Conditions: Primary Myelofibrosis (MF) Post-Polycythemia Vera (PV) MF Post-Essential Thrombocythemia (ET) MF
Keywords: Primary Myelofibrosis (MF) Post-Polycythemia Vera (PV) MF Post-Essential Thrombocythemia (ET) MF post-PV MF post-ET MF INC424 Ruxolitinib Myelofibrosis MF
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 120
Healthy volunteers: no

Brief summary:
The objective of this study was to determine the efficacy of INC424 as assessed by reduction in spleen volume in patients with primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF. The safety and tolerability of INC424 and the effects of INC424 on patient reported outcomes and the duration of response as assessed by reduction in spleen volume was also assessed.

Detailed description:

Arms:
arm 1: Ruxolitinib was taken twice daily, unless instructed. Starting dose 15 mg BID for patients with baseline platelet count of 100,000/μL to 200,000/μL (inclusive) or 20 mg BID for those with baseline platelet count \>200,000/μL (approximately 12 hours apart: morning and night), increased or decreased per standardized dosing paradigm.

Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: INC424 Tablet for oral use, provided in 5 mg bottles. The dosage strength was 5 mg/tablet INC424 phosphate (free base equivalent).

Protocol document:
Prot_000.pdf: 
Oncology Clinical Development & Medical Affairs 
Ruxolitinib (INC424) 
Clinical Trial Protocol CINC424A2202 / NCT01392443
A multi-national open-label phase II study of the JAK 
inhibitor INC424 in patients with primary myelofibrosis, 
post-polycythemia vera myelofibrosis or post-essential 
thrombocythemia myelofibrosis 
Authors 
 
Document type 
Oncology Clinical Trial Protocol 
EUDRACT number 
Not applicable 
Version number 
00 (Original protocol) 
Development phase 
II 
Document status 
Final 
Release date 
15-Apr-2011
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Protocol Summary 
Study title: 
A multi-national open-label phase II study of the JAK inhibitor INC424 in patients with primary 
myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis 
Study phase: 
Phase II 
Study objectives: 
The primary objective of this study is to determine the efficacy of INC424 as assessed by reduction in 
spleen volume. The secondary objectives are to determine the safety and tolerability of INC424, to 
evaluate the effects of INC424 on patient reported outcomes and the duration of response as 
assessed by reduction in spleen volume. 
 
 
Study population: 
Patients with primary myelofibrosis (PMF) or myelofibrosis (MF) evolving from polycythemia vera (PV) 
or essential thrombocythemia (ET), who have a palpable spleen measuring 5 cm or greater below the 
costal margin and are classified as high risk or intermediate-2 risk according to the risk stratification by 
the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Patients must 
be 18 years of age or older with an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0-2, and have adequate hematologic (absolute neutrophil count ≥1,000/µL and platelet count 
≥100,000/µL), renal, and hepatic function. Patients must have discontinued all drugs used to treat 
underlying MF no later than 28 days prior to Baseline. 
Overview of study design: 
This is an Asian multi-national phase II open-label study evaluating the efficacy and safety of INC424 
in patients with PMF or post-PV/ET MF. The study is comprised of 4 phases; the Screening phase, the 
Baseline phase, the Treatment phase, and Follow-up. After the Screening and Baseline phases, 
patients who meet all the eligibility criteria will start treatment with INC424. INC424 is self-administered 
orally, and the starting dose will be determined based on Baseline platelet count; patients with 
Baseline platelet count of 100,000/µL to 200,000/µL will begin dosing at 15 mg twice daily (BID), and 
those with Baseline platelet count higher than 200,000/µL will begin dosing at 20 mg BID. A 
standardized dosing paradigm will be used to determine dose adjustments for safety and efficacy so 
that each patient is titrated to their most appropriate dose. The minimum and maximum doses will be 5 
mg BID (or 5 mg once daily if used with a concomitant strong CYP3A4 inhibitor) and 25 mg BID, 
respectively. Patients will receive INC424 until the patients have access to treatment through 
commercial supplies (if applicable by local regulations) or the patients are permanently discontinued 
from the study, whichever comes first. A Follow-up Visit will be held 30 days after the last dose of 
study drug.  
The primary efficacy endpoint will be based on the proportion of patients achieving ≥35% reduction in 
spleen volume from Baseline to Week 24 as measured by magnetic resonance imaging (MRI) or 
computed tomography (CT) scan in applicable patients. The secondary efficacy endpoints will be the 
changes in scores assessed both by the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and by Seven-day modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 from Baseline to Week 24, best response rate and the 
duration of maintenance of a ≥35% reduction from Baseline in spleen volume. Safety and tolerability 
will be assessed by monitoring the frequency, duration and severity of adverse events, performing 
physical exams, and evaluating changes in vital signs, electrocardiograms (ECGs), serum chemistry, 
hematology and urinalysis results. 


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The target number of patients will be 110, and an interim analysis is planned when the first 50 patients 
have completed Week 24 Visit or have discontinued from the study prior to Week 24. 
Statistical considerations: 
The sample size for this study is based on the single-sample binomial test (normal approximation). 
Based on the results obtained in Study INCB 18424-351, the proportion of patients on this study 
achieving ≥35% reduction in spleen volume from Baseline to Week 24 as measured by MRI (or CT 
scan) is expected to be 0.35. From the aspect of clinical benefit in patients with PMF or post-PV/ET 
MF, a threshold of 0.2 was set for null hypothesis. If the study had no interim analysis (1-stage 
approach), the required sample size of 110 provides power of 0.951 with one-sided type I error rate of 
0.025 under response rate of 0.2 and 0.35 for null and alternative hypotheses. The power for the group 
sequential (i.e. 2-stage) design accruing 110 total patients with the same final timepoint boundary 
(≥31/110) and an interim analysis conducted after 50 patients using an O’Brien-Fleming type interim 
analysis boundary (≥19/50) is approximately 0.95. Therefore, the effect of the interim analysis on the 
overall study power is negligible. 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
1 
Background ........................................................................................................................ 11 
1.1 
Overview of pathogenesis, epidemiology and current treatments of 
myelofibrosis ......................................................................................................... 11 
1.2 
Introduction to investigational treatment ............................................................... 12 
1.2.1 
Overview of INC424 ............................................................................. 12 
2 
Rationale ............................................................................................................................ 17 
2.1 
Study rationale and purpose ................................................................................... 17 
2.2 
Rationale for the study design ............................................................................... 18 
2.3 
Rationale for dose and regimen selection .............................................................. 18 
3 
Objectives and endpoints ................................................................................................... 21 
4 
Study design ...................................................................................................................... 23 
4.1 
Description of study design ................................................................................... 23 
4.2 
Timing of interim analyses .................................................................................... 24 
4.3 
Definition of end of the study ................................................................................ 24 
4.4 
Early study termination .......................................................................................... 24 
5 
Population .......................................................................................................................... 24 
5.1 
Patient population .................................................................................................. 24 
5.2 
Inclusion criteria .................................................................................................... 25 
5.3 
Exclusion criteria ................................................................................................... 26 
6 
Treatment ........................................................................................................................... 27 
6.1 
Investigational treatment, supportive treatment .................................................... 27 
6.1.1 
Dosing regimen ..................................................................................... 27 
6.1.2 
Treatment duration ................................................................................ 28 
6.2 
Dose modification .................................................................................................. 28 
6.2.1 
Dose increase for inadequate efficacy ................................................... 28 
6.2.2 
Dose modification for safety ................................................................. 30 
6.2.3 
Dose reductions for concomitant CYP inhibitor usage ......................... 32 
6.2.4 
Treatment discontinuation ..................................................................... 32 
6.3 
Concomitant medications ...................................................................................... 33 
6.3.1 
Permitted concomitant therapy ............................................................. 33 
6.3.2 
Restricted/allowed therapies ................................................................. 34 


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6.3.3 
Prohibited therapies ............................................................................... 34 
6.3.4 
Optional dose tapering strategy in the event of drug discontinuation ... 34 
6.4 
Patient numbering .................................................................................................. 35 
6.5 
Study drug supply .................................................................................................. 35 
6.5.1 
Study drug preparation and dispensation .............................................. 35 
6.5.2 
Study drug packaging and labeling ....................................................... 36 
6.5.3 
Drug supply and storage ........................................................................ 36 
6.5.4 
Drug compliance and accountability ..................................................... 36 
6.5.5 
Disposal and destruction ....................................................................... 37 
7 
Description of study visits ................................................................................................. 37 
7.1 
Schedule of observations ....................................................................................... 37 
7.1.1 
Screening evaluations ............................................................................ 44 
7.1.2 
Baseline evaluations .............................................................................. 44 
7.1.3 
On-treatment evaluations ...................................................................... 45 
7.1.4 
End of treatment evaluations ................................................................. 46 
7.1.5 
Follow-up evaluations ........................................................................... 47 
7.2 
Assessment types ................................................................................................... 47 
7.2.1 
Efficacy assessments ............................................................................. 47 
7.2.2 
Safety and tolerability assessments ....................................................... 48 
 
 51 
 
 53 
7.2.5 
Other assessments ................................................................................. 54 
8 
Safety monitoring and reporting ........................................................................................ 55 
8.1 
Adverse events ....................................................................................................... 55 
8.1.1 
Definitions and reporting ...................................................................... 55 
8.1.2 
Laboratory test abnormalities ................................................................ 56 
8.2 
Serious adverse events ........................................................................................... 56 
8.2.1 
Definitions ............................................................................................. 56 
8.2.2 
Reporting ............................................................................................... 57 
8.3 
Pregnancies ............................................................................................................ 57 
8.4 
Warnings and precautions ...................................................................................... 58 
8.5 
Data Monitoring Committee .................................................................................. 58 
8.6 
Steering Committee ............................................................................................... 58 
9 
Data collection and management ....................................................................................... 58 
9.1 
Data confidentiality ............................................................................................... 58 
9.2 
Site monitoring ...................................................................................................... 59 
9.3 
Data collection ....................................................................................................... 59 


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9.3.1 
Laboratory tests ..................................................................................... 59 
9.3.2 
Spleen imaging ...................................................................................... 60 
 
 60 
9.4 
Database management and quality control ............................................................ 60 
10  Statistical methods and data analysis ................................................................................ 61 
10.1 
Analysis sets .......................................................................................................... 61 
10.1.1 
Full Analysis Set ................................................................................... 61 
10.1.2 
Safety population .................................................................................. 61 
10.1.3 
Per-Protocol Set .................................................................................... 61 
 
 61 
 
 61 
10.2 
Patient demographics/other Baseline characteristics ............................................. 61 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 62 
10.4 
Primary objective ................................................................................................... 62 
10.4.1 
Variable ................................................................................................. 62 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 62 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 63 
10.4.4 
Supportive analyses ............................................................................... 63 
10.5 
Secondary objectives ............................................................................................. 63 
10.5.1 
Change in EORTC QLQ-C30 score from Baseline to Week 24 ........... 63 
10.5.2 
Change in total symptom score from Baseline to Week 24 as 
measured by Seven-day modified MFSAF v2.0 ................................... 63 
10.5.3 
Best response rate .................................................................................. 64 
10.5.4 
Duration of maintenance of a greater or equal 35% reduction from 
Baseline in spleen volume ..................................................................... 64 
10.5.5 
Safety..................................................................................................... 64 
 66 
 66 
 67 
 68 
10.7 
Interim analysis ...................................................................................................... 68 
10.8 
Sample size calculation .......................................................................................... 69 
10.9 
Power for analysis of key secondary variables ...................................................... 70 
11  Ethical considerations and administrative procedures ...................................................... 70 
11.1 
Regulatory and ethical compliance ........................................................................ 70 
11.2 
Responsibilities of the Investigator and IRB/IEC/REB......................................... 70 


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11.3 
Informed Consent procedures ................................................................................ 70 
11.4 
Discontinuation of the study .................................................................................. 71 
11.5 
Publication of study protocol and results............................................................... 71 
11.6 
Study documentation, record keeping and retention of documents ....................... 71 
11.7 
Confidentiality of study documents and patient records ....................................... 72 
11.8 
Audits and inspections ........................................................................................... 72 
11.9 
Financial disclosures .............................................................................................. 72 
12  Protocol adherence ............................................................................................................ 72 
12.1 
Amendments to the protocol .................................................................................. 72 
13  References (available upon request) .................................................................................. 73 
14  Appendices ........................................................................................................................ 75 
Appendix I - The 2008 WHO criteria for PMF, PV and ET ............................................. 76 
Appendix II- IWG-MRT recommended criteria for post-PV/ET MF ............................... 78 
Appendix III - Information regarding effectiveness of contraceptive methods ................ 79 
 80 
Appendix V - Restricted/prohibited medications .............................................................. 81 
 
List of figures 
Figure 1-1 
Mean reduction in palpable spleen length in Study INCB 18424-
251 ......................................................................................................... 15 
Figure 1-2 
Proportion of patients with at least 50% reduction in total symptom 
score in Study INCB018424-251 who began dosing at 15 mg BID ..... 16 
Figure 6-1 
Strategies for dose increase because of inadequate efficacy at Week 
4 ............................................................................................................. 29 
 
List of tables 
Table 2-1 
Baseline and percent change from Baseline in spleen length at 
week 24 by initial and average dose in Study INCB 18424-251 .......... 19 
Table 2-2 
Summary of treatment-related adverse events reported in at least 
greater or equal 5 % of subjects in Study INCB 18424-251 ................. 20 
Table 2-3 
Summary of maximum grade greater or equal 3 post-baseline 
thrombocytopenia events by initial treatment group in Study INCB 
18424-251 ............................................................................................. 20 
Table 3-1 
Objectives and related endpoints .......................................................... 22 
Table 6-1 
Dose and treatment schedule ................................................................. 27 
Table 6-2 
Dose reduction of INC424 for safety in patients with platelet count 
declines .................................................................................................. 30 


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Table 6-3 
Restarting or increasing INC424 dose after safety interruption or 
dose reduction for hematologic safety .................................................. 31 
Table 6-4 
Preparation and dispensing ................................................................... 36 
Table 6-5 
Packaging and labeling ......................................................................... 36 
Table 6-6 
Supply and storage ................................................................................ 36 
Table 7-1 
Visit evaluation schedule ...................................................................... 38 
Table 7-2 
Visit evaluation schedule (continued) ................................................... 41 
Table 7-3 
ECOG performance status scale ............................................................ 50 
 
 52 
 
 53 
Table 10-1 
Criteria for Clinically Notable Vital Sign Abnormalities ..................... 66 
Table 10-2 
Design properties of the proposed two stage group sequential 
design .................................................................................................... 69 


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List of abbreviations 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
AUC 
Area under the plasma concentration-time curve 
BDM 
Biometrics and Data Management 
BID 
Bis in diem (Twice daily) 
BMI 
Body mass index 
Cmax 
Maximum observed plasma concentration 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DLT 
Dose limiting toxicity 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire 
ET 
Essential thrombocythemia 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplantation 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INC424 
INCB018424, ruxolitinib 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IWG-MRT 
International Working Group for Myelofibrosis Research and Treatment 
JAK 
Janus kinase 
LLOQ 
Lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Myelofibrosis 


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MFSAF 
Myelofibrosis Symptom Assessment Form 
MPN 
Myeloproliferative neoplasm 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamic(s) 
 
 
PHI 
Protected health information 
PK 
Pharmacokinetic(s) 
PMF 
Primary myelofibrosis 
PPS 
Per-protocol Set 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PV 
Polycythemia vera 
QD 
Quaque die (Once daily) 
QOL 
Quality of life 
QTcF 
QT interval corrected according to Friderica’s formula 
RAP 
Report and Analysis plan 
REB 
Research Ethics Board 
SAE 
Serious adverse event 
SAF 
Safety population 
SC 
Steering Committee 
SEC 
Safety event category 
STAT 
Signal transducers and activators of transcription 
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2 
Elimination half life 
TNF-α 
Tumor Necrosis Factor α 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 


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1 
Background 
1.1 
Overview of pathogenesis, epidemiology and current treatments 
of myelofibrosis 
Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) originating from a clonal 
hematopoietic stem cell. MF can present as primary myelofibrosis (PMF) or evolve from 
underlying polycythemia vera (PV) or essential thrombocythemia (ET). Regardless of 
whether MF develops as PMF or from PV or ET, it is characterized by a clonal stem cell 
proliferation associated with production of elevated levels of several inflammatory cytokines, 
which causes collagen fibrosis in the bone marrow. The abnormal bone marrow milieu results 
in release of hematopoietic stem cells into the blood, extramedullary hematopoiesis, and 
organomegaly at these sites. The incidence of PMF has been estimated at 0.5 to 1.5 cases per 
100,000 people, and it occurs most commonly in the sixth to seventh decade of life (Thiele et 
al. 2008). Clinically, MF is characterized by progressive anemia, massive splenomegaly due 
to extramedullary hematopoiesis, severe constitutional symptoms, a hypermetabolic state, 
cachexia, and premature death. The most common causes of death are progressive marrow 
failure leading to infection or hemorrhage, and transformation to acute leukemia.  
Recently, a gain-of-function mutation in the Janus kinase-2 (JAK2) gene, specifically 
1849G>T (encoding V617F), has been identified in over 95% of patients with PV and 60% of 
patients with ET and PMF (Vannucchi et al. 2009). JAK2 is a member of the JAK family 
kinases, a non-receptor tyrosine kinase associated with signal transductions of a considerable 
number of cytokines and growth factors (Levine et al. 2007). For example, erythropoietin, 
thrombopoietin and granulocyte macrophage colony stimulating factor are all known to signal 
through receptors that utilize JAK2. The JAK2V617F mutation alters the JAK2 tyrosine 
kinase making it constitutively active. As a result, polycythemia, thrombocythemia and 
leukocytosis can develop independently from growth factor regulation. Cumulative evidence 
has revealed that JAK2 plays a critical role in the pathogenesis of MPN by activating a 
number of downstream pathways involved in the proliferation and survival of malignant cells 
such as STAT (signal transducers and activators of transcription). It was shown that also in 
patients lacking a confirmed JAK2 mutation, STAT is activated suggesting dysregulated JAK 
activity regardless of the JAK2 mutation status (Verstovsek et al. 2010).  
Survival in MF varies with the presence or absence of specific risk factors including age of 
greater than 65 years, presence of constitutional symptoms of weight loss, fever, or night 
sweats, anemia (hemoglobin [Hgb] less than 10 g/dL), leukocytosis (white blood cell [WBC] 
greater than 25,000/µL), and a circulating blast percentage of 1% or greater. It was 
demonstrated that patients with no risk factors fell into a low risk group with a median 
survival of approximately 11 years, patients with one risk factor fell into an intermediate-1 
risk group with a median survival of approximately 8 years, patients with two risk factors fell 
within an intermediate-2 risk group with a median survival of 48 months, and patients with 3 
or more risk factors formed a high risk group with a median survival of 27 months (Cervantes 
et al. 2009).  
Currently, there are no curative therapies for MF except for allogeneic hematopoietic stem 
cell transplantation (HSCT). Allogeneic HSCT may provide a cure, although it is only 


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applicable to a small fraction of patients who are young and fit for the procedure and have a 
suitable donor. Moreover, allogeneic HSCT is associated with a considerable risk of 
treatment-related morbidity and mortality. Other therapeutic options include hydroxyurea, 
busulfan, 6-mercaptopurine, anagrelide, thalidomide, lenalidomide, interferon, corticosteroids, 
androgens, hematopoietic growth factors, splenectomy, and splenic irradiation, none of which 
has been shown to improve survival (Kroger et al. 2008). Even if symptom control is 
successfully achieved with these treatments, response is not durable.  
1.2 
Introduction to investigational treatment 
1.2.1 
Overview of INC424 
INCB018424 phosphate designated INC424 throughout, represents a novel, potent, reversible 
and selective inhibitor of JAK1- and JAK2-STAT signaling pathways, and is currently under 
development for treatment of MPN. 
1.2.1.1 
Non-clinical experience 
INC424 potently inhibits JAK1 and JAK2 (half maximal inhibitory concentration [IC50] 0.4 to 
1.7 nM), yet it does not significantly inhibit (<30% inhibition) a broad panel of 28 kinases 
when tested at 200 nM (approximately 100 x the average IC50 value for JAK enzyme 
inhibition) and does not inhibit JAK3 at clinically relevant concentrations. INC424 retains 
activity against the JAK2V617F mutant and is effective in reducing splenomegaly in mice 
inoculated with cells carrying this mutation. 
Effects of INC424 noted in 6-month rat and 12-month dog repeat dose toxicology studies 
were primarily myelosuppressive in nature and are believed to be associated with the 
mechanism of action of INC424. Genetic toxicology assessments (evaluations of INC424 in 
the bacterial mutagenicity assay, in vitro chromosome aberration assay, and in vivo 
micronucleus assay) in rats were negative. In safety pharmacology evaluations, an adverse 
decrease in minute volume in a respiratory study in female rats only was noted at the highest 
dose. In a cardiovascular evaluation of INC424 in dogs, electrocardiogram (ECG) parameters 
and ventricular repolarization were unaffected at all doses; whereas the compound lowered 
blood pressure and increased heart rate compared to vehicle control at the highest dose 
evaluated. In embryo-fetal assessments in rat and rabbit, maternal toxicity and minimal 
embryo-fetal toxicity were noted at the highest doses evaluated. INC424 was not teratogenic 
in either rat or rabbit. No effects were noted on reproductive performance or fertility in male 
or female rats. Increases in post-implantation loss were noted at the higher doses.  
More detailed information on pharmacology of INC424, single and multiple dose 
pharmacokinetic (PK) studies conducted in multiple species and nonclinical safety evaluations 
can be found in the Investigator’s Brochure (IB). 
1.2.1.2 
Clinical experience 
Clinical Pharmacology 
Following oral, single-dose administration in the fasted state, INC424 was absorbed rapidly, 
typically attaining peak plasma concentrations within 1 to 3 hours after administration for all 


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doses. After attaining Cmax, the INC424 plasma concentrations declined with a mean terminal-
phase t1/2 of approximately 3-5 hours. The mean INC424 Cmax and AUC increased with 
approximately linear proportionality to dose for the entire dose range evaluated of 5 to 
200 mg. There was no significant food effect on absorption or exposure. A double-blind, 
randomized, placebo-controlled, single dose escalation study (Study [INCB 18424-131]) has 
been conducted to investigate the food effect, where Tmax, Cmax and AUC in particular were 
determined. The main conclusion was that overall magnitude of the food effect on the INC424 
exposure is not expected to be clinically significant. 
INC424 is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the 3A4 isozyme. Systemic exposure of INC424 was appreciably 
increased (AUC 2-fold higher) when given in combination with ketoconazole, a potent 
CYP3A4 inhibitor, with a similar effect observed on the pharmacodynamic (PD) activity 
(cytokine-induced STAT3 phosphorylation). CYP3A4 inducers significantly decreased the 
exposure to INC424, with essentially no difference observed on the PD activity. This suggests 
that CYP3A4 induction with rifampin results in metabolism of INC424 to active metabolites 
which also inhibit JAKs.  
INC424 was given as a single 25 mg dose to subjects with varying degrees of renal function 
(Study [INCB 18424-142]) and to subjects with varying degrees of hepatic dysfunction or 
with normal hepatic function (Study [INCB 18424-137]). Mild, moderate or severe 
impairment of renal function had no statistically significant effect on pharmacokinetic (PK) or 
PD parameters; subjects requiring dialysis showed prolonged PD activity without a 
demonstrable effect on INC424 clearance. The mean total AUCs of INC424 were 88%, 29% 
and 66% higher, respectively, in subjects with mild, moderate and severe hepatic impairment 
compared to subjects with normal hepatic function. INC424 Cmax was not significantly 
different for subjects with various degrees of hepatic impairment compared with healthy 
subjects following single-dose administration. Terminal half-life of INC424 was increased in 
subjects with hepatic impairment by approximately 2-fold compared to healthy controls. The 
subjects with severe hepatic impairment showed modestly protracted PD activity compared to 
the other hepatically impaired subjects who displayed PD activity similar to the healthy 
controls. 
In addition to these studies conducted in western countries, the pharmacokinetics of INC424 
in Japanese healthy volunteers was recently investigated (Study [CINC424A1101]). 
Following oral administration to Japanese healthy volunteers, INC424 was rapidly absorbed, 
and peak plasma concentrations were reached 0.5 hours after dose administration. Exposure of 
INC424 increased proportionately with dose. The short half life (2-3 hours) relative to the 12 
hour dose interval is consistent with no accumulation observed after multiple dosing 
Additional details as to the clinical pharmacology of INC424 may be found in the IB. 
Clinical Safety in Healthy Volunteers 
INC424 has been administered in single or multiple doses to over 130 western healthy 
subjects. In single dose studies, INC424 has been safe and well tolerated with adverse events 
generally mild in intensity, reversible and of similar incidence following INC424 treatment 
compared with placebo or with other control treatments.  


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In a 10-day multiple dose study, a total of 71 healthy volunteers in 6 cohorts received doses of 
50 mg once daily (QD), 100 mg QD, 15 mg twice daily (BID), 25 mg BID or 50 mg BID 
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 subjects. 
Neutropenia was noted in 3 subjects 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 subject 
and was reported as a serious adverse event (SAE). There was a decline in mean absolute 
neutrophil count (ANC) values and to a lesser extent, mean WBC values, with INC424 doses 
of 15 mg BID 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 BID was determined to be the 
maximum tolerated doses (MTD) in this study based on the dose limiting toxicity (DLT) of 
neutropenia. Doses of 50 mg QD and 100 mg QD were well tolerated. 
A thorough 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 is that there appears 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. 
In the phase I study with Japanese healthy volunteers (Study [CINC424A1101]), INC424 was 
found to be well tolerated up to 100 mg single-dosing as well as 25 mg BID multiple-dosing 
for 7 days.  
For additional details related to studies conducted in Healthy volunteers, consult the IB. 
Clinical Safety and Efficacy in MF Patients 
Study [INCB 18424-251] is a phase I/II open-label study of INC424 in patients with PMF or 
post-PV/ET MF. As of December 31, 2009, 154 patients have been enrolled at twice daily 
dose regimens of 10 mg BID to 50 mg BID, 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 BID or 15 mg BID, and can increase up to 20 mg BID or 25 mg BID. 
Data from the ongoing Study [INCB 18424-251] demonstrate marked and durable reductions 
in spleen size. In this study, spleen size has been measured as palpable length below the left 
costal margin. Figure 1-1 illustrates the mean reduction in absolute spleen size (measured 
from the costal margin) for all participants in the study.  


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Figure 1-1 
Mean reduction in palpable spleen length in Study INCB 18424-251 
 
The numbers above the bar graphs are the denominators of how many individuals were followed for 
that period of time, and the numbers in the bar graphs are the percentage reduction in palpable spleen 
length compared with Baseline. 
Treatment with INC424 is associated with a prompt decrease in spleen size that is durable 
over many months. Ad hoc subgroup analysis showed the proportion of responding patients in 
the pooled 15 mg BID and 25 mg BID groups (most effective regimens) to be similar among 
patients with or without the JAK2V617F mutation. 
Disease progression of MPN is associated with weight loss and cachexia. Dysregulation and 
abnormal elevation of a variety of pro-inflammatory cytokines may produce a hypercatabolic 
state which contributes to the weight loss and wasting seen in patients with MF. After an 
initial weight loss (presumably due to the rapid decrease in splenomegaly and hepatomegaly 
and loss of ascites and/or pleural effusions) there is a gain in total body weight that appears to 
be dose-dependent. Weight gains are present in most patients, including those with BMI at 
Baseline in the lowest quartile (BMI below  22). 
For the patients with available data, there was a prompt shift in the Eastern Cooperative 
Oncology Group (ECOG) performance scores in individuals with scores of 1 or 2 towards a 
score of 0, and this improvement was maintained over 96 weeks of therapy. The modified 
Myelofibrosis Symptom Assessment Form (MFSAF) developed by Mesa et al. (2007) and 
based on an international internet-based survey of over 1,000 patients with MPN, is being 
used to probe a range of constitutional symptoms that are related to splenomegaly (including 
impaired ability to move around and early satiety) and elevated cytokines (including fatigue, 
night sweats and pruritus). Figure 1-2 illustrates the symptoms response for patients who 
initiated their individualized optimized regimens at a starting dose of 15 mg BID. 


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Figure 1-2 
Proportion of patients with at least 50% reduction in total symptom 
score in Study INCB018424-251 who began dosing at 15 mg BID 
 
In summary, INC424 is associated with prompt and marked reduction in spleen size, gains in 
total body weight, improvement in ECOG performance status scores and improvement in 
constitutional symptoms that can be debilitating in this patient population. At this time, 
studies demonstrate that the response to INC424 therapy is independent of JAK2 V617F 
mutational status. 
INC424 has been well tolerated by this aged population with advanced disease. Adverse 
events regardless of relationship to the drug occurring in at least 20% of the 154 patients 
included in the safety database through December 31, 2009 were restricted to anemia (48%, 
74 patients), thrombocytopenia (45%, 70 patients), diarrhea (29%, 44 patients), and fatigue 
(23%, 36 patients). Most non-hematologic adverse events were mild to moderate in severity 
and considered unrelated to study drug administration. Both anemia and thrombocytopenia 
can be explained by JAK-inhibition, and are therefore not unexpected. Thrombocytopenia 
represents the DLT in the MF population. Patients initially assigned to the 50 mg BID dose 
group had an incidence of Grade 3 thrombocytopenia of 60% (3 of 5 patients) and of Grade 4 
thrombocytopenia of 20% (1 of 5 patients). The 25 mg BID dose group, the largest dose group 
examined, had incidences of Grade 3 and 4 thrombocytopenia of 36% and 11% (12 and 5 of 
47 patients), respectively. For the 25 mg BID dose group, patients exhibiting these Grade 3 or 
4 declines in platelets had, in general, entered the study with platelet counts below 
200,000/µL. In a subsequent cohort, patients were assigned to an initial dose of 15 mg BID 
provided their Baseline platelet count was >200,000/µL; the incidence of Grade 3 
thrombocytopenia was markedly reduced (1 of 35 patients) and there were no Grade 4 events. 
For nearly all patients, thrombocytopenia was rapidly reversible and manageable with dose 
interruption and/or reduction. Anemia, though dose dependent, largely reflects the low 
hemoglobin status at Baseline in this disease population. Because of the advanced disease 
present in many of the participants in Study [INCB 18424-251], there are a number of SAEs 


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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. 
Based on the promising results from Study [INCB 18424-251], 2 separate phase III studies are 
underway in US, Canada, and Australia (Study [INCB 18424-351]) and Europe (Study 
[CINC424A2352]). Study [INCB 18424-351] is a randomized, double-blind trial which 
compares INC424 to placebo. Study [CINC424A2352] is a randomized, open-label trial 
which compares INC424 to best available therapy as determined by the Investigator for each 
individual patient randomized to the control group. For these studies, the primary endpoint is 
the proportion of patients achieving ≥35% reduction in spleen volume at Week 24 (Study 
[INCB 18424-351]) or at Week 48 (Study [CINC424A2352]) compared to Baseline. At this 
time, the results of the initial analysis of Study [INCB 18424-351] are available. A total of 
309 patients were enrolled in the study. In the primary endpoint assessment, the proportion of 
patients achieving ≥35% reduction in spleen volume from Baseline to Week 24 was 41.9% in 
patients randomized to INC424 versus 0.7% in those randomized to placebo (p<0.0001). A 
statistical significance was also observed in the key secondary endpoint, symptomatic 
improvement as measured by the modified MFSAF. The safety profile of INC424 appeared to 
be consistent with the previous studies. 
2 
Rationale 
2.1 
Study rationale and purpose 
INC424 is a potent selective inhibitor of JAK1- and JAK2-STAT signaling pathways. These 
signaling pathways play a critical role in the pathogenesis of MPN, which forms the basis of 
development of INC424 for the treatment of MPN.  
Current therapies for MF have limited efficacy, and most countries have no drugs approved 
for this indication. Most patients are managed initially with a wait-and-see approach, since the 
goal of treatment is palliative and not disease-modifying. However, certain drugs approved for 
other indications have been tried with limited success. The most commonly used drug is 
hydroxyurea, used primarily to control splenomegaly and elevated WBC and/or platelet 
counts. Other chemotherapy agents such as busulfan, 6-mercaptopurine, pipobroman, or 
thioguanine have been used. Immunomodulatory agents such as thalidomide, lenalidomide 
and interferon-α are sometimes employed. Agents aimed primarily at constitutional symptoms 
(such as prednisone), thrombocythemia (such as anagrelide), or even non-specific marrow-
toxic agents (such as radiophosphorus or cladribine) have been tried. Splenectomy and splenic 
irradiation have been used to control spleen-related symptoms. No approach however is 
considered to be the standard of care, or is associated with sufficient disease control (Kroger 
et al. 2008).  
The encouraging results from the phase I/II study in patients with MF support further studies 
in this patient population, and 2 phase III studies are underway in Western countries. However, 
no clinical trial has been conducted in Asian countries and a limited number of Asian patients 
have been enrolled on any study. An Asian multi-national phase II open-label study of 


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INC424 (Study [CINC424A2202]) in patients with PMF or post-PV/ET MF is therefore 
planned. The purpose of this study is to evaluate the efficacy and safety of INC424 in Asian 
MF patients. The primary objective is to determine the efficacy of INC424 as assessed by 
reduction in spleen volume at 24 weeks. The secondary objectives are to determine the safety 
and tolerability of INC424, to evaluate the effects of INC424 on patient reported outcomes as 
assessed by the European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire score (EORTC QLQ-C30) and Seven-day modified MFSAF v2.0, and the 
duration of response as assessed by reduction in spleen volume. 
 
 
 
2.2 
Rationale for the study design 
This is a phase II open-label study evaluating the efficacy and safety of INC424 in MF 
patients with PMF or post-PV/ET MF. Patient population, dosing regimen, and assessments 
are basically in accordance with the phase III studies described above. The study will include 
only patients with poor prognosis who are at high risk or intermediate-2 risk according to the 
International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria 
(Cervantes et al. 2009). The Screening and Baseline phases should not exceed 42 days 
combined. The length of these phases accommodates time required for discontinuation of all 
drugs used to treat MF at least 28 days prior to Baseline and the assessment of all inclusion 
and exclusion criteria and the Baseline assessment. The primary endpoint will be the 
proportion of patients achieving ≥35% reduction in spleen volume from Baseline to Week 24, 
which is based on an objective measure of spleen volume. Splenomegaly is a major source of 
morbidity and determinant of quality of life in MF patients (Mesa 2009). According to the 
IWG-MRT consensus panel a 50% reduction in palpable spleen length is considered clinically 
important (Tefferi et al. 2006). In Study [INCB 18424-251], a median decrease of ~35% in 
spleen volume by MRI was observed with corresponding palpable spleen length in the same 
patients reduced by up ~50%. Based on these data, a ≥35% reduction in spleen volume was 
selected as a clinically meaningful reduction as assessed by objective imaging. In accordance 
with the ongoing phase III studies and in order to obtain the most objective clinical data, 
magnetic resonance imaging (MRI) has been chosen as the primary modality of spleen 
volume measurement, and the spleen volume will be calculated by independent imaging. 
Patients who are not candidates for MRI will be evaluated with sequential computed 
tomography (CT). The primary endpoint will be assessed after 24 weeks of therapy. A safety 
Follow-up Visit will be held 30 (+10) days following the last dose of study drug in order to 
effectively evaluate post-treatment safety and tolerability. Patients who are benefiting from 
study drug will continue study treatment until they have access to treatment through 
commercial supplies, if applicable by local regulations. 
2.3 
Rationale for dose and regimen selection 
INC424 is self-administered orally. In the phase I/II study in MF patients, Study [INCB 
18424-251], twice daily dose regimens from 10 mg BID to 50 mg BID were examined. Based 
on the ongoing efficacy and safety data, there appears to be some individual variability in 
terms of sensitivity to thrombocytopenia and also clinical response, such that an optimal dose 


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for a given individual is likely to be between 10 mg BID and 25 mg BID, and that some 
opportunity for individual titration of dose within this range might offer the best balance of 
safety and efficacy for any individual patient. Therefore, patients enrolled in Study [INCB 
18424-251] since August 2008 have initiated therapy at 15 mg BID, unless platelet count at 
Baseline was <200,000/µL, in which case initial dosing was at 10 mg BID. For these patients, 
the study protocol dictates a mandatory dose increase of 5 mg BID at Week 4 (to doses of 20 
mg BID or 15 mg BID, respectively) for inadequate efficacy and adequate platelet count and 
ANC levels. A second, optional dose increase may occur at Week 8.  
Table 2-1 shows the preliminary efficacy data based on the initial dose and average dose in 
Study [INCB 18424-251]. In this study, the majority of subjects were titrated to the most 
appropriate dosage; therefore, it is of interest to assess efficacy based on the average dose 
received. In general, a dose response was seen based on the average dose received with higher 
median percent reduction from Baseline in spleen length seen with higher doses.  
Table 2-1 
Baseline and percent change from Baseline in spleen length at week 
24 by initial and average dose in Study INCB 18424-251 
Statistic 
≤ 10 mg BID 
>10-≤15 mg BID
>15-≤20 mg BID
>20-≤25 mg BID 
>25 mg BID 
Baseline, cm 
n 
27 
32 
 
34 
4 
Mean (SD) 
19.81 (7.4) 
18.50 (5.6) 
 
20.32 (6.1) 
16.25 (8.0) 
Median 
19.00 
17.50 
 
20.00 
19.00 
Percent change from Baseline at Week 24 based on initial treatment 
n 
18 
28 
 
32 
3 
Mean (SD) 
-50.9 (32.3) 
-54.4 (30.6) 
 
-54.1 (35.4) 
-65.7 (51.7) 
Median 
-50.802 
-53.5 
 
-54.087 
-90.909 
Percent change from Baseline at Week 24 based on average treatment 
n 
21 
27 
14 
17 
2 
Mean (SD) 
-47.4 (32.1) 
-41.9 (34.1) 
-61.5 (29.9) 
-69.9 (27.3) 
-95.5 (6.4) 
Median 
-47.058 
-42.105 
-60.833 
-76 
-95.454 
Table 2-2 presents a summary of treatment-related adverse events occurring in ≥5% of 
subjects in all initial treatment groups in Study [INCB 18424-251]. Treatment-related AEs 
that occurred in ≥5% of subjects were restricted to thrombocytopenia, anemia, weight increase, 
diarrhea, and fatigue. Although anemia was the most frequently reported AE, overall, 
thrombocytopenia was the most frequently reported treatment-related AE.  


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Table 2-2 
Summary of treatment-related adverse events reported in at least 
greater or equal 5 % of subjects in Study INCB 18424-251 
 
10 mg BID 
15 mg BID 
25 mg BID 
Preferred Term, n (%) 
(N=30) 
(N=35) 
(N=47) 
Any event 
21 (70.0) 
22 (62.9) 
41 (87.2) 
Thrombocytopenia 
12 (40.0) 
8 (22.9) 
29 (61.7) 
Anemia 
5 (16.7) 
6 (17.1) 
22 (46.8) 
Weight increased 
2 (6.7) 
0 
3 (6.4) 
Diarrhea 
0 
6 (17.1) 
4 (8.5) 
Fatigue 
3 (10.0) 
3 (8.6) 
2 (4.3) 
Thrombocytopenia represents the DLT for INC424 in the MF population. Table 2-3 presents a 
summary of the maximum Grade 3 or 4 events of thrombocytopenia by initial treatment group. 
Thrombocytopenia occurred more often in patients with a Baseline platelet count of less than 
200x109 per liter. Notably, the incidence of thrombocytopenia to date at 15 mg BID, including 
those patients with subsequent dose escalations to 20 mg BID and 25 mg BID, is similar to 
that of the 10 mg BID dose group. Also, thrombocytopenia showed increasing frequency at 
doses of 25 mg BID. 
Table 2-3 
Summary of maximum grade greater or equal 3 post-baseline 
thrombocytopenia events by initial treatment group in Study INCB 
18424-251 
 
10 mg BID 
15 mg BID 
25 mg BID 
 
(N=30) 
(N=35) 
(N=47) 
Maximum post-Baseline thrombocytopenia, n (%) 
Grade 3 
6 (20.0) 
1 (2.9) 
12 (25.5) 
Grade 4 
0 
0 
5 (10.6) 
Based on these data, in Study [CINC424A2202] as well as ongoing western phase 3 studies 
(Study [INCB-18424-351] and [CINC424A2352]), 15 mg BID will be the starting dose for all 
patients entering the study with a platelet count between 100,000/µL and 200,000/µL 
(inclusive), whereas 20 mg BID will be the starting dose for all patients entering the study 
with a platelet count >200,000/µL. With this dosing scheme, patients with higher platelet 
counts will start at a dose more likely to result in robust spleen reduction, while patients with 
a lower platelet level will begin with a dose that appears to have a very low incidence of 
thrombocytopenia. An optional dose increase of 5 mg BID for inadequate efficacy will occur 
at Week 4, provided platelet counts and ANC levels are in a satisfactory range. Mandatory 
dose decreases for safety reasons will be dictated by platelet count and ANC levels. These 
dose increases and decreases are summarized in Section 6.2.  
The pharmacokinetics of INC424 in Japanese healthy volunteers (preliminary results of Study 
[CINC424A1101]) was similar to those in healthy volunteers studied in Western trials ([INCB 
18424-131], [INCB 18424-132], [INCB 18424-138]). This is consistent with the fact that the 
primary metabolic enzyme of INC424 is CYP3A4 and ethnic differences are not expected in 
this enzyme expression or activity. These results suggest that the pharmacokinetics in an 
Asian population will be similar to the western population. 


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3 
Objectives and endpoints 
Primary Objective 
• To determine the efficacy of INC424 as assessed by reduction in spleen volume 
Secondary Objectives 
• To determine the safety and tolerability of INC424 
• To evaluate the effects of INC424 on patient reported outcomes 
• To evaluate the duration of response as assessed by reduction in spleen volume 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
 
Objective 
Endpoint 
Analysis 
Primary 
To determine the 
efficacy of INC424 
as assessed by 
reduction in spleen 
volume 
- 
Proportion of patients achieving ≥35% 
reduction in spleen volume from 
Baseline to Week 24 as measured by 
MRI (or CT scan in applicable 
patients) 
Refer to 
Section 10.4 
Secondary 
To determine the 
safety and 
tolerability of 
INC424 
- 
Safety and tolerability will be assessed 
by monitoring the frequency, duration 
and severity of adverse events, 
performing physical exams, and 
evaluating changes in vital signs, 
electrocardiograms (ECGs), serum 
chemistry, hematology and urinalysis 
results. Toxicity will be assessed using 
the Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03. 
Refer to 
Section 10.5.5 
Secondary 
To evaluate the 
effects of INC424 
on patient reported 
outcomes 
- 
Change in EORTC QLQ-C30 score 
from Baseline to Week 24 
- 
Change in total symptom score from 
Baseline to Week 24, as assessed by 
Seven-day modified MFSAF v2.0 
Refer to 
Sections 10.5.1 
and 10.5.2 
Secondary 
To evaluate the 
duration of 
response as 
assessed by 
reduction in spleen 
volume 
- 
Best response rate 
- 
Duration of maintenance of a ≥35% 
reduction from Baseline in spleen 
volume 
Refer to 
Sections 10.5.3 
and 10.5.4 


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4 
Study design 
4.1 
Description of study design 
This is an Asian multi-national phase II open-label study evaluating the efficacy and safety of 
INC424 in patients with PMF or post-PV/ET MF who have splenomegaly of at least 5 cm 
below the costal margin by manual palpation, and 2 or more risk factors (intermediate-2 or 
high risk) defined by the International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT) (Cervantes et al. 2009). The study will be conducted in four Asian 
countries, i.e., China, Japan, Korea and Taiwan. The target number of patients for this study is 
110 in total (see Section 10.8).  
The study is composed of 4 phases. 
Screening Phase 
Screening evaluations will be performed to determine the eligibility for the study, and should 
be conducted between Day -42 and Day -8. 
Baseline Phase 
Baseline evaluations will be performed in patients who have signed the Informed Consent 
Form (ICF) and meet all the eligibility criteria in the Screening phase. Procedures for the 
Baseline Visit will be conducted between Day -7 and Day -1. The Baseline MRI scan will be 
conducted between Day -28 and Day -7 to allow ample time for the central reader to verify 
image quality prior to the initial administration of study drug. Bone marrow aspiration and 
biopsy will be conducted between Day -42 and Day -1. 
Treatment Phase  
After the Screening and Baseline phases, patients who meet all the eligibility criteria will be 
able to start treatment with INC424. The starting dose of INC424 will be determined based on 
Baseline platelet count; patients with Baseline platelet count of 100,000/µL to 200,000/µL 
will begin dosing at 15 mg BID, and those with Baseline platelet count higher than 
200,000/µL will begin dosing at 20 mg BID. A standardized dosing paradigm will be used to 
determine dose adjustments for safety and efficacy so that each patient is titrated to their most 
appropriate dose (see Section 6.2).  
In order not to withhold INC424 from patients who are benefiting from the treatment, INC424 
will be made available until the patients have access to treatment through commercial supplies 
(if applicable by local regulations) or the patients are permanently discontinued from the 
study, whichever comes first. 
Follow-up  
A safety Follow-up Visit will be conducted 30 (+10) days following the last dose of study 
drug was received. 


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4.2 
Timing of interim analyses 
A single interim analysis is planned when the first 50 patients have completed Week 24 Visit 
or have discontinued from the study prior to Week 24. The primary aim of the interim 
analysis is to assess the efficacy and safety of INC424 in Asian MF patients and to achieve an 
earlier regulatory filing to health authorities with the interim efficacy and safety data. If this 
interim analysis shows at least the pre-specified number of responders (see Section 10.7), the 
Steering Committee (SC) will discuss the safety and efficacy results, and will make a final 
decision on the applicability of a submission. Irrespective of this decision, the study will move 
to the second stage in order to enroll additional patients so that the primary analysis will be 
performed with approximately 110 patients in total. The alpha for the final analysis will be 
adapted to alpha spent at the interim analysis (see Section 10.7).  
4.3 
Definition of end of the study 
The end of the study (last patient last visit) will occur after all patients in the study have 
completed their last assessment as per protocol. Patients who are benefiting from study drug 
will continue study treatment unless one or more withdrawal criteria (Section 7.1.4.1) are met 
and if the treatment with INC424 is considered the patient’s best therapeutic option by the 
Investigator. The study treatment will continue until the patients have access to study drug 
through commercial supplies, if applicable by local regulations. The last assessment for each 
patient is the Follow-up Visit that occurs 30 days after the last dose of study drug. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.4.1 for a withdrawn patient. The Investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. The Investigator will be responsible for informing 
Institutional Review Board (IRB) and/or Independent Ethics Committee (IEC) of the early 
termination of the trial. 
5 
Population 
5.1 
Patient population 
Male or female individuals 18 years of age or older will be eligible if they have been 
diagnosed with PMF or post-PV/ET MF, have a palpable spleen measuring 5 cm or greater 
below the costal margin, and have 2 or more risk factors as defined by IWG-MRT (Cervantes 
et al. 2009). Patients are allowed to have received prior therapy for MF. Patients who are 
receiving therapy for MF must discontinue all drugs used to treat MF at least 28 days prior to 
Baseline.  
The Screening phase is defined as the period beginning on the day that written Informed 
Consent is given. The Screening plus Baseline phases cannot exceed 42 consecutive days 
prior to the first dose of study drug. Patients enrolled in the study cannot participate in any 
concurrent clinical study of other investigational agents or devices, or receive any other 


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therapies for MF during the study. 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.  
A written ICF must be obtained according to the local guidelines before the start of any 
Screening procedures. 
5.2 
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 have been diagnosed with PMF or post-PV/ET MF, irrespective of the JAK2 
mutation status. The diagnosis should be made in the best determination of the 
Investigator based upon the 2008 World Health Organization (WHO) criteria (Thiele et al. 
2008) for PMF, and upon the IWG-MRT criteria (Barosi et al. 2008) for post-PV/ET MF 
3. Patients must have a palpable spleen measuring 5 cm or greater from the costal margin to 
the point of greatest splenic protrusion 
4. Patients must have 2 or more risk factors (intermediate-2 or high risk) as defined by IWG-
MRT (Cervantes et al. 2009). The risk factors are: 
• Age >65 years 
• Presence of constitutional symptoms (weight loss, fever, night sweats) 
• Marked anemia (Hgb <10 g/dL)* or packed red blood cell transfusion-requiring 
• Leukocytosis (history of WBC >25,000/µL) 
• Circulating blasts ≥1% 
 
*Hgb <10 g/dL must be demonstrated during the Screening Visit for patients who are not 
transfusion dependent. Patients receiving regular transfusions of packed red blood 
cells will be considered to have Hgb <10 g/dL for the purpose of evaluation of risk 
factors. 
5. Patients with circulating blast count of <10% 
6. Patients with an ECOG performance status of 0-2 
7. Patients with adequate bone marrow reserve as follows: 
• Absolute neutrophil count (ANC) ≥1,000/µL and 
• Platelet count ≥100,000/µL without the assistance of growth factors, thrombopoietic 
factors or platelet transfusions 
8. Patients must not currently have the option of stem cell transplantation, either because 
they are not a candidate, or because a suitable donor is not available 
9. Patients must have discontinued all drugs used to treat underlying MF no later than 28 
days prior to the first Baseline assessment (except for the MRI scan and bone marrow 
examinations) 
10. Patients who have not previously received treatment with a JAK inhibitor 


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5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with impaired liver or renal function as demonstrated by: 
• Direct bilirubin ≥2 x upper limit of laboratory normal (ULN) 
• Alanine aminotransferase (ALT) >2.5 x ULN 
• Creatinine >2.0 mg/dL 
2. Patients with clinically significant bacterial, fungal, mycobacterial, parasitic or viral 
infection (Patients with acute bacterial infections requiring antibiotic use should delay 
Screening/enrollment until the course of antibiotic therapy has been completed) 
3. Patients with active hepatitis A, B, C, or HIV-positivity at Screening, defined as positivity 
for IgM-HA Ab test, HBs Ag test, HCV Ab test or HIV Ab test. Patients who are negative 
for HBs Ag test but positive for either HBs Ab test or HBc Ab test will be excluded if 
HBV-DNA test is positive  
4. Patient must not have any concomitant malignancies and must be fully recovered from 
treatment for any other malignancy with no evidence of persistent disease 
5. Patients with any history of significant congenital or acquired bleeding disorder 
6. Patients with any history of platelet counts <50,000/µL or ANC <500/µL except during 
treatment for MPN or treatment with cytotoxic therapy for any other reason 
7. Patients who have had splenic irradiation within 12 months prior to Screening 
8. Patients undergoing treatment with hematopoietic growth factor receptor agonists (i.e., 
erythropoietin, granulocyte colony stimulating factor, romiplostim, eltrombopag) at any 
time within 14 days prior to Screening or 28 days prior to Baseline 
9. Patients under ongoing treatment with another investigational medication not intended for 
MF or having been treated with such an investigational medication within 14 days prior to 
Baseline or within 6-half lives of the investigational product, whichever is longer 
10. Patients with a history of myocardial infarction or acute coronary syndrome within 6 
months prior to Screening 
11. Patients with currently uncontrolled or unstable angina 
12. Patients with currently rapid or paroxysmal atrial fibrillation 
13. Resting heart rate >110 beats per minute 
14. Resting systolic blood pressure >160 mm Hg 
15. Resting diastolic blood pressure >100 mm Hg 
 
16. Patients who are unable to comprehend or are unwilling to sign the ICF 
17. Patients with active alcohol or drug addiction that would interfere with their ability to 
comply with the study requirements 
18. Females who are pregnant or currently breastfeeding 
19. Patients of childbearing potential who are unwilling to take appropriate precautions (from 
Screening through Follow-up) to avoid fathering a child or becoming pregnant 
• Females are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 


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profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 
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. 
• For females of childbearing potential, appropriate precautions should be “highly 
effective” in preventing the occurrence of pregnancy (Appendix III). These methods 
should be communicated to the patients and their understanding confirmed  
• For males, condom during dosing and for 5 times the terminal t1/2 (about 15 hours) is 
required. 
20. Patients with any concurrent condition that, in the Investigator’s opinion, would 
jeopardize the safety of the patient or compliance with the protocol 
6 
Treatment 
6.1 
Investigational treatment, supportive treatment 
The Investigator will instruct the patient to take 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. 
INC424 tablets will be administered orally, without regard to food, in an outpatient setting in 
accordance with specified dosing schedules. 
 
 
On all other days corresponding to study visits, 
patients will take the morning dose of study drugs prior to the visit. 
6.1.1 
Dosing regimen 
The dosage strength is 5 mg/tablet INC424 phosphate (free base equivalent). 
The starting dose of INC424 tablets will be determined based on Baseline platelet count as 
shown in Table 6-1. 
Table 6-1 
Dose and treatment schedule 
Study 
treatment 
Pharmaceutical 
form and route of 
administration 
Dose 
Frequency 
INC424 
Tablet for oral use 
Starting dose 15 mg BID for patients with 
Baseline platelet count of 100,000/µL to 
200,000/µL (inclusive) or 20 mg BID for 
those with Baseline platelet count 
>200,000/µL (approximately 12 hours 
apart : morning and night), to be 
increased or decreased per standardized 
dosing paradigm (see Section 6.2) 
Twice daily, unless 
instructed 
A standardized dosing paradigm will be used to determine dose adjustments for safety and 
efficacy so that each patient is titrated to their most appropriate dose (see Section 6.2). Doses 


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will not exceed 25 mg BID and will not be less than 5 mg BID (or 5 mg QD if used with a 
concomitant strong CYP3A4 inhibitor). 
6.1.2 
Treatment duration 
Patients who are benefiting from study drug will continue study treatment unless one or more 
withdrawal criteria (Section 7.1.4.1) are met and if the treatment with INC424 is considered 
the patient’s best therapeutic option by the Investigator. The study treatment will continue 
until the patients have access to study drug through commercial supplies, if applicable by 
local regulations. 
6.2 
Dose modification 
6.2.1 
Dose increase for inadequate efficacy 
6.2.1.1 
Dose increase at Week 4 
As indicated in Section 6.1.1, the initial dose of INC424, will be determined by the Baseline 
platelet count. Figure 6-1 shows dose increase strategies because of inadequate efficacy at 
Week 4. At Week 4, dose increase of INC424 is allowed for patients who show inadequate 
efficacy as demonstrated by palpable spleen length below the costal margin that has been 
reduced by <40% at the Week 4 Visit relative to Baseline, if all of the following conditions 
are met:  
• The patient must have had a platelet count ≥150,000/µL at every assessment since 
Baseline 
• The patient must have had ANC ≥1,000/µL at every assessment since Baseline 


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Figure 6-1 
Strategies for dose increase because of inadequate efficacy at Week 4  
Patients with Inadequate Response at Week 4
Starting Dose
20 mg BID
Starting Dose
15 mg BID
And
ANC  always >1,000/µL
ANC is/was <1,000/µL
PLT always >150,000/µL
And
ANC  always >1,000/µL
PLT is/was <150,000/µL
ANC is/was <1,000/µL
New Dose
25 mg BID
No Increase 
In Dose
New Dose
20 mg BID
No Increase
In Dose
PLT always >150,000/µL
Or 
PLT is/was <150,000/µL
Or 
 
PLT = Platelet count, ANC = Absolute neutrophil count 
6.2.1.2 
Dose increase beyond Week 4 
After Week 4, dose increase of INC424 is allowed for patients who show an increase in 
spleen length by manual palpation by 2 cm or greater compared to the on-study nadir (lowest 
palpable spleen measurement during the study, including Baseline), if all of the following 
conditions are met:  
• The dose increase may only occur in the 4-week period following the study visit at which 
a regularly scheduled MRI occurs (i.e., the 4 weeks following Week 12, 24, 36, etc) 
• The MRI for that study visit must have been performed 
• The platelet count and ANC levels for that visit must be available 
• The patient must not have had a prior safety-related dose reduction 
• The patient must have had a platelet count ≥150,000/µL at every assessment since 
Baseline 
• The patient must have had ANC ≥1,000/µL at every assessment since Baseline 
• The dose increase may only be an increase of 5 mg BID 
• The total dose may never exceed 25 mg BID 
Following a dose increase, platelet count and ANC levels should be assessed both 2 and 4 
weeks after the dose increase by an Extra Visit. The Extra Visit may be skipped if it takes 
place within 7 days of any other study visit. 
Dose adjustment for safety, and reinstitution of doses as described in Section 6.2.2 will apply 
whether the patient is on the original dose, or a dose that was increased for lack of efficacy. 


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6.2.2 
Dose modification for safety 
6.2.2.1 
Interruption or dose reduction 
For all patients, there are mandatory dose decreases or interruptions for hematologic and non- 
hematologic safety that might be observed while on INC424 therapy. In addition to mandatory 
dose interruption or decrease, there are mandatory criteria for permanent discontinuation of 
INC424 (see Section 7.1.4.1). 
For hematologic safety, dosing must be held if platelet counts decline below 50,000/µL, or if 
ANC falls below 500/µL while receiving INC424. Doses must be decreased for platelet count 
values <125,000/µL as shown in Table 6-2 with optional restarting or resuming prior dose 
after recovery (see Section 6.2.2.2). In order to provide sufficient data to make the dose 
adjustment decisions, it is recommended that hematology parameters be obtained at least 
weekly for platelet count <100,000/µL or ANC <1,000/µL and at least two times weekly for 
platelet count <50,000/µL or ANC <500/µL. The dose reduction strategy in Table 6-2 covers 
the starting doses (15 mg BID and 20 mg BID), possible doses after an increase for 
inadequate efficacy (20 mg BID and 25 mg BID), and doses that might be present after a prior 
dose reduction (down to 5 mg BID). 
Table 6-2 
Dose reduction of INC424 for safety in patients with platelet count 
declines 
Platelet Count at Time 
of Decline 
(in thousands) 
▼Dose at the Time of Platelet Decline▼ 
25 mg BID 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
 
▼Dose that MUST be Instituted▼ 
≥125 K/µL 
No dose reduction required 
100 to <125 K/µL 
20 mg BID 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
75 to <100 K/µL 
10 mg BID 
10 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
50 to <75 K/µL 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
<50 K/µL 
MUST HOLD DOSING 
Severe anemia may be managed by transfusion therapy as necessary. If hemoglobin cannot be 
maintained ≥6.5 g/dL despite the use of transfusion therapy, study treatment must be 
discontinued (see Section 6.2.4). 
For non-hematologic safety, dosing must be held if a Grade 3 or greater study drug-related 
non-hematologic toxicity occurs.  
Patients whose treatment is interrupted due to an adverse event or abnormal laboratory value 
must be followed at least once a week for 4 weeks, and subsequently at 4-week intervals, until 
resolution or stabilization of the event, whichever comes first. If a patient requires a dose 
delay of ≥8 weeks because of hematologic or non-hematologic toxicities, then the patient 
must be discontinued from the study. 
Additionally, in a patient who develops hepatic impairment or end-stage renal failure 
requiring dialysis during the study, a caution should be exercised in administering study drug 
as the patient may receive higher drug exposure. For a patient with hepatic impairment, as a 
general guidance, it is recommended that the dose be reduced by 50%, then the patient be 


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carefully monitored and the dose titrated accordingly. For a patient with end-stage renal 
failure requiring dialysis, it is recommended that the Investigator consult with the Sponsor for 
further advice. 
6.2.2.2 
Restarting or resuming previous dose 
Dosing may be restarted or increased following recovery of platelet counts and/or ANC to 
acceptable levels as illustrated in Table 6-3, provided platelets counts are ≥50,000/µL and 
ANC levels are ≥500/µL. 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 selected. 
The objective for restarting or escalating after a reduction for safety is to find the highest safe 
dose of INC424 for each patient, with increases in dose generally not more than in increments 
of 5 mg BID and not more often than every 2 weeks. Patients who are restarting after a 
reduction for thrombocytopenia may not receive doses above 20 mg BID maximum. Similarly, 
ANC levels that decline to <500/µL necessitate immediate dose interruption. ANC level 
recovery to above 500 /µL but less than 750/µL will allow dosing to be restarted at 5 mg BID, 
and ANC levels above 750/µL but <1000/µL may restart at 10 mg BID. ANC level increases 
to above 1,000/µL will allow a further dose increase to a maximum of 20 mg BID. 
After restarting using the guidelines in Table 6-3, if it is found that a patient cannot tolerate 
the lowest allowed dose (5 mg BID, or 5 mg QD if used with a concomitant strong CYP3A4 
inhibitor, see Section 6.2.3) due to platelets falling below 50,000/µL, neutrophils falling 
below 500/µL, or hemoglobin falling below 6.5 g/dL despite the use of packed red blood cell 
transfusion therapy to treat anemia, drug must be permanently discontinued (Section 6.2.4). 
Table 6-3 
Restarting or increasing INC424 dose after safety interruption or dose 
reduction for hematologic safety 
Current Platelet Count 
(in thousands) 
▼ Dose Restart or Dose Increase Guidelines ▼ 
<50 K/µL 
Continue hold 
50 to <75 K/µL 
5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID 
75 to <100 K/µL 
10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID 
100 to <125 K/µL 
15 mg BID 
≥125 K/µL 
20 mg BID 
Current ANC Level 
▼ Dose Restart or Dose Increase Guidelines ▼ 
<500/µL 
Continue hold 
500 to <750/µL 
5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID 
750 to < 1,000/µL 
10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID 
1,000 to <1,500/µL 
15 mg BID for at least 2 weeks; if stable may increase to 20 mg BID 
≥1,500/µL 
20 mg BID 


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All non-hematologic toxicities that have a study drug-related causality should be resolved to 
no higher than Grade 1 before dosing resumes. It is recommended that the Investigator consult 
with the Sponsor before restarting or increasing dosing following recovery of non-
hematologic toxicities. 
Patients whose treatment is interrupted due to splenectomy may be allowed to restart dosing, 
if fully recovering from the surgery within 12 weeks of the dosing interruption. 
6.2.3 
Dose reductions for concomitant CYP inhibitor usage 
INC424 is metabolized in the liver by the cytochrome (CYP) P450 metabolizing enzyme 
system, predominantly by the 3A4 isozyme. With concomitant dosing of strong CYP 
inhibitors such as oral ketoconazole, plasma exposure of INC424 increases approximately 2-
fold. Thus, a dose reduction of up to 50% for INC424 is appropriate for patients who take 
ketoconazole or other strong CYP3A4 inhibitors as concomitant medication. BID doses will 
be decreased to the corresponding QD doses as follows: 
• If dose is 25 mg BID, change dose to 25 mg QD 
• If dose is 20 mg BID, change dose to 20 mg QD 
• If dose is 15 mg BID, change dose to 15 mg QD 
• If dose is 10 mg BID, change dose to 10 mg QD 
• If dose is 5 mg BID, change dose to 5 mg QD 
Strong inhibitors of CYP3A4 include oral ketoconazole, clarithromycin, itraconazole, 
nefazodone, telithromycin (Flockhart 2007, Appendix V). Based on the very low overall 
bioavailability of topical ketoconazole, no dosage adjustment is needed for use with topical 
ketoconazole. 
Once the course of therapy using a CYP 3A4 inhibitor has been completed, the patient should 
resume their prior BID dose regimen of INC424 beginning the next day. 
6.2.4 
Treatment discontinuation 
If study drug is interrupted for any reason for more than 8 weeks, dosing may not be restarted, 
except in the case of splenectomy, for which a maximum 12-week period of study drug 
interruption is permitted (see Section 6.2.2). Although study guidelines provide for dose 
reduction/interruption, the following guidelines should be used to determine whether 
permanent discontinuation of study drug is necessary. 
6.2.4.1 
Discontinuation criteria for disease progression 
The following events are considered disease progression.  
• A ≥25% increase in spleen volume by MRI compared to Baseline: the Investigator will be 
notified via the central reader 
• Splenic irradiation 
• Leukemic transformation as defined by a bone marrow or a peripheral blood blast count of 
≥20% 
• Splenectomy 


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In the event that a patient experiences leukemic transformation, requires therapy with splenic 
irradiation, or experiences a ≥25% increase in spleen volume by MRI compared to Baseline, 
study drug must be permanently discontinued.   If a patient undergoes splenectomy, and the 
Investigator believes that it is in the patient’s benefit to continue therapy with INC424 due to 
symptomatic improvement, the patient may continue therapy assuming s/he has fully 
recovered from the splenectomy procedure within 12 weeks. 
6.2.4.2 
Discontinuation criteria for adverse events 
For hematologic safety, study drug must be permanently discontinued if the lowest allowed 
dose (5 mg BID, or 5 mg QD if used with a concomitant strong CYP3A4 inhibitor) is not 
tolerated due to the following: 
• Platelets cannot be maintained ≥50,000/µL 
• ANC cannot be maintained ≥500/µL 
• Hemoglobin cannot be maintained ≥6.5 g/dL despite the use of transfusion therapy (or if 
the patient will not accept blood transfusions) 
For non-hematologic safety, study drug must be permanently discontinued if the lowest 
allowed dose (5 mg BID, or 5 mg QD if used with a concomitant strong CYP3A4 inhibitor) is 
not tolerated due to the following: 
• The occurrence of a Grade 4 laboratory abnormality that is considered related to study 
drug, and is clinically significant in the view of the Investigator. Exceptions not requiring 
study withdrawal include but are not limited to serum iron, total bilirubin not accompanied 
by direct bilirubin of 2 x ULN, triglycerides, total cholesterol, HDL cholesterol, or 
abnormalities in urinalysis not accompanied by at least a Grade 3 elevation of serum 
creatinine 
• Recurrence of a Grade 4 clinical event (non-laboratory based) after re-challenge with 
study drug. Exceptions not requiring study withdrawal include but are not limited to 
fatigue, insomnia, obesity, constitutional symptoms (disabling but not life threatening), 
salivary gland changes, arthritis, and joint effusion 
Study drug MAY be permanently discontinued for a Grade 4 clinical event that has NOT been 
confirmed upon rechallenge with the study drug, at the discretion of the Investigator. 
Patients whose treatment is permanently discontinued due to an adverse event or abnormal 
laboratory value must be followed at least once a week for 4 weeks, 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 SAEs for 30 days following the last dose of 
INC424. 
6.3 
Concomitant medications 
6.3.1 
Permitted concomitant therapy 
Patient must be told to notify the study site about any new medications he/she takes after the 
start of study drug. All concomitant medications and treatments must be recorded in the eCRF. 
Any prior medication received up to 28 days prior to the first dose of study drug will be 


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recorded in the eCRF. All prior medications used to treat MF disease will be recorded. All 
concomitant treatments during the trial will also be recorded in the eCRF.  
6.3.2 
Restricted/allowed therapies 
The following medications have restrictions on use or doses or require changes to the way in 
which INC424 is administered during the study: 
• Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day 
are prohibited, unless use is part of an INC424 dose tapering strategy (see Section 6.3.4) 
• In patients for whom warfarin or heparin use will be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored and dose of 
anti-coagulant adjusted accordingly 
• Hematopoietic growth factor receptor agonists (i.e., erythropoietin, granulocyte colony 
stimulating factor, romiplostim, eltrombopag) are not recommended. INC424 may 
interfere with efficacy, and they may cause an increase in spleen size 
• Low dose aspirin (≤150 mg/day) and non steroidal anti-inflammatory agents 
(acetaminophen, ibuprofen) may be used. Aspirin in doses exceeding 150 mg per day is 
prohibited 
• Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Flockhart 2007, Appendix 
V): 
• When concomitant administration of a strong inhibitor of CYP3A4 is required for 
patient management, the dose of INC424 tablets must be adjusted (see Section 6.2.3).  
• The use of strong CYP3A inducers is prohibited (Section 6.3.3) 
• The use of mild-to-moderate inhibitors or inducers of CYP3A4 (Appendix V) is 
discouraged; alternative therapies should be considered wherever possible. Should 
one of these medications be medically necessary, its use should be documented; 
however dose adjustment of INC424 is not required 
6.3.3 
Prohibited therapies 
The following medications are prohibited during the study: 
• Any investigational medication other than INC424. Use of such medications within 14 
days or 6 half-lives, whichever is longer, prior to the Baseline and during the study 
through the Follow-up Visit is prohibited 
• Use of any other drugs for MF including hydroxyurea, interferon, thalidomide, busulfan, 
lenalidomide or anagrelide is not permitted within 28 days prior to Baseline and at any 
time during participation in the study  
• Potent inducers of CYP3A4 (rifampin and St. John’s Wort) are not permitted 
6.3.4 
Optional dose tapering strategy in the event of drug discontinuation 
When a decision is made to permanently discontinue INC424 for reasons other than low 
platelet counts, ANC levels, or hemoglobin, a dose tapering strategy may be considered, 
based on evaluation of the condition of the patient, current dosing regimen and the clinical 
judgment of the Investigator. If considered to be medically necessary, the Investigator may 


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use any treatment to manage withdrawal from INC424 including a gradual tapering of study 
drug dosage over 1-2 weeks or use of other medications to manage clinical signs and/or 
symptoms caused by discontinuation. Short-term courses of corticosteroids have been used to 
moderate the withdrawal of INC424 and may be considered as part of a tapering strategy. 
Corticosteroids may be started prior to, or concurrent with, INC424 tapering in anticipation of 
the possibility of occurrence of withdrawal symptoms. 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 (see Section 6.2.4). 
6.4 
Patient numbering 
Each patient is identified in the study by a Patient number with a length of 9 digits, which is a 
combination of his/her Site ID and subject number (the last 5 digit of the Patient number) 
when the patient is first enrolled. The Site ID is assigned by the Sponsor to the Investigative 
site. Upon signing the ICF, the subject number is assigned by the Investigator. At each site, 
the first patient is assigned subject number 1, and subsequent patients are assigned 
consecutive numbers (i.e., the second patient is assigned subject number 2, the third patient is 
assigned subject number 3).  
After the confirmation of the inclusion and exclusion criteria, the Investigator will send an 
enrollment form (if patient is eligible) to the Sponsor by fax or e-mail. The Sponsor will then 
notify the registration confirmation to the study site. The Investigator or designee will notify 
the initiation of treatment in each patient to the Sponsor by fax or e-mail. The starting dose of 
study drug will be determined by the Investigator, based on Baseline platelet count (see 
Section 6.1.1). 
If the patient fails to be started on treatment for any reason, the reason will be entered into the 
Screening log eCRF. The Sponsor must be notified within 7 days that the patient was not 
started on treatment. 
6.5 
Study drug supply 
6.5.1 
Study drug preparation and dispensation 
The Investigator will instruct the patient to take 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. 
The study drug 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. 


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Table 6-4 
Preparation and dispensing 
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 
6.5.2 
Study drug 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 6-5 
Packaging and labeling 
Study drugs 
Packaging 
Labeling (and dosing frequency) 
INC424 
Tablets in bottle 
INC424 5 mg 
6.5.3 
Drug supply and storage 
INC424 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 6-6 
Supply and storage 
Study drugs 
Supply 
Storage 
INC424 
Centrally supplied by Sponsor 
Refer to study drug label 
6.5.4 
Drug compliance and accountability 
6.5.4.1 
Drug compliance 
Compliance will be assessed by the Investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
patient visit and promptly entered in the eCRFs.  
6.5.4.2 
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. 
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 


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drug accountability ledger to the Sponsor monitor or to the Sponsor address provided in the 
Investigator folder at each site. 
6.5.5 
Disposal and destruction  
The drug supply can be destroyed at the local Sponsor facility, Drug Supply group or third 
party, as appropriate. 
7 
Description of study visits 
7.1 
Schedule of observations 
Table 7-1 lists all of the required assessments and indicates with an “X” the visits when they 
are performed. All data obtained from these assessments must be supported in the patient’s 
source documents. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column). 


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Table 7-1 
Visit evaluation schedule 
  
Category 
Reference 
to 
assessment 
types 
Screening 
Baseline 
Treatment Phase (± 7day Window ) 
*Day1 has no time window 
**Only for Day14, ± 3 Day Window 
Visit Number 
  
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day 
  
  
-42 to 
-8 
-28 to 
-7 
-7 to -
1 
1* 
14** 
28 
56 
84 
112 
140 
168 
210 
252 
294 
336 
Week 
  
  
-6 to   
-2 
-4 to   
-2 
-1 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
42 
48 
Informed Consent 
S 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
S 
5.2 / 5.3 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Send a enrollment form 
S 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Notification of the treatment start 
S 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history / Prior medications 
D 
7.1.1.2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
D 
7.2.2.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.4 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Comprehensive physical 
examination 
S 
7.2.2.2 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Targeted physical examination 
S 
7.2.2.2 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Measurement of spleen by 
palpation 
D 
7.2.1.2 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
D 
7.2.2.5 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Vital signs 
D 
7.2.2.3 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
12-lead ECG 
D 
7.2.2.7.1 
X 
 
(X) 
 
 
X 
 
X 
 
 
X 
 
 
 
X 


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Category 
Reference 
to 
assessment 
types 
Screening 
Baseline 
Treatment Phase (± 7day Window ) 
*Day1 has no time window 
**Only for Day14, ± 3 Day Window 
Visit Number 
  
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day 
  
  
-42 to 
-8 
-28 to 
-7 
-7 to -
1 
1* 
14** 
28 
56 
84 
112 
140 
168 
210 
252 
294 
336 
Week 
  
  
-6 to   
-2 
-4 to   
-2 
-1 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
42 
48 
Seven-day modified MFSAF v2.0 
questionnaires 
D 
7.2.1.3 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
EORTC QLQ-C30 questionnaires 
D 
7.2.1.3 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
MRI of abdomen (or CT) 
D 
7.2.1.1 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
Hematology 
D 
7.2.2.6.1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry 
D 
7.2.2.6.2 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Lipid panel 
D 
7.2.2.6.5 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
Coagulation  
D 
7.2.2.6.6 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
Screening for hepatitis virus and 
HIV 
S 
7.2.2.6.7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
D 
7.2.2.6.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
D 
7.2.2.6.4 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
D 
7.2.2.6.3 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 


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Category 
Reference 
to 
assessment 
types 
Screening 
Baseline 
Treatment Phase (± 7day Window ) 
*Day1 has no time window 
**Only for Day14, ± 3 Day Window 
Visit Number 
  
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Day 
  
  
-42 to 
-8 
-28 to 
-7 
-7 to -
1 
1* 
14** 
28 
56 
84 
112 
140 
168 
210 
252 
294 
336 
Week 
  
  
-6 to   
-2 
-4 to   
-2 
-1 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
42 
48 
Concomitant medications 
D 
6.3.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion history/status 
D 
6.3.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
D 
7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense INC424  
S 
6.5.1 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INC424 morning dose at the study 
site 
D 
7.2.3.1 
 
 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
Drug accountability assessment  
S 
6.5.4.2 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INC424 dosing 
D 
6.1 
 
 
 
Continuous 


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Table 7-2 
Visit evaluation schedule (continued) 
  
Category 
Reference 
to 
assessment 
types 
INC424 
dose 
increased 
or 
restarted 
(+/- 3 
days) 
Treatment Phase (+/- 7 days) 
End of 
Treatment 
Follow up (Study Evaluation 
Completion) (+10 days) 
Visit Number 
 
 
Extra 
15, 17, 
19, etc. 
16, 18, 20, etc. 
777 
778 
Day  
 
 
 
378, 
462, 
546, 
and q12 
weeks 
420, 504, 588, and q12 weeks 
 
30 days after End of Treatment 
Week 
 
 
2 and 4 
weeks 
after 
dose 
increased 
or 
restarted 
54, 66, 
78, and 
q12 
weeks 
60, 72, 84, and q12 weeks 
***only q24 weeks, e.g., 72, 96, 120 
****only q48 weeks, e.g., 96, 144, 
192 
 
 
Weight 
D 
7.2.2.4 
 
 
X 
X 
X 
Comprehensive physical examination 
S 
7.2.2.2 
 
 
X*** 
 
X 
Targeted physical examination 
S 
7.2.2.2 
X 
X 
X 
X 
 
Measurement of spleen by palpation 
D 
7.2.1.2 
X 
X 
X 
X 
X 
ECOG performance status 
D 
7.2.2.5 
X 
 
X 
X 
 
Vital signs 
D 
7.2.2.3 
X 
 
X 
X 
X 
12-lead ECG 
D 
7.2.2.7.1 
 
 
X*** 
X 
X 
Seven-day modified MFSAF v2.0 
questionnaires 
D 
7.2.1.3 
 
 
X 
 
 
MRI of abdomen (or CT) 
D 
7.2.1.1 
 
 
X*** 
 
 


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Category 
Reference 
to 
assessment 
types 
INC424 
dose 
increased 
or 
restarted 
(+/- 3 
days) 
Treatment Phase (+/- 7 days) 
End of 
Treatment 
Follow up (Study Evaluation 
Completion) (+10 days) 
Visit Number 
 
 
Extra 
15, 17, 
19, etc. 
16, 18, 20, etc. 
777 
778 
Day  
 
 
 
378, 
462, 
546, 
and q12 
weeks 
420, 504, 588, and q12 weeks 
 
30 days after End of Treatment 
Week 
 
 
2 and 4 
weeks 
after 
dose 
increased 
or 
restarted 
54, 66, 
78, and 
q12 
weeks 
60, 72, 84, and q12 weeks 
***only q24 weeks, e.g., 72, 96, 120 
****only q48 weeks, e.g., 96, 144, 
192 
 
 
Hematology 
D 
7.2.2.6.1 
X 
X 
X 
X 
X 
Serum chemistry 
D 
7.2.2.6.2 
 
 
X 
X 
X 
Lipid panel 
D 
7.2.2.6.5 
 
 
X*** 
 
 
Coagulation  
D 
7.2.2.6.6 
 
 
X*** 
X 
 
Serum pregnancy test 
D 
7.2.2.6.4 
 
 
 
 
X 
Urine pregnancy test 
D 
7.2.2.6.4 
 
X 
X 
X 
 
Urinalysis 
D 
7.2.2.6.3 
 
 
X*** 
X 
X 


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Category 
Reference 
to 
assessment 
types 
INC424 
dose 
increased 
or 
restarted 
(+/- 3 
days) 
Treatment Phase (+/- 7 days) 
End of 
Treatment 
Follow up (Study Evaluation 
Completion) (+10 days) 
Visit Number 
 
 
Extra 
15, 17, 
19, etc. 
16, 18, 20, etc. 
777 
778 
Day  
 
 
 
378, 
462, 
546, 
and q12 
weeks 
420, 504, 588, and q12 weeks 
 
30 days after End of Treatment 
Week 
 
 
2 and 4 
weeks 
after 
dose 
increased 
or 
restarted 
54, 66, 
78, and 
q12 
weeks 
60, 72, 84, and q12 weeks 
***only q24 weeks, e.g., 72, 96, 120 
****only q48 weeks, e.g., 96, 144, 
192 
 
 
Concomitant medications 
D 
6.3.1 
X 
X 
X 
X 
X 
Transfusion history/status 
D 
6.3.1 
X 
X 
X 
X 
X 
Adverse events 
D 
7.2.2.1 
X 
X 
X 
X 
X 
Dispense INC424  
S 
6.5.1 
 
X 
X 
 
 
Drug accountability assessment  
S 
6.5.4.2 
X 
X 
X 
X 
 
INC424 Dosing 
D  
6.1 
Continuous 
 
 


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7.1.1 
Screening evaluations 
Prospective participants will be scheduled for a Screening Visit by site staff. The window for 
this visit is Day -42 to Day -8. As noted in Inclusion criteria (Section 5.2), all drugs used to 
treat underlying MF must be discontinued no later than 28 days prior to the first Baseline 
assessment (except for the MRI scan and bone marrow examinations) for patients to enroll in 
the study. Site staff should inform patients to come to the study site after an overnight fast of 
at least 8 hours or since midnight on the day. The required Screening procedures will be 
scheduled to accommodate the discontinuation of prior MF medications by 28 days prior to 
Baseline. Informed Consent must be obtained before any study specific procedures including 
the discontinuation of any prior MF medications are conducted. 
A patient who has a laboratory test result(s) or 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 re-test result is likely to be within the acceptable range to 
satisfy the eligibility criteria, but should be completed within the Screening period. In this 
case, the patient will not be required to sign another ICF, and the original patient number 
assigned will be used. In the event that the laboratory test(s) cannot be performed within 5 
weeks of the Screening period, or the re-test(s) do not meet the eligibility criteria or the 
patient’s medical condition has changed significantly during the Screening period so that the 
eligibility 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, the same patient number will be assigned, 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 for the study. Once the number of 
patients screened and enrolled in the study is likely to assure target enrollment, the Sponsor 
may, at its discretion, close the study to further screening. At this time, patients who screen 
fail will not be permitted to re-screen. 
7.1.1.1 
Information to be collected on screening failures 
Patients who sign the ICF but fail to be started on treatment for any reason will be considered 
a screen failure. The reason for not being started on treatment will be entered on the Screening 
log eCRF and each patient’s demographic information will be on the Demography eCRF and 
informed consent date on the Informed Consent eCRF. No other data will be entered into the 
clinical database for patients who are screen failures.  
7.1.1.2 
Patient demographics and other characteristics 
Complete demographic information (birth date, sex, race, ethnicity, weight, and height) will 
be obtained at Screening along with a complete medical and medication history, and will be 
recorded in the appropriate eCRF.  
7.1.2 
Baseline evaluations 
The results from the Screening evaluations will be reviewed to determine if the patient 
continues to meet the eligibility requirements as specified in the protocol. After confirming 
that the patient has signed the ICF and meets all the eligibility criteria, the Investigator will 


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send an enrollment form to the Sponsor by fax or e-mail. The Sponsor will then notify the 
registration confirmation to the study site. 
Procedures for the Baseline Visit may be conducted between Day -7 and Day -1 except for the 
MRI scan (Day -28 and Day -7) and bone marrow examinations (Day -42 and Day -1). Blood 
sampling for hematology (to be measured at the study site) and serum chemistry (to be 
measured at the central laboratory) should be performed so that the results are available before 
the intended Study Day 1. Patients must be reminded to arrive for the Baseline blood sample 
collection after an overnight fast of at least 8 hours. 
The MRI scan should be conducted between Day -28 and Day -7 prior to allow ample time for 
the central reader to verify image quality prior to the initial administration of study drug. 
Image verification must be received before the patient starts study treatment. In the event that 
the image is determined by the central reader to have been performed incorrectly, the Baseline 
MRI should be rescheduled. 
All evaluations should be recorded in the source documents. 
7.1.3 
On-treatment evaluations 
The Investigator or designee will notify the initiation of treatment in each patient to the 
Sponsor at Day 1 by fax or e-mail. On-treatment evaluations are scheduled for study visits at 
Day 1, and at the end of Weeks 2, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, and every 6 weeks 
thereafter. At the study site where hematology results are not available within the day, patients 
will attend the study site 1 to 3 days prior to the Visit day to provide blood samples so that the 
hematology results are available at the study visit. In addition, patients will visit the study site 
for Extra Visits to provide blood samples for hematology both 2 and 4 weeks after restarting 
or increasing the dose of INC424. The Extra Visit may be skipped if it takes place within 7 
days of any other study visit. Blood draws for hematology at Extra Visits need not be fasted. 
Women of childbearing potential will be monitored regularly for pregnancy status, by urine 
pregnancy tests as indicated in Table 7-1. If a positive urine pregnancy test occurs, a serum 
test should be performed to confirm the result. If local requirements mandate more frequent 
testing, applicable sites must adhere to these requirements even if scheduled visits are less 
frequent. 
Between study visits, patients will self-administer INC424 twice daily as instructed, morning 
and evening (at approximately 12-hour intervals), in an outpatient setting. After 4 weeks of 
treatment (Week 4 Visit), patients may have the dose of INC424 increased because of 
inadequate efficacy. This efficacy assessment for dose increase at Week 4 will be based on 
palpable spleen length (See Section 6.2.1.1). At this visit or anytime during the study, the dose 
may be adjusted for safety. See Section 6.2 for criteria for mandatory reduction, interruption, 
or discontinuation of study drug based upon results of safety monitoring. Patients should call 
the Investigator or designated research staff if they experience any unexpected and 
unfavorable signs and/or symptoms. 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.  


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If it is determined at any study visit that the patient will discontinue study drug that day, then 
that study visit will be the End of Treatment Visit, and the End of Treatment Visit procedures 
will be followed.  
7.1.4 
End of treatment evaluations 
Patients who discontinue study drug should be scheduled for a visit as soon as possible, at 
which time all of the assessments listed for the End of Treatment Visit (Table 7-1) will be 
performed. At a minimum, all patients who discontinue study treatment, including those who 
refuse to return for a final visit, will be contacted for safety evaluations during the 30 days 
following the last dose of study drug. 
Patients who discontinue study treatment should be considered withdrawn from the study after 
the final visit assessments are performed or when it is clear that the patient will not return for 
these assessments. 
If a study discontinuation occurs, or if the patient fails to return for visits, the Investigator 
must determine the primary reason for a patient’s withdrawal from the study and record this 
information on the End of Treatment eCRF page. 
7.1.4.1 
Criteria for end of treatment 
Patients may choose to discontinue study treatment at any time without penalty of 
jeopardizing their health care or loss of benefits to which the patient is otherwise entitled. 
Every reasonable effort should be made to determine the reason for the treatment 
discontinuation, which should be recorded in the eCRF. 
A patient may discontinue study treatment if, in the Investigator’s medical judgment, the 
patient is non-compliant with the study requirements. 
A patient must discontinue study treatment if she becomes pregnant, or if he intends to father 
a child during the anticipated duration of study participation. 
Patients must discontinue study treatment for one of the following reasons: 
• Death 
• Adverse event(s) (refer to Section 6.2.4.2) 
• Consent is withdrawn 
• Disease progression (refer to Section 6.2.4.1) Lost to follow-up 
• Non compliance with taking study drug 
• Non compliance with study procedures 
• Termination of the clinical trial by the Sponsor 
• New cancer therapy 
• Other, i.e., if study drug has been interrupted for 8 weeks or more for any reason, except 
in the case of splenectomy where a maximum of 12 weeks of drug interruption is 
permitted, further participation would be injurious to the patient’s health or well being in 
the Investigator’s medical judgment, administrative reasons 


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Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
or abnormal laboratory value must be followed at least once a week for 4 weeks, 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 SAEs for 30 days following 
the last dose of INC424. 
7.1.5 
Follow-up evaluations 
Follow-up evaluations will be performed 30 (+10) days after the completion of the End of 
Treatment Visit or following the last dose of study drug. If the patient receives new cancer 
therapy after being withdrawn from treatment, Follow-up evaluations may be performed 
before 30 days following the last dose of study drug.  
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the Investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, i.e., dates of telephone calls, registered letters, 
etc. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
7.2.1.1 
Imaging 
The primary measure of spleen size will be by MRI. MRI of the abdomen will be performed 
at Baseline, and at visits corresponding to Weeks 12, 24, 36, 48 and every 24 weeks thereafter 
for all patients on study. MRI will be performed with a body coil because the objective is to 
measure organ volume, not to find very small lesions. MRIs will be performed by local 
radiologists who will be instructed not to provide a quantitative measure of spleen volume, 
but may provide a qualitative assessment such as enlarged, smaller, larger, etc. However, 
should a quantitative result be provided to the Investigator, this will not be considered a 
protocol violation, and the patient will still be evaluable. The scans from an individual patient 
will be read by a central reader upon transfer from the site radiologist. Spleen volume will be 
obtained by outlining the circumference of the organ and determining the volume using the 
validated technique of least squares. The MRI will not determine spleen length below the 
costal margin, as there are no validated approaches for determining this measurement. When a 
post-treatment assessment indicates that a patient has experienced a ≥ 25% increase in spleen 
volume compared to Baseline, the Investigator will be notified from a central reader. MRI is 
the preferred method for obtaining spleen volume data. However, CT scans may be performed 
if the patient is not a candidate for MRI (because of the presence of metal clips in the body, or 
because of claustrophobia, for example). CT scans will be similarly processed by the same 
central laboratory as used for MRIs.  Both for MRI and CT, procedure specific trainings for 
scanning and image capture will be provided by the Vendor. Generally, the same method 
(MRI or CT) should be used for all visits for a given patient unless a new contraindication to 
the use of MRI (i.e., pacemaker insertion) occurs. Please contact the Sponsor if a modality 
change is required. 


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7.2.1.2 
Spleen length 
Spleen length will be assessed by manual palpation at the study visits indicated in Table 7-1, 
and will be used to determine if dose increases for lack of efficacy should be considered. 
Investigators will be provided with a soft centimeter ruler so that palpable spleen length is 
measured in centimeters and not in finger breadths. The edge of the spleen shall be 
determined by palpation from the costal margin to the point of greatest splenic protrusion. 
7.2.1.3 
Patient reported outcomes assessment 
Patient reported outcomes regarding the impact of MF on patients will be assessed using the 
EORTC QLQ-C30 and Seven-day modified MFSAF questionnaires. Patients must complete 
the questionnaires before other clinical assessments at any given study visit. 
The EORTC QLQ-C30 instructions will be provided as separate documents. The protocol 
assessment questionnaires should be completed in the same order and for each patient to 
ensure that the patient is answering these as consistently as possible.  
Symptoms of MF will be assessed using Seven-day modified MFSAF v2.0. Symptoms 
assessed will include filling up quickly/early satiety, abdominal discomfort, abdominal pain, 
inactivity, night sweats, itching, and bone/muscle pain. Detailed directions for the 
administration of Seven-day modified MFSAF v2.0 diary will be provided in a separate 
document.  
7.2.2 
Safety and tolerability assessments 
Safety and tolerability assessments will consist of evaluating adverse events, laboratory 
parameters including hematology, chemistry and urinalysis, body weight, physical 
examinations, vital signs and ECG monitoring.  
7.2.2.1 
Adverse events 
Adverse events will be monitored continuously during the study. Patients will be instructed to 
report all adverse events during the study and patients will be assessed for the occurrence of 
adverse events throughout the study. All adverse events (serious and non-serious) must be 
recorded in the source documents and promptly entered in the eCRF regardless of the 


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assumption of a causal relationship with study drug. The definition, reporting, and recording 
requirements for adverse events are described in Section 8.1. 
7.2.2.2 
Physical examination 
A comprehensive or targeted physical examination will be performed at the study visits 
indicated in Table 7-1. A comprehensive physical examination will include the examination 
of general appearance, 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 comprehensive examination will include body systems as 
indicated by patient symptoms, adverse events, prior physical examination, past medical 
history or other findings as determined by the Investigator. A targeted physical examinations 
will include body systems as indicated by patient symptoms, adverse events, prior physical 
examinations, or other findings as determined by the Investigator. The targeted examination 
will always include liver and spleen, and assessment of edema. Both comprehensive and 
targeted examinations will include a measurement of the size of spleen palpation (except Day 
1). Measurement of spleen length by manual palpation will be performed as described in 
Section 7.2.1.2. 
7.2.2.3 
Vital signs 
Vital signs (sitting blood pressure, sitting pulse, respiratory rate and body temperature) will be 
collected at the study visits indicated in Table 7-1. 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. 
7.2.2.4 
Height and weight 
Height in centimeters (cm) only at Screening and body weight (to the nearest 0.1 kilogram 
[kg] in indoor clothing, but without shoes) at study visits indicated in Table 7-1will be 
measured. 
7.2.2.5 
Performance status 
The performance status will be assessed according to the ECOG performance status scale 
(Table 7-3). For the schedule of the ECOG performance status scale assessments, see Table 7-
1. 


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Table 7-3 
ECOG performance status scale 
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, i.e., 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 al. (1982). 
7.2.2.6 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected except for 
hematology, serum and urine pregnancy tests, other urine analysis and serology for hepatitis 
virus and HIV which will be performed locally. Details on the collections, shipment of 
samples and reporting of results by the central laboratory are provided to Investigators in the 
Laboratory Manual. For the schedule of the laboratory assessments, see Table 7-1. 
7.2.2.6.1 Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
including reporting of % of blasts, reticulocytes, and platelet count will be measured locally.  
7.2.2.6.2 Clinical chemistry 
Albumin, alkaline phosphatase, ALT, amylase, AST, bilirubin (total and direct), BUN, 
calcium, chloride, creatinine, gamma glutamyl transferase, glucose, iron, lactate 
dehydrogenase, lipase, phosphorus, potassium, sodium, total protein, and uric acid will be 
measured. Blood samples should be collected after an overnight fast of at least 8 hours (Note: 
this is not required if medically contraindicated, such as certain patients with diabetes who 
must eat with each morning’s insulin). 
7.2.2.6.3 Urinalysis 
Urine analysis (dipstick) will be performed locally to record pH and specific gravity, bilirubin, 
blood, glucose, ketones, leukocytes, protein, and urobilinogen. 
7.2.2.6.4 Pregnancy and assessments of fertility 
All women of childbearing potential will have a serum β-hCG test at Screening and at the last 
Follow-up Visit. At all other visits, the patients will have a urine pregnancy test. A positive 
urine pregnancy test requires immediate interruption of study drug until serum β-hCG is 
performed and found to be negative. If positive, the patient must be discontinued from the 
study. All the pregnancy tests will be performed locally. Women of childbearing potential will 
be monitored regularly for pregnancy status, either by serum or urine pregnancy tests as 
described in the study schedule. If local requirements mandate more frequent testing, 
applicable sites must adhere to these requirements even if scheduled visits are less frequent.  


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7.2.2.6.5 Lipid panel 
Lipid panel evaluated will consist of Total cholesterol, Triglycerides, LDL, HDL, and HS-
CRP will be evaluated. 
7.2.2.6.6 Coagulation test 
Prothrombin time (PT) and partial thromboplastin time (PTT) will be measured. For PT, both 
time (sec) and international normalized ratio (INR) will be requested. 
7.2.2.6.7 Screening for hepatitis virus and HIV 
IgM-HA Ab test, HBs Ag test, HBs Ab test, HBc Ab test, HCV Ab test and HIV Ab test will 
be evaluated at Screening. In patients who are negative for HBs Ag test but positive for either 
HBs Ab test or HBc Ab test, HBV-DNA test should be performed locally to check the 
eligibility for this study.  
7.2.2.6.8 Immunology 
CD34+ cell count will be measured and reported as % and an absolute cell count estimated by 
multiplying the percentage by white blood cell count.  
7.2.2.7 
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG) 
Standard 12 lead ECG will be performed at study visits indicated in Table 7-1. At Baseline, an 
ECG will be performed only if the ECG at Screening includes an abnormality deemed 
clinically significant. Interpretation of the tracing must be made by a qualified physician and 
documented on the ECG eCRF page. Each ECG tracing should be labeled with the study 
number, patient initials (where regulations permit), patient number, date, and kept in the 
source documents at the study site. Clinically significant abnormalities present after the 
patient signed Informed Consent except for screening failure patients should be reported on 
the adverse events eCRF page. Clinically significant findings must be discussed with the 
Sponsor prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after Informed Consent must be recorded on the adverse events eCRF page. 


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7.2.5 
Other assessments 
No additional tests will be performed on patients entered into this study. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event for the purposes of this protocol is defined as the appearance of (or 
worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that 
occur after patient’s signed Informed Consent has been obtained. Abnormal laboratory values 
or test results occurring after Informed Consent constitute adverse events only if they induce 
clinical signs or symptoms, are considered clinically significant, require therapy (i.e., 
hematologic abnormality that requires transfusion), or require changes in study drug(s). 
With exception of screening failure patients, adverse events that begin or worsen after 
Informed Consent should be recorded in the Adverse Events eCRF. Conditions that were 
already present at the time of Informed Consent should be recorded in the Medical History 
eCRF. Adverse event monitoring should be continued for at least 30 days following the last 
dose of study treatment. Adverse events (including lab abnormalities that constitute adverse 
events) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate adverse event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03. If CTCAE grading does not exist for an adverse event, the severity of 
mild, moderate, severe, and life-threatening, or Grade 1-4, will be used. CTCAE Grade 5 
(death) will not be used in this study; rather, information about deaths will be collected in the 
End of Treatment or Study Evaluation Completion eCRF page. 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) 
• Reasonable possibility that adverse event is related to study treatment: (no, yes)  
• Start and end dates, unless unresolved at final exam 
• Action taken with respect to study drug (none, dose adjusted, temporarily interrupted, 
permanently discontinued 
• Whether it is serious, as per SAE definition provided in Section 8.2. 
Unlike routine safety assessments, SAEs are monitored continuously and have special 
reporting requirements, see Section 8.2. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.  
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to 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. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or 
require changes in study treatment), should be recorded on the Adverse Events eCRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (i.e. 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. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported adverse event, it is not necessary to separately record the 
lab/test result as an additional event.  
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not 
automatically indicate a SAE unless it meets the definition of serious as defined below and/or 
as per Investigator’s discretion. A dose hold or medication for the lab abnormality may be 
required by the protocol in Section 6.2.2 and should not contribute to designation of a lab 
parameter abnormality as a SAE:  
8.2 
Serious adverse events 
8.2.1 
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 the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• 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 


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• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
8.2.2 
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 Sponsor or designee within 24 hours of learning of its 
occurrence. Any SAEs experienced after this at least 30 day period should only be reported to 
the Sponsor or designee if the Investigator suspects a causal relationship to 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. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one should be reported separately as a new 
event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form. The Investigator must assess and record the relationship of each SAE to each specific 
study drug (if there is more than one study drug), complete the SAE Report Form in English, 
and send the completed, signed form by fax within 24 hours to the Sponsor. 
The telephone and telefax number of the Sponsor’s contact persons, 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 IB (new occurrence) and is thought to be 
related to the Sponsor’s study drug, a Sponsor’s associate may urgently require further 
information from the Investigator for Health Authority reporting. The Sponsor 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. 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 


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and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
8.4 
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 IB. 
Additional safety information collected between IB updates will be communicated in the form 
of Investigator Notifications. This information will be included in the patient Informed 
Consent and should be discussed with the patient during the study as needed. 
8.5 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be established.  
8.6 
Steering Committee 
A Steering Committee (SC) will be appointed by the Sponsor. The SC will have members 
external to the Sponsor, Investigators participating in the trial, as well as Sponsor 
representatives. The SC will ensure transparent management of the study according to the 
protocol through the approval of modifications and recommendations as circumstances 
require. Together with the Sponsor representatives, the SC will also develop 
recommendations for publications of study results including authorship rules. Details on the 
SC related-procedures are summarized in the Charter. 
9 
Data collection and management 
9.1 
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. 


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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. 
9.2 
Site monitoring 
Before study initiation, Novartis 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 signed ICF (a signed copy is given 
to the patient). 
The Investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of Informed Consent, adherence to the inclusion/exclusion 
criteria 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. 
9.3 
Data collection 
The designated Investigator staff will enter the data required by the protocol into the eCRF. 
The eCRFs have been built using fully validated secure web-enabled 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. Automatic validation programs check for data 
discrepancies in the eCRFs, and allow modification or verification of the entered data by the 
Investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.  
After database lock, the Investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the study site. 
9.3.1 
Laboratory tests 
Laboratory tests including serum chemistry, lipid panel and coagulation tests will be 
performed at central laboratory. The results will be transmitted electronically to a designated 
CRO.  


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9.3.2 
Spleen imaging 
The primary measure of spleen volume will be by MRI (or CT scan in applicable patients). 
The scans from an individual patient will be read by a central reader upon transfer from the 
site radiologist. MRI is the preferred method for obtaining spleen volume data. However, CT 
scans may be performed if the patient is not a candidate for MRI for medical contraindication. 
CT scans will be similarly processed by the same central laboratory as used for MRIs. 
Procedure specific training for scanning and image capture will be provided by the Vendor. 
The same method (MRI versus CT) must be used for all visits for a given patient unless a new 
contraindication to the use of MRI (i.e., pacemaker insertion) occurs. 
 
 
 
 
 
9.4 
Database management and quality control 
Novartis personnel or a designated CRO will review the data entered by staff at the 
Investigator’s site for completeness and accuracy. Electronic data queries stating the nature of 
the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the Investigator’s site via the EDC system. Designated Investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
 data of spleen imaging readings will be processed 
centrally and the results for patients enrolled into treatment will be sent electronically to 
Novartis or a designated CRO. 
 
 
  
The occurrence of any protocol deviations will be monitored throughout the study. After these 
actions have been completed and the database has been declared to be complete and accurate, 
it will be locked and made available for data analysis. Any changes to the database after that 
time can only be made by joint written agreement between the Novartis Global Head of BDM 
and the Global Therapeutic Area Head. 


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10 
Statistical methods and data analysis 
The cutoff date of data for the clinical study report (CSR) will be when all the patients either 
complete the Week 24 Visit or discontinue the study, whichever comes first. The primary 
analysis will be performed at that date of data cutoff. An interim analysis is planned to be 
performed when the first 50 patients either complete the Week 24 Visit or discontinue the 
study. Additionally, follow-up efficacy and safety data will also be summarized in a separate 
report.  
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of INC424.  
10.1.2 
Safety population 
The Safety population (SAF) consists of all patients who received at least one dose of INC424 
and had at least one safety evaluation post-Baseline. This analysis set will be used for all 
safety analyses.  
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of all patients in the FAS who did not meet the criteria 
for major protocol deviations.  
10.2 
Patient demographics/other Baseline characteristics 
Demographic and other Baseline data (including disease characteristics) will be summarized 
descriptively for the FAS. Qualitative data such as sex and gender will be summarized by 
means of the contingency table. Quantitative data such as age and body weight will be 
summarized descriptively including the mean, standard deviation, median, minimum and 
maximum. 
Medical history will be tabulated with the number and percentage of patients with medical 
history for each system/organ class.  


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All demographic and other Baseline data will also be listed.  
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The duration of exposure in days to INC424 will be defined as the time between the date of 
last dosing and the date of first dosing. It includes periods of temporary interruptions of 
INC424. The duration of exposure will be calculated for each patient, and will be summarized 
descriptively.  
The average daily dose (mg/day) will also be calculated on a per patient basis. It is defined as 
the ratio of the cumulative dose to the duration of exposure. The average daily dose will be 
summarized descriptively.  
The number and percentage of patients with dose change/dose interruption (dose change to 
zero mg) will be calculated by the reason for dose change.  
Concomitant medications will be listed in detail and tabulated by WHO drug class.  
10.4 
Primary objective 
The primary objective is to determine the efficacy of INC424 as assessed by reduction in 
spleen volume.  
10.4.1 
Variable 
The primary efficacy variable is the proportion of patients achieving ≥35% reduction in 
spleen volume from Baseline to Week 24 as measured by MRI (or CT scan).  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The primary analysis will be based on a single-sample binomial test (normal approximation) 
at the one-sided 2.5% significance level, analyzed in the FAS. Note that a patient with a 
missing spleen volume at Baseline will be excluded from the denominator in the primary 
efficacy analysis. A patient with a missing spleen volume at Week 24 will be considered as 
having not achieved the ≥35% reduction. Patients who drop out of the study due to any reason 
prior to Week 24 Visit will be considered as having not achieved the ≥35% reduction.  
The statistical hypotheses are 
       H0: p ≤ 0.2 versus H1: p > 0.35, 
where p is the proportion of patients achieving ≥35% reduction in spleen volume from 
Baseline to Week 24 as measured by MRI (or CT scan). The null hypothesis will be tested 
with one one-sided single-sample binomial test (normal approximation) using an overall type 
I error rate of 2.5%. 
The study has a group sequential design and includes a single interim analysis when the first 
50 patients either complete the Week 24 Visit or discontinue the study. The boundaries for the 
single-sample binomial test will be determined using an alpha-spending function (Lan and 
DeMets 1983) which approximates the boundaries of (O’Brien and Fleming 1979). For 
example, if exactly 50 patients are included in the interim analysis, then the p-value from the 


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single-sample binomial test must be ≤0.001 to be considered statistically significant. Note that 
the study will subsequently continue to the final analysis regardless of the statistical 
significance reached at the interim analysis. When 110patients are exactly included in the 
final analysis, then the p-value must be ≤0.024 to be considered statistically significant. The 
statistical analysis will be performed using the actual numbers observed at the cut-off date for 
the interim and the final analyses, the corresponding boundaries will be derived from the pre-
specified alpha-spending function. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Missing record for spleen volume will not be imputed. 
10.4.4 
Supportive analyses 
An analysis on the PPS will be repeated for the primary efficacy variable. 
The primary efficacy variable will be summarized within each of the following subgroups: 
• Sex: male or female. 
• Country: Japan, Korea, Taiwan or China. 
• Baseline prognostic category: Intermediate-2 or High. 
• Previous use of hydroxyurea: use or non-use. 
• Starting dose: 15 mg BID or 20 mg BID. 
Other subgroups may also be considered.  
10.5 
Secondary objectives 
The secondary objectives are to determine the safety of INC424 and to evaluate changes in 
patient reported outcomes as assessed by the EORTC QLQ-C30 score and Seven-day 
modified MFSAF v2.0, and to evaluate the duration of response as assessed by reduction in 
spleen volume. 
10.5.1 
Change in EORTC QLQ-C30 score from Baseline to Week 24 
Data from the EORTC QLQ-C30 questionnaire will be analyzed using the standardized scores. 
The change from Baseline will be calculated with the data collected at the Baseline Visit as 
the Baseline. The 5 functional scales, 3 symptom scales, 1 global health status/QOL scales, 
and 6 single-item scales will be summarized with descriptive statistics by scheduled visit. 
10.5.2 
Change in total symptom score from Baseline to Week 24 as 
measured by Seven-day modified MFSAF v2.0 
The change in total symptom score from Baseline will be tabulated with descriptive statistics 
by scheduled visit. All individual scores will also be tabulated with descriptive statistics by 
scheduled visit. 
The percentage of patients who have ≥50% reduction in total symptom score at Week 24 will 
be estimated with 95% confidence interval. 


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10.5.3 
Best response rate  
The best response rate is defined as the proportion of patients achieving ≥35% reduction in 
spleen volume from Baseline at any post-baseline assessment. The best response rate will be 
estimated with 95% confidence interval.  
10.5.4 
Duration of maintenance of a greater or equal 35% reduction from 
Baseline in spleen volume 
For patients who had at least one ≥ 35% reduction in spleen volume from Baseline at post-
baseline, the duration of response will be calculated. The start date of the duration is defined 
as the first spleen volume measurement that is ≥ 35% reduction from Baseline, and the end 
date is defined as the earliest of the following: 
• Death 
• Any protocol-defined event of disease progression (see Section 6.2.4.1) 
Censoring date is defined as the date of the last adequate assessment of the spleen volume. 
Patients who had more than 1 consecutive missing spleen volume assessment will be censored 
at the last adequate assessment prior to the consecutive missing assessments, regardless of the 
occurrence of a subsequent death or any event of disease progression.  
The duration of response will be evaluated using a Kaplan-Meier estimate. Note that the 
analysis will be performed only for patients who achieved a ≥35% reduction in spleen volume.  
10.5.5 
Safety 
10.5.5.1 Analysis set and grouping for the analyses 
For all safety analyses, the SAF will be used. All listings and tables will be presented by 
Subject ID. 
The overall observation period will be divided into two mutually exclusive segments: 
• Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of INC424 
• On-treatment period: from day of first dose of study drug to 30 days after last dose of 
INC424 
10.5.5.2 Adverse events 
Summary tables for adverse events have to include only adverse events that started or 
worsened during the on-treatment period, the treatment-emergent adverse events. However, 
all safety data (including those from the pre and post-treatment periods) will be listed and 
those collected during the pre-treatment are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from Baseline) will 
be summarized by system organ class and or preferred term, severity (based on CTCAE 
grades), type of adverse event, relation to study treatment. Deaths reportable as SAEs and 
non-fatal serious adverse events will be listed by patient and tabulated by type of adverse 
event. 


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Specific safety event categories (SEC) may 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 INC424. Specific SECs are to be defined by the Clinical 
Team with regular updates as necessary and described in the 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. 
10.5.5.3 Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03, tthe 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 summaries will be generated separately for hematology, serum chemistry, 
urinary laboratory tests and coagulation: 
• Frequency table for newly occurring on-treatment Grade 3 or 4 
• 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. 
In addition to the above mentioned tables and listings, 
 for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP. 
10.5.5.4 Other safety data 
12-lead ECGs 
12-lead ECGs including PR, QRS, QT, QTcF, QTcB, and RR intervals will be obtained for 
each patient during the study in accordance with the Schedule of Observations, and will be 
summarized descriptively. For the calculation of changes and percent changes in cardiac 
intervals, the average of intervals from the Screening and Baseline recordings will be used as 
the Baseline for comparison of all post-Baseline intervals.  
The proportion of patients with the following outliers in QT, QTcF, or QTcB intervals will be 
calculated and tabulated by scheduled visit: 
• A measured value of >450 ms 
• A measured value of >480 ms 
• A measured value of >500 ms 
• A change from Baseline of >30 ms 


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• A change from Baseline of >60 ms 
Other ECG parameters will also be analyzed as appropriate.  
Vital signs 
Vital signs including systolic blood pressure, diastolic blood pressure, respiratory rate, body 
temperature, and pulse will be taken in the seated position for each patient during the study.  
The proportion of patients with vital signs out of the following normal ranges will be 
calculated: 
Table 10-1 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic Blood Pressure 
>160 mm Hg 
<85 mm Hg 
Diastolic Blood Pressure 
>95 mm Hg 
<50 mm Hg 
Respiratory rate 
> 24 per minute 
< 8 per minute 
Temperature 
≥37.5°C 
≤35.0°C 
Sitting pulse 
≥120 bpm 
≤50 bpm 
The change in weight (kg) and BMI (kg/m2) from Baseline will be summarized descriptively 
by scheduled visit. 
A shift table comparing Baseline with worst on-treatment result will be generated. Also, all 
vital signs will be listed by patient.  
10.5.5.5 Tolerability 
The number and percentage of patients who have a dose modification due to a treatment-
related adverse event will be summarized by type of dose modification (omission, dose 
reduction, and permanent discontinuation) and preferred term. A listing of all patients 
receiving INC424 who have a dosing change will include the new dose, interruption, or 
stopping as well as day since first dose. 


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10.7 
Interim analysis 
A single interim analysis is planned to be performed when the first 50 patients either complete 
the Week 24 Visit or discontinue the study (information fraction is 45.5% for 110 patients, the 
required sample size for this study). The interim analysis will be performed to show the 
outstanding efficacy at the interim time-point: there is no futility look. However, note that this 
trial will not be stopped even if outstanding efficacy was seen at the interim time-point. The 
primary aim of the interim analysis is to assess the efficacy and safety of INC424 in Asian 
MF patients earlier and to achieve an earlier regulatory filing to health authorities with the 
interim efficacy and safety data. If this interim analysis shows at least the pre-specified 
number of responders, the Steering Committee (SC) will discuss the safety and efficacy 
results, and will make a final decision on the applicability of a submission.  
Test boundaries will be determined using the alpha spending function described by (Lan and 
DeMets 1983) which approximates the boundaries of (O’Brien and Fleming 1979). 
The planned study design was confirmed to fulfill the above conditions via simulations in 
EAST version 5.3, and the corresponding simulated probabilities and further simulation 
results are given in Table 10-2. 


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Table 10-2 
Design properties of the proposed two stage group sequential design 
 
First interim 
Final analysis 
Planned sample size 
50 
110 
Information fraction (%) 
45.5 
100.0 
Cumulative power 
0.345 
0.951 
Stopping boundary (to reject null hypothesis) 
 
 
     Z-value 
3.126 
1.965 
     Number of required responders 
19 
31 
If the exact number of patients analyzed at the interim and final analyses deviates from 50 and 
110 respectively, the actual critical boundaries will be recalculated using the alpha-spending 
function defined above. In particular, the critical boundary to be used at the interim analysis 
will be derived from the pre-specified error spending function using the actual number of 
patients analyzed and assuming 110 patients in the final analysis. Further, the critical value for 
the final analysis will be calculated using the exact number of patients analyzed at the date of 
data cutoff, and considering the alpha-level spent at the interim analysis, in order to achieve a 
cumulative type I error smaller than or equal to 2.5%. 
The interim data will be analyzed by statistician in Novartis Japan BDM (Biometrics and Data 
Management; not independent statistician) because of open-label study and the results will be 
reviewed by the Steering Committee and pre-determined associates in Novartis who can have 
an access to the interim results. Therefore, no DMC will be established.  
10.8 
Sample size calculation 
The sample size calculation was made using EAST version 5.3. 
Study [INCB 18424-351] is a randomized, double-blind, placebo-controlled study comparing 
the efficacy and safety of INC424 to a matched placebo in patients with PMF or post-PV/ET 
MF. In this study, the same primary efficacy variable, i.e., proportion of patients achieving 
≥35% reduction in spleen volume from Baseline to Week 24 as measured by MRI (or CT 
scan), is evaluated. The result of Study [INCB 18424-351] provided a response rate of 41.9% 
in INC424 group while 0.7% in placebo group.  
The sample size for this study is based on the single-sample binomial test (normal 
approximation). Based on the results obtained in Study [INCB 18424-351], the proportion of 
patients on this study achieving ≥35% reduction in spleen volume from Baseline to Week 24 
as measured by MRI (or CT scan) is expected to be 0.35. From the aspect of clinical benefit in 
patients with PMF or post-PV/ET MF, a threshold of 0.2 was set for null hypothesis.  
An interim analysis is planned in this study. If the study had no interim analysis (1-stage 
approach), the required sample size of 110 provides power of 0.951 with one-sided type I 
error rate of 0.025 under response rate of 0.2 and 0.35 for null and alternative hypotheses.  
The power for the group sequential (ie, 2-stage) design accruing 110 total patients with the 
same final timepoint boundary (≥31/110) and an interim analysis conducted after 50 patients 
using an O’Brien-Fleming type interim analysis boundary (≥ 19/50) is approximately 0.95. 
Therefore, the effect of the interim analysis on the overall study power is negligible. 


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10.9 
Power for analysis of key secondary variables 
Not applicable.  
11 
Ethical considerations and administrative procedures 
11.1 
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. 
11.2 
Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed Informed Consent Form (ICF) must be reviewed and approved 
by a properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. A signed and dated statement that the 
protocol and Informed Consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. Prior to study start, the Investigator is required to sign a 
protocol signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to Novartis monitors, auditors, Novartis Clinical 
Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs and 
regulatory authorities as required. 
11.3 
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. 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. The date when a patient’s Informed Consent was actually 
obtained will be captured in their eCRFs. 
Novartis will provide Investigators in a separate document with a proposed 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 Novartis before submission to the IRB/IEC/REB, and a copy of the approved 
version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study drug 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. 


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11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as Clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of patients. As part of participating in a 
Novartis-sponsored study, each study site will permit authorized representatives of the 
Sponsor(s) and regulatory agencies to examine (and when required by applicable law, to 
copy) clinical records for the purposes of quality assurance reviews, audits and evaluation of 
the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, patients’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, X-rays, and patient files 
and records kept at the pharmacy, at the laboratories, and medico-technical departments 
involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The eCRF is the primary data collection instrument for the 
study. The Investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported in the eCRF and all other required reports. Data reported on the eCRF, that 
are derived from source documents, should be consistent with the source documents or the 
discrepancies should be explained. All data requested on the eCRF must be recorded. For 
electronic CRFs an audit trail will be maintained by the system. The Investigator should retain 
records of the changes and corrections to paper CRFs. 
The Investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The Investigator/institution should take measures to 
prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the clinical trial unless Sponsor provides written 


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permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The Investigator must ensure anonymity of the patients; patients must not be identified by 
names in any documents submitted to Novartis. Signed ICFs and patient enrollment log must 
be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who is directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the Investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. If 
the Investigator feels a protocol deviation would improve the conduct of the study this must 
be considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR. 
12.1 
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 Novartis, Health Authorities where required, and the IRB/IEC/REB. 
Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the Investigator is expected to take any immediate action required for the safety 
of any patient included in this study, even if this action represents a deviation from the 
protocol. In such cases, Novartis should be notified of this action and the IRB/IEC/REB at the 
study site should be informed within 10 working days. 


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13 
References (available upon request) 
Barosi G, Mesa RA, Thiele J, et al. (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; 
22:437-8. 
Cervantes F, Dupriez B, Pereira A, et al. (2009) New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood; 113:2895-901. 
Flockhart DA (2007) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine. Internet. Available from 
<http://medicine.iupui.edu/clinpharm/ddis/table.asp> (Accessed 24 February 2011) 
Lan KKG and DeMets DL (1983) Discrete sequential boundaries for clinical trials. 
Biometrika; 70:659-63. 
Levine RL, Pardanani A, Tefferi A, et al. (2007) Role of JAK2 in the pathogenesis and 
therapy of myeloproliferative disorders. Nature Rev Cancer; 7:673-83. 
Manoharan A, Horsley R, Pitney WR (1979) The reticulin content of bone marrow in acute 
leukaemia in adults. Br J Haematol; 43:185–90. 
Mesa RA, Niblack J, Wadleigh M, et al. (2007) The burden of fatigue and quality of life in 
myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD 
patients. Cancer; 109:68-76. 
Mesa RA (2009) How I treat symptomatic splenomegaly in patients with myelofibrosis. 
Blood; 113:5394-400. 
Kroger N and Mesa RA (2008) Choosing between stem cell therapy and drugs in 
myelofibrosis. Leukemia; 22:474-86. 
O’Brien PC and Fleming TR (1979) A multiple testing procedure for clinical trials. 
Biometrics; 35:549-56. 
Oken MM, Creech RH, Tormey DC, et al. (1982) Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol; 5:649-655. 
Tefferi A, Barosi G, Mesa RA, et al. (2006) International Working Group (IWG) consensus 
criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for 
Myelofibrosis Research and Treatment (IWG-MRT). Blood; 108:1497-503. 
Tefferi A and Vardiman JW (2008) Classification and diagnosis of myeloproliferative 
neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic 
algorithms. Leukemia; 22:13-22. 
Thiele J, Kvasnicka HM, Tefferi A, et al. (2008) Primary myelofibrosis. WHO classification 
of tumors of haematopoietic and lymphoid tissues. 4th ed; Lyon:International Agency for 
Research on Cancer,44-7. 


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Trussell J (2004) Contraceptive failure in the United States. Contraception; 70:89-96. 
Vannucchi AM, Guglielmelli P, Tefferi A (2009) Advances in understanding and 
management of myeloproliferative neoplasms. CA Cancer J Clin; 59:171-91. 
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; 363:1117-27. 


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14 
Appendices 
List of Appendices 
Appendix I 
The 2008 WHO criteria for PMF, PV and ET (Tefferi et al. 2008) 
Appendix II 
IWG-MRT recommended criteria for post-PV/ET MF (Barosi et al. 2008) 
Appendix III 
Information regarding effectiveness of contraceptive methods 
Appendix IV 
Bone marrow biopsy and aspirate evaluations  
Appendix V 
 Restricted and prohibited medications 


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Appendix I - The 2008 WHO criteria for PMF, PV and ET 
(Tefferi et al. 2008)  
Diagnostic criteria for PMF1 
Major criteria 
• Presence of megakaryocyte proliferation and atypia, accompanied by either reticulin or collagen 
fibrosis OR in the absence of significant reticulin fibrosis, the megakaryocyte changes must be 
accompanied by an increased marrow cellularity characterized by granulocytic proliferation and 
often decreased erythropoiesis (i.e., prefibrotic cellular-phase disease) 
• Not meeting WHO criteria for PV, CML, MDS or other myeloid disorders 
• Demonstration of JAK2V617F or other clonal marker (i.e., MPL W515K/L) OR in the absence of the 
above clonal markers no evidence of secondary bone marrow fibrosis 
Minor criteria 
• Leukoerythroblastosis 
• Increased serum lactate dehydrogenase level 
• Anemia 
• Splenomegaly 
Diagnostic criteria for PV2 
Major criteria 
• Hemoglobin >18.5 g/dL in men, >16.5 g/dL in women OR other evidence of increased red cell 
volume3 
• Presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation 
Minor criteria 
• Bone marrow biopsy showing hypercellularity for age with trilineage myeloproliferation 
• Serum erythropoietin level below the normal reference range 
• Endogenous erythroid colony formation in vitro 
Diagnostic criteria for ET4 
• Sustained platelet count ≥450 x 109/L 
• Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with 
increased numbers of enlarged, mature megakaryocytes. No significant increase or left-shift of 
neutrophil granulopoiesis or erythropoiesis 
• Not meeting WHO criteria for PV or PMF, BCR-ABL-positive CML, or MDS or other myeloid 
neoplasm 
• Demonstration of JAK2V617F or other clonal marker OR in the absence of JAK2V617F, no 
evidence of reactive thrombocytosis 
WHO = World Health Organization, PMF = primary myelofibrosis, PV= polycythemia vera, CML = 
chronic myeloid leukemia, ET = essential thrombocythemia, MDS = myelodysplastic syndrome 
1Diagnosis of PMF requires all three major criteria and two minor criteria. 
2Diagnosis of PV requires meeting either both major criteria and one minor criterion OR the first major 
criterion and two minor criteria. 
3Hemoglobin or hematocrit >99th percentile of reference range for age, sex or altitude of residence 
OR red cell mass >25% above mean normal predicted or hemoglobin >17 g/dL (men) or >15 g/dL 


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(women) if associated with a sustained increase of >2 g/dL from Baseline that cannot be attributed to 
correction of iron deficiency. 
4Diagnosis of ET requires all four criteria. 


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Appendix II- IWG-MRT recommended criteria for post-PV/ET MF 
(Barosi et al. 2008)  
Diagnostic criteria for post-PV MF1 
Required criteria 
• Documentation of a previous diagnosis of PV as defined by the WHO criteria 
• Bone marrow fibrosis Grade 2-3 (on 0-3 scale)2 or Grade 3-4 (on 0-4 scale)3 
Additional criteria 
• Anemia4 or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive 
therapy) or cytoreductive treatment for erythrocytosis 
• A leukoerythroblastic peripheral blood picture 
• Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable 
splenomegaly 
• Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5 ºC) 
Diagnostic criteria for post-ET MF5 
Required criteria 
• Documentation of a previous diagnosis of ET as defined by the WHO criteria 
• Bone marrow fibrosis Grade 2-3 (on 0-3 scale)2 or Grade 3-4 (on 0-4 scale)3 
Additional criteria 
• Anemia4 and a ≥2 g/dL decrease from Baseline hemoglobin level 
• A leukoerythroblastic peripheral blood picture 
• Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly palpable 
splenomegaly 
• Increased LDH (above reference level) 
• Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, 
unexplained fever (>37.5 ºC) 
IWG-MRT = International Working Group for Myelofibrosis Research and Treatment, PV= 
polycythemia vera, ET = essential thrombocythemia, MF = myelofibrosis, WHO = World Health 
Organization, LDH = lactate dehydrogenase 
1Diagnosis of post-PV MF requires all required criteria and two additional criteria. 
2Grade 2-3 according to the European classification (Thiele et al. 2005): diffuse, often coarse fiber 
network with no evidence of collagenization (negative trichrome stain) or diffuse, coarse fiber network 
with areas of collagenization (positive trichrome stain). 
3Grade 3-4 according to the standard classification (Manoharan et al. 1979): diffuse and dense 
increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen 
and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis. 
4Below the reference range for appropriate age, sex, gender and altitude considerations. 
5Diagnosis of post-ET MF requires meeting all required criteria and two additional criteria. 


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Appendix III - Information regarding effectiveness of contraceptive 
methods 
For patients participating in the study, female patients will be required to use highly effective 
contraception as described below. The duration of contraception in case highly effective 
contraception is required is during dosing and for 5 times the terminal t1/2 (about 15 hours).  
• Total abstinence  
• Sterilization  
• Combination of any two of the following (a+b OR a+c OR b+c):  
a. Use of oral, injected or implanted hormonal methods of contraception  
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)  
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository  


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Appendix V - Restricted/prohibited medications 
These medications are restricted or prohibited in combination with INC424: 
Restricted medications 
Use of all CYP3A4 inhibitors or inducers is discouraged as they may have effects on plasma 
levels of INC424. Alternative therapies should be considered, if available. 
CYP3A4 inhibitors 
CYP3A4 inducers 
Other restricted therapies 
Strong1 
• 
clarithromycin 
• 
itraconazole 
• 
ketoconazole 
• 
nefazodone 
• 
telithromycin 
Moderate 
• 
aprepitant 
• 
erythromycin 
• 
fluconazole 
• 
grapefruit juice 
• 
verapamil 
 
Weak to Moderate 
• 
diltiazem 
 
Weak 
• 
cimetidine 
 
All other inhibitors; 
• 
amiodarone 
• 
chloramphenicol 
• 
delaviridine 
• 
diethyl-dithiocarbamate 
• 
fluvoxamine 
• 
gestodene 
• 
imatinib 
• 
mibefradil 
• 
mifepristone 
• 
norfloxacin 
• 
norfluoxetine 
• 
starfruit 
• 
voriconazole 
Weak to moderate 
• 
barbiturates 
• 
carbamazepine 
• 
glucocorticoids 
• 
modafinil 
• 
nevirapine 
• 
oxcarbazepine 
• 
phenobarbital 
• 
phenytoin 
• 
pioglitazone 
• 
rifabutin 
• 
Aspirin is permitted only below 
150mg/day; acetaminophen or 
ibuprofen may be used 
• 
Hematopoietic growth factor 
receptor agonists (i.e., 
erythropoietin) or granulocyte 
colony stimulating factor 
(romiplostim, eltrombopag) are not 
recommended; they may result in 
an increase in spleen size, and 
study drug efficacy may be 
compromised 
• 
Anti-coagulant/anti-platelet 
medications should be 
administered with careful 
consideration of any 
thrombocytopenia 
1Dose modification of INC424 is required if any of these medications are used concomitantly with INC424 
(see Section 6.2.3). 


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Prohibited medications 
Systemic steroids (i.e. predonisone >10 mg) 
Aspirin >150 mg/day 
Any other investigational medication  
Any other medication for myelofibrosis: hydroxyurea, busulfan, interferon, lenalidomide, 
thalidomide, anagrelide 
Potent CYP3A4 Inducers: rifampin St. John’s Wort 
 

SAP_001.pdf: 
Clinical Development
INC424/ruxolitinib/Jakavi®/
CINC424A2202 / NCT01392443
A multi-national open-label phase II study of the JAK 
inhibitor INC424 in patients with primary myelofibrosis, 
post-polycythemia vera myelofibrosis or post-essential 
thrombocythemia myelofibrosis
Statistical Analysis Plan (SAP) for final CSR
Author:
Document type:
SAP Documentation
Document status:
Final
Release date:
4-Aug-2017
Number of pages:
22
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
INC424A/INC424A2202
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)


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SAP
INC424A/INC424A2202
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ............................................................................................................8
2.2.1
Subgroup of interest ................................................................................8
2.3
Patient disposition, demographics and other baseline characteristics .....................9
2.3.1
Patient disposition...................................................................................9
2.3.2
Demographics and baseline data.............................................................9
2.3.3
Medical history and current medical conditions .....................................9
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................9
2.4.1
Study treatment / compliance..................................................................9
2.4.2
Prior, concomitant and post therapies ...................................................10
2.5
Analysis of the primary objective..........................................................................10
2.6
Analysis of the key secondary objective ...............................................................10
2.7
Analysis of secondary efficacy objective(s)..........................................................10
2.8
Safety analyses.......................................................................................................11
2.8.1
Adverse events (AEs)............................................................................11
2.8.2
Deaths....................................................................................................14
2.8.3
Laboratory data .....................................................................................14
2.8.4
Other safety data ...................................................................................14
15
15
2.11
Patient-reported outcomes .....................................................................................16
16
16
2.14
Interim analysis......................................................................................................17
3
Sample size calculation .....................................................................................................18
4
Change to protocol specified analyses ..............................................................................18
5
Appendix ...........................................................................................................................18


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INC424A/INC424A2202
5.1
Imputation rules.....................................................................................................18
5.1.1
Study drug .............................................................................................18
5.1.2
AE date imputation ...............................................................................18
5.1.3
Concomitant medication date imputation .............................................18
5.2
AEs coding/grading ...............................................................................................20
5.3
Laboratory parameters derivations ........................................................................20
5.4
Statistical models...................................................................................................20
5.4.1
Primary analysis ....................................................................................20
5.4.2
Key secondary analysis .........................................................................21
5.5
Rule of exclusion criteria of analysis sets..............................................................21
6
Reference...........................................................................................................................22


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SAP
INC424A/INC424A2202
List of abbreviations
AE
Adverse Event
bpm
Beats per minute
AESI
Adverse Events of special interest
CRS
Compound Case Retrieval Strategy’ Sheet
CSR
Clinical Study Report
CT
Computer Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DBL
Database Lock
DI
Dose Intensity
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EORTC
European Organization for Research and Treatment of Cancer
FAS
Full Analysis Set
IWG-MRT
International Working Group for Myelofibrosis Research and Treatment
MedDRA
Medical Dictionary for Regulatory Affairs
MF
Myelofibrosis
MFSAF
Myelofibrosis Symptom Assessment Form
MRI
Magnetic Resonance Imaging
ms
Millisecond
PD
Protocol Deviation
PD
Pharmacodynamics
PET-MF
Post Essential Thrombocytemia-Myelofibrosis
PK
Pharmacokinetic
PMF
Primary Myelofibrosis
PPS
Per-Protocol Set
PPV-MF
Post Polycythemia Vera-Myelofibrosis
PT
Preferred Term
QoL
Quality of Life
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SI
Standard International
SMQ
Standard MedDRA Query
SOC
System Organ Class
WBC
White Blood Cell


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the final Clinical Study 
Report (CSR) of study CINC424A2202, a phase II, open-label, multi-center study of the JAK 
inhibitor INC424.
A single interim analysis was conducted when the first 50 patients had completed the Week 
24 visit or discontinued from the study prior to the Week 24 visit. The aim of the interim 
analysis was to assess the efficacy and safety of INC424 in Asian MF patients and to achieve 
an earlier regulatory filing to health authorities with the interim efficacy and safety data. The 
efficacy, safety 
 analyses have been performed for 120 patients since the interim 
analysis showed the positive result. The analysis plan of CSR for Week 24 was documented in
“CINC424A2202 RAP Module 3 Detailed statistical methodology Amendment 2” and the 
results were presented in “the Week 24 CSR” released on Sep 4 2013.
1.1
Study design
This is an Asian multi-national phase II open-label study evaluating the efficacy and safety of 
INC424 in patients with PMF or post-PV/ET MF who have splenomegaly of at least 5 cm 
below the costal margin by manual palpation, and 2 or more risk factors (intermediate-2 or 
high risk) defined by the International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT) (Cervantes et al. 2009). The study is conducted in four Asian 
countries, i.e., China, Japan, Korea and Taiwan.
1.2
Study objectives and endpoints
Table 1-1 shows objectives and endpoints for this study.
Table 1-1
Objectives and endpoints
Objective
Endpoint
Primary
To determine the efficacy of INC424
as assessed by reduction in spleen
volume
Proportion of patients achieving ≥35% 
reduction in spleen volume from Baseline to 
Week 24 as measured by MRI (or CT scan in 
applicable patients)
Secondary
To determine the safety and tolerability 
of INC424
Safety and tolerability will be assessed by 
monitoring the frequency, duration and 
severity of adverse events, performing 
physical exams, and evaluating changes in 
vital signs, electrocardiograms (ECGs), 
serum chemistry, hematology and urinalysis
results. Toxicity will be assessed using the 
Common Terminology Criteria for Adverse 
Events (CTCAE) v4.03.
Secondary
To evaluate the effects of INC424
on patient reported outcomes
Change in EORTC QLQ-C30 score from 
Baseline to Week 24.
Change in total symptom score from 
Baseline to Week 24, as assessed by 


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INC424A/INC424A2202
Objective
Endpoint
Seven-day modified MFSAF v2.0
Secondary
To evaluate the duration of response 
as assessed by reduction in spleen 
volume
Best response rate
Duration of maintenance of a ≥35% reduction
from Baseline in spleen volume
2
Statistical methods
2.1
Data analysis general information
The final CSR analysis will be performed by Novartis. SAS® version 9.4 (or later version if 
available at time of database lock) will be used to perform all data analyses and to generate 
tables, figures and listings.
Unless otherwise specified, categorical data will be summarized by frequency count and 
percentages. Percentages will be calculated using the number of subjects in the relevant 
population or subgroup as the denominator.
The final analysis will be performed after final Data Base Lock (DBL).
2.1.1
General definitions
Study drug and study treatment
Both study drug and study treatment refer to INC424.
Date of first administration of study drug
The date of first administration of study drug is defined as the first date when a nonzero dose 
of study drug is administered and recorded on the dose administration record (DAR) page of 
the electronic case report form (eCRF).
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered and recorded on DAR page of the eCRF.


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Study day
Study day 1 is the date of first administration of study drug. 
The study day for all assessments will be calculated as follows:
1. If date of assessment occurred on or after the start of study treatment, then
Study day = Date of assessment - Start date of study treatment + 1. 
2. If date of assessment occurred before the start of study treatment, then
Study day = Date of assessment - Start date of study treatment. 
The study day will be displayed in the data listings.
Baseline
Unless otherwise specified, the baseline measurement for any parameter is defined as the last 
non-missing pre-dose value (scheduled or unscheduled) before the first administration of 
study drug.
On-treatment assessment/event
On-treatment period is from day of first dose of study drug to 30 days after last dose of
INC424.
2.2
Analysis sets
Full Analysis Set (FAS)
FAS comprises all patients who received at least one dose of INC424.
Safety set (SAF)
Safety set consists of all patients who received at least one dose of INC424 and had at least 
one safety evaluation post-Baseline. This analysis set will be used for all safety analyses.
Per-Protocol Set (PPS)
PPS consists of all patients in the FAS who are considered to be sufficiently com pliant with 
the protocol.
2.2.1
Subgroup of interest
All results by subgroups were reported in “the Week 24 CSR” and not applicable in this 
document.


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2.3
Patient disposition, demographics and other baseline 
characteristics
2.3.1
Patient disposition
Patient disposition will be summarized using FAS.
2.3.2
Demographics and baseline data
Summary of all baseline and demographics were reported in “the Week 24 CSR” and not 
applicable in this document.
2.3.3
Medical history and current medical conditions
Summary of relevant medical history and current medical conditions were reported in “the 
Week 24 CSR” and not applicable in this document.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure/follow-up and dose intensity (DI)
The duration of exposure is defined as the time from first (non-zero) dose to the last date 
patient was known to have been taking study drug (i.e., last known treatment date).
That is, the following algorithm will be used to calculate the duration of exposure for patients 
who took at least one dose of the study drug:

Duration of exposure (days) = [(date of last administration of study drug) – (date of first 
administration of study drug) + 1]
The duration includes the periods of temporary interruption.
The duration of exposure will also be summarized using week/month as time unit. They will 
be calculated as [Duration of exposure in days] divided by 7/30.4375.  
Cumulative dose is defined as the total dose given during the study treatment exposure.  Dose 
intensity (DI) is defined as:
DI (mg/day) = Cumulative dose given (mg) / Duration of exposure (days).
Cumulative dose and dose intensity will be calculated using descriptive statistics. 
Dose intensity will be plotted by week.
Relative dose intensity will be defined as follows:
Relative dose intensity (%) = DI*100/Assigned total daily dose (i.e. starting dose)
A plot of mean daily total dose over time by starting dose will be generated for the overall 
population.


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Relative dose intensity and dose intensity will be summarized using descriptive statistics by 
time-interval and starting dose(15 mg BID or 20 mg BID). 
A line graph of mean daily total dose over time by starting dose will be generated for the 
overall population.  
Dose reduction/interruption
The number and percentage of patients with at least one dose reduction and dose interruption 
(dose change to zero dose for limited duration) will be calculated, respectively.  The 
associated reasons for dose reduction and dose interruption will be summarized separately. 
2.4.2
Prior, concomitant and post therapies
Concomitant medication and significant non-drug therapies before/after the start of study drug 
were reported in “the Week 24 CSR” and not applicable in this document.
2.5
Analysis of the primary objective
Primary analysis was conducted and the result was reported in “the Week 24 CSR” and not 
applicable in this document.
2.6
Analysis of the key secondary objective
Not Applicable.
2.7
Analysis of secondary efficacy objective(s)
Most secondary analyses were reported in “the Week 24 CSR” and not applicable in this 
document. The below analyses which were previously performed will be repeated with 
updated data for the final analysis.
Best response rate
The best response rate is defined as the proportion of patients achieving ≥ 35% reduction in 
spleen volume from Baseline at any post-baseline assessment.  The best response rate will be 
estimated with an associated 95% confidence interval based on the normal approximation.  
Duration of maintenance of a greater or equal to 35% reduction from Baseline 
in spleen volume
For patients who had at least one ≥35% reduction in spleen volume from Baseline at post-
baseline, the duration of response will be calculated.  The start date of the duration is defined 
as the first spleen volume measurement that is ≥35% reduction from Baseline, and the end 
date of the response duration is defined as the earliest of the following: 

Death.

A ≥25% increase in spleen volume by MRI compared to Baseline.

Splenic irradiation.


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
Leukemic transformation as defined by a bone marrow or a peripheral blood blast count 
of ≥20%.

Splenectomy.
In the event that a patient experiences leukemic transformation, requires therapy with splenic 
irradiation, or experiences a ≥25% increase in spleen volume by MRI compared to Baseline, 
the study drug must be permanently discontinued.  Therefore, the end date of the duration will 
be defined as the earliest date for one of the following for patient with any event of disease 
progression:

Date of death.

Assessment date of spleen volume with a ≥25% increase compared to Baseline measured 
by MRI.

Date of leukemic transformation captured on the e-CRF page “Leukemic transformation”. 

Date of Splenic irradiation/Splenectomy captured on either the “Concomitant 
medications/Significant non-drug therapies”
or “Antineoplastic therapies since 
discontinuation of study drug” e-CRF pages.
If a patient undergoes splenectomy, and the investigator believes that it is in the patient ’s best 
interest to continue treatment with INC424 due to symptomatic improvement, the patient may 
continue treatment assuming she/he has fully recovered from the splenectomy procedure 
within 12 weeks.  Even if she/he continues therapy with INC424, the event will be assumed to 
have occurred for that patient.  Note that the date of splenectomy will be recorded on the e -
CRF page “Concomitant medications/Significant non-drug therapies” if that patient continues 
treatment with INC424. 
The censoring date is defined as the date of the last adequate assessment of spleen volume for 
patients with no event of disease progression.  Patients who had more than 1 consecutive 
missing spleen volume assessment will be censored at the last adequate assessment prior to 
the consecutive missing assessments, regardless of the occurrence of a subsequent death or 
any event of disease progression. 
The duration of response will be evaluated using a Kaplan-Meier estimate.  Note that the 
analysis will be performed only for patients who achieved a least one ≥35% reduction in 
spleen volume at any time on study. 
2.8
Safety analyses
For all safety analyses, the safety set will be used.
2.8.1
Adverse events (AEs)
In this study, an adverse event is defined as the appearance of (or worsening of any pre -
existing) undesirable sign(s), symptom(s), or medical condition(s) that occur after a patient’s 
signed Informed Consent has been obtained. With exception of screening failure patients, 
adverse events that begin or worsen after Informed Consent will be recorded in the Adverse 
Events eCRF.


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Summary tables for adverse events have to include only adverse events that started or 
worsened during the on-treatment period, the treatment-emergent adverse events. Listings will 
include all reported AEs in the database (except AEs that started after the study completion 
date) and such AEs that have an onset prior to Study Day 1 are to be flagged in the listing. 
Both system organ class (SOC) and preferred term (PT) as listed by the Medical Dictionary 
for Regulatory Activities (MedDRA, the latest version) will be used for all AE summaries. 
The following summaries will be produced:

Overall summary of adverse events

Adverse events, regardless of study drug relationship, by primary system organ class

Adverse events, regardless of study drug relationship, by preferred term

Adverse events, regardless of study drug relationship, by primary system organ class and 
preferred term

Adverse events, regardless of study drug relationship, by study period, primary system 
organ class and preferred term

Adverse events suspected to be related to study drug, by preferred term

Adverse events suspected to be related to study drug, by primary system organ class and 
preferred term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term

Adverse events leading to discontinuation, regardless of study drug relationship, by 
preferred term

Adverse events leading to discontinuation, regardless of study drug relationship, by 
primary system organ class and preferred term

Adverse events leading to dose adjustment or study drug interruption, regardless of study 
drug relationship, by preferred term

Adverse events leading to dose adjustment or study drug interruption, regardless of study 
drug relationship, by primary system organ class and preferred term
Clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov, the following summaries will be produced:

On-treatment AEs (i.e., treatment-emergent AEs) which are not serious AEs with an 
incidence greater than 5% and on on-treatment serious AEs by primary system organ class 
and preferred term

Serious AEs suspected to be related to study treatment by primary system organ class and 
preferred term
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same system organ class and preferred term:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE


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For occurrence, the presence of at least one serious AE / serious AE suspected to be related to 
study treatment / non-serious AE has to be checked in a block e.g., among AE's in a ≤ 1 day 
gap block, if at least one serious AE is occurring, then one occurrence is calculated for that 
serious AE.
The number of deaths resulting from serious AEs suspected to be related to study treatment 
and serious AEs irrespective of study treatment relationship will be provided by primary 
system organ class and preferred term.
2.8.1.1
Adverse events of special interest / grouping of AEs
The following Adverse Events of special interest (AESIs) will be defined:

Thrombocytopenia

Erythropenia (Anemia)

Leukopenia

Hemorrhage (all AEs)

Hemorrhage (Bruising)

Hemorrhage (GI bleeding)

Hemorrhage (Intracranial haemorrhage)

Hemorrhage (Other hemorrhage events)

Herpes zoster

Urinary tract infections

Tuberculosis

Opportunistic infections

Pneumonia

Sepsis and septic shock

Other infections

Infections and infestations (SOC)

Infections and infestations (SOC) without tuberculosis

Elevated transaminases

Malignancies

Progressive multifocal leukoencephalopathy (PML)

Dizziness

Weight gain

Non-melanoma skin cancer (NMSC)

Hepatitis B reactivation (possible)

Lipid abnormalites

Ischemic events

Hypertension (SMQ)
Selection rules are documented in the ‘Compound Case Retrieval Strategy’ Sheet (CRS) 
MedDRA 20.0 version 1.0 (or later version if available at the time point of output generation).


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The following summary will be done for each AESI group:

Overall summary of adverse events of special interest
The following summaries also will be done for each SMQ: Erythropenia, Thrombocytopenia 
and Leukopenia:

Time to first newly reported grade 3 or 4

Duration of newly reported grade 3 or 4
2.8.2
Deaths
On-treatment deaths will be displayed and all deaths will be listed.
2.8.3
Laboratory data
Clinical laboratory tests including hematology, clinical chemistry, urinalysis, lipid panel, 
coagulation test, and immunology will be done for each patient during the study in accordance 
with the ‘Visit Evaluation Schedule’ described in the protocol. If specific safety issue arise, 
additional, unscheduled laboratory tests/analyses may be done at the discretion of the 
investigators.  A central laboratory will be used for analysis of all specimens collected except 
for hematology, pregnancy tests, other urine analysis and serology for hepatitis virus and HIV 
which will be performed locally. 
Laboratory data reported will be graded by programming based on the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0.3, where applicable. A severity grade of 0 
will be assigned when the value is within normal limits. (In the case when a laboratory normal 
range overlaps into the higher (i.e., non-zero) CTC grade, the laboratory value will still be 
taken as within normal limits and assigned a CTC grade of zero.) Some parameters may be 
converted in Standard International (SI) units if laboratory measurement with any other unit 
was reported. For the summarization of laboratory measurements and listing of laboratory 
measurements, SI unit will be used as default with original or converted measurements. 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 summary will be produced for laboratory parameters in hematology:

Shift tables using CTC grades to compare baseline to the worst on-treatment value 
All laboratory data will be listed with updated data for the final analysis. Patient with 
abnormal hematology values will be also listed. 
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
12-lead ECGs including QTcF, QTcB, QT, HR, PR, QRS and RR will be measured for each 
patient during the study in accordance with the Visit Evaluation Schedule, and will be 
summarized descriptively. For the calculation of absolute change in cardiac intervals, the 
average of intervals from the Screening and Baseline recordings will be used as the Baseline 
for comparison of all post-Baseline intervals. 


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The overall interpretation of abnormality (Table 2-1) will be presented.
Table 2-1
Notable electrocardiogram values
Parameters
Type of abnormality
Criterion
QT, QTcF and 
QTcB
Change from Baseline
New absolute value
Increase  > 30 ms to ≤ 60 ms
Increase > 60 ms
> 450 ms to ≤ 480 ms
> 480 ms to ≤ 500 ms
> 500 ms
HR
Change from Baseline
Decrease > 25% and resultant HR < 50 bpm
Increase > 25% and resultant HR > 100 bpm
PR
Change from Baseline
Increase > 25% and resultant PR > 200 ms
Decrease >25% and resultant PR <75 ms
QRS
Change from Baseline
Increase > 25% and resultant QRS > 110 ms
Decrease >25 % and resultant QRS < 50 ms
All abnormalities recorded on the e-CRF will be listed by patient. Also, all ECGs will be 
listed with updated data for the final analysis.
2.8.4.2
Vital signs
Vital signs including systolic blood pressure, diastolic blood pressure, respiratory rate, body 
temperature, and pulse will be taken in the seated position for each patient during the study. 
Criteria for abnormal vital signs is given in Table 2-2.
Table 2-2
Criteria for Clinically Notable Vital Sign Abnormalities
Parameter
High Threshold
Low Threshold
Systolic Blood Pressure
>160 mm Hg
<85 mm Hg
Diastolic Blood Pressure
>95 mm Hg
<50 mm Hg
Respiratory rate
>24 per minute
<8 per minute
Temperature
≥37.5°C
≤35.0°C
Sitting pulse
≥120 bpm
≤50 bpm
All vital signs will be listed with updated data for the final analysis.


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2.11
Patient-reported outcomes
Outputs of all EORTC QLQ-C30 and summary of Seven-day modified MFSAF 
questionnaires were reported in “the Week 24 CSR” and not applicable in this document. The 
Change in total symptom score by Seven-day modified MF-SAF v2.0 questionnaire will be 
summarized and listed with updated data for the final analysis.


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2.14
Interim analysis
A single interim analysis was conducted by the Novartis statistician.
With regard to detailed plan for the interim analysis, please refer to Section 4.9 in 
“CINC424A2202 RAP Module 3 Detailed statistical methodology Amendment 2”.


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3
Sample size calculation
The planned sample size of 110 was determined based on the single-sample binomial test 
(normal approximation). 
Study INCB 18424-351 is a randomized, double-blind, placebo-controlled study comparing 
the efficacy and safety of INC424 to a matched placebo in patients with PMF or post-PV/ET 
MF. In this study, the same primary efficacy variable, i.e., proportion of patients achieving ≥
35% reduction in spleen volume from Baseline at Week 24 as measured by MRI (or CT scan),
is evaluated. The result of Study INCB 18424-351 provided a response rate of 41.9% in 
INC424 group while a response rate of 0.7% was observed in the placebo group. 
Based on the results obtained in Study INCB 18424-351, the proportion of patients on this 
study achieving ≥35% reduction in spleen volume from Baseline at Week 24 as measured by 
MRI (or CT scan) is expected to be 0.35. From the aspect of clinical benefit i n patients with 
PMF or post-PV/ET MF, a threshold of 0.2 was set for the null hypothesis. 
An interim analysis is planned in this study. If the study had no interim analysis (1 -stage 
approach), the required sample size of 110 provides power of 0.951 with one-sided type I 
error rate of 0.025 under response rate of 0.2 and 0.35 for null and alternative hypotheses .  
The power for the group sequential (i.e., 2-stage) design accruing 110 total patients with the 
same final time-point boundary (≥31/110) and an interim analysis conducted after 50 patients 
using an O’Brien-Fleming type interim analysis boundary (≥ 19/50) is approximately 0.95. 
Therefore, the effect of the interim analysis on the overall study power is negligible.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Not applicable.
5.1.2
AE date imputation
Concomitant medication (CMD) imputation rules in Section 5.1.3 will be applied for AE date 
imputation.
5.1.3
Concomitant medication date imputation
The following Table 5-1 explains the notation used in the logic matrix. Please note that, if the 
date is completely missing, it will not be imputed.


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Table 5-1
CMD/ treatment date abbreviations
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date (TRTSTD)
Not used
TRTM
TRTY
The following matrix Table 5-2 describes the possible combinations and their associated 
imputations. In the boxes the upper text indicates the imputation and the lower text indicates 
the relationship of the CMD start date to the treatment start date (TRTSTD).
Table 5-2
CMD partial date imputation algorithm
MON MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY MISSING
( C )
Uncertain
( C )
Uncertain
( C )
Uncertain
( C )
Uncertain
YYYY < TRTY
( D )
Before TRTSTD
( A )
Before TRTSTD
( A )
Before TRTSTD
( A )
Before TRTSTD
YYYY = TRTY
( C )
Uncertain
( A)
Before TRTSTD
( C )
Uncertain
( B )
After TRTSTD
YYYY > TRTY
( E )
After TRTSTD
( B )
After TRTSTD
( B )
After TRTSTD
( B )
After TRTSTD
The following Table 5-3 is the legend to the above table.
Table 5-3
CMD/treatment date relationship and imputation legend
Relationship
Before TRTSTD
Partial date indicates CMD start date prior to Treatment Start Date
After TRTSTD
Partial date indicates CMD start date after Treatment Start Date
Uncertain
Partial date insufficient to determine relationship of CMD start date 
to Treatment Start Date
Imputation calculation
( A )
15MONYYYY
( B )
MAX( 01MONYYYY, TRTSTD+1 )
( C )
TRTSTD+1
( D )
01JULYYYY
( E )
01JANYYYY
5.1.3.1
Prior therapies date imputation
CMD imputation rules in Section 5.1.3 will be applied for prior therapies imputation with 
exception that for scenario (B) will be replaced to be ‘Treatment Start Date (TRTSTD) - 1’.
5.1.3.2
Post therapies date imputation
CMD imputation rules in Section 5.1.3 will be applied for post therapies imputation.
5.1.3.3
Other imputations
Not applicable.


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5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. MedDRA version in effect prior to database lock will be used for CSR AE 
reporting.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
5.3
Laboratory parameters derivations
CTC grading for blood differentials is based on absolute values. However, this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.
In order to derive the corresponding absolute normal range, the rule to be applied depends on 
the availability of the % range and the absolute range for the differential:

If absolute range is NOT missing (% range is or is not missing), then use the absolute 
range provided by the site.

If % range is NOT missing and absolute range is missing, then the % normal limits (i.e., 
LLN and ULN) are divided by 100 and multiplied by the corresponding normal limits of 
WBC count, e.g., for neutrophils (NEU):
LLN for NEU count = (LLN for WBC count) x (LLN for NEU%value / 100),
ULN for NEU count = (ULN for WBC count) x (ULN for NEU%value / 100)
5.4
Statistical models
5.4.1
Primary analysis
Not applicable.


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5.4.2
Key secondary analysis
Not applicable.
5.5
Rule of exclusion criteria of analysis sets 
All non-minor protocol deviations (any PD leading to exclusion from any analysis data set) 
are given in Table 5-4.  The complete list of protocol deviations is given in VAP module 3 
(Protocol Deviations).  
Table 5-4
Major protocol deviations
Deviation 
code
Text description
Severity 
code
I02
Unconfirmed diagnosis of PMF, PPV-MF or PET-MF
0
I03
Patient without a palpable spleen >= 5 cm
1
I04
Patient without 2 or more risk factors
1
I10
Patient had previous therapy with a JAK2 inhibitor
1
E07
Patient had splenic irradiation within 12 months prior to screening
1
E09
Patient being treated with another investigational drug not intended for 
MF or having been treated with such a drug within 14 days prior to 
Baseline or 6-half lives of the drug, whichever is longer
1
E16
Patient is unable to comprehend or is unwilling to sign the ICF
8
C01
Patient with no post-baseline safety assessments
5
C02
Patient with no post-baseline spleen volume assessment
1
M03
Use of any investigational medication other than INC424 during the 
study
2
M04
Use of any other drugs for MF including hydroxyurea, interferon, 
thalidomide, busulfan, lenalidomide or anagrelide during the study
2
M05
Use of potent CYP3A4 inducers
20
Table 5-5 shows the subject classification based on the severity code for each analysis 
population.
Table 5-5
Subject classification
Population
Severity code
0
1
2
5
8
20
FAS
No
Yes
Yes*
Yes
No
Yes
PPS
No
No
Yes*
Yes
No
Yes
SAF
Yes
Yes
Yes*
No
No
Yes
PAS
No
Yes
Yes*
Yes
No
No
Note: ‘Yes’ means inclusion in the analysis set, ‘No’ means 
exclusion from the analysis set. 
* means that partial data post-deviated date will NOT be 
used for any analyses. 


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6
Reference

Cervantes F, Dupriez B, Peteira A, et al. (2009) New prognostic scoring system for 
primary myelofibrosis based on a study of the International Working Group for 
Myelofibrosis Research and Treatment. Blood; 113:2895-901.