be 
independently further escalated, provided that this decision is supported by the BLRM with 
EWOC. Escalation for stratum 2 can be continued up to the dose level at which the MSSD 
criteria have been met for stratum 1, but not higher.
Dose escalation levels are listed in the Table 5-2. A minimum of 9 evaluable patients must be 
treated at the dose declared to be the MSSD, for each stratum.
5.1.2.5
Safety expansion phase
Once the MSSD of INC424 is identified for both strata in the dose escalation phase of this 
study, additional patients will be enrolled and treated at this dose in order to further evaluate 
its safety and tolerability and to obtain estimates of efficacy, with the purpose of establishing 
that this dose is suitable for use in the low-platelet population of patients with MF. Patients 
from both strata can be enrolled simultaneously during the safety expansion phase. If the 
MSSD is identical in both strata, all patients in the safety expansion phase will be treated with
the same dose. Prior to Amendment 4, twenty patients (10 patients from each stratum), in 
addition to the patients treated at the MSSD during the dose escalation phase, were to be 
evaluated during this part of the study. If the MSSD proves not to be well tolerated with 
further experience and via continuous update of the Bayesian logistic regression model during 
this safety expansion phase, then a lower dose may be evaluated to twenty additional patients 
(10 patients from each stratum).
With the approval of Amendment 4, all new patients enrolled to Stratum 1’s safety expansion
phase will be given the 10 mg BID dose, instead of the 15 mg BID dose level previously 
evaluated as the MSSD.  This will allow 10 mg BID to be evaluated as the starting dose.  
Approximately 20 patients will be evaluated at this dose level in Stratum 1, inclusive of the 
patients already enrolled into this dose during the dose escalation phase, OR the Last Patient’s 
First Visit (LPFV) will occur on 01 September 2017, whichever comes first.  Patients already 
taking the 15 mg BID dose in Stratum 1’s safety expansion phase will continue to take their 
assigned dose.  Stratum 2 will maintain its original enrollment requirement of 10 patients at 
the MSSD.
The criteria for continuation of treatment and dose modification guidelines employed during 
the dose escalation phase will also be followed during safety expansion phase. Dose
escalation above the MSSD will not be allowed.
5.1.2.6
Dose cohort modification
Dose level cohorts are listed in Table 5-2. Possible changes in dose administration according 
to the BLRM include, but are not limited to, (a) expansion of the current dose group to further 
assess suspected treatment-related adverse events, (b) termination of any further escalation of 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 54
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
study drug. Investigators will receive written confirmation from the Sponsors notifying them 
that enrollment has been increased or decreased, or that no further enrollment will occur.
5.1.2.7
Intra-patient escalation
Intra-patient dose escalation will only be permitted after Study Day 56. During the course of 
the study, patients can be dose-escalated to the next higher dose level only once every two 
cycles (each cycle is 28 days), provided that ALL of the following criteria are met:

inadequate efficacy is seen with the current dose level, as defined by observation of one or 
both of the following:

not achieving at least a 50% reduction in palpable spleen length compared to Study 
Day 1

lack of meaningful improvement in disease symptoms based on the Investigator’s 
expert judgment.

no treatment-related toxicity has occurred with the current dose level, resulting in 
treatment reduction or interruption or discontinuation in the previous 56 days.
For the first 24 weeks of treatment for an individual patient, the dose-escalation requirements 
will be as follows:

the maximum dose with which the patient is to be treated does not exceed 15 mg b.i.d. and 
has been evaluated with at least 3 patients for a minimum of 28 days in that stratum, with 
no more than 1 out of 3 patients experiencing DLT

the minimum PLT count during the first 24 weeks period is ≥ 50 x109/L OR ≥ 75% of the 
baseline PLT count the current dose level is lower than the MSSD.
For treatment beyond the first 24 weeks, the dose-escalation requirements will be as follows:

the maximum dose with which the patient is to be treated is the higher of: the MSSD 
established for that stratum OR 10 mg bid

the minimum PLT count at the time of the escalation is ≥ 50 x109/L AND is ≥ 75% of the 
baseline PLT count if a patient experienced a PLT count ≤ 50 x109/L OR ≤ 75% of the 
baseline PLT count beyond the first 24 weeks, a dose escalation may be discussed with the 
sponsor. If a patient experiences a second episode of PLT count ≤ 50 x109/L or ≤ 75% of 
the baseline PLT count (if it is suspected to be drug related), no further dose escalation 
will be allowed.
The rules for intra-patient escalation described above are also applicable to patients who have 
undergone one and only one dose reduction. Conversely, dose reduction rules (described in 
the Section 5.1.3) also apply to patients who undergo dose escalation. Once a patient 
undergoes a dose reduction due to treatment-related toxicity, the patient may not have a dose 
increase unless they have been on a stable dose for at least 28 days with no dose interruptions.
Patients who have experienced treatment-related ≥ grade 3 toxicity of any nature aside from 
thrombocytopenia or grade 4 thrombocytopenia may not dose escalate a second time to the 
dose level at which this toxicity was seen.
For patients who undergo dose escalation, PLT counts must be obtained at least weekly for 4 
weeks, and then at least every second week for the next 4 weeks. Thereafter, they may resume 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 55
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
monthly evaluations. Further recommendation can be given during the T/C meetings, on an 
individual basis.
Consultation with the Sponsors must occur prior to any intra-patient dose escalation.
5.1.2.8
Dose-limiting toxicity (DLT)
Dose-limiting toxicity (DLT) will be defined as the occurrence of any of the treatment-
related toxicities occurring up to and including Study Day 28, which are listed in Table 5-3, 
using the Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
For the purpose of dose-escalation decisions, only DLTs will be necessarily considered and 
included in the BLRM. However, adverse events, which occur after Study Day 28 and meet 
all the criteria for the DLT definition apart from the timing of occurrence, will be considered 
in ultimate decisions of dose escalation and determinations of how many patients should be 
evaluated at a given dose level. Prior to enrolling patients into a higher dose level, all adverse 
events will be reviewed for all patients at the current and the previous dose levels.
For toxicities which, by definition, require a time-window for them to be defined as DLTs 
(grade 3 non-hematologic toxicity for ≥ 7 consecutive days), a subsequent visit(s) and/or 
laboratory assessment(s) must be scheduled accordingly, in order for this toxicity to qualify as 
a DLT. For example, if a grade 3 non-hematologic toxicity is observed, it must be also 
observed at least 7 days later, with no intervening lower grades, in order to qualify as a DLT.
Table 5-3
Criteria for defining dose-limiting toxicities
Toxicity
Any of the following treatment-related criteria (occurring through Study Day 28)
Hematology
PLT counts < 25 x109/L*
grade 4 neutropenia (ANC < 0.5 x109/L)*
grade ≥3 febrile neutropenia*
Other AEs
any grade thrombocytopenia requiring PLT transfusion
any grade ≥ 2 hemorrhagic event
grade ≥ 2 serum bilirubin with coincident direct bilirubin ≥0.5 mg/dL
grade 3 non-hematologic toxicity for ≥ 7 consecutive days
grade 4 non-hematologic toxicity
* At the discretion of the Investigator, laboratory values can be confirmed with a second assessment. In this case, 
only the result of the second assessment will be considered valid and final.
Patients who experience a DLT will have their therapy with INC424 interrupted and will be 
followed as described in the Table 5-4. After recovery from the toxicity in question, if the 
Investigator believes that it is in the patient’s best interest to resume therapy with INC424, the 
patient may resume therapy, only after consultation with the Sponsors, according to the 
guidelines described in the Section 5.1.3 and the Table 5-4.
However, the patient must be permanently discontinued from study medication and 
withdrawn from the study, if any of the following DLTs occur:

any grade ≥ 3 hemorrhagic event

2nd episode of grade ≥3 febrile neutropenia

grade 3 renal toxicity for ≥ 7 consecutive days

grade 4 renal toxicity
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 56
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

grade 4 serum bilirubin with direct bilirubin ≥ 0.5 mg/dL

grade 4 non-hematologic toxicity
If, from Study Day 1 through Study Day 28, a patient misses > 6 consecutive doses of 
treatment or > 20% of the planned study drug doses, the patient will not be evaluable for 
DLTs. The patient can continue in the study, but another patient has to be enrolled at the same 
dose level and stratum in order to reach the required number of patients in the cohort.
5.1.2.9
Follow-up for dose-limiting toxicities
Patients whose treatment is discontinued or interrupted due to a DLT, must be followed until 
resolution or stabilization of the DLT event, whichever comes first, as described in Section 
6.1.4.
In the case of PLT transfusion that is considered unrelated to the treatment with INC424 (e.g., 
car accident causing bleeding and subsequent PLT transfusion despite grade ≤ 3 
thrombocytopenia), then no measures should be taken, other than those related to the 
management of the event (Table 5-4). If the event for which the PLT transfusion was given is 
considered related to the treatment with INC424, then both the PLT toxicity-handling 
guidelines and the hemorrhagic event-handling guidelines should be taken into account.
In case of a hemorrhagic event of any grade (CTCAE grade 1 included) the Investigator is 
advised to perform coagulation tests and albumin assessment.
5.1.2.9.1 Hematologic toxicity

In the case of grade 4 thrombocytopenia, assessment of PLT count is recommended to be 
repeated daily, Monday through Friday, until resolution to grade ≤3 thrombocytopenia (it 
is at the Investigator’s discretion to perform PLT count assessments during weekends). 
The subsequent follow-up should be done as described in Section 5.1.4 and in Table 6-2.

In the case of grade 4 neutropenia, assessment of ANC count is recommended to be 
repeated at least twice a week until resolution to grade ≤3 neutropenia. The subsequent 
follow-up should be done as described in Section 5.1.4 and in Table 6-2 and Table 6-4.
5.1.3
Dose modification and dose delay
All dose modifications should be based on the worst preceding toxicity. Patients may be 
allowed dose reductions to 5 mg qd (dose level (-1)). Dose reductions more than one level at a 
time will not be allowed, except for thrombocytopenia, in which case different rules for dose 
reductions apply (Table 5-4). Note that the maximum allowed doses are quoted in the part of 
Table 5-4 where guidelines for dose reduction due to thrombocytopenia are provided; lower 
doses may be used at investigator discretion. It is recommended that patients who are dose 
reduced for thrombocytopenia have more frequent hematology assessments. PLT counts must 
be obtained at least weekly for 4 weeks, and then at least every second week for the next 4 
weeks. Thereafter, they may resume monthly evaluations.
Recovery of platelet counts will allow dose increases according to the guidelines in Table 5-5. 
Note that once a dose is re-escalated, any subsequent declines in platelet count will require
that Table 5-4 be used to determine the new lower dose, or dose interruption.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 57
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Dose level (-1) is the lowest acceptable dosing level for a patient participating in the study. If 
a patient cannot tolerate dose level (-1), then he/she must be discontinued from study
medication and withdrawn from the study (see Table 5-2 for dose level definitions).
Dose modifications for toxicities occurring during the DLT-definition period (Study Day 1 
through Study Day 28), and considered as treatment-related, will not be allowed until the 
toxicity qualifies as a DLT. After a toxicity event has been characterized as a DLT, a patient 
can resume therapy with a reduced INC424 dose according to the guidelines provided in the 
Section 5.1.2.7. Dose modification recommendations after Study Day 28 are described in the 
Table 5-4.
Any dose modifications must be recorded on the Dosage Administration Record eCRF.
5.1.4
Treatment interruption and treatment discontinuation
Patients may continue treatment with INC424 for the duration of the study or until they 
experience unacceptable toxicity that precludes any further treatment, disease progression, 
and/or at the discretion of the Investigator. Patients will be discontinued from the study if they 
withdraw consent, or if the treating physician judges that further therapy with INC424 is no 
longer in the patient’s best interest.
Criteria for interruption and re-initiation of INC424 treatment are summarized in the Table 5-
4. A patient must discontinue treatment with INC424 if, after treatment is resumed at a lower 
dose, the same toxicity recurs with the same or worse severity. If a patient requires a dose 
delay of > 28 days, then the patient must be discontinued from the study. Patients who 
discontinue from the study for a treatment-related adverse event or a treatment-related 
abnormal laboratory value must be followed as described in Section 6.1.4.
Grading of toxicity will be according to CTCAE Version 4.03.
Doses may be restarted and subsequently increased, according to the Table 5-6, provided that 
platelet counts recover to ≥35 x109/L and ANC counts recover to ≥0.75 x109/L and there is 
no other toxicity that precludes dosing of the patient. Note that once a dose has been restarted, 
subsequent declines in platelet or ANC count will require that Table 5-4 be used to determine 
the new lower dose or dose interruption. It is required that patients who have restarted dosing
have more frequent hematology assessments. PLT and ANC counts must be obtained at least 
weekly for 4 weeks, and then at least every second week for the next 4 weeks. Thereafter, 
they may resume monthly evaluations (exception: for grade 4 thrombocytopenia or 
neutropenia events please refer to Section 5.1.2.9.1).
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 58
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 5-4
Criteria for interruption and re-initiation of INC424 treatment – Recommended dose modifications
Study Day 1 through Study Day 28
Study Day 29 to End of Treatment (EOT)
Worst Toxicity 
(CTCAE Grade 
unless otherwise 
specified)
Treatment related toxicity
Non-treatment related toxicity
Causality of toxicity and relation to the treatment with INC424 is based on the 
Investigator’s expert judgment
Hematological
Neutropenia
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose level
Continue at same dose level
Continue at same dose level
*Hold dosing
Continue at same dose level
Continue at same dose level
Continue at same dose level
Hold dosing
Continue at same dose level
Continue at same dose level
Continue at same dose level
Hold dosing
* qualifies as a DLT
In case of grade 4 neutropenia, follow-up rules according to Section 5.1.2.9.1.
For dose restart guidelines, see Table 5-6.
Grade ≥3 febrile 
neutropenia (ANC 
<1.0 x109/L, isolated 
fever ≥38.3°C or 
sustained fever 
>38°C for more than 
1 hour)
* Hold dosing until resolved to afebrile 
neutropenia ≤ grade 2, then ↓ 1 dose 
level** †
Hold dosing until resolved to afebrile 
neutropenia ≤ grade 2, then continue at 
same dose level ‡
Hold dosing until resolved to afebrile neutropenia ≤ 
grade 2, and:
if not related to INC424, then continue at same dose 
level***
if related to INC424, then ↓ 1 dose level***
* qualifies as a DLT
** Resume therapy according to the 
rules of Section 5.1.2.7.
† If 2nd episode, then discontinue
‡ If 2nd episode, then discontinue
*** If a second episode of grade ≥3 febrile neutropenia 
occurs within 28 days, whether related or unrelated, 
the patient must discontinue
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 59
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Study Day 1 through Study Day 28
Study Day 29 to End of Treatment (EOT)
Worst Toxicity 
(CTCAE Grade 
unless otherwise 
specified)
Treatment related toxicity
Non-treatment related toxicity
Causality of toxicity and relation to the treatment with INC424 is based on the 
Investigator’s expert judgment
Hemorrhagic event of any kind
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose level
* Hold dosing until resolved completely, 
then ↓ 1 dose level
** Discontinue
** Discontinue
Continue at same dose level
Hold dosing until resolved completely, then 
continue at same dose level
Hold dosing until resolved completely, then 
continue at same dose level
Hold dosing until resolved completely, then 
↓ 1 dose level***
If not related to INC424, then continue at same dose 
level
If related to INC424, then hold dosing until resolved 
completely, then continue at same dose level
Hold dosing until resolved completely, and
if not related to INC424, then continue at same dose 
level
if related to INC424, then ↓ 1 dose level
Hold dosing until resolved completely, and
if not related to INC424, then continue at same dose 
level
if related to INC424, then discontinue
Hold dosing until resolved completely, and
if not related to INC424, then ↓ 1 dose level
if related to INC424, then discontinue
* qualifies as a DLT. Resume therapy 
according to the rules of Section 5.1.2.7.
** qualifies as a DLT.
*** the patient has to be substituted
In case of a hemorrhagic event of any grade the Investigator is advised to perform coagulation tests and albumin assessment
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 60
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Study Day 1 through Study Day 28
Study Day 29 to End of Treatment (EOT)
Worst Toxicity 
(CTCAE Grade 
unless otherwise 
specified)
Treatment related toxicity
Non-treatment related toxicity
Causality of toxicity and relation to the treatment with INC424 is based on the 
Investigator’s expert judgment
Renal
Serum Creatinine
Grade 1
Grade 2
Grade 3
Grade 4
Continue at same dose level
Continue at same dose level
Continue at same dose level, and
if duration ≥7 days*, then discontinue
* Discontinue
Continue at same dose level
Continue at same dose level
Hold dosing until resolved to ≤ grade 1, then 
continue at same dose level
Hold dosing until resolved to ≤ grade 1, then 
continue at same dose level
Continue at same dose level
If related to INC424, then either continue at same 
dose level or hold dosing until resolved to ≤ grade 1, 
then continue at same dose level†
If not related to INC424, then continue at same dose 
level
If related to INC424**, then either continue at same 
dose level or hold dosing until resolved to ≤ grade 1, 
then continue at same dose level†. In any case, if 
duration ≥7 days, then discontinue.
If not related to INC424, then either continue at same 
dose level or hold dosing until resolved to ≤ grade 1, 
then continue at same dose level†,
If related to INC424, then discontinue
If not related to INC424, then hold dosing until 
resolved to ≤ grade 1, then continue at same dose 
level
* qualifies as a DLT
** If a second episode of grade 3 serum creatinine 
occurs related to INC424, then the patient must 
discontinue
† at the discretion of the Investigator
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 61
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Study Day 1 through Study Day 28
Study Day 29 to End of Treatment (EOT)
Worst Toxicity 
(CTCAE Grade 
unless otherwise 
specified)
Treatment related toxicity
Non-treatment related toxicity
Causality of toxicity and relation to the treatment with INC424 is based on the 
Investigator’s expert judgment
Hepatic
Total bilirubin
Grade 1
Grade 2 or 3
Grade 4
Continue at same dose level
If Direct Bilirubin < 0.5 mg/dL, then 
continue at same dose level
If Direct Bilirubin ≥ 0.5*, then hold 
dosing until Direct Bilirubin < 0.5 mg/dL, 
then ↓ 1 dose level
If Direct Bilirubin < 0.5 mg/dL, then 
continue at same dose level
If Direct Bilirubin ≥ 0.5*, then discontinue
Continue at same dose level
If Direct Bilirubin < 0.5 mg/dL, then continue 
at same dose level
If Direct Bilirubin ≥ 0.5, then hold dosing 
until Direct Bilirubin < 0.5 mg/dL, then 
continue at same dose level
If Direct Bilirubin < 0.5 mg/dL, then continue 
at same dose level
If Direct Bilirubin ≥ 0.5, then discontinue**
Continue at same dose level
If Direct Bilirubin < 0.5 mg/dL, then continue at same 
dose level
If Direct Bilirubin ≥ 0.5, then hold dosing until Direct 
Bilirubin < 0.5 mg/dL, and
if not related to INC424, then continue at same dose 
level
if related to INC424, then ↓ 1 dose level
If Direct Bilirubin < 0.5 mg/dL, then continue at same 
dose level
If Direct Bilirubin ≥ 0.5, then discontinue
* qualifies as a DLT. Resume therapy 
according to the rules of Section 5.1.2.7.
** the patient has to be substituted
Patients who develop new onset hepatic impairment (Direct Bilirubin ≥0.5 mg/dL) must have coagulation tests and albumin assessment.
Other adverse events
Grade 1
Continue at same dose level
Continue at same dose level
If related to INC424, then either continue at same 
dose level or ↓ 1 dose level†
If not related to INC424, then continue at same dose 
level
Grade 2
Continue at same dose level
Continue at same dose level
If related to INC424, then either continue at same 
dose level or ↓ 1 dose level†
If not related to INC424, then continue at same dose 
level
Grade 3
Continue at same dose level, and:
if duration ≥7 days*, then hold dosing 
until resolved to ≤ grade 1, then ↓ 1 
dose level
Hold dosing until resolved to ≤ grade 1, then 
continue at same dose level
If related to INC424, then ↓ 1 dose level†
If not related to INC424, then continue at same dose 
level
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 62
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Study Day 1 through Study Day 28
Study Day 29 to End of Treatment (EOT)
Worst Toxicity 
(CTCAE Grade 
unless otherwise 
specified)
Treatment related toxicity
Non-treatment related toxicity
Causality of toxicity and relation to the treatment with INC424 is based on the 
Investigator’s expert judgment
Grade 4
** Discontinue
Hold dosing until resolved to ≤ grade 1 or 
baseline grade, then continue at same dose 
level
If related to INC424, then discontinue
If not related to INC424, then hold dosing until 
resolved to ≤ grade 1 or acceptable grade, then 
continue at same dose level
* qualifies as a DLT and resume therapy 
according to the rules of Section 5.1.2.7.
** qualifies as a DLT
† at the discretion of the Investigator
Isolated values of CTCAE grade ≤ 3 alkaline phosphatase values will not require dose modification or interruption
Thrombocytopenia (PLT count at time of decline)
≥ 75 x109/L
50 - 74 x109/L
35 - 49 x109/L
25 - 34 x109/L
< 25 x109/L
Continue at same dose level
Continue at same dose level
Continue at same dose level
Continue at same dose level
* Hold dosing
* qualifies as a DLT. If resolved to ≤ 
grade 2, resume therapy according to 
the rules of Table 5-6.
Dose at the Time of the Platelet Decline
5 mg qd
5 mg 
b.i.d.
5 mg q.AM / 
10 mg q.PM
10 mg b.i.d.
10 mg q.AM / 15 
mg q.PM
15 mg b.i.d.
New Maximum Dose That Must be Instituted
Continue at same dose level
Continue at same dose level
10 mg b.i.d.†
10mg b.i.d.†
Continue at same dose level‡
Continue at same dose
5 mg b.i.d.
5 mg b.i.d.
5 mg b.i.d.
5 mg b.i.d.
5 mg qd
5 mg qd
5 mg qd
5 mg qd
5 mg qd
5 mg qd
Discontinue
Hold dosing
†Patients from stratum 1 ‡Patients from stratum 2
In cases of grade 4 thrombocytopenia, follow-up rules according to Section 5.1.2.9.1.
For dose escalation or dose restart guidelines, see Table 5-5 and Table 5-6.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 63
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 5-5
Dose escalation guidelines and allowed maximum doses for patients 
who have previously decreased dosing for thrombocytopenia
Current Platelet Count
Dose re-escalation guidelines (NOTE: maximum doses are 
given, lower doses may be used at Investigator’s discretion)
25 x109/L - 34 x109/L
Continue at 5 mg qd until platelet counts ≥ 35 x109/L
35 x109/L - 49 x109/L
Continue at 5 mg b.i.d. until platelet counts ≥ 50 x109/L
≥ 50 x109/L
May increase dose by 5 mg qd each cycle (28 days) provided 
platelet count remains ≥ 50 x109/L, up to the dose where platelet 
counts first declined and dose reduction occurred
Table 5-6
Dose restart guidelines and allowed maximum doses for patients who 
have previously interrupted dose for grade 4 thrombocytopenia or 
grade 4 neutropenia
Current platelet count
Dose restart guidelines (NOTE: maximum doses are given, 
lower doses may be used at investigator’s discretion)
<35 x109/L in a patient who is currently 
holding dose
Must continue to hold
35 - 49 x109/L in a patient who is recovering 
from a dose hold
5 mg qd for 2 weeks, then increase in 5 mg qd increments, no 
faster than once every cycle (28 days), provided platelet counts ≥ 
50 x109/L
≥ 50 x109/L in a patient who is recovering 
from a dose hold
5 mg b.i.d. for at least 2 weeks, then may proceed with 5 mg qd 
dose increases, no more frequently than once every cycle (28 
days), and provided platelets remain ≥ 50 x109/L, up to the dose 
where platelet counts first declined < 25 x109/L
Current ANC count
Dose restart guidelines (NOTE: maximum doses are given, 
lower doses may be used at investigator’s discretion)
<0.75 x109/L in a patient who is currently 
holding dose
Must continue to hold
0.75 – 1.00 x109/L in a patient who is 
recovering from a dose hold
5 mg qd for 2 weeks, then increase in 5 mg qd increments, no 
faster than once every cycle (28 days), provided ANC counts >
1.00 x109/L
> 1.00 x109/L in a patient who is recovering 
from a dose hold
5 mg b.i.d. for at least 2 weeks, then may proceed with 5 mg qd 
dose increases, no more frequently than once every cycle (28 
days), and provided ANC remain > 1.00 x109/L, up to a maximum 
dose of 5 mg qd BELOW the dose where ANC counts first 
declined < 0.50 x109/L
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. Also, the maximum dose should always be 5 mg qd BELOW the dose where platelet 
counts first declined < 25 x109/L or ANC counts first declined < 0.5 x109/L.
5.1.5
Dose reduction of INC424 for concomitant CYP inhibitor usage
INC424 is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the 3A4 isozyme. With concomitant dosing of potent CYP3A4 
inhibitors such as systemic ketoconazole clarithromycin, itraconazole, nefazodone and 
telithromycin (Appendix 7), plasma exposure of INC424 increases approximately 2-fold. 
Patients under therapy with a potent CYP3A4 inhibitor cannot be enrolled in the study. Use of 
CYP3A4 inhibitors during the study is strongly discouraged, and investigators should 
consider alternative therapies wherever possible. However, if the use of a potent CYP3A4 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 64
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
inhibitor is necessary for the sake of patient’s safety, then a dose reduction of ~ 50% for 
INC424 is appropriate. The following dose-reduction rules should be followed:

If dose is 5 mg qd, treatment with INC424 has to be interrupted

If dose is 5 mg b.i.d., change dose to 5 mg qd

If dose is 5 mg q.AM / 10 mg q.PM, change dose to 5 mg qd

If dose is 10 mg b.i.d., change dose to 10 mg qd

If dose is 10 mg q.AM / 15 mg q.PM, change dose to 5 mg b.i.d.

If dose is 15 mg b.i.d., change dose to 15 mg qd
NOTE: once the course of therapy using a CYP3A4 inhibitor has been completed, the patient 
may resume his/her prior dose level of INC424 beginning the next day.
5.1.6
Optional dose tapering strategy for INC424 in the event of 
discontinuation
When INC424 therapy is stopped, return of constitutional symptoms associated with elevated 
cytokines (e.g. night sweats, fever, fatigue) that had been suppressed while on therapy is 
expected. When a decision is made to permanently discontinue INC424 therapy for reasons 
other than for hematologic safety, 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, so that symptoms may return to pre-treatment condition more slowly. 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 events occurring after discontinuation. Short-term courses of 
corticosteroids at doses > 10 mg/day have been used in patients with MF 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 for a period of time as least 
through the continued administration on INC424 and 30 days after for AEs.
5.1.7
Rescue medication
Not applicable.
5.1.8
Permitted concomitant therapy
The patient needs to notify the investigative 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 and blood transfusions) administered after the patient
starts treatment with study drug must be listed on the Concomitant medications/Significant 
non-drug therapies after start of study drug eCRF.
5.1.9
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:
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 65
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day 
are not permitted, unless use is part of an INC424-dose tapering strategy (see 
Section 5.1.6).

During the study, the concomitant use of potent systemic CYP3A4 inhibitors is strongly 
discouraged. However, when such a concomitant administration of a potent systemic 
CYP3A4 inhibitor (ketoconazole, clarithromycin, itraconazole, nefazodone and 
telithromycin, see Appendix 7) is required for subject management, the dose of INC424 
must be adjusted as described in Section 5.1.5. Based on the low overall bioavailability of 
topical ketoconazole, with very low systemic levels seen following topical administration, 
no dose adjustment of INC424 is needed for use with topical ketoconazole. No dose 
adjustments are necessary when INC424 is co-administered with erythromycin, or by 
extension, with other moderate or weak inhibitors of CYP3A4, including grapefruit juice 
(see Appendix 7).

During the study, the use of moderate CYP3A4 inducers (e.g., rifabutin, carbamazepine, 
and phenytoin) is discouraged, and investigators should seek alternatives where possible. 
No dose adjustment will be used when moderate CYP3A4 inducers are co-administered 
with INC424. However, any concomitant use of moderate CYP3A4 inducers (e.g., 
rifabutin, carbamazepine, phenytoin, see Appendix 7) must be documented.

Granulocyte growth factors are not allowed while study medication is being administered 
but may be used for severe neutropenia at the Investigator’s discretion while study 
medication is being withheld.
5.1.10
Prohibited concomitant therapy
The following medications are prohibited during the study:

Any prior or 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 during the study through the Safety Follow-up 
Visit is prohibited.

Use of the potent inducers of CYP3A4 (such as rifampin and St John’s Wort), is not 
permitted at any time during participation in the study (see Appendix 7 for a list of 
CYP3A4 inducers).

Any regular use of drugs that interfere with coagulation or inhibit PLT function (except 
low doses aspirin ≤ 125 mg/day which are allowed) and non-steroidal anti-inflammatory 
drugs (NSAIDs). For a complete list, see Appendix 4.

Any other medication for myelofibrosis during the treatment period: hydroxyurea, 
busulfan, interferon, lenalidomide, thalidomide, anagrelide.
5.1.11
Hormonal contraception allowed/excluded
Females of childbearing potential will be requested to use the combination of two highly 
effective contraception methods that have been determined to be at least 99% effective as 
indicated in Exclusion Criterion #2 (see Section 4.2 and Appendix 3).
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 66
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
5.2
Study drug(s)
5.2.1
Packaging and labeling
INC424 will be provided in bottles. Medication labels will be in the local language and 
comply with the legal requirements of each country. They will include storage conditions for 
the drug but no information about the patient.
Table 5-7
Packaging and labeling
Study drugs
Packaging
Labeling (and dosing frequency)
INC424
Tablets in bottle
Labels with no reference to dosing
5.2.2
Supply, receipt and storage
INC 424 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 designated 
assistants have access. Upon receipt, the INC424 should be stored according to the 
instructions specified on the drug labels.
Table 5-8
Supply and storage of study drugs
Study drugs
Supply
Storage
INC424
Centrally supplied by Sponsors
Refer to study drug label
5.2.3
Dispensing and preparation
The study medication packaging has a 2-part label. Investigator staff will add the patient
number on the label. Immediately before dispensing the package to the patient, Investigator
staff will detach the outer part of the label from the packaging and affix it to the source 
document (Drug Label Form) for that patient’s unique patient number.
Table 5-9
Dispensing and preparation
Study Drugs
Dispensing
Preparation
INC424
Tablets including instructions for administration are dispensed by study 
personnel on an outpatient basis.
Patients will be provided with adequate supply of study drug for self-
administration at home until their next scheduled study visit.
Not applicable
5.2.4
Drug compliance and accountability
5.2.4.1
Drug compliance
Compliance with the INC424 regimen will be calculated by the Sponsors based on the drug 
accountability documented by the site staff and the review of the paper treatment-compliance 
diary completed by the patient and will be monitored by the Sponsors/designee (pill counts in 
accordance with the relevant Standard Operating Procedures). A patient will be considered 
sufficiently compliant with INC424 treatment if they have taken at least 83.3% of their 
prescribed dose over the total duration of study drug dosing.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 67
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
5.2.4.2
Drug accountability
The Investigator or designee must maintain an accurate record of the shipment and dispensing 
of study drug in a drug accountability ledger. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study drug and packaging on a regular basis, at the end of the study or at the time 
of study drug discontinuation. Study investigative site will need to keep used and unused 
study drug for monitor to source verify drug accountability. Patients will also be asked to 
complete the paper treatment-compliance diary and carry it with them at each Study Visit.
At study close-out, and, as appropriate during the course of the study, the Investigator will 
return all used and unused study drug, packaging, drug labels, and a copy of the completed 
drug accountability ledger to the Sponsors monitor or to the Sponsors address provided in the 
Investigator folder at each site.
5.2.5
Disposal and destruction
The drug supply can be destroyed at the local Sponsors facility, Drug Supply group or third 
party, as appropriate, after drug accountability. Any destruction of medication has to be 
approved / initiated by the monitor.
6
Visit schedule and assessments
6.1
Study flow and visit schedule
With the implementation of Amendment 4, Table 6-1, Table 6-2, and Table 6-3 list all of the 
assessments and indicate with an “X” the visits when they are performed. All data obtained 
from these assessments must be supported by data in the patient’s source document. The 
tables indicate which data are entered into the database (D) and which data remain in source 
documents only (S) (column category). Assessments that generate data for database entry and 
which are recorded on eCRFs are listed using the eCRF name. Assessments that are 
transferred to the database electronically (e.g., laboratory data) are listed by test name.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 68
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 6-1
Visit evaluation schedule post amendment 4 - Core study period (from screening to Day 168)
Category
Reference 
to 
assessment 
types
Screening
Day 1 to Day 28
Day 29 to
Day 56
Day 57 to Day 168
For EOT and FU visits-Refer to Table 6-2 and 6-3
(± 1-day 
window)
(+ 3 
days)
(± 2-
days)
(± 3-days window)
Visit no.
1
2
3
4
5
6
7
8
9
10
Study Day
-21 to -7
1
15
29
43
57
85
113
141
168
Obtain Informed 
Consent
D
6.1.1 / 10.3.
Before 
screening
Demography
D
6.1.1.3.
X
Inclusion/exclusion 
criteria
D
4.1 / 4.2.
X
Discuss pregnancy 
prevention methods
S
5.1.11.
X
Prior antineoplastic 
therapy
D
6.1.1.3.
X
Relevant medical 
history/current medical 
conditions
D
6.1.1.3.
X
Measurement of spleen 
by palpation
D
6.2.1 / 
6.2.2.1.
X
X
X
X
X
X
X
X
X
X
Vital signs
D
6.2.2.2.
X
X
X
X
X
X
X
X
X
X
Height
D
6.2.2.3.
X
Weight
D
6.2.2.3.
X
X
X
X
X
X
X
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 69
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Category
Reference 
to 
assessment 
types
Screening
Day 1 to Day 28
Day 29 to
Day 56
Day 57 to Day 168
For EOT and 
FU visits-Refer 
to Table 6-2 
and 6-3
(± 1-day 
window)
(+ 3 
days)
(± 2-
days)
(± 3-days window)
Visit no.
1
2
3
4
5
6
7
8
9
10
Study Day
-21 to -7
1
15
29
43
57
85
113
141
168
Complete physical 
examination
D
6.2.2.1.
X
X
X
X
X
X
X
X
Short physical 
examination
D
6.2.2.1.
X
X
ECOG performance 
status
D
6.2.2.4.
X
X
X
X
X
X
X
X
ECG
D
6.2.2.7.1.
X
X
X
X
X
Laboratory Assessments
Serum chemistry tests
D
6.2.2.5.3 / 
Appendix 12
X
X
X
X
X
X
X
X
X
Hematology
D
6.2.2.5.1 / 
Appendix 12
X
X
X
X
X
X
X
X
X
X
Coagulation test
D
6.2.2.5.2 / 
Appendix 12
X
X
X
X
X
X
Serum Pregnancy Test
D
6.2.2.5.4.
X
Urine Pregnancy Test
D
6.2.2.5.4.
X
X
X
X
X
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 70
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Category
Reference 
to 
assessment 
types
Screening
Day 1 to Day 28
Day 29 to
Day 56
Day 57 to Day 168
For EOT and 
FU visits-Refer 
to Table 6-2 
and 6-3
(± 1-day 
window)
(+ 3 
days)
(± 2-
days)
(± 3-days window)
Visit no.
1
2
3
4
5
6
7
8
9
10
Study Day
-21 to -7
1
15
29
43
57
85
113
141
168
Blood sampling for PK 
(not applicable for 
patients in safety 
expansion phase)
D
6.2.3.
X
X
X
X
Prior/concomitant 
medications
D
6.1.1.3 / 
5.1.8, 5.1.9, 
5.1.10, 
5.1.11.
X
X
X
X
X
X
X
X
X
X
Adverse events
D
7.1.
X
X
X
X
X
X
X
X
X
X
INC424 morning dose at 
site
D
6.2.3.2.
X
X
Drug accountability 
assessment (Return of 
INC424 review of paper 
compliance diary)
D
5.2.4.2.
X
X
X
X
X
X
X
X
Dispense INC424
D
5.2.3.
X
X
X
X
X
X
X
X
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 71
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 6-2
Visit evaluation schedule post amendment 4 - Extension study period and End of Treatment
Category
Reference to 
assessment 
types
Extension period
(± 7-days window)
Extension 
visits (UK 
patients 
only)
End of 
treatment
(Core or 
Extension)
/ [UK only: 
Week 156
and EOT]
End of 
follow-up
(± 3-days 
window)
(Core or 
Extension)
Visit no.
11
12
13
14
15
16, 17, etc
Study Week
Week 36
(Day 252)
Week 48
(Day 336)
Week 60
(Day 420)
Week 72
(Day 504)
Week 84
(Day 588)
Week 96+ 
q12 weeks 
thru Week 
144
Week 168 
+ q12 
weeks thru 
LPFV + 
156 weeks
Last / 
Week 156
30 days 
after last 
dose
Measurement of spleen by 
palpation
D
6.2.1 / 6.2.2.1.
X
X
X
X
X
X
X
X
Vital signs
D
6.2.2.2.
X
X
X
X
X
X
X
X
Weight
D
6.2.2.3.
X
X
X
X
X
X
X
X
Complete physical 
examination
D
6.2.2.1.
X
Short physical examination
D
6.2.2.1.
X
X
X
X
X
X
X
ECOG performance status
D
6.2.2.4.
X
X
X
X
X
X
X
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 72
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Category
Reference to 
assessment 
types
Extension period
(± 7-days window)
Extension 
visits (UK 
patients 
only)
End of 
treatment
(Core or 
Extension)
/ [UK only: 
Week 156
and EOT]
End of 
follow-up
(± 3-days 
window)
(Core or 
Extension)
Visit no.
11
12
13
14
15
16, 17, etc
Study Week
Week 36
(Day 252)
Week 48
(Day 336)
Week 60
(Day 420)
Week 72
(Day 504)
Week 84
(Day 588)
Week 96+ 
q12 weeks 
thru Week 
144
Week 168 
+ q12 
weeks thru 
LPFV + 
156 weeks
Last / 
Week 156
30 days 
after last 
dose
ECG
D
6.2.2.7.1.
X
If before 
Day 168
Prior/concomitant 
medications
D
6.1.1.3 / 5.1.8, 
5.1.9, 5.1.10, 
5.1.11.
X
X
X
X
X
X
X
X
X
Adverse events
D
7.1.
X
X
X
X
X
X
X
X
X
Drug accountability 
assessment (Return of 
INC424 review of paper 
compliance diary)
D
5.2.4.2.
X
X
X
X
X
X
X
X
Dispense INC424
D
5.2.3.
X
X
X
X
X
X
X
Antineoplastic therapies used 
for MF since discontinuation 
of INC424
D
6.1.5.
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 73
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 6-3
Laboratory assessment schedule post amendment 4 – Extension study period
Category
Reference to assessment types
Extension period
(± 7-days window)
Extension visits (UK 
patients only)
End of Treatment
(Core or 
Extension) / [UK 
only: Week 156
and EOT]
Endpoint 
follow up (+ 3-
days window)
(Core or 
Extension)
Visit No.
Clinic Visits
Study Week
Weeks 36,48, 60, 72, 84, 96, 108, 
120, 132 & 144
Week 168 + q12 
weeks
Last
Week 156
30 days after 
last dose
Serum chemistry 
tests
D
6.2.2.5.3. / ALT, AST, Alkaline 
phosphatase, Total and Direct 
Bilirubin, Albumin, Lactate 
dehydrogenase, Creatinine, BUN, 
Sodium, Potassium, Glucose, 
Calcium, Uric acid (Appendix 12)
X
No lab  visits  required after  Week 156
X
X
if occurs in Core 
Phase
Hematology
D
6.2.2.5.1. / Complete Blood Count 
(CBC) Differential, including 
reporting of % blasts, Platelets 
(Appendix 12)
X
X
X
Urine Pregnancy 
test
D
6.2.2.5.4.
X
X
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 74
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
6.1.1
Screening examination
Prospective participants will be scheduled for a Screening visit by site staff. The window for 
this visit is Day -21 to Day -7. Site staff should inform patients to come to the clinic after an 
overnight fast of at least 8 hours or since midnight on the day that blood will be drawn for 
laboratory assessments. Informed consent must be obtained before any study specific 
procedures are conducted.
A patient who has a laboratory test result(s), apart from an ECG finding that does not satisfy 
the eligibility criteria may have the test(s) repeated once. These tests may be repeated as soon 
as the Investigator believes that the retest result is likely to be within the acceptable range to 
satisfy the entrance criteria, but should be completed within 13 days of the original Screening 
Visit date. In this case, the patient will not be required to sign another ICF, and the original 
patient ID number assigned by the Investigator will be used. In the event that the laboratory 
test(s) cannot be performed within 13 days of the original Screening Visit, or the re-test(s) do 
not meet the entrance criteria (apart from platelet count, see also Section 6.1.1.1) or the 
patient’s medical condition has changed significantly during the screening period so that 
inclusion/exclusion criteria are no longer met, the patient is considered a Screen failure, and 
must be discontinued from the study. If the patient and Investigator choose to re-screen the 
patient, the patient must sign a new ICF, a new patient ID number will be assigned by the 
Investigator, and all required Screening activities must be performed when the patient is re-
screened for participation in the study. An individual patient may only re-Screen once per 
stratum for the study. Once the number of patients screened and enrolled in the respective 
dose cohort and stratum is likely to assure target enrollment, the Sponsors may, at its 
discretion, close the dose cohort and stratum study to further screening. In this case, patients 
who screen fail will not be permitted to re-Screen.
6.1.1.1
Eligibility screening
Patients must meet all inclusion and exclusion criteria at Screening or at Day 1 in order to be 
eligible to proceed to the Treatment Phase of the study.
The platelet count value needs to be within the permitted range at Screening OR at Day 1 to
qualify the patient for enrolment for the respective stratum. Platelet count re-tests are
authorized at Screening within 13 days and at the planned day of first study treatment within 7 
days. Therefore any of the 4 platelet count values (at screening, at screening re-test, at the 
planned day of first study treatment or at its re-test) may qualify the patient in the study. The 
day at which the treatment will eventually start will be defined as the Study Day 1. If the 
platelet count value is not within the permitted range neither at Screening nor at Study Day 1
nor at the re-tests, the patient will be considered a screen failure.
Patient eligibility will be confirmed by the investigative staff and captured within the source 
documents maintained at the site. This information will be made available during planned 
interim monitoring visits and compared against the clinical database for accuracy. Only when 
eligibility has been confirmed will the patient be assigned to a treatment stratum and dose 
level. Additionally, investigative site staff will enter patient information into the eCRF, and 
automated queries will be generated for immediate resolution should patient eligibility be in 
question based on the patient information entered.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 76
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
141, and 168).    Thereafter, in the extension study period, the on-treatment study visits will 
be every 12 weeks from Day 168 (on Days 252, 336, 420, 504, 588, etc.) through Week 144 
and an EOT visit scheduled for Week 156. There will not be any required laboratory-only 
visits.
[The above paragraph will read as follows for the United Kingdom only: 
For UK patients only, with the implementation of Amendment 4, during the core treatment 
period, from screening until Day 168, on-treatment study visits are scheduled every 2 weeks 
in the first 8 weeks (Study Days 1, 15, 29, and 43), then every 4 weeks until Day 168 (Study 
Days 57, 85, 113, 141, and 168).  Thereafter, in the extension study period, the on-treatment 
study visits will be every 12 weeks from Day 168 (on Days 252, 336, 420, 504, 588, etc.) 
through Week 156. After Week 156, patients will return to the site every 12 weeks until LPFV 
plus 156 weeks, when the EOT visit will be performed.  There will not be any required 
laboratory-only visits.]
For all patients, core treatment period visit windows are as follows: Day 15 has a ± 1-day 
window, Day 29 has a +3 day window, Day 43 has a ± 2-days window, Study Days 57, 85, 
113, 141, and 168 have a ± 3-days window. Extension study period visits have a ± 7-day visit
window.
Patients should be told to arrive for all Study Visits after an overnight fast of at least 8 hours,
with exception for morning medications for any other medical indication e.g. hypertension 
should be taken with a small amount of water. However Study Visits should still be conducted 
if the patient does not adhere to fasting requirements and this will not be considered a protocol 
violation. If, at any time during the study, a patient experiences unexpected signs or 
symptoms, additional safety evaluations should be conducted at a regular Study Visit or 
unscheduled visit.
[For United Kingdom patients only:
Since UK patients can continue beyond the 3 year treatment period, study visits will continue 
to occur every 12 weeks after Week 156. However, for these subsequent visits, ONLY the 
following summary eCRFs should be completed: Adverse events, Concomitant Medications, 
Dose Administration Records, Transfusions, and Non-drug Therapies and Procedures.
Laboratory assessments, vital signs, and physical examination findings will not be captured in 
the eCRF (unless constituting an adverse event), but will be recorded in the source documents 
at the study center.
At end of treatment and at study discontinuation, all UK patients, including those with visits 
after Week 156, are required to complete the end of treatment and study evaluation 
completion assessments. The corresponding eCRFs will need to be completed.]
6.1.4
Discontinuation of Study Treatment/ Study
Patients may voluntarily discontinue from study treatment and from the study for any reason 
at any time. If a patient decides to discontinue from the study treatment/ study , the 
investigator should make a reasonable effort (e.g., telephone, e-mail, letter) to understand the 
primary reason for this decision (or as per local regulation) and record this information in the 
patient’s chart and on the appropriate eCRF pages. Patients may be considered withdrawn if 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 77
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
they state an intention to withdraw, fail to return for visits, or become lost to follow-up for 
any other reason.
The investigator should discontinue study treatment and discontinuation from the study for a 
given patient if he/she believes that continuation would be detrimental to the patient’s well-
being.
Study treatment must be discontinued and study participation ended under the following 
circumstances:

Emergence of the following treatment related adverse events or lab abnormalities (see 
Section 5.1.2.8 and Table 5-4:
o
Grade 3 or 4 hemorrhagic event of any kind
o
Second episode of grade > 3 febrile neutropenia (ANC < 1.0 x 109/L, with a single 
temperature of ≥ 38.3 °C or a sustained temperature of ≥ 38 °C for more than one 
hour)
o
Grade 3 renal toxicity for ≥ 7 consecutive days
o
Grade 4 renal toxicity
o
Grade 4 serum bilirubin with direct bilirubin > 0.5 mg/dL
o
Grade 4 non-hematologic toxicity
o
Grade 4 serum creatinine related to treatment from Day 1 to Day 28
o
Second episode of grade 3 or 4 serum creatinine from Study Day 29
o
Grade 4 other adverse event
o
Platelet counts reduce < 25 x 109/L while taking INC424 at 5mg qd

Pregnancy

The following deviations from the prescribed dose regimen:
o
Interruption of study treatment for > 28 days regardless of reason
o
If after 2 dose reductions and after the treatment has resumed at the lower dose, the 
same toxicity recurs with the same or worse severity (except for thrombocytopenia, 
anemia, and neutropenia)
o
If a patient cannot tolerate dose level (-1) (5 mg qd), which is the lowest acceptable 
dosing level for this study.

There is disease progression (see Section 6.2.1). As an exception, if, despite disease 
progression which is documented by > 40% increase in spleen size and not by leukemic 
transformation, the Investigator believes that it is in the patient’s best interest to continue 
therapy with INC424 due to symptomatic improvement, the patient may continue therapy, 
only after consultation with the Sponsors.

Use of prohibited treatments (refer to Appendix 1) as determined by Novartis

Patient undergoes splenic irradiation

Patient undergoes splenectomy. As an exception, patients who participate in the safety 
expansion phase of the study are allowed to continue in the study, provided that they have 
fully recovered from the surgery and are discharged from the hospital.

Death
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 78
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

Any other protocol deviation that results in a significant risk to the patient’s safety

Patient has completed 3 years of treatment and another treatment option is available

Patient is non-complaint with the protocol 

Study is terminated by the Sponsor
Patients whose treatment is interrupted or permanently discontinued from the study due to an 
Adverse Event or abnormal laboratory value must be followed at least once a week for 30 
days, and subsequently at 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. All patients will be followed for Adverse Events and Serious Adverse 
Events for 30 days following the last dose of INC424.
Patients who discontinue study treatment and study participation should return for the 
assessments indicated in Table 6-1, Table 6-2, and Table 6-3 for safety reasons. If they fail to 
return for these assessments for unknown reasons, every effort (e.g. telephone, email, letter) 
should be made to contact them as specified in Section 6.1.6. 
6.1.4.1
Replacement policy
Patients withdrawn from the study will not be replaced.
However, if, from Study Day 1 through Study Day 28, a patient misses > 6 consecutive doses
of treatment or > 20% of the planned study drug doses, the patient can continue in the study 
without being evaluable for DLTs. Consequently, another patient has to be enrolled into the 
same dose level and stratum in order to reach the required number of patients in the cohort.
6.1.5
Follow up for safety evaluations
All patients, including those who discontinue study treatment and those who refuse to return 
for an EOT visit, will be contacted for safety evaluations 30 days after the last dose of study 
treatment. Patients must be followed for the occurrence of Adverse Events, Serious Adverse 
Events, concomitant medications, antineoplastic therapies used for treating myelofibrosis 
disease since discontinuation of study drug, and transfusion use. Patients whose treatment is 
interrupted or permanently discontinued due to an adverse event, including abnormal 
laboratory value, must be followed until resolution or stabilization of the event, whichever 
comes first. See Table 6-1, Table 6-2, and Table 6-3 for a complete list of assessments for the 
30 day follow up evaluation. 
Data collected should be added to the Adverse Events eCRF and the Concomitant 
Medications eCRF.
6.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show “due diligence” by contacting 
the patient, family, or family physician as agreed in the informed consent and by documenting 
in the source documents the steps taken to contact the patient (e.g. dates of telephone calls, 
registered letters, etc.).  A patient should not be considered lost to follow-up until due 
diligence has been completed.  Patients lost to follow up should be recorded as such on the 
appropriate Disposition eCRF.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 79
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
6.1.7
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.  Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visit assessments, and does not want any 
further study related contact.
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation.  All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations).
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. 
telephone, e-mail, letter) to understand the primary reason for this decision (or as per local 
regulation) and record this information.
Study treatment must be discontinued and no further assessments conducted.
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
6.2
Assessment types
6.2.1
Efficacy
Efficacy is a secondary endpoint in this study. The primary response assessment will consist 
of measurement of the spleen length by manual palpation at the end of week 24 (Study Day 
168) in comparison to the Study Day 1 measurement. Patients who have a ≥ 50% reduction in 
spleen size by palpation compared to the initial measurement at Study Day 1 will be 
considered as responders, otherwise they will be considered non-responders. Spleen length 
measurements will continue to be measured after Week 24 to evaluate spleen length and 
percent change from baseline over time. In addition spleen lengths measurements will be 
conducted at every study visit in order to exclude disease progression, which is a criterion for 
patient withdrawal (see Table 6-1, Table 6-2, Table 6-3 and Section 6.1.4.1). Disease 
progression will be documented by > 40% increase in spleen size by palpation compared to 
the initial measurement at Study Day 1 or by disease symptoms progression based on the 
Investigator’s expert judgment or by leukemic transformation (as evidenced by bone marrow 
blast counts of at least 20%, or peripheral blast counts of at least 20% lasting at least 2 
weeks).
The edge of the spleen shall be determined by palpation, and measured in centimeters, from 
the costal margin to the point of greatest splenic protrusion. Investigators will be provided 
with a soft centimeter ruler so that palpable spleen length is measured in centimeters and not 
in finger breadths. No imaging studies of any kind will be required for efficacy assessments.
6.2.2
Safety and tolerability
Safety will be monitored by assessing as well as collecting of the adverse events at every visit. 
For details on AE collection and reporting, refer to Section 8.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 80
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
6.2.2.1
Physical examination, weight, height
A complete physical examination will be performed, as noted in Table 6-1, Table 6-2, and 
Table 6-3. It will include the examination of general appearance and vital signs (blood 
pressure [BP], respiratory rate, temperature and pulse), skin, head, eyes, ears, nose, neck 
(including thyroid), throat, lungs, heart, abdomen (liver, spleen), back, lymph nodes, edema 
and extremities, vascular and neurological. In addition, the examination will include body 
systems as indicated by patient symptoms, AEs, prior physical examination, past medical 
history or other findings as determined by the Investigator. Measurement of spleen size, 
assessed by palpation and measured in centimeters using a soft ruler, from the costal margin 
to the point of greatest splenic protrusion, will be performed at every visit. The above 
described detailed physical examination will be conducted during the Screening Visit, the first 
day of every treatment cycle, the End of Treatment visit, and the follow up visit (Table 6-1, 
Table 6-2, and Table 6-3). During the intermediate visits of the cycles 1 and 2, only short 
physical examinations will be performed, which will include general appearance and vital 
signs (blood pressure [BP], respiratory rate, temperature and pulse), skin, lungs, heart, 
abdomen (liver, spleen), edema and extremities, body systems as indicated by patient
symptoms, AEs, and measurement of spleen size (Table 6-1, Table 6-2, and Table 6-3).
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 is signed must be 
recorded on the Adverse Event page of the patient’s eCRF.
6.2.2.2
Vital signs
Vital signs (blood pressure, pulse, respiratory rate and body temperature) will be collected 
according to the Visit Schedule outlined in Table 6-1, Table 6-2, and Table 6-3. Vital signs 
will be taken with the patient in the sitting position after 5 minutes of rest. Body temperature 
may be measured orally or via ear.
6.2.2.3
Height and weight
Height in centimeters (cm) will be measured only at screening. Body weight in kilograms (to 
the nearest 0.1 kilogram [kg] in indoor clothing, but without shoes) will be measured during 
the Screening Visit, the first day of every treatment cycle, the End of Treatment visit, and the 
follow up visit (Table 6-1, Table 6-2, and Table 6-3).
6.2.2.4
Performance status
The performance status will be assessed according to the ECOG performance status scale as 
noted in Table 6-1, Table 6-2, and Table 6-3. The ECOG performance status is graded on a 
six point scale (range 0 to 5): 0=Asymptomatic (Fully active, able to carry on all pre-disease 
activities without restriction); 1=Symptomatic but completely ambulatory (Restricted in 
physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature. For example, light housework, office work); 2=Symptomatic, < 50% in bed during the 
day (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=Symptomatic, > 50% in bed, but not bedbound 
(Capable of only limited self-care, confined to bed or chair 50% or more of waking hours); 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 82
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
6.2.2.7
Cardiac assessments
6.2.2.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed:

at screening

at Study Days 1, 29, 85, 168

at the End of Treatment visit if before Day 168
Interpretation of the tracing must be made locally by a physician and documented on the ECG 
section of the eCRF. Each ECG tracing should be labeled with the study number, patient
initials, 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 page of the eCRF. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events page.
6.2.3
Pharmacokinetics
6.2.3.1
Rationale for incorporating pharmacokinetic evaluations
Pharmacokinetic evaluations incorporated in this study will aim to:
1. Compare the low-PLT MF population with the MF population enrolled in the phase I/II 
[INCB 18424-251] and the phase III [INCB 18424-351] and [INCB 18424-352] studies.
2. Compare safety and efficacy profiles (sensitivity to exposure) of this population to 
[INCB 18424-251], [INCB 18424-351], and [INCB 18424-352] study populations in order 
to make dose recommendations for low-platelet MF if there is a clinically significant 
difference.
6.2.3.2
Pharmacokinetic blood sample collection and handling
Eight blood samples for pharmacokinetic (PK) analyses will be collected from patients over 4 
visits in accordance with the study schedule.
Three PK samples will be taken at Study Day 1 visit after completion of screening visit and 
administration of study drug (Sample #1: 15 minutes to 45 minutes post dose, Sample #2: 1 to 
3 hours post dose, and Sample #3: 4-12 hours post dose). Patients will withhold the morning 
dose of INC424 on the Study Day 15 visit. At the study clinic, Sample #4 will be drawn, just 
prior to administration of the morning dose of study drug, followed by Sample #5 at 15 
minutes to 45 minutes post dose and Sample #6 1 to 3 hours post dose. Sample #7 will be 
randomly drawn at Study Day 29 visit, and Sample #8 will be randomly drawn at Study Day 
57 visit (see Table 6-4).
The exact date and time of the PK blood draws will be recorded along with the dates, times, 
and mg doses of the last dose of INC424 that preceded the blood draw and any other doses on 
the day of the blood draw that precede the blood draw. The actual dose regimen from the prior 
day should also be recorded. Patients that arrive for the Study Day 15 visit having already 
taken their morning dose should be reminded to come back within the next 2 days for the PK 
collection without having taken their morning dose. Patients that arrive for Study Day 15 visit, 
Study Day 29 visit, and Study Day 57 visit and are not sure of the time of their last dose 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 83
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
should be reminded to come back within the next 2 days for PK collection with the time of 
their last dose. Instructions for sample preparation and shipping will be provided in a 
laboratory manual.
For each patient, the observed plasma concentration of INC424 will be determined in samples 
drawn at visits described in the schedule of observations. The time of the prior dose will be 
recorded on a patient reminder card, and this information will be entered onto the eCRF.
With implementation of amendment 3, PK blood sampling will no longer be required for 
patients entering into the safety expansion phase.
Table 6-4
Sample collection time windows for population pharmacokinetic 
assessments
Study Day 1 Visit
3 samples on the first day of 
dosing
Study Day 15 visit
3 samples
Study 
Day 29
visit
1 sample
Study 
Day 57
Visit
1 sample
Assess
ment
0.25-0.75 
hours 
post-study 
drug 
administr
ation
1-3 hours 
post-study 
drug 
administr
ation
4-12 
hours 
post-
study 
drug 
administr
ation
Trough: 
0.5 hour 
prior to 
study 
drug 
administr
ation*
0.25-0.75 
hours 
post-
study 
drug 
administr
ation
1-3 hours 
post-
study 
drug 
administr
ation
0-24 
hours 
post-
study 
drug
0-24 
hours 
post-
study 
drug
Sample 
No
1
2
3
4
5
6
7
8
Plasma 
sample
X**
X**
X**
X**
X**
X**
X
X
* Sample collected 8-16 hours post-study drug for b.i.d. dose regimen. Study drug administered approximately 30 
min after sample collection.
**Plasma samples at these time points are collected on the same day on the single visit specified.
6.2.3.3
Analytical method
The plasma samples will be analyzed for INC424 by a validated LC/MS/MS assay, carried 
out by the Sponsors’ designee. Plasma concentrations of INC424 will be determined 
following a liquid/liquid extraction procedure using methyl-t butyl ether (MTBE) with 13C4-
INC424 (INCB028452) as the internal standard. Chromatography will be performed with a 
Phenomenex Synergi 4µ Polar-RP 80A (30 x 2 mm) column under isocratic conditions and a 
mobile phase consisting of 55% acetonitrile and 45% 2mM ammonium acetate aqueous 
solution. LC/MS/MS analysis will be performed using a positive Turbo IonSpray® interface 
on a Sciex API-3000 and multiple reaction monitoring (MRM). Using 50 µL plasma, this 
assay produces linear results over a plasma concentration range of 1.0-1000 nM for INC424, 
corresponding to the lower and upper quantitative limits, respectively.
6.2.4
Other assessments
6.2.4.1
Pharmacodynamics
6.2.4.1.1 Rationale for incorporating pharmacodynamic evaluations
Pharmacodynamic evaluations incorporated in this study will aim to:
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 86
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Adverse Events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an Adverse Event, the 
severity of mild, moderate, severe, and life-threatening, or grades 1-4, will be used. CTCAE 
grade 5 (death) will not be used in this study; rather, information about deaths will be 
collected through a Death form. The occurrence of Adverse Events should be sought by non-
directive questioning of the patient 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 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)

Causality to the Adverse Event (reasonable possibility that the AE is related to the study 
drug). Since this is an open-label study, the relationship to study drug is only assessed for 
INC424. For study investigative sites in EU: if the AE is serious, then the causality to 
INC424 needs to be assessed to comply with requirements according to the EU Clinical 
Studies Directive.

Start and end dates, unless unresolved at the follow-up visit

Action taken with respect to study drug (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)

Whether it is serious, as per SAE definition provided in Section 7.2.
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements, see Section 7.2.
All Adverse Events should be treated appropriately. Treatment may include one or more of 
the following: no action taken (i.e. further observation only); study drug dosage 
adjusted/temporarily interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication given; non-drug therapy given; patient hospitalized/patient’s 
hospitalization prolonged. The action taken to treat the adverse event 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 drug, the 
interventions required to treat it, and the outcome.
Disease progression should not be regarded or reported as an Adverse Event itself unless 
associated with a separate Adverse Event.
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 87
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
7.1.2
Laboratory test abnormalities
7.1.2.1
Definitions and reporting
Abnormal laboratory values or test results that constitute adverse events or underlying 
conditions should not be reported separately in addition to the respective adverse events or 
underlying diagnosis.
Additionally, laboratory abnormalities that are considered clinically significant due to 
induction of clinical signs or symptoms, or requiring concomitant therapy (e.g. any 
hematologic abnormality that requires transfusion or cytokine treatment) or changes in study 
medication, should be recorded on the Adverse Events eCRF. Whenever possible, a diagnosis, 
rather than a symptom should be provided (e.g. anemia instead of low hemoglobin). 
Laboratory abnormalities that meet the criteria for Adverse Events should be followed until 
they have returned to normal or an adequate explanation of the abnormality is found.
Laboratory abnormalities, that do not meet the criteria of clinical significance, as judged by 
the Investigator, 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. Dose modifications described in the 
Table 5-4 for lab abnormalities should not contribute to designation of a lab parameter 
abnormality as a SAE.
7.2
Serious adverse events
7.2.1
Definitions
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 MF, 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

Any SAEs that are expected due to MF, including if the SAE is a primary outcome 
measure, and whether there has been a clear agreement with regulators not to consider 
these as SAEs, provided the information is collected elsewhere
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 88
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
7.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to the Sponsors or designee within 24 hours of learning of its 
occurrence. Any SAEs experienced after this 30-day period should only be reported to the 
Sponsors or designee if the Investigator suspects a causal relationship to the study drug. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode within 24 hours of the Investigator receiving the follow-up 
information. A 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 the study drug, 
complete the SAE Report Form in English, and send the completed, signed form by fax within 
24 hours to the Sponsors’ Integrated Medical Safety (IMS) department.
The telephone and telefax number of the contact persons in the local department of Integrated 
Medical Safety (IMS), 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 person 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 and whether the patient continued or withdrew from study 
participation.
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the Sponsors’ study drug, a Sponsors’ associate may urgently 
require further information from the investigator for Health Authority reporting. Sponsors
may need to issue an Investigator Notification (IN), to inform all investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries.
7.2.3
Emergency unblinding of treatment assignment
Not applicable. This will be an open-label study.
7.3
Pregnancies
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
the Sponsors 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.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 89
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the Sponsors. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the Sponsors’ study drug of any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form.
7.4
Warnings 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 (IN). This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
7.5
Data Monitoring Committee
Not applicable.
7.6
Steering Committee
Not applicable.
8
Data review and management
8.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients 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 patient 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.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 90
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
8.2
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, Sponsors’
personnel (or designated CRO) 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 the eCRFs, the adherence to the 
protocol 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 recorded on eCRFs must be traceable to source documents in the 
patient's file. 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, including 
electronic documents if that is the source, to confirm their consistency with the eCRF entries. 
Sponsors monitoring standards require full verification for the presence of informed consent, 
adherence to the inclusion/exclusion criteria and documentation of SAEs. Additional checks 
of the consistency of the source data with the eCRFs are performed according to the study-
specific monitoring plan.
8.3
Data collection
The designated investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (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 the data to be confirmed or corrected in a timely manner 
before it is reviewed by the data management (DM) group. Before transfer to the Sponsors (or 
designated CRO) via a secure network the investigator must certify that the data entered into 
the Electronic Case Report Forms are complete and accurate. After database lock, the 
investigator will receive a CD-ROM or paper copies of the patient data for archiving at the 
investigative site.
8.4
Database management and quality control
Data will be entered into the study database by the designated investigator site staff.
Following data entry into the eCRFs, Sponsors personnel (or designated CRO) will review the 
data entered by investigational staff for completeness and accuracy. Electronic data queries 
stating the nature of the problem and requesting clarification will be created for all other 
discrepancies and missing values and sent to the investigative site via the EDC system. 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 92
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
The data will be summarized with respect to demographic and baseline characteristics, 
occurrence of dose-limiting toxicities (DLTs), efficacy observations and measurements, safety 
observations and measurements, and pharmacokinetic/pharmacodynamic measurements.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
All data will be listed unless otherwise specified.
9.1
Analysis sets
In general, data summaries will be presented by dose levels unless otherwise stated. Dose 
levels may be combined for summary purposes based on the observed outcomes. For 
example, it may be prudent to summarize according to starting dose received as: lower than 
MSSD, MSSD, and higher than MSSD. DLT outcomes will be summarized separately by 
dose level and stratum. Additional key safety information, such as incidence of hematologic 
adverse events and labs, may be summarized separately by stratum.
9.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
medication.
9.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication. 
Patients will be analyzed according to the study treatment (regimen) they actually received.
A precise definition of “actually received” will be added in the RAP.
9.1.3
Dose-determining Set
The Dose-determining Set (DDS) consists of all patients from the safety set who either (i) 
meet the minimum exposure criterion and have sufficient safety evaluations as defined below, 
or (ii) discontinue due to DLT. The patients in the DDS enrolled in the dose-finding part of 
the study will be the patients used for determination of the MSSD.
A patient is considered to have met the minimum exposure criterion and to have had sufficient 
safety evaluations if they have not missed > 20% of the planned doses and no more than 6 
consecutive doses in the first 28 days, and have completed all required safety evaluations 
through Study Day 28.
9.1.4
Pharmacokinetic analysis set
The Pharmacokinetic Analysis Set (PAS) consists of all patients with at least one evaluable 
pre-dose plasma PK sample at any visit. A pre-dose plasma PK sample is defined as evaluable 
if it is received within 3 hours of the scheduled time (e.g., between 8-16 hours following the 
previous day dosing).
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 93
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
9.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be summarized descriptively by dose level for the 
FAS. Categorical data will be presented as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
9.3
Treatments (study drug, concomitant therapies, compliance)
The dose and duration of INC424 will be listed and summarized by dose level using 
descriptive statistics. Data may be presented by cycle in addition to over the entire study 
duration. The daily dose will be summarized using descriptive statistics by dose level and will 
be listed by patient.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug will be summarized for the safety set.
Compliance to the study protocol will be assessed by reporting the number and type of 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized. Compliance to study drug, for the period from Study Day 1 to end of treatment, 
will be summarized by categories of < 83.3% vs. ≥83.3% and will be reported by dose level 
or combination of dose levels as appropriate.
9.4
Primary objective
The primary objective of the study is to determine the maximum safe starting dose (MSSD) of 
INC424 given orally, twice-a-day, in a 28-day cycle to patients with myelofibrosis who have 
baseline platelet counts belonging to 1 of 2 strata: (1) [75 - 100 x 109 / L) or (2) [50 - 75 x 109
/ L).
The corresponding primary analysis method is an adaptive Bayesian logistic regression model 
guided by escalation with overdose control (EWOC) (Babb et al 1998). A prior distribution 
for the model parameters is derived based on experience with INC424 in adult patients in 
clinical study [INCB 18424-251], which was the dose-finding study in patients with 
myelofibrosis that preceded the pivotal phase III studies [INC424A-351] and [INC424A-352]
(see Section 1.2.4). This prior distribution is then updated after each cohort of patients in each 
stratum with the DLT data from the current study. A detailed description of the used 
methodology can be found in Section 9.4.2 and Appendix 13.
9.4.1
Variable
Estimation of the MSSD in the dose-escalation part of the study will be based upon the 
estimation of the probability of DLT for patients in the DDS. This probability is estimated 
from the model described in Section 9.4.2.
The definition of DLT is provided in Section 5.1.2.7.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 94
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
9.4.2
Statistical hypothesis, model, and method of analysis
Statistical model
The statistical model for MSSD estimation will be based on a 3-parameter Bayesian logistic 
regression model. Let π(d) be the probability of DLT at total daily dosed (in mg), and let d*
denote a reference dose of INC424. Then the 3-parameter logistic model relating the log-odds 
for a DLT to the dose and stratum is of the form
logit(π(d)) = log(α) + β log(d/d*) + γI{pt is in stratum 2},
where logit(π(d))= loge((d)/(1-(d))), α, β > 0, and -∞ < γ < ∞. Doses are rescaled as d/d*, and 
as a consequence α is equal to the odds of the probability of DLT at d* for a patient in stratum 
1. If a patient is from stratum 2, the indicator I{pt is in stratum 2} takes the value 1, otherwise it 
takes the value zero. Therefore, γ may be interpreted as the log-odds ratio for the probability 
of DLT between patients from stratum 2 to patients from stratum 1.
Prior specifications
The derivation of the final prior for usage in this study was a several step process which 
capitalized on the data observed in the 117 patients treated in the [INCB 18424-251] study at 
1 of 4 b.i.d. schedules as described in this section. The general approach was as follows:
Step 1: A Bayesian logistic regression model was applied to the [INCB 18424-251] data using 
dose and baseline platelet count (as a continuous variable) as covariates, which resulted in 
posterior estimates for the model parameters, and the effect of the baseline platelet count 
when treated as a continuous covariate.
Step 2: Using the model from Step 1, the estimated probabilities of DLTs were determined for 
the patients in stratum 1 of the current study. Since the assumed mean baseline platelet count 
in stratum 1 is 87 x109/L (i.e., the midpoint of the range permitted in stratum 1), an 
extrapolation of the model relative to the [INCB 18424-251] data was required. In addition, an 
adjustment to the variance estimates was required to account for “between trial 
heterogeneity”. Note that in stratum 1, the indicator applied to γ is zero, so the only model 
parameters are log (α) and log (β).
Step 3: The adjusted posterior estimates, as described in Step 2 and which are labeled as 
“Predicted”, were assigned 90% relative weight for the final prior. The remaining 10% weight 
was allocated to an additional “Low toxicity” prior that was developed to ensure the final 
prior could react reasonably well to data early on that are inconsistent with the prior from Step 
2.
Step 4: A minimally informative prior for γ was developed assuming a relatively strong (i.e.
conservative) stratum 2 effect.
The final prior for the current study, as well as the resulting DLT prior probability estimates 
for each stratum, are provided in Table 9-1.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 95
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 9-1
Final prior for the current study
Prior distributions for the current study: Priors for log (α) and log (β) are normally distributed
Means
log (α), log (β)
Standard deviations
log (α), log (β)
Correlation
Weight
Predicted
-1.010, -0.259
0.876, 0.918
-0.103
0.9
Low toxicity
-1.447, -0.385
1.095, 1.412
-0.065
0.1
Covariate (γ)
log(1.5)
0.354
N/A
N/A
Prior probabilities of under-dosing, targeted, and over-dosing for any DLT
Total daily 
dose
Prior probabilities that P(any DLT) is in 
interval
Mean
Standard 
deviation
2.5%
50%
97.5%
[0.0,0.16)
[0.16,0.33)
[0.33,1.00]
Stratum 1
10mg
0.624
0.255
0.121
0.155
0.143
0.001
0.113
0.529
15mg
0.523
0.309
0.168
0.189
0.151
0.006
0.151
0.570
20mg
0.426
0.353
0.221
0.222
0.156
0.018
0.187
0.605
25mg
0.334
0.386
0.281
0.255
0.160
0.036
0.223
0.637
30mg
0.249
0.395
0.355
0.289
0.165
0.053
0.261
0.670
Stratum 2
10mg
0.502
0.274
0.224
0.207
0.180
0.001
0.159
0.654
15mg
0.393
0.312
0.296
0.250
0.186
0.008
0.209
0.691
20mg
0.298
0.334
0.369
0.290
0.189
0.025
0.255
0.720
25mg
0.215
0.339
0.446
0.329
0.191
0.048
0.300
0.748
30mg
0.150
0.321
0.529
0.368
0.193
0.070
0.346
0.776
Note: bold values indicate doses not meeting the overdose criterion.
Further details describing the steps outlined above are provided below.
Step 1
Data from study [INCB 18424-251] were used to derive an informative bivariate normal prior 
for the model parameters (log(α), log(β)). A 3-parameter Bayesian logistic regression model 
of the following form was used:
logit(πi) = log(αh) + βhlog(di/d*) + γh(log(ci) – c*),
where di is the total daily dose and ci the baseline platelet count of the i-th subject, logit(πi) = 
log[πi/{1- πi}], d* = 30mg (total daily dose) is the reference dose of INC424, c* = (log(c1) + 
log(c2) + … + log(cN))/N is the arithmetic mean of the logarithm of the baseline platelet 
counts of the N subjects evaluated in the study, αh, βh > 0 and -< γh < . πi denotes the 
probability of a DLT of the i-subject accounted for his/her baseline platelet count. Note also 
that subscript h was used to denote parameters which were used the fit the data from the study 
i.e. αh, βh and γh. This is done in order to distinguish them from the parameters α, β and γ 
which will be estimated in the current study.
To predict the expected DLT probability πpred at dose d and a certain level of baseline platelet 
count cpred, the above model was used in the following way:
logit(πpred,d) = log(αh) + βhlog(d/d*) + γh(log(cpred) – c*).
The exact procedure is then given as follows:
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 96
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

A non-informative prior for (log(αh), log(βh)) and for γh was derived in the following way:

The median DLT rate at the reference dose (30mg total daily dose) and at c* was 
assumed 1/3, i.e. mean(log(αh)) = log(1/2)

A doubling in dose was assumed to double the odds of DLT, i.e. mean(log(βh)) = 0

The standard deviations of the two parameters were set to 2, such that the bivariate 
normal distribution covers approximately 95% of the probability space

The correlation was set to 0, assuming independence of log(αh) and log(βh)

A non-informative prior for γh was assumed by specifying a normal prior distribution 
with mean 0 and standard deviation 2. Note that the 95% interval of this distribution 
allows for a more than 50-fold increase / decrease in odds depending on the covariate 
value

Data from 117 evaluable patients of the [INCB 18424-251] study (see Appendix 13 for the 
data) were added into the model in order to estimate log(αh), log(βh) and γh. The posterior 
distributions when the data were added into the model can be found in Table 9-2.
Table 9-2
Posterior estimates for BLRM based on study [INCB 18424-251]
Posterior distribution of log(αh), log(βh), data of study [INCB 18424-251], c* = 5.663
Parameter
Means
Standard deviations
Correlation
log(αh), log(βh )
-1.474, -0.324
0.260, 0.822
-0.383
γh
-0.383
0.396
N/A
Step 2
The model from Step 1 was used to predict the DLT probability with accompanying 95% 
credible intervals for the doses to be tested in the study (total daily dose = 10mg, 15mg, 20mg, 
25mg and 30mg) for a value of baseline platelet count = 87. This value corresponds 
approximately to the expected mean baseline platelet count in stratum 1. A multivariate 
normal distribution for parameters (log(α), log(β)) was derived based on the predicted 
quantiles such that this distribution fits the predicted dose-response relationship for a baseline 
platelet count of 87. The predicted quantiles are given in Table 9-3.
The assumption about between-trial heterogeneity was captured in the prior distributions of 
the standard deviation of (log(α),log(β)), denoted by τ1 and τ2. Both τ1 and τ2 were assumed to 
follow a log-normal distribution with mean log(0.5) and standard deviation 0.01, assuming 
substantial between-trial heterogeneity. The resulting distribution can be found in Table 9-3.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 97
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table 9-3
Predicted probability of DLT quantiles for stratum 1 and distribution of 
log(alpha), log(beta) after accounting for between trial heterogeneity
Predicted quantiles for doses to be tested in study for cpred = log(87)
dose (total, daily)
2.5th quantile
Median
97.5th quantile
10mg
0.022
0.122
0.371
15mg
0.045
0.165
0.403
20mg
0.069
0.203
0.431
25mg
0.093
0.237
0.463
30mg
0.114
0.268
0.494
Distribution for log(α), log(β) accounting for between-trial heterogeneity with τ1, τ2 ~ lognormal(0.5,0.012)
Parameter
Means
Standard deviations
Correlation
log(α), log(β)
-1.010, -0.259
0.876, 0.918
-0.103
Step 3
In order for the model to allow for the case that the predicted distribution assumes too high 
toxicity in stratum 1, the prior distribution was set up as a mixture distribution. This mixture 
consists of the predicted prior distribution and a low-toxicity distribution which assumes the 
same dose-response relationship for stratum 1 as was seen in study [INCB 18424-251]
regardless of baseline platelet count, but accounting for between-trial heterogeneity. The exact 
procedure to derive the low-toxicity distribution was a follows:

A non-informative prior for (log(α), log(β)) was derived in the same manner as for the 
main prior as listed in Step 1 above.

Data from 117 evaluable patients of the [INCB 18424-251] study (see Appendix 13 for the 
data) were added into the model in order to estimate log(α), log(β). The posterior 
distributions when the data were added into the model can be found in Table 9-4.

The assumption about heterogeneity was captured in the prior distributions of the standard 
deviation of (log(α), log(β)), denoted by τ1 and τ2. Both τ1 and τ2 were assumed to follow a 
log-normal distribution with mean log(0.75) and standard deviation 0.01, assuming 
substantial to large between-trial heterogeneity. The resulting distribution can be found in 
Table 9-4.
Table 9-4
Distributions of model parameters and final prior distribution
Posterior distribution of log(α), log(β) using data from study [INCB 18424-251].
Parameter
Means
Standard deviations
Correlation
log(α), log(β)
-1.443, -0.395
0.258, 0.942
-0.401
Distribution for log(α), log(β) accounting for between-trial heterogeneity with τ1, τ2 ~ lognormal(0.75,0.012)
Parameter
Means
Standard deviations
Correlation
log(α), log(β)
-1.447, -0.385
1.095, 1.412
-0.065
Step 4
A prior for the covariate (stratum indicator) parameter, γ, was developed by assuming that 
patients from the population defined in stratum 2 will have a higher probability of 
experiencing a DLT at a given dose level than patients from the population defined by stratum 
1. Since there are no data available for this estimation, a conservative estimate was developed 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 98
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
based on clinical judgment that set the stratum 2 effect equal to a 1.5 times higher risk in the 
odds of a DLT at a given dose vs. a patient from Stratum 1. A Normal distribution was 
assumed with this prior mean and with a variance scaled so that the 97.5th percentile 
corresponds to a 3 times higher risk on the odds scale, which implies a standard deviation 
equal to 0.354. This final prior is also given in Table 9-1.
Dose recommendation
After each cohort of patients is completed within a stratum, the posterior distribution for the 
model parameters will be obtained by simulation. The posterior distributions of the model 
parameters are used to derive the posterior distributions for (d). The posterior distributions for 
(d) will be summarized by the following three intervals

[0,16%) under-dosing

[16%,33%) targeted toxicity

[33%,100%] excessive toxicity
Following the principle of dose-escalation with overdose control (EWOC) (Babb et al 2008)
and (Neuenschwander et al 2008), after each cohort of patients the recommended dose is the 
one with the highest posterior probability of DLT in the target interval [16%, 33%) among the 
doses fulfilling the overdose criteria, namely that there is less than 25% chance that the true 
rate of DLT falls in the excessive toxicity interval. Note that the dose that maximizes targeted 
toxicity is the best estimate of the MSSD, but it may not be a safe dose according to the 
overdose criteria if the amount of data is insufficient. Ideally, if enough data are available, the 
dose recommended for the next cohort and the best estimate of the MSSD will coincide.
The dose recommended by the adaptive BLRM for each stratum may be regarded as 
information to be integrated with a clinical assessment of the toxicity profiles observed thus 
far in determining the next dose to be investigated.
The first 3 patients enrolled in the study must be enrolled from stratum 1. These 3 patients 
will be enrolled at the first dose level. Once both at least 6 patients from stratum 1 are 
confirmed to be in the DDS and dose level 3 is allowed for enrolment in stratum 1, then 
patients from stratum 2 may be enrolled. These 3 patients will be enrolled at the first dose 
level. Once all patients in a cohort have data sufficient for determination of their inclusion or 
exclusion from the DDS, their data will be reviewed, together with all previously reviewed 
data, for dose selection for patients in the next cohort. As an exception, the model will be re-
evaluated before enrollment of any additional patients to the cohort if 2 patients in the cohort 
experience DLT before the enrollment of the 3rd patient.
9.4.3
Handling of missing values/censoring/discontinuations
During the dose-finding part of the trial, one additional patient may be enrolled in each cohort 
for each patient who does not meet the criteria necessary for inclusion in the dose-determining 
set. During the dose expansion part of the trial, one additional patient may be enrolled for 
each patient who does not meet the criteria necessary for inclusion in the safety set. At the 
time of the study report, patients will have continuing events (e.g., adverse events) 
summarized using the data cut-off date as the date of completion, with an indication within 
the listings that the event is continuing.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 100
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). SECs will be further defined in the 
study Report and Analysis Plan (RAP). For each specified SEC, number and percentage of 
patients with at least one event part of the SEC will be reported.
DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade, type, and dose level. The DDS will be used for these summaries.
9.5.2.3
Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 (NCI 2009), the study’s biostatistical and reporting team will grade 
laboratory data accordingly. For laboratory tests covered by CTCAE, a grade 0 will be 
assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology and 
biochemistry laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4 (see below for details)

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
Time to onset of grade 3 or higher SECs will be summarized by dose level.
9.5.2.4
Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs
Definitions of notably abnormal results will be part of the RAP.

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
Data from other tests (e.g., electrocardiogram or vital signs) will be listed, notable values 
flagged, and any other information collected will be listed as appropriate.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 101
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
9.5.2.5
Tolerability
Not applicable.
9.5.3
Resource utilization
Not applicable.
9.5.5
Pharmacokinetics, pharmacodynamics and pharmacokinetics-
pharmacodynamics
9.5.5.1
Pharmacokinetic data analysis
The pharmacokinetics of INC424 in this patient population will be estimated by population 
modeling methodology. INC424 plasma concentrations will be analyzed using NONMEM 
software. The data from this study may be combined with data from other clinical studies to 
improve parameter estimation.
9.5.5.2
Pharmacodynamic data analysis
Attempts will be made to characterize the dose/exposure-response relationship read outs of 
pharmacology, safety and efficacy collected during the study. Relationships between these 
exposures measures and spleen size, plasma cytokines, platelets, and presence of any dose 
limiting toxicity will be initially summarized graphically by selected visits of interest, e.g. 
Study Day 15, Study Day 29, and Study Day 57. If there is evidence of a useful exposure-
response relationship, then it will be quantified by an appropriate regression model, e.g., 
logistic regression.
9.5.5.3
Pharmacokinetic-pharmacodynamic data analysis
The relationship between pharmacokinetic model predicted concentrations/parameters and 
pharmacologic, safety and efficacy read outs are planned. A longitudinal analysis of platelets 
(absolute values or change from predose) using predicted pharmacokinetics and baseline 
platelet value as covariates will be performed to assess platelet change over time.
INC424 plasma concentrations will be analyzed using population PK using NONMEM. PK 
data may be combined with data from other clinical studies to improve PK parameter 
estimation. The population PK model will be used to derive estimates of individual steady-
state exposure measures using the initial planned dose regimen for the patients in study 
INC424A2201 (e.g., total mg dose on Day 1, Cmin, Cmax, and Cavg computed over 24 hours).
A longitudinal population PK/PD analysis of platelets will be performed to assess platelets 
incorporating dose interruptions and dose changes over time if thrombocytopenia is the DLT 
of most concern and alternative dose regimens or dose adjustment strategies need to be 
considered for potential use in new clinical studies.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 104
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
appropriate per the CTT. Approximately 21 patients are planned within each stratum in the 
dose-finding portion of the study assuming 3 patients treated at each dose level and 5 dose 
levels tested. Once the MSSD is determined, an additional 10 patients will be enrolled per 
stratum in the safety expansion phase in order to further evaluate the endpoints on patients 
starting at the MSSD.Based on a review of the interim analysis data, a decision was made to 
expand the 10 mg BID starting dose for Stratum 1.  Following the approval of Amendment 4, 
new patients enrolled to Stratum 1’s safety expansion phase will begin treatment with 
ruxolitinib at 10 mg BID. In line with the original sample size specification for the MSSD 
cohorts (i.e. > 9 patients for dose escalation phase and 10 patients for safety expansion phase), 
approximately 20 patients in total will be enrolled, including those already enrolled at the 10 
mg BID dose level in Stratum 1. 
Patients already taking the 15 mg BID dose in Stratum 1’s safety expansion phase will 
continue to take their assigned dose.  Stratum 2 will maintain its original enrollment 
requirement of 10 patients at the MSSD.
Thus, as of Amendment 4, the approximate number of patients planned to be enrolled in the 
Dose-Determining Set (DDS) for this study is 72.
10
Ethical considerations and administrative procedures
10.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with 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.
10.2
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 
Sponsors 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 Sponsors monitors, auditors, Sponsors Clinical 
Quality Assurance representatives, designated agents of Sponsors, IRBs/IECs/REBs and 
regulatory authorities as required.
10.3
Informed consent procedures
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 
patient. In cases where the patient’s representative gives consent, the patient should be 
informed about the study to the extent possible given his/her understanding. If the patient is 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 105
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
capable of doing so, he/she should indicate assent by personally signing and dating the written 
informed consent document or a separate assent form. Informed consent must be obtained 
before conducting any study-specific procedures (i.e. all of the procedures described in the 
protocol). The process of obtaining informed consent should be documented in the patient 
source documents.
Sponsors will provide Investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the Investigator
must be agreed to by Sponsors before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Sponsors monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
10.4
Discontinuation of the study
Sponsors reserve 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 3.9.
10.5
Publication of study protocol and results
Sponsors assure 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.
10.6
Study documentation, record keeping and retention of 
documents
The Investigator must ensure that all records pertaining to the conduct of the clinical study, 
informed consent forms, drug accountability records, source documents, and other study 
documentation are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.
The Investigator must not destroy any records associated with the study without receiving 
approval from the Sponsors. The Investigator must notify the Sponsors in the event of 
accidental loss or destruction of any study records. If the Investigator leaves the institution 
where the study was conducted, the Sponsors must be contacted to arrange alternative record 
storage options.
Whenever possible, an original recording of an observation must be retained as the source 
document. However, a photocopy of a record is acceptable provided it is legible and is a 
verified copy of the original document.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 106
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
All eCRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in 
compliance with applicable record retention regulations. The Sponsors will retain the original 
eCRF data and audit trail.
10.7
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 Sponsors. Signed informed consent forms and patient 
enrollment log must be kept strictly confidential to enable patient identification at the site.
10.8
Audits and inspections
Source data/documents must be available to inspections by Sponsors or designee or Health 
Authorities.
10.9
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.
11
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact Sponsors 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 
Sponsors and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
11.1
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 Sponsors, 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, Sponsors should be notified of this action and the IRB/IEC/REB at 
the study site should be informed within 10 working days.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 107
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
12
References (available upon request)
Babb J, Rogatko A, Zacks S (1998). Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med.; 17 (10):1103-20.
Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research 
and Treatment (IWG-MRT) (2008). Proposed criteria for the diagnosis of post-polycythemia 
vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the 
International Working Group for Myelofibrosis Research and Treatment. Leukemia; 
22(2):437-38.
Cervantes F, Dupriez B, Pereira A, et al (2009). A new prognostic scoring system for 
primarymyelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood; 113:2895-2901.
Deeg HJ, Gooley TA, Flowers ME, et al (2003). Allogeneic hematopoietic stem cell 
transplantation for myelofibrosis. Blood; 102:3912-8.
Elliott M, Verstovsek S, Dingli D, et al (2007). Monocytosis is an adverse prognostic factor 
for survival in younger patients with primary myelofibrosis. Leuk Res. 31(11): 1503-9.
Ferenci P, Lockwood A, Mullen K, et al (2002). Hepatic encephalopathy--definition, 
nomenclature, diagnosis, and quantification: final report of the working party at the 11th 
World Congresses of Gastroenterology, Vienna, 1998. Hepatology; 35(3):716–21.
Incyte Corporation (2009). Investigator’s Brochure INC424 Phosphate Capsules/Tablets, 
Version 8, September.
Mesa RA, Niblack J, Wadleigh M, et al (2007). The Burden of Fatigue and Quality of Life in 
Myeloproliferative Disorders (MPDs). Cancer; 109:68-76.
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) online at the NCI website, http://ctep.cancer.gov/reporting/ctc.html.
Neuenschwander B, Branson M, Gsponer T (2008). Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med.; 27 (13):2420-39.
Oken MM, Creech RH, Tormey DC, et al (1982). Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol.; 5(6):649-55.
Quintas-Cardama A, Vaddi K, Liu P, et al (2010). Preclinical characterization of the selective 
JAK1/JAK2 inhibitor INCB018424: implications for the treatment of myeloproliferative 
neoplasms. Blood; Epub ahead of print.
Slichter SJ (2004). Relationship between platelet count and bleeding risk in thrombocytopenic 
patients. Transfusion Medicine Reviews; 18;153-167.
Tefferi A, Vardiman JW (2008). Classification and diagnosis of myeloproliferative 
neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic 
algorithms. Leukemia; 22:14-22.
Trussell J (2004). Contraceptive failure in the United States. Contraception.;70:89–96.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 108
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Verstovsek S, Kantarjian H, Mesa RA, et al (2010). Safety and efficacy of INCB018424, a 
JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med.; 16;363(12):1117-27.
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://www.wma.net/e/policy/b3.htm>.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 109
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
13
Appendices
List of Appendices

Classification and diagnosis of myeloproliferative neoplasms and proposed criteria for the 
diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis

Information Regarding Effectiveness of Contraceptive Methods

Drugs that interfere with coagulation or inhibit platelet function

Hepatic encephalopathy grading according to West Haven Criteria

MDRD-eGFR Formula

CYP3A4 Inhibitors and Inducers

New York Heart Association (NYHA) Functional Classification

Eastern Cooperative Oncology Group (ECOG) Performance Status

Clinical Laboratory Tests

Prior calibration, hypothetical dose escalation scenarios, and operating characteristics of 
the Bayesian logistic regression model
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 110
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 1
Classification and diagnosis of myeloproliferative neoplasms and proposed 
criteria for the diagnosis of post-polycythemia vera and post-essential 
thrombocythemia myelofibrosis
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 111
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 1a
Classification and diagnosis of myeloproliferative neoplasms: The 2008 World 
Health Organization Criteria and point-of-care diagnostic algorithms (Tefferi 
and Vardiman, 2008)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 112
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 113
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 114
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 115
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 116
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 117
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 118
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 119
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 120
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 121
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 1b
Proposed criteria for the diagnosis of post-polycythemia vera and post-
essential thrombocythemia myelofibrosis: a consensus statement from the 
International Working Group for Myelofibrosis Research and Treatment
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 122
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 124
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 3
Information regarding effectiveness of contraceptive methods
Females of childbearing potential will be requested to use the combination of two highly 
effective contraception methods.
For female patients participating in the study:
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 30 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) 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). For female subjects on the study the 
vasectomized male partner should be the sole partner for that subject. 
* 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 or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone 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. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
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) 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. 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 125
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 4
Drugs that interfere with coagulation or inhibit PLT function.
Antiplatelet 
Agents
Anticoagulant 
Agents
Procoagulant 
Agents
Synthetic 
inhibitors of 
factor Xa
Thrombolytic 
Agents
Direct 
thrombin 
inhibitors
NSAIDs and 
Acetaminophen
Food supplements
Aspirin
(more than 125 
mg/day)
Heparin
Aminocaproic 
Acid
Fondaparinux
Urokinase
Argatroban
Ibuprofen, Naproxen, 
Fenoprofen, Ketoprofen, 
Flurbiprofen, Oxaprozin, 
Indomethacin, Sulindac, 
Etodolac, Ketorolac, 
Diclofenac, Nabumetone, 
Piroxicam, Meloxicam, 
Tenoxicam, Droxicam, 
Lornoxicam, Isoxicam, 
Mefenamic acid, 
Meclofenamic acid, 
Flufenamic acid, 
Tolfenamic acid
Nattokinase (extracted 
and from a Japanese 
food called natto)
Ticlopidine
Warfarin
Desmopressin
Idraparinux
Streptokinase
Lepirudin
Clopidogrel
Dicumarol
Anistreplase
Bivalirudin
Lumbrokinase (present 
in the earthworm 
Lumbricus bimastus)
Prasugrel
Phenprocoumon
Tissue 
plasminogen 
activators (t-Pa):
Alteplase
Reteplase
Tenecteplase
Dabigatran
Cilostazol
Acenocoumarol
Abciximab
Anisindione
Eptifibatide
Dalteparin
Tirofiban
Danaparoid
Dipyridamole
Enoxaparin
Epoprostenol
Tinzaparin
Phenindione
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 126
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 5
Hepatic encephalopathy grading according to West Haven Criteria
Grade
Symptoms
1
Trivial lack of awareness; Euphoria or anxiety; Shortened attention span; Impaired 
performance of addition or subtraction
2
Lethargy or apathy; Minimal disorientation for time or place; Subtle personality 
change; Inappropriate behavior
3
Somnolence to semi-stupor, but responsive to verbal stimuli; Confusion; Gross 
disorientation
4
Coma (unresponsive to verbal or noxious stimuli)
(Ferenci et al 2002)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 127
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 6
MDRD-eGFR Formula
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 128
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 7
CYP3A4 inhibitors and inducers
Medications that can induce CYP3A4
Strong inducers
Moderate inducers
Weak inducers
Unclassified inducers
avasimibe
bosentan
amprenavir
topiramate
carbamazepine
efavirenz
aprepitant
phenobarital
etravirine
armodafinil (R-modafinil)
phenytoin
modafinil
dexamethasone
rifabutin
nafcillin
echinacea
rifampin
ritonavir
garlic
St. John's wort
talviraline
gingko
tipranavir
glycyrrhizin
methylprednisolone
nevirapine
oxcarbazepine
pioglitazone
prednisone
pleconaril
rufinamide
troglitazone
Note:
Inducer classification:

Strong inducers may result in a substrate AUC decreased by ≥ 80%.

Moderate inducers may result in a substrate AUC decreased by 50-80%.

Weak inducers may result in a substrate AUC decreased by 20-50%.
This list is compiled based on the FDA’s “Guidance for Industry, Drug Interaction Studies”, the Indiana 
University School of Medicine’s Drug Interactions Database, and the University of Washington’s Drug 
Interaction Database. This list may not be comprehensive and may be updated periodically. Refer to 
Novartis Oncology Clinical Pharmacology Internal Memorandum, Drug-drug interactions (DDI) 
Database (last updated 30 August 2010) for update or more details.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 129
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Medications that can inhibit CYP3A4
Strong inhibitors
Moderate inhibitors
Weak inhibitors
clarithromycin
amprenavir
alprazolam
conivaptan
aprepitant
AMD070
indinavir
atazanavir
amlodipine
itraconazole
cimetidine
azithromycin
ketoconazole
ciprofloxacin
bicalutamide
lopinavir
darunavir
cranberry juice
mibefradil
diltiazem
chlorzoxazone
nefazodone
elvitegravir
cilostazol
nelfinavir
erythromycin
cyclosporine
posaconazole
fluconazole
fluvoxamine
ritonavir
grapefruit juice
ginkgo
saquinavir
imatinib
goldenseal
telithromycin
schisandra sphenanthera
isoniazid
troleandomycin
tipranavir
lacidipine
voriconazole
tofisopam
M100240
verapamil
nilotinib
oral contraceptives (e.g. drospirenone, 
norgestimate, and ethinyl estradiol)
peppermint oil
propiverine
ranitidine
ranolazine
roxithromycin
Seville orange juice
sitaxentan
tabimorelin
Note:
Inhibitor classification:

Strong inhibitors may result in a substrate AUC > 5-fold increase.

Moderate inhibitors may result in a substrate AUC ≥ 2-fold increase and < 5-fold increase.

Weak inhibitors may result in a substrate AUC ≥ 1.25-fold increase and < 2-fold increase.
This list is compiled based on the FDA’s “Guidance for Industry, Drug Interaction Studies”, 
the Indiana University School of Medicine’s Drug Interactions Database, and the University 
of Washington’s Drug Interaction Database. This list may not be comprehensive and may be 
updated periodically. Refer to Novartis Oncology Clinical Pharmacology Internal 
Memorandum, Drug-drug interactions (DDI) Database (last updated 30 August 2010) for 
update or more details.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 130
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 8
New York Heart Association (NYHA) Functional Classification
NYHA 
Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity. E.g., shortness of 
breath when walking, stair climbing, etc.
II
Mild symptoms (mild shortness of breath and/or angina pain) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity (e.g. walking short distances, ~ >20 - 100m). Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest, mostly bed bound 
patients
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 132
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 133
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 134
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 135
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 11
Eastern Cooperative Oncology Group (ECOG) 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, eg, 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
Source: (Oken et al1982)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 136
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 12
Clinical Laboratory Tests
Serum Chemistry
Hematology
Coagulation
ALT
Complete Blood Count (CBC)
INR
AST
Alkaline phosphatase
Differential including reporting 
of % blasts
PTT
Total bilirubin
D-dimer or FDP
Direct bilirubin
Albumin
Platelets
Fibrinogen
Lactate dehydrogenase
Creatinine
BUN
Sodium
Potassium
Glucose
Calcium
Uric acid
Other
Pregnancy Test:
Female patients of childbearing 
potential only; serum test at 
Screening and Follow-up. Urine 
test at subsequent visits per the 
Description of Study Visits 
(Section 6)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 137
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Appendix 13
Prior calibration, hypothetical dose escalation scenarios, and operating 
characteristics of the Bayesian logistic regression model
Statistical models and dose recommendation
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will guide the dose-escalation to determine the maximal 
safe starting dose (MSSD) of INC424. The model will use accumulated data on observed 
DLTs at each dose level and stratum. Bayesian inference will be used to assess the risks of 
overdose at each dose level. The use of Bayesian response adaptive models for Phase I studies 
has been advocated by the European Medicines Agency (EMA) guideline on small 
populations (2006) and by (Rogatko et al 2007) and is one of the key elements of the Food 
and Drug Administration’s (FDA) Critical Path Initiative. For this trial a 3-parameter 
Bayesian logistic regression model will be used in order to establish the safety of oral INC424 
treatment in patients with myelofibrosis and platelet counts between 50 x109/L and 100 
x109/L.
INC424 is currently being evaluated in two randomized, pivotal studies, [INCB18424-351]
and [INCB18424-352], in patients with myelofibrosis and baseline platelet counts > 100 
x109/L. In these trials, the starting dose of INC424 is platelet dependent: patients with platelet 
counts between 100 x109/L and 200 x109/L begin at 15 mg b.i.d., and patients with platelet 
counts > 200 x109/L begin at 20 mg b.i.d.
The doses used in the above mentioned pivotal studies were determined based on data 
collected in a Phase I/II, dose-finding study, [INCB18424-251]. In [INCB18424-251], a total 
of 154 patients at a total of 8 different starting doses were explored, both in b.i.d. and q.d. 
schedules. Table A provides a summary of the number of patients treated at each of the 4 
starting b.i.d. dose levels (n = 117), and Table B provides the patient-level data used to derive 
this summary. In addition, the total number of patients with a “DLT” (as defined in this 
current protocol [CINC424A2201]) was retrospectively determined. It is this retrospectively 
applied DLT definition that is summarized in Table A and Table B.
Table A
Incidence of DLTs by starting dose level in the Phase I/II study 
[INCB18424-251] for patients who started on a b.i.d. regimen, 
where DLT is defined as in the current protocol
Dose schedule
Total daily dose (mg)
No of 
patients
No (%) of patients with DLTs
b.i.d.
20 mg
30 mg
50 mg
100 mg
30
35
47
5
4 / 30 (13.3)
4 / 35 (11.4)
17 / 47 (36.2)
1 / 5 (20.0)
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 138
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Table B
DLT data from all patients starting at a b.i.d. dose schedule in 
Study [INCB18424-251]. Data provided are baseline platelet count 
(x109/L) and an indicator variable for observation of a DLT per the 
current study criteria (1 = yes, 0 = no)
Total daily dose
20 mg
Total daily dose
30 mg
Total daily dose
50 mg
Total daily dose
100 mg
476,0
226,0
998,1
319,0
174,0
318,1
647,0
611,0
372,0
667,0
360,0
151,0
268,0
283,1
298,0
102,1
113,0
639,0
454,0
394,0
125,1
245,0
170,1
761,0
605,0
214,1
231,0
208,0
426,0
115,0
468,0
163,0
574,0
240,0
285,0
162,0
593,0
116,1
483,0
478,0
277,0
119,0
637,0
805,1
130,0
624,0
871,0
156,1
211,0
810,0
117,0
285,0
832,0
103,0
425,0
170,1
424,0
622,0
210,1
208,0
288,0
148,0
596,0
209,0
118,0
444,1
454,0
286,0
336,0
237,0
138,0
425,0
317,0
1195,1
218,0
304,0
193,0
133,0
231,0
223,0
223,0
602,0
483,0
123,0
544,0
214,0
153,0
247,0
184,0
195,0
449,0
147,1
147,1
683,0
118,1
379,0
245,1
468,1
415,1
316,0
138,0
351,0
315,1
220,1
372,0
372,0
202,0
168,0
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 139
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Total daily dose
20 mg
Total daily dose
30 mg
Total daily dose
50 mg
Total daily dose
100 mg
380,1
131,0
215,0
338,1
263,0
202,1
324,0
250,0
343,1
After the patients in each cohort have completed at least 28 days of treatment, the prior 
distribution will be updated with the accumulated DLT data. Posterior probabilities for the 
rate of DLT by stratum will be summarized from the model. Selection of the next dose will be 
based on these probabilities as well as on other safety and laboratory data.
See Section 9.4.2 of the protocol for BLRM and for an elaborate explanation of the derivation 
of the prior.
Hypothetical dose escalation scenarios
In order to show how the Bayesian model reacts, different hypothetical scenarios were 
investigated. The designs should make reasonable decisions during a study based on the 
observed toxicities particularly in early cohorts. Table C shows on-study decisions made for 
each of 4 different specified hypothetical DLT observations based on the BLRM. Note that 
per the protocol design, stratum 2 does not begin enrollment until dose level 3 (total daily 
dose = 20 mg) has been declared open in stratum 1.
Table C
Hypothetical dose escalation scenario (S1 = Stratum 1, S2 = 
Stratum 2)
Scenario
Cohort
Total Daily Dose 
Received
Number of DLTs / 
Number of patients
Recommended Total Daily 
Dose (mg) for Next Cohort
1
1 (S1)
2 (S1)
3 (S1), 1 (S2)
10 mg (S1)
15 mg (S1)
20 mg (S1), 10 mg (S2)
0 / 3 (S1)
≤ 1 / 3 (S1)
≤ 1 / 3 (S1), 0 / 3 (S2)
15 mg (S1)
20 mg (S1), 10 mg (S2)
25 mg (S1), 15 mg (S2)
2 (all S1)
1
2
3
10 mg
10 mg
10 mg
1 / 3
1 / 3
≥ 1 / 3
10 mg
10 mg
STOP
3 (all S1)
1
10 mg
≥ 2 / 3
STOP
4 (all S1)
1
2
3
4
10 mg
15 mg
10 mg
15 mg
0 / 3
2 / 3
0 / 3
1 / 3
15 mg
10 mg
15 mg
15 mg
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 140
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Simulated operating characteristics
In the previous Section, some individual hypothetical scenarios were investigated to 
understand how the BLRM reacts within a clinical trial. In this Section, the performance of 
the BLRM over many trials is investigated via simulation. This approach allows for an 
understanding of how the BLRM behaves on average based on an assumed “truth”, i.e., 
assuming the true underlying relationship between dose and probability of DLT were known.
Hypothetical true relationships between dose and probability of DLT
A total of 4 different true relationships between dose and probability of DLT [P(DLT)] were 
assumed. For each scenario, the relationship between dose and P(DLT) is specified for each 
stratum.
Figure A displays the assumed P(DLT) for INC424 doses for the four scenarios. For scenarios 
1 and 3, no stratum effect is assumed.
Figure A
Dose-DLT relationship of the different scenarios (solid line = 
stratum 1, dashed line = stratum 2)
10
15
20
25
30
0.0
0.4
0 8
P(DLT)
Scenario 1
10
15
20
25
30
0.0
0.4
0 8
Scenario 2
10
15
20
25
30
0.0
0.4
0.8
NC424 Total Daily Dose (mg)
P(DLT)
Scenario 3
10
15
20
25
30
0.0
0.4
0.8
NC424 Total Daily Dose (mg)
Scenario 4
Simulation parameters
A total of 1000 trial simulations were used for each scenario and the total minimum number 
of DLTs to control the declaration of MSSD was fixed to one. No more than 1 dose level was 
allowed to be increased in single step.
The number of patients to enroll in each cohort and stopping rules used to declare MSSD were 
defined as:

Cohort size: 3

Approximate number of patients enrolled: 31
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 141
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201

Minimum number of patients treated at the recommended MSSD: 9
Metrics
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were:

Probability of recommending a target dose as the MSSD (correct final decision) (I)

Probability of recommending a dose with true P(DLT) ≥ 33.3% as the MSSD (patient risk) 
(II)

Probability of recommending a dose with true P(DLT) < 16% as the MSSD (III)

MSSD < smallest positive dose (i.e. 10mg) (IV)

Average proportion of patients receiving a target dose on study (V)

Average proportion of patients receiving a dose with true P(DLT) ≥ 33.3% on study (VI)

Average proportion of patients receiving a dose with true P(DLT) < 16% on study (VII)

Average number of patients per study (VIII)
Results
The simulated operating characteristics presented below show that the model performs well 
under the wide range of hypothetical scenarios investigated.
Table D and Table E summarize the results from the simulations performed for both strata.
Table D
Summary metrics of simulations for Stratum 1
Scenario
I
II
III
IV
V
VI
VII
VIII
1
.537
.306
.146
.011
.327
.308
.365
21
2
.362
.074
.418
.146
.309
.146
.545
18
3
.961
0
.012
.027
.723
0
.276
21
4
.963
0
.018
.019
.711
0
.289
21
Table E
Summary metrics of simulations for Stratum 2
Scenario
I
II
III
IV
V
VI
VII
VIII
1
.358
.064
.475
.103
.306
.126
.568
18
2
.143
.125
0
.732
.575
.426
0
9
3
.841
0
.073
.086
.655
0
.345
20
4
.674
.136
.047
.143
.589
.176
.235
18
Figure B shows the proportions of patients receiving INC424 falling into the different toxicity 
intervals for the four hypothetical scenarios. In this figure, the proportion of patients treated in 
the targeted toxicity interval is 33%, 31%, 72% and 71% for scenarios 1, 2, 3 and 4, 
respectively, in stratum 1, and 31%, 58%, 66%, and 59%, respectively, in stratum 2. The 
proportion of patients treated in the over-dosing interval is higher than 25% in 2 situations. In 
Scenario 1, stratum 1, 31% of patients are treated in the over-dosing interval. This is due to 
the relatively low P(DLT) that is possible in this interval (40%). In Scenario 2, stratum 2, 43% 
of patients are treated in the over-dosing interval. However, this is due to the simulation 
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 142
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
assumption that all doses in the study are in the overdosing interval. This assumption is 
extreme since it assumes a greater than 9 times odds of DLT at the first dose level for patients 
in stratum 2 relative to stratum 1. Most of the simulations (72%) for this scenario in this 
stratum resulted in [correctly] declaring an MSSD that was below the range under study.
Figure B
Proportions of patients receiving targeted dose, who are under-
dosed or who are over-dosed
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0.8
Scenario 1
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0.8
Scenario 2
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0 8
Scenario 3
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0 8
Scenario 4
The MSSD dose selections under the four hypothetical scenarios are presented in Figure C. 
The MSSD dose selection in the over-dosing interval occurs in less than 25% in all but 1 of 
the strata in one of the scenarios (Scenario 1, stratum 1), where it is 30.6%. This is due to the 
underlying DLT probability rate in the lowest dose in the over-dosing interval, where the 
P(DLT) is 40%.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST

Novartis / Incyte Corp.
Confidential
Page 143
Amended Protocol Version 04 – Clean
Protocol No. CINC424A2201
Figure C
MSSD dose selection under different dose-toxicity scenarios
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0.8
Scenario 1
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0.8
Scenario 2
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0 8
Scenario 3
Underdosing
Target Dosing
Overdosing
Stratum 1
Stratum 2
0.0
0.4
0 8
Scenario 4
References (available upon request)
Babb J, Rogatko A, Zacks S (1998). Cancer phase I clinical trials: efficient dose escalation 
with overdose control. Stat Med; 17: 1103-1120.
Neuenschwander B, Branson M, Gsponer T (2008). Critical aspects of the Bayesian approach 
to phase I cancer trials. Statistics in Medicine; 27: 2420-2439.
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010). Summarizing Historical 
Information on Controls in Clinical Trials. Clin Trials; 7(1): 5-18.
This document (
 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 7/31/2015 6:08:42 PM, signing status at this time:  Completed (3 of 3 signatures) 
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 13:56:25 CEST
Approved for report publication by 
 in 
 at Fri, 31 Jul 2015 02:08:30 PM EDT
Approved for report publication by 
 in 
 at Fri, Jul 31, 2015 10:00:10 CEST