Clinical trial NCT04629508
Conditions: Myelofibrosis Polycythemia Vera Thrombocythemia
Keywords: Myelofibrosis Post-PV Myelofibrosis Post-ET Myelofibrosis LIMBER LIMBER-213 MF Myeloproliferative Neoplasms
Sponsor: Incyte Corporation
Start date: 2021-07-12; Completion date: 2023-08-24
Enrollment: 4 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a 2-part study. In Part 1, participants will be dosed at 2 different dose levels in order to select the RP2D for Part 2 of the study.

Detailed description:

Arms: arm 1: Participants will be dosed at different dose levels with a maximum of up to 9 participants per dose level. arm 2: Participants will be dosed at the recommended Phase 2 dose (RP2D) identified in Part 1.
Interventions: intervention 1: itacitinib
Intervention descriptions: intervention 1: itacitinb Immediate Release (IR) will be dosed orally twice a day

Protocol documents:
Prot_SAP_000.pdf: 
Official Title:    A 2-Part, Phase 2, Open-Label Study of the Safety, Tolerability, and Efficacy 
of 
Itacitinib 
Immediate 
Release 
in 
Participants 
With 
Primary 
Myelofibrosis or Secondary Myelofibrosis (Post-Polycythemia Vera 
Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis) Who 
Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy
NCT Number: 
 NCT04629508 
Document Date: Protocol Amendment 1: 19-January-2022


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Protocol INCB 39110-213 Am 1 
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TITLE PAGE 
Clinical Study Protocol 
 
 
INCB 39110-213 
A 2-Part, Phase 2, Open-Label Study of the Safety, Tolerability, and 
Efficacy of Itacitinib Immediate Release in Participants With Primary 
Myelofibrosis or Secondary Myelofibrosis (Post–Polycythemia Vera 
Myelofibrosis or Post–Essential Thrombocythemia Myelofibrosis) Who 
Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy 
 
Product: 
INCB039110 
IND Number: 
113,428 
EudraCT Number: 
2020-003123-42 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
03 SEP 2020 
Protocol Amendment 1: 
19 JAN 2022 
 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 


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INVESTIGATOR'S AGREEMENT 
I have read the INCB 39110-213 Protocol Amendment 1 (dated 19 JAN 2022) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................9 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Background .................................................................................................................18 
2.2. 
Study Rationale ...........................................................................................................18 
2.2.1. 
Scientific Rationale for Study Design ........................................................................19 
2.2.2. 
Justification for Dose ..................................................................................................20 
2.3. 
Benefit/Risk Assessment ............................................................................................20 
2.3.1. 
Potential Risks ............................................................................................................20 
2.3.1.1. 
Itacitinib SR Studies for Myelofibrosis ......................................................................20 
2.3.1.2. 
Itacitinib IR Studies in Healthy Adults .......................................................................21 
2.3.2. 
Potential Benefits ........................................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY DESIGN .......................................................................................................25 
4.1. 
Overall Design ............................................................................................................25 
4.1.1. 
Part 1:  Dose Escalation of Itacitinib IR .....................................................................25 
4.1.2. 
Recommended Phase 2 Dose Definition ....................................................................26 
4.1.3. 
Part 2:  Dose Expansion ..............................................................................................26 
4.2. 
Overall Study Duration ...............................................................................................27 
4.3. 
Study Termination ......................................................................................................27 
5. 
STUDY POPULATION .............................................................................................28 
5.1. 
Inclusion Criteria ........................................................................................................28 
5.2. 
Exclusion Criteria .......................................................................................................29 
5.3. 
Lifestyle Considerations .............................................................................................31 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................31 
5.4. 
Screen Failures ............................................................................................................32 
5.5. 
Replacement of Participants .......................................................................................32 
5.6. 
Data Monitoring Committee .......................................................................................32 


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6. 
STUDY TREATMENT ..............................................................................................33 
6.1. 
Study Treatment Administered ...................................................................................33 
6.2. 
Preparation, Handling, and Accountability ................................................................33 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................34 
6.4. 
Study Treatment Compliance .....................................................................................34 
6.5. 
Dose-Limiting Toxicity and Determination of Recommended Phase 2 Dose ...........34 
6.5.1. 
Definition of a Dose-Limiting Toxicity ......................................................................34 
6.5.2. 
Procedures for Cohort Review and Dose Escalation ..................................................35 
6.6. 
Dose Modifications .....................................................................................................35 
6.6.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................36 
6.6.2. 
Follow-Up of Dose-Limiting Toxicities .....................................................................36 
6.6.3. 
Criteria and Procedures for Dose Interruptions and Modifications of Study 
Drug ............................................................................................................................36 
6.6.3.1. 
Part 1 ...........................................................................................................................36 
6.6.3.2. 
Part 2 ...........................................................................................................................37 
6.6.4. 
Criteria for Permanent Discontinuation of Study Drug ..............................................38 
6.6.5. 
Permitted Medications and Procedures ......................................................................38 
6.6.6. 
Restricted Medications and Procedures ......................................................................39 
6.6.7. 
Prohibited Medications and Procedures .....................................................................39 
6.7. 
Treatment After the End of the Study .........................................................................39 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
WITHDRAWAL ........................................................................................................40 
7.1. 
Discontinuation of Study Treatment ...........................................................................40 
7.1.1. 
Reasons for Discontinuation .......................................................................................40 
7.1.2. 
Discontinuation Procedures ........................................................................................40 
7.2. 
Participant Withdrawal From the Study .....................................................................41 
7.3. 
Lost to Follow-Up.......................................................................................................41 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................42 
8.1. 
Administrative and General Procedures .....................................................................42 
8.1.1. 
Informed Consent Process ..........................................................................................42 
8.1.2. 
Screening Procedures ..................................................................................................43 
8.1.3. 
Interactive Response Technology Procedure ..............................................................43 
8.1.4. 
Distribution of Reminder Cards and Diaries ..............................................................43 


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8.1.5. 
Demography and Medical History ..............................................................................43 
8.1.5.1. 
Demographics and General Medical History .............................................................43 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................44 
8.2. 
Efficacy Assessments .................................................................................................44 
8.2.1. 
Spleen Palpation .........................................................................................................44 
8.2.2. 
Imaging .......................................................................................................................44 
8.2.3. 
Patient-Reported Outcomes ........................................................................................44 
8.2.3.1. 
Myelofibrosis Symptom Assessment Form Electronic Symptom Diary ....................44 
8.2.3.2. 
Patient Global Impression of Change .........................................................................44 
8.2.3.3. 
EORTC QLQ-C30 ......................................................................................................45 
8.2.4. 
Health Economics .......................................................................................................45 
8.3. 
Safety Assessments .....................................................................................................45 
8.3.1. 
Adverse Events ...........................................................................................................45 
8.3.1.1. 
Surveillance and Management of Infections ..............................................................46 
8.3.2. 
Physical Examinations ................................................................................................46 
8.3.3. 
Vital Signs ..................................................................................................................46 
8.3.4. 
Electrocardiograms .....................................................................................................46 
8.3.5. 
Laboratory Assessments .............................................................................................47 
8.3.5.1. 
Local Laboratory Assessments ...................................................................................47 
8.3.5.2. 
Pregnancy Testing ......................................................................................................49 
8.3.5.3. 
Serology ......................................................................................................................49 
 
49 
 
50 
8.6. 
Extension Period .........................................................................................................50 
8.7. 
Unscheduled Visits .....................................................................................................51 
8.8. 
End of Treatment and/or Early Termination ..............................................................51 
8.9. 
Follow-Up ...................................................................................................................51 
8.9.1. 
Safety Follow-Up ........................................................................................................51 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................52 
9.1. 
Definition of Adverse Event .......................................................................................52 
9.2. 
Definition of Serious Adverse Event ..........................................................................53 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........54 


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9.4. 
Reporting of Serious Adverse Events .........................................................................56 
9.5. 
Emergency Unblinding of Treatment Assignment .....................................................58 
9.6. 
Pregnancy ...................................................................................................................58 
9.7. 
Warnings and Precautions ..........................................................................................58 
9.8. 
Product Complaints ....................................................................................................58 
9.9. 
Treatment of Overdose ...............................................................................................59 
10. 
STATISTICS ..............................................................................................................60 
10.1. 
Sample Size Determination ........................................................................................60 
10.2. 
Populations for Analysis .............................................................................................61 
10.3. 
Level of Significance ..................................................................................................61 
10.4. 
Statistical Analyses .....................................................................................................61 
10.4.1. 
Primary Analysis ........................................................................................................61 
10.4.1.1. 
Part 1 ...........................................................................................................................61 
10.4.1.2. 
Part 2 ...........................................................................................................................61 
10.4.2. 
Secondary Analysis ....................................................................................................62 
10.4.3. 
Safety Analyses ..........................................................................................................62 
10.4.3.1. 
Adverse Events ...........................................................................................................62 
10.4.3.2. 
Clinical Laboratory Tests ...........................................................................................62 
 
63 
 
63 
 
63 
10.5. 
Interim Analysis ..........................................................................................................64 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................65 
11.1. 
Investigator Responsibilities .......................................................................................65 
11.1.1. 
Identification of the Coordinating Principal Investigator ...........................................66 
11.2. 
Data Management .......................................................................................................66 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................67 
11.4. 
Financial Disclosure ...................................................................................................68 
11.5. 
Publication Policy .......................................................................................................68 
11.6. 
Study and Site Closure................................................................................................69 
12. 
REFERENCES ...........................................................................................................70 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................71 
APPENDIX B. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .......................................................................................72 
APPENDIX C. CYTOCHROME P450 AND P-GLYCOPROTEIN INHIBITORS 
AND CYTOCHROME P450 INDUCERS ................................................................73 
APPENDIX D. INSTRUCTION TO PARTICIPANTS FOR HANDLING 
ITACITINIB IR ..........................................................................................................74 
APPENDIX E. MANAGEMENT OF POTENTIAL HY'S LAW CASES ................................75 
APPENDIX F. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS .......................................................................................................79 
APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES ...........................81 
 


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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................11 
Table 2: 
Key Study Design Elements .......................................................................................12 
Table 3: 
Schedule of Activities (Part 1) ....................................................................................14 
Table 4: 
Schedule of Laboratory Assessments (Part 1) ............................................................15 
Table 5: 
Schedule of Activities (Part 2) ....................................................................................16 
Table 6: 
Schedule of Laboratory Assessments (Part 2) ............................................................17 
Table 7: 
Simulation of Pharmacodynamic Effects of Itacitinib ................................................20 
Table 8: 
Objectives and Endpoints ...........................................................................................23 
Table 9: 
Dose Escalation, Elimination, and Selection Boundaries for a Target DLT 
Rate of 33% for Dose Level 1 in Part 1 ......................................................................25 
Table 10: Dose De-Escalation, Elimination, and Selection Boundaries if Dose Is 
Escalated to Dose Level 2 ...........................................................................................26 
Table 11: Exclusionary Laboratory Values ................................................................................30 
Table 12: Study Treatment Information .....................................................................................33 
Table 13: Definition of Dose-Limiting Toxicity ........................................................................35 
Table 14: Guidelines for Interruption and Restarting of Study Drug .........................................37 
Table 15: Required Laboratory Analytes ....................................................................................48 
 
49 
 
50 
Table 18: Populations for Analysis .............................................................................................61 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema:  Part 1 ....................................................................................13 
Figure 2: 
Study Design Schema:  Part 2 ....................................................................................13 
Figure 3: 
Power Curves for Values of n = 30, 40, and 50 ..........................................................60 
 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BID 
twice daily 
BOIN 
Bayesian optimal interval 
CI 
confidence interval 
Correl 
correlative 
COVID-19 
coronavirus disease 2019 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIPSS 
Dynamic International Prognostic Scoring System 
DLT 
dose-limiting toxicity 
 
 
ECG 
electrocardiogram 
EDC 
electronic data capture 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire 
EOT 
end of treatment 
ET 
essential thrombocythemia 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FLT3 
FMS-like tyrosine kinase 3 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IR 
immediate release  
IRB 
institutional review board 


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Abbreviations and 
Special Terms 
Definition 
IRT 
interactive response technology 
IWG-MRT 
International Working Group- Myelofibrosis Research and Treatment 
JAK 
Janus kinase 
LDL 
low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFSAF 
myelofibrosis symptom assessment form 
MPN 
myeloproliferative neoplasm 
Part 1 
dose escalation  
Part 2 
dose expansion 
PD 
pharmacodynamic 
PET 
post–essential thrombocythemia myelofibrosis 
PGIC 
patient global impression of change 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetic 
PMF 
primary myelofibrosis 
PPV-MF 
post–polycythemia vera myelofibrosis 
PRBC 
packed red blood cells 
PRO 
patient-reported outcome 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
PV 
polycythemia vera 
QD 
once daily 
RP2D 
recommended Phase 2 dose 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SoA 
schedule of activities 
SR 
sustained release 
SRR 
splenic response rate 
STAT 
signal transducer and activator of transcription 
TEAE 
treatment-emergent adverse event, AEs reported for the first time or worsening 
of a pre-existing event after first dose of study treatment 
TSS 
total symptom score 
ULN 
upper limit of normal 
WBC 
white blood cell 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A 2-Part, Phase 2 Open-Label Study of the Safety, Tolerability, and Efficacy of 
Itacitinib Immediate Release in Participants With Primary Myelofibrosis or Secondary 
Myelofibrosis (Post–Polycythemia Vera Myelofibrosis or Post–Essential Thrombocythemia 
Myelofibrosis) Who Have Received Prior Ruxolitinib and/or Fedratinib Monotherapy 
Protocol Number:  INCB 39110-213 
Objectives and Endpoints: 
Table 1 presents the primary and secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Part 1:  To evaluate the safety and tolerability of 
itacitinib IR and select the RP2D for Part 2 of the 
study. 
Safety and tolerability through assessments of 
frequency and severity of AEs; changes in clinical 
safety assessments; changes in clinical laboratory 
parameters. 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to spleen volume reduction 
at Week 24. 
SRR at Week 24, where SRR is defined as the 
proportion of participants who have a reduction in 
spleen volume (by imaging) of at least 35% when 
compared with baseline. 
Secondary 
Part 2:  To evaluate the safety and tolerability of 
itacitinib IR at the RP2D. 
Safety and tolerability through assessments of 
frequency and severity of AEs; changes in clinical 
safety assessments; changes in clinical laboratory 
parameters. 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to MF symptom 
improvement at Week 24, in those patients with a 
baseline TSS ≥ 10. 
TSS response rate at Week 24, where TSS 
response is defined as the proportion of 
participants who achieve at least 50% reduction in 
TSS over the 28 days immediately before the end 
of Week 24 compared with the 7 days 
immediately before the initiation of itacitinib IR 
(baseline). 
Part 2:  To evaluate the efficacy of itacitinib IR 
with respect to improvement of quality of life. 
The mean change (from Day 1 vs Week 12 and 
Week 24) in the 5 multi-item functional scale 
scores and the multi-item global health status 
scale score (EORTC QLQ-C30). 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to PGIC. 
The percentage of participants categorized as 
improved on the Week 24 PGIC. 
Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 


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Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
PMF or secondary MF (PPV-MF or PET-MF)  
Population 
Participants with PMF or secondary MF (PPV-MF or PET-MF) who have 
received prior ruxolitinib and/or fedratinib monotherapy. 
Number of 
Participants 
Part 1 will include up to 18 participants:  3 to 9 evaluable participants in 
2 cohorts with at least 9 participants treated with the RP2D. 
Part 2 will include up to 55 participants treated with the RP2D. 
Study Design 
Open-label, 2-part study with a dose-escalation period during Part 1 to 
determine a RP2D for itacitinib IR and an expansion period during Part 2 to 
further evaluate the efficacy of the RP2D. 
Estimated Duration 
of Study 
Participation 
Up to 35 days for screening, then continuous treatment for at least 24 weeks.  
Participants may remain on treatment as long as they are receiving clinical 
benefit and have not met any criteria for study withdrawal.  There will be a 
30-day safety follow up visit once treatment is complete.  It is estimated that 
an individual will participate for approximately 12 months. 
DMC 
Internal 
Treatment Groups and Duration: 
This is a 2-part study to evaluate 2 dose levels of itacitinib IR in Part 1 and the RP2D in Part 2.  
In Part 1, 3 to 9 evaluable participants will be enrolled at Dose Level 1 (itacitinib IR 300 mg 
BID).  The evaluable participants in Dose Level 1 will be observed for the specified DLT 
observation period (28 days) before the next dose cohort begins enrollment.  Dose Level 2 is 
itacitinib IR 600 mg BID.  The study design schema for Part 1 is presented in Figure 1. 
In Part 2, 55 participants will be enrolled at the RP2D.  Participants may remain on treatment as 
long as they are receiving clinical benefit and have not met any criteria for study withdrawal.  
The study design schema for Part 2 is presented in Figure 2. 
As of NOV 2021, 4 participants were treated with itacitinib IR 300 mg BID.  The study is closed 
to enrollment and no additional participants will be treated.  The ongoing participants will move 
to the extension period, regardless of where they are in the study, and continue to remain on 
study treatment until withdrawal criteria are met.  Part 2 is no longer applicable. 


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Figure 1: 
Study Design Schema:  Part 1 
 
 
Figure 2: 
Study Design Schema:  Part 2 
 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.  All study assessments as well as laboratory assessments will be 
performed as indicated in the SoA (Table 3 and Table 4). 


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Table 3: 
Schedule of Activities (Part 1) 
 
Screening 
Baseline 
Day 1 Day 7 Day 14 Day 21 Day 28 
Monthlya 
(Q28D) 
Extension 
Periodb 
Q8W 
EOT or 
Early 
Termination 
Safety 
Follow-Up 
30 to 37 Days 
After Last Dose 
Evaluation/window 
Day −35 to −1 
Day −7 to −1 
 
± 2 d 
± 2 d 
± 2 d 
± 3 d 
± 5 d 
± 5 d 
± 5 d 
 
Informed consent/eligibility criteria 
review 
X 
 
 
 
 
 
 
 
 
 
 
Screening splenomegaly assessmentc 
X 
 
 
 
 
 
 
 
 
 
 
Prior medical & medication history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Transfusion history/statusd 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Taper of ruxolitinib or fedratinibe 
X 
 
 
 
 
 
 
 
 
 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs/body weight/heightg 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
X 
X 
 
 
 
MRI/CT for spleen volumeh 
 
X 
 
 
 
 
 
 
 
 
 
Dispense and/or bring MFSAF v4.0 
diary to visit 
 
Xi 
X 
X 
X 
X 
X 
X 
 
 
 
Modified MFSAF v4.0 diary 
 
Diary completed each evening at home 
 
 
 
ECOG status 
 
X 
 
 
 
 
 
 
 
 
 
PGIC 
 
 
 
 
 
 
X 
 
 
 
 
Dispense reminder card 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Contact IRT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administer study drug at visit 
 
 
X 
 
 
 
X 
 
 
 
 
Dispense study drug 
 
 
X 
 
 
 
X 
X 
X 
 
 
Drug accountability assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
a Monthly visits (every 28 days) between Day 28 and Week 24. 
b Extension period occurs after Week 24.  The participant may continue on treatment until they are no longer receiving benefit. 
c Splenomegaly assessment by palpation or spleen volume as measured by MRI/CT. 
d Record number of units of PRBC transfused from 12 weeks before the first dose of itacitinib IR. 
e Taper of ruxolitinib, fedratinib, or other MF-directed therapies should be started as soon as possible during screening and must be completed by Day −22. 
f A comprehensive physical exam should be performed at screening.  A targeted physical exam may be performed for all visits after screening (see Section 8.3.2). 
g Height at screening only. 
h MRI is preferred; however, CT is acceptable. 
i Baseline symptom burden assessment must be conducted Day −7 to Day −1. 


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Table 4: 
Schedule of Laboratory Assessments (Part 1) 
 
Screening Baseline Day 1 
Weekly 
(Q7D)a 
Week 4 
(D28) 
Week 8 
(D56) 
Week 12 
(D84) 
Week 16 
(D112) 
Week 20 
(D140) 
Week 24 
(D168) 
Extension 
Period 
Visits 
(Q8W 
After 
Week 24) 
EOT or 
Early 
Termination 
Safety 
Follow-Up 
30 to 37 Days 
After Last 
Dose 
Evaluation window 
Day −35 
to −1 
Day −7 
to −1 
Day 1 
± 2 d 
± 3 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
 
Fasting 
 
 
X 
X 
X 
 
X 
 
 
X 
 
 
 
Local laboratory assessments 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood smear 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
Coagulation panel 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
Fasting lipid panel 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology for HIV, HAV, 
HBV, HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
a Weekly laboratory assessment (every 7 days) between Day 1 and Day 28. 
 
 
 
 
 
 


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Table 5: 
Schedule of Activities (Part 2) 
 
Screening Baseline Day 1 
Week 4 
(D28) 
Week 8 
(D58) 
Week 12 
(D84) 
Week 16 
(D112) 
Week 20 
(D140) 
Week 24 
D(168) 
Extension 
Perioda 
(Q12W) 
EOT or 
Early 
Termination 
Safety 
Follow-Up 
30 to 37 Days 
After Last 
Dose 
Evaluation/window 
Day −35 
to −1 
Day −7 
to −1 
Day 1 
± 3 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
 
Informed consent/eligibility criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
Screening splenomegaly assessmentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior medical & medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion history/statusc 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Taper ruxolitinib or fedratinibd 
X 
 
 
 
 
 
 
 
 
 
 
 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinatione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spleen palpation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs/body weight/heightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
MRI/CT for spleen volumeg 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
Dispense and/or bring MFSAF v4.0 diary to 
visit 
 
Xh 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Modified MFSAF v4.0 diary 
 
Diary completed each evening at home 
 
 
 
ECOG status 
 
X 
 
 
 
 
 
 
 
 
 
 
PGIC 
 
 
 
X 
 
X 
 
 
X 
X 
X 
 
EORTC QLQ-C30 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Dispense reminder card 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Contact IRT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administer study drug during visit 
 
 
X 
X 
 
 
 
 
 
 
 
 
Dispense study drug 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Drug accountability assessment 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
a Extension period occurs after Week 24.  The participant may continue on treatment until they are no longer receiving benefit. 
b Splenomegaly assessment by palpation or spleen volume as measured by MRI/CT. 
c Record number of units of PRBC transfused from 12 weeks before the first dose of itacitinib IR. 
d Taper of ruxolitinib, fedratinib, or other MF-directed therapies should start as soon as possible and must be completed by Day −22. 
e A comprehensive physical exam should be performed at screening.  A targeted physical exam may be performed for all visits after screening (see Section 8.3.2). 
f Height at screening only. 
g MRI is preferred; however, CT is acceptable. 
h Baseline symptom burden assessment must be conducted Day −7 to Day −1. 


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Table 6: 
Schedule of Laboratory Assessments (Part 2) 
 
Screening 
Baseline 
Day 1 
Week 4 
(D28) 
Week 8 
(D58) 
Week 12 
(D84) 
Week 16 
(D112) 
Week 20 
(D140) 
Week 24 
(D168) 
Extension 
Period 
Visits 
(Q12W 
After 
Week 24) 
EOT or 
Early 
Termination 
Safety 
Follow-Up 
30 to 37 Days 
After Last 
Dose 
Evaluation window 
Day −35 
to Day −1 
Day −7 to 
Day−1 
Day 1 
± 3 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 5 d 
± 7 d 
Fasting 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
Local laboratory assessments 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Peripheral blood smear 
 
X 
 
 
 
X 
 
 
X 
 
 
 
Coagulation panel 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
Fasting lipid panel 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy test 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serology for HIV, HAV, HBV, 
HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. 
INTRODUCTION 
2.1. 
Background 
The classic Philadelphia chromosome-negative MPNs include PV, ET, and PMF.  Myelofibrosis 
can present as a de novo disorder (PMF) or evolve secondarily from previous PV or ET 
(PPV-MF or PET-MF; Mesa et al 2007).  Regardless of whether MF is a primary or secondary 
disorder, it is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis 
(Tefferi 2005).  Clinical presentation may include splenomegaly, anemia, and burdensome 
symptoms including night sweats, early satiety, abdominal pain, and extreme fatigue 
(Cervantes 2014).  Many of these symptoms appear to be associated with a proinflammatory 
state caused by excessive levels of circulating cytokines (Hasselbalch 2013).  The molecular 
pathogenesis of MF is characterized by dysregulation of JAK/STAT signaling networks, which 
has crucial roles in cytokine- and growth factor-mediated regulation of cellular responses, 
including normal hematopoiesis and inflammation (Tefferi 2005).  In general, overactivation of 
JAK2 plays a role in malignant myeloproliferation, whereas aberrant JAK1 signaling contributes 
to many of the other clinical characteristics of the disease, including the symptoms associated 
with the proinflammatory state (Mascarenhas et al 2017). 
Consequently, targeting the JAK-STAT pathway was a focus of therapeutic development and led 
to the approval of ruxolitinib, a potent JAK1 and JAK2 inhibitor (Verstovsek et al 2010).  
Although ruxolitinib results in clinically meaningful improvements in splenomegaly and 
symptoms and affects long-term outcomes, there is a subset of patients for whom ruxolitinib fails 
to provide adequate or sustained response (Harrison et al 2020).  In 2019, fedratinib, a JAK2 and 
FLT3 inhibitor was approved for adult patients with intermediate-2 or high-risk primary or 
secondary MF (Talpaz and Kiladjian 2020). 
2.2. 
Study Rationale 
This 2-part, Phase 2 study is designed to determine the RP2D, safety, tolerability, and efficacy of 
itacitinib IR in participants with MF who have had a relapse or an intolerance to ruxolitinib 
and/or fedratinib monotherapy.  The SR formulation of itacitinib has been shown to result in 
meaningful improvement of MF-related symptoms in a significant proportion of patients and 
spleen volume responses in a smaller proportion of patients.  Itacitinib IR facilitates JAK2 
inhibition that increases with higher, twice-a-day dosing.  This study is designed to determine 
whether there is a tolerable and safe dosing regimen of itacitinib IR that will result in clinically 
significant responses in symptoms and spleen volume reduction in patients who have already 
received ruxolitinib and/or fedratinib monotherapy. 
As of NOV 2021, 4 participants were treated with itacitinib IR 300 mg BID.  The study is closed 
to enrollment and no additional participants will be treated.  The ongoing participants will move 
to the extension period, regardless of where they are in the study, and continue to remain on 
study treatment until withdrawal criteria are met.  Part 2 is no longer applicable. 


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2.2.1. 
Scientific Rationale for Study Design  
Because thrombopoietin and erythropoietin signal through JAK2, ruxolitinib or fedratinib 
treatment may be associated with dose-dependent thrombocytopenia and anemia that, in some 
instances, contribute to the inadequate responses.  In addition, the relative contribution of JAK1 
and JAK2 inhibition to the therapeutic benefit of ruxolitinib was unclear.  This raised the 
question of the potential benefit of selective JAK1 inhibition without JAK2 inhibition. 
This led to a Phase 2 study of itacitinib SR in adults with intermediate- or high-risk MF.  
Itacitinib SR is a potent inhibitor of JAK1 with low in vitro affinity for JAK2 (> 20-fold 
selectivity for JAK1 over JAK2) and other members of the JAK family (> 100-fold selectivity 
for JAK1 over JAK3 and TYK2; data on file).  Of 10, 45, and 32 participants enrolled in the 
100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 
64.4%, and 68.8% completed Week 24.  A ≥ 50% reduction in TSS was achieved by 35.7% and 
28.6% of participants in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg 
once-daily cohort at Week 12 (primary endpoint) and 24, respectively.  For the 200 mg 
twice-daily dose cohort, the SRRs were 5.4% and 12.9% at Week 12 and Week 24, respectively.  
For the 600 mg once-daily cohort, the SRRs were 9.7% and 14.7% at Week 12 and Week 24, 
respectively.  The investigators noted that itacitinib SR resulted in relief of MF-related symptoms 
and limited hematologic toxicity in a significant proportion of participants but that adequate 
spleen volume responses were noted in a smaller proportion of patients (Mascarenhas 
et al 2017). 
Itacitinib SR was formulated to preserve the selectivity for JAK1 versus JAK2 and to maintain 
JAK1 inhibition over the dose administration interval.  In contrast, itacitinib IR facilitates JAK2 
inhibition that increases with higher twice-a-day dosing.  This IR formulation promises to offer 
significant JAK1 inhibition but also moderate JAK2 inhibition to better address the proliferative 
features of the disease.  This particular balance of JAK1 to JAK2 inhibition could serve an unmet 
need for patients who have failed ruxolitinib and/or fedratinib monotherapy due to inadequately 
addressed MF-related symptoms, whether due to severe symptom burden or due to dose 
limitations exerted by the cytopenias expected with more robust inhibition of JAK2.  
Consequently, this study will include patients who have previously received ruxolitinib and/or 
fedratinib monotherapy.  The primary endpoint will be SRR at Week 24.  
Participants with MF have been treated with itacitinib SR in a Phase 2 study at doses of 100 mg 
BID, 200 mg BID, and 600 mg daily.  The most common nonhematologic AEs of any grade, 
regardless of causality for the 200 mg BID dose were fatigue, constipation, and cough.  At this 
dose, Grade 3 anemia was observed in 38.1% of participants, and ≥ Grade 3 thrombocytopenia 
was observed in 35.6% of participants.  Itacitinib IR has been given to healthy participants up to 
doses of 600 mg in repeated weekly doses (Day 1, Day 8, Day 15, and Day 22) with no deaths or 
serious or severe TEAEs.  Additional details are provided in Section 2.3.1. 
In Part 1 of this study, a BOIN design will be used to identify a safe and tolerable dose of 
itacitinib IR.  The dose in Part 1 will then be given to an expanded cohort of patients (Part 2) to 
assess efficacy. 


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2.2.2. 
Justification for Dose 
Through simulations, 2 itacitinib IR doses, 300 mg BID and 600 mg BID, were selected in order 
to approach maximal JAK2 inhibition in the range of 50% to 70% and average JAK2 inhibition 
in the range of 20% to 30% similar to ruxolitinib.  The immediate release of itacitinib still has 
greater JAK1 inhibition compared with JAK2 inhibition (Table 7). 
Itacitinib PD effects were projected based on PK/PD direct link models between the projected or 
observed mean plasma concentrations and inhibition of phosphorylation of STAT3 following 
cytokine stimulations.  Itacitinib PK data was simulated with a population PK model developed 
from study INCB 39110-101. 
Table 7: 
Simulation of Pharmacodynamic Effects of Itacitinib 
Compound 
Pharmacodynamic 
Marker 
Dose 
Average Inhibition 
Over the Dosing 
Interval 
Maximal 
Inhibition 
Inhibition at 
Trough (End of 
Dosing Interval) 
Itacitinib IR 
JAK1 
200 mg BID IR 
48.4 
79.4 
23.3 
300 mg BID IR 
54.5 
83.7 
28.6 
400 mg BID IR 
59.2 
86.4 
33.3 
600 mg BID IR 
64.5 
89.2 
39.2 
800 mg BID IR 
68.5 
91.0 
44.1 
JAK2 
200 mg BID IR 
15.3 
47.0 
2.39 
300 mg BID IR 
20.2 
56.9 
3.50 
400 mg BID IR 
24.6 
64.1 
4.69 
600 mg BID IR 
30.4 
72.2 
6.63 
800 mg BID IR 
35.2 
77.4 
8.60 
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of itacitinib may be found in the IB. 
As of DEC 2019, 30 clinical studies with itacitinib have been completed or are ongoing.  A total 
of 1303 participants, including 501 healthy adult participants, have received at least 1 dose of 
itacitinib. 
2.3.1. 
Potential Risks 
2.3.1.1. 
Itacitinib SR Studies for Myelofibrosis 
INCB 39110-209 is a Phase 2 open-label study of itacitinib SR in combination with low-dose 
ruxolitinib or itacitinib SR alone following ruxolitinib in participants with MF.  In Study 
INCB 39110-209, 10 participants had received at least 1 dose of itacitinib 600 mg QD 
monotherapy as of the data cutoff date.  According to preliminary data, all participants reported 
at least 1 TEAE.  The most frequently reported TEAEs (≥ 20% of participants) were diarrhea, 
anemia, and fatigue in 40.0% of participants; dyspnea, pyrexia, and nausea in 30.0% of 
participants; and thrombocytopenia, abdominal pain, abdominal pain upper, constipation, 
vomiting, urinary tract infection, and decreased appetite in 20.0% of participants.  Serious 


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TEAEs were reported in 4 participants (40.0%); no participants had more than 1 serious TEAE.  
One participant (10.0%) had a fatal TEAE (muscle hemorrhage) that was not considered related 
to itacitinib.  One participant (10.0%) discontinued itacitinib monotherapy because of a TEAE 
(fatigue, malaise, and decreased appetite).  Also in INCB 39110-209, 13 participants had 
received at least 1 dose of itacitinib 200 mg QD + ruxolitinib as of the data cutoff date.  
According to preliminary data, 11 participants (84.6%) reported at least 1 TEAE.  The most 
frequently reported TEAEs (≥ 20% of participants) were diarrhea (4 participants, 30.8%) and 
anemia, fatigue, abdominal pain, and dizziness (3 participants, 23.1%).  No fatal TEAEs 
occurred.  Serious TEAEs were reported for 3 participants (23.1%); no participants had more 
than 1 serious TEAE.  No TEAEs leading to discontinuation of itacitinib were reported. 
INCB 39110-230 was a Phase 2a, open-label, multiple Simon 2-stage study of itacitinib SR in 
participants with PMF, PPV-MF, or PET-MF.  Eighty-seven participants received at least 1 dose.  
The most common TEAEs that occurred in more than 20% of participants were fatigue, anemia, 
thrombocytopenia, upper respiratory infection, nausea, constipation, and diarrhea.  
2.3.1.2. 
Itacitinib IR Studies in Healthy Adults 
Itacitinib IR has only been studied in healthy adults.  In Study INCB 39110-101, single doses of 
the IR formulation were administered to 39 participants beginning at 10 mg and escalated to 
1000 mg.  Itacitinib was formulated as powder-in-capsule with excipients.  Single-dose 
administration of itacitinib was well-tolerated.  There was no trend in the overall incidence of 
TEAEs with increasing doses.  No SAEs were reported, and the majority of TEAEs reported 
were mild in severity and had resolved by the end of the study.  No trends or clinically 
significant changes were noted in clinical laboratory, vital sign, or ECG data after administration 
of itacitinib, with the exception of expected transient decreases in mean ANC observed at all 
dose levels.  Itacitinib exhibited reduced hematologic toxicity when compared with other 
pan-JAK inhibitors as a result of its approximate 10-fold selectivity for JAK1 over JAK2. 
In INCB 39110-102, itacitinib IR was compared with itacitinib SR.  Seventy-two participants 
were enrolled in 1 of 4 treatment groups.  To compare itacitinib IR 300 mg versus itacitinib SR 
300 mg, participants received 3 single doses (Day 1, Day 8, and Day 15) with one cohort 
receiving an additional dose with a fraction of the dose administered as radiolabeled itacitinib for 
the purpose of metabolic profiling.  Two other cohorts in this study explored food effect and the 
PK of a 25 mg SR tablet formulation.  The safety results concluded that itacitinib IR was 
generally well-tolerated.  There were no deaths, serious TEAEs or severe TEAEs.  There were no 
clinically meaningful changes or trends regarding clinical chemistry, urinalysis or coagulation 
results.  There were no clinically meaningful changes or trends regarding vital signs, ECGs, or 
physical examinations. 
In Study INCB 39110-105, test formulations of itacitinib (SR and IR tablets) were generally safe 
and well-tolerated when administered as single oral doses to healthy adult participants.  As of the 
data cutoff date, 129 participants have been exposed to at least 1 dose of itacitinib in this study.  
There were no deaths or serious TEAEs.  Two participants (1.6%) withdrew from the study with 
an AE as the primary reason for discontinuation; 1 of the AEs leading to withdrawal (upper 
respiratory tract infection) was treatment-emergent and was considered to be treatment-related 
by the investigator.  According to preliminary data, the most frequently reported TEAE was 
headache (16 participants, 12.4%).  The only other TEAEs reported in more than 2 participants 


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were nausea and vessel puncture site hemorrhage (7 participants each, 5.4%) and upper 
respiratory tract infection and contact dermatitis (3 participants each, 2.3%).  
In this study, patients will be treated with itacitinib IR 300 mg BID and potentially with 600 mg 
BID, depending on the observation of DLTs in this dose-escalation period of the study.  With 
these doses and the IR formulation, it is anticipated that greater JAK1 and JAK2 inhibition will 
be observed compared with the prior studies of the SR and IR formulations.  Consequently, there 
may be a greater frequency of the most common nonhematologic and hematologic AEs including 
fatigue, anemia, thrombocytopenia, nausea, constipation, and diarrhea. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of itacitinib may be found in the itacitinib Investigator's Brochure. 
2.3.2. 
Potential Benefits 
The immediate release formulation of itacitinib promises to offer significant JAK1 inhibition but 
also moderate JAK2 inhibition to better address the proliferative features of the disease. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 8 presents the objectives and endpoints. 
Table 8: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
Part 1:  To evaluate the safety and tolerability of 
itacitinib IR and select the RP2D for Part 2 of the 
study. 
Safety and tolerability through assessments of 
frequency and severity of AEs; changes in clinical 
safety assessments; changes in clinical laboratory 
parameters. 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to spleen volume reduction 
at Week 24. 
SRR at Week 24, where SRR is defined as the 
proportion of participants who have a reduction in 
spleen volume (by imaging) of at least 35% when 
compared with baseline. 
Secondary 
Part 2:  To evaluate the safety and tolerability of 
itacitinib IR at the RP2D. 
Safety and tolerability through assessments of 
frequency and severity of AEs; changes in clinical 
safety assessments; changes in clinical laboratory 
parameters. 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to MF symptom 
improvement at Week 24, in those patients with a 
baseline TSS ≥ 10. 
TSS response rate at Week 24, where TSS 
response is defined as the proportion of 
participants who achieve at least 50% reduction in 
TSS over the 28 days immediately before the end 
of Week 24 compared with the 7 days 
immediately before the initiation of itacitinib IR 
(baseline). 
Part 2:  To evaluate the efficacy of itacitinib IR 
with respect to improvement of quality of life. 
The mean change (from Day 1 vs Week 12 and 
Week 24) in the 5 multi-item functional scale 
scores and the multi-item global health status 
scale score (EORTC QLQ-C30). 
Part 2:  To evaluate the efficacy of itacitinib IR at 
the RP2D with respect to PGIC. 
The percentage of participants categorized as 
improved on the Week 24 PGIC. 


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Table 8: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
As of NOV 2021, 4 participants were treated with itacitinib IR 300 mg BID.  The study is closed 
to enrollment and no additional participants will be treated.  The ongoing participants will move 
to the extension period, regardless of where they are in the study, and continue to remain on 
study treatment until withdrawal criteria are met.  Part 2 is no longer applicable. 
4.1.1. 
Part 1:  Dose Escalation of Itacitinib IR 
In Part 1 of the study, itacitinib IR 300 mg BID will be the first dose level and 600 mg BID will 
be the second dose level.  Additional dose levels and schedules may also be evaluated if 
indicated by emerging safety, 
 data.  Dose escalation, de-escalation, selection, and 
elimination will follow the BOIN design algorithm (Liu and Yuan 2015).  Based on safety 
considerations, simulations, and expert input, a target DLT rate of 33% during the first 28 days 
of treatment was selected.  Under BOIN design, when at least 3 participants have been treated, if 
the probability is > 95% that the observed toxicity rate is above the target DLT rate of 33%, then 
this dose level and higher dose levels will be eliminated.  If the lowest dose level is eliminated, 
dose escalation will be terminated.  At each dose level, participants will be added to the cohort in 
groups of 3.  A minimum of 3 and a maximum of 9 participants will be enrolled at each dose 
level; a minimum of 3 evaluable participants is required prior to any dose decision.  Table 9 and 
Table 10 describe the dose escalation, de-escalation, elimination, and selection boundaries 
corresponding to a target DLT rate of 33%, that will be used for Dose Level 1 and Dose Level 2, 
respectively. 
Table 9: 
Dose Escalation, Elimination, and Selection Boundaries for a Target DLT 
Rate of 33% for Dose Level 1 in Part 1 
Action 
Dose Level 1:  300 mg BID 
First Group of 
3 Participants 
After Adding Second 
Group of 3 Participants 
After Adding Third 
Group of 3 Participants 
Go to next dose level (escalate 
dose to Dose Level 2) 
0 of 3 participants with 
DLT 
1 of 6 participants with 
DLT 
2 of 9 participants with 
DLT 
Add another 3 participants at 
current dose level (retain dose) 
1 of 3 participants with 
DLT 
2 of 6 participants with 
DLT 
– 
Eliminate dose and terminate 
dose escalation  
At least 2 of 
3 participants with DLTs 
At least 3 of 
6 participants with DLTs 
At least 4 of 
9 participants with DLTs 
Select current dose level as 
RP2D for Part 2 of the study 
– 
– 
3 of 9 participants with 
DLTa 
a If dose is de-escalated from Dose Level 2, and ≤ 3 of 9 participants has a DLT, then Dose Level 1 can be selected as the RP2D. 


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Table 10: 
Dose De-Escalation, Elimination, and Selection Boundaries if Dose Is 
Escalated to Dose Level 2 
Action 
Dose Level 2:  600 mg BID 
First Group of 
3 Participants 
After Adding Second 
Group of 3 Participants 
After Adding Third 
Group of 3 Participants 
Continue adding groups of 
3 participants until 9 participants have 
been treated 
0-1 of 3 participants 
with DLTs 
≤ 2 of 6 participants with 
DLT 
– 
De-escalate dosea 
2 of 3 participants 
with DLTs 
3 of 6 participants with 
DLT 
4-5 of 9 participants with 
DLTs 
Eliminate dosea 
3 of 3 participants 
with DLTs 
4 of 6 participants with 
DLTs 
6 of 9 participants with 
DLTs 
Select current dose level as RP2D for 
Part 2 of the study 
– 
– 
≤ 3 of 9 participants with 
DLT 
a Dose will be de-escalated to Dose Level 1 and additional participants will be dosed according to the boundaries in Table 8. 
The dose escalation will continue until at least 1 of the following occurs: 
• The maximum sample size in Part 1 has been reached; 
• At least 6 participants have been treated with the RP2D that will be used in Part 2 of 
the study; 
• All doses levels have been eliminated and a RP2D cannot be identified for use in 
Part 2 of the study. 
In Part 1, dose interruptions may be implemented based on toxicity; dose reductions will not be 
permitted during the DLT observation period (Day 1-28).  Intraparticipant dose escalation is not 
permitted in Part 1 of the study, until a RP2D is determined (see Section 6.5.2). 
At the discretion of the sponsor, in order to further investigate safety, efficacy, 
 
 additional participants may be enrolled to replace nonevaluable participants at any 
dose level that has not been eliminated due to toxicity. 
Treatment with investigational product will continue until either disease progression, participant 
refusal, or unacceptable toxicity occurs, whichever occurs first, unless the investigator and 
medical monitor agree to treatment beyond progression based on individual benefit/risk 
assessments. 
4.1.2. 
Recommended Phase 2 Dose Definition 
The RP2D is the dose chosen for further investigation in Part 2 based on results from Part 1. 
4.1.3. 
Part 2:  Dose Expansion 
Approximately 55 participants will be included in Part 2, the dose expansion period of the study.  
Participants who do not meet eligibility requirements of the study may be replaced.  Evaluation 
of the safety and tolerability will be performed throughout the study and efficacy will be 
periodically evaluated.  Participants will be analyzed for efficacy based on spleen volume 
reduction and symptom improvement (see Section 10). 


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4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF.  The end of the study is defined as the 
date of the last visit of the last participant in the study or last scheduled procedure shown in the 
SoA for the last participant in the study globally. 
A participant is considered to have completed the study if he/she has completed the EOS visit.  
The end of the study may be designated as the timepoint when the last participant completes all 
study required assessments.  At this point, a database lock of the study may occur to allow the 
analysis of the study data. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC of the study's 
completion or early termination, send a copy of the notification to the sponsor or sponsor's 
designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively if, for example, required by regulatory decision 
or upon advice of the DMC.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and the regulatory bodies of the decision and reason for 
termination of the study.  The DMC will recommend termination of the study if warranted, as 
described in Section 5.6 as well as the DMC charter. 


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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Aged 18 years or older at the time of signing the informed consent 
2. Diagnosis of primary MF meeting the 2016 WHO criteria for overt PMF or secondary 
MF (PPV-MF or PET-MF) meeting the 2008 IWG-MRT criteria. 
3. At least Intermediate 1 risk MF according to the DIPSS. 
4. Prior treatment with ruxolitinib and/or fedratinib monotherapy: 
a. Previously treated with ruxolitinib and/or fedratinib monotherapy for PMF or 
secondary MF for not more than 6 months if treatment was discontinued due to 
recurrent Grade 4 thrombocytopenia; ≥ Grade 3 anemia, hemorrhage, or hematoma; 
or allergy/other intolerance to ruxolitinib or fedratinib 
OR  
b. Currently receiving ruxolitinib or fedratinib monotherapy for PMF or secondary MF: 
− For at least 3 months with initial response but regrowth of spleen on imaging or 
by palpation compared with baseline;  
OR 
− For at least 28 days if treatment is complicated by recurrent Grade 4 
thrombocytopenia; ≥ Grade 3 anemia, hemorrhage, or hematoma; or allergy/other 
intolerance to ruxolitinib or fedratinib. 
5. Splenomegaly defined as palpable spleen at least 5 cm below the left costal margin or 
volume ≥ 450 cm3 on imaging assessed during screening. 
6. Allogeneic stem cell transplant not planned. 
7. Platelet ≥ 50 × 109/L at screening. 
8. Ability to comprehend and willingness to sign a written ICF for the study. 
9. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Male participants with childbearing potential must agree to take appropriate 
precautions to avoid fathering children (with at least 99% certainty) from screening 
through 90 days after the last dose of study drug(s)/treatment and must refrain from 
donating sperm during this period.  Permitted methods that are at least 99% effective 
in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed.  


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b. Women participants with childbearing potential must have a negative serum 
pregnancy test at screening and before the first dose on Day 1 and must agree to take 
appropriate precautions to avoid pregnancy (with at least 99% certainty) from 
screening through safety follow-up.  Permitted methods that are at least 99% effective 
in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed. 
c. Women participants without childbearing potential (ie, surgically sterile with a 
hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea) are 
eligible. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Prior treatment with a JAK inhibitor other than ruxolitinib or fedratinib 
2. Record of ≥ 10% myeloid blasts in the peripheral blood (on peripheral blood smear) or 
bone marrow prior to or at the time of screening 
3. For participants on ruxolitinib or fedratinib, unable to be tapered from that treatment over 
the course of 14 days without corticosteroids, hydroxyurea, or other agents 
4. Treatment with ruxolitinib, fedratinib or other MF-directed therapy (approved or 
investigational) within 2 weeks of Day 1 
5. Prior splenectomy or splenic irradiation within 6 months before receiving the first dose of 
itacitinib 
6. Unable or unwilling to undergo serial MRI or CT scans for spleen volume measurement 
7. Unable or unwilling to complete MFSAF v4.0 diary on a daily basis during the study 
8. ECOG performance status ≥ 3 (see Appendix B)   
9. Life expectancy less than 24 weeks 
10. Not willing to receive RBC or platelet transfusions 
11. Participants with laboratory values at screening defined in Table 11. 


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Table 11: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a 
Platelets 
< 50 × 109/L 
b 
Hemoglobin 
≤ 8 g/dL 
c 
ANC 
≤ 1.0 × 109/L 
d 
WBCs 
≤ 1.5 × 109/L 
Hepatic 
e 
ALT 
≥ 2.5 × ULN 
f 
AST 
≥ 2.5 × ULN 
g 
Bilirubin/total bilirubin 
≥ 2.0 × ULN 
h 
Alkaline phosphatase 
≥ 2.5 × ULN 
i 
Lactate dehydrogenase 
> 3 × ULN in the absence of hemolysis 
Renal 
k 
Creatinine clearance 
≤ 40 mL/minute based on Cockcroft-Gault formula OR 
≤ 40 mL/min/1.73 m2 using the Modification of Diet in 
Renal Disease Formula OR 
≤ 40 mL/minute based on a 24-hour urine for creatinine 
clearance 
Coagulation 
l 
International normalized ratio or PT 
> 1.5 × ULN 
m 
aPTT 
> 1.5 × ULN 
12. Significant concurrent, uncontrolled medical condition, including but not limited to the 
following:   
a. Gastrointestinal 
Significant gastrointestinal disorder that could interfere with absorption, 
metabolism, or excretion of study drug/treatment. 
− Inability of the participant to swallow and retain oral medication. 
b. Cardiovascular 
Participants with impaired cardiac function or clinically significant cardiac disease 
unless approved by medical monitor/sponsor: 
− New York Heart Association Class III or IV cardiac disease, including preexisting 
clinically significant ventricular arrhythmia, congestive heart failure, or 
cardiomyopathy. 
− Unstable angina pectoris. 


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− Acute myocardial infarction ≤ 6 months before study participation. 
− Other clinically significant cardiovascular disease (ie, ≥ uncontrolled Grade 3 
hypertension.) 
13. History or presence of an abnormal ECG that, in the investigator’s opinion, is clinically 
meaningful according to the guidance provided in Section 8.3.4.  
14. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or 
antiviral treatment.  Participants with acute infections requiring treatment should delay 
screening/enrollment until the course of therapy has completed and the event is 
considered resolved.  Prophylactic antibiotics will be permitted. 
15. Hepatitis:  Evidence of HBV or HCV infection or risk of reactivation.  Participant cannot 
be positive for HBV DNA, HCV RNA, HBsAg, or anti–hepatitis B core antibody. 
Note:  Participants with no prior history of HBV infection who have been vaccinated 
against HBV and who have a positive antibody against HBV antigen test as the only 
evidence of prior exposure may participate in the study. 
16. Known HIV infection.   
17. Current use of prohibited medication as described in Section 6.6.7. 
18. Inability or unlikeliness of the participant to comply with the dose schedule and study 
evaluations, in the opinion of the investigator. 
19. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
20. Women who are pregnant or breastfeeding. 
21. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of itacitinib IR and attending required study visits; 
pose a significant risk to the participant; or interfere with interpretation of study data. 
22. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including:  inability to self-administer itacitinib IR; difficulty attending 
required study visits; a comorbid condition that poses a significant risk to the participant 
or may interfere with interpretation of study data. 
The following participants are excluded in France:  vulnerable populations according to 
article L.1121-6 of the French Public Health Code and adults under legal protection or 
who are unable to express their consent per article L.1121-8 of the French Public Health 
Code. 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are required.  
5.3.1. 
Meals and Dietary Restrictions 
Participants should be instructed to refrain from the consumption of pomegranates or 
pomegranate juice, and grapefruit or grapefruit juice, as these are known to inhibit cytochrome 
CYP3A enzymes and may increase exposure to itacitinib IR. 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error.  Additionally, a participant who fails screening may 
repeat the screening process 1 time if the investigator believes that there has been a change in 
eligibility status.  Participants who rescreen must reconsent and be assigned a new participant 
number. 
5.5. 
Replacement of Participants 
Participants may be replaced for any of the following reasons: 
• In Part 1, any participant who withdraws from treatment before the completion of the 
DLT observation period for any reason other than a DLT (eg, not evaluable for DLT), 
may be replaced to ensure a minimum number of evaluable participants. 
• In Part 2, participants who do not meet the eligibility requirements of the study may be 
replaced. 
5.6. 
Data Monitoring Committee 
This study will use an internal DMC to monitor safety and efficacy at the planned analyses.  The 
DMC is comprised of an internal, autonomous group who are formally appointed by the sponsor.  
The DMC will periodically review the accumulating safety and efficacy data by treatment group, 
including the futility analysis, to provide advice on whether to continue, modify, or terminate a 
study based on a benefit-risk assessment.  Additional details regarding the DMC will be provided 
in the DMC charter.   


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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Administered 
Itacitinib IR will be self-administered in the form of 100 mg tablets. 
Table 12 presents the study treatment information. 
Table 12: 
Study Treatment Information 
 
Study Treatment 
Study treatment name: 
Itacitinib IR 
Dosage formulation: 
Immediate release tablets 
Unit dose strengths: 
100 mg tablets and 300 mg tablets 
Dose levels: 
300 mg BID and 600 mg BID 
Route of administration:  
PO 
Administration instructions: 
Itacitinib should be taken with water and regardless of 
food.  
 
  
Packaging and labeling: 
Itacitinib IR will be provided in high-density 
polyethylene bottles.  Each bottle will be labeled as 
required per country requirement.  Each container will be 
labeled as required per country requirement. 
Storage: 
Ambient conditions (15°C to 30°C, or 59°F to 86°F) 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment.  All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of itacitinib IR to the study site. 
• Inventory of itacitinib IR at the site. 
• Participant use of the itacitinib IR including pill counts from each supply dispensed. 
• Return of itacitinib IR to the investigator or designee by participants. 


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The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified itacitinib IR.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of itacitinib IR 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
itacitinib IR back to the sponsor or its designee for destruction according to institutional SOPs.  
If local procedures mandate on-site destruction of investigational supply, the site should (where 
local procedures allow) maintain the investigational supply until the study monitor inspects the 
accountability records in order to evaluate compliance and accuracy of accountability by the 
investigative site.  At sites where the itacitinib IR is destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 
Instruction to participants for handling itacitinib IR is provided in Appendix D. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
This is an open-label study; no comparisons will be made between participants or against 
historical controls.  Measurements of safety and efficacy are objective measurements, and only 
comparisons to pretreatment conditions will be made. 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with itacitinib IR will be calculated by the sponsor based on the drug accountability 
documented by the site staff and monitored by the sponsor/designee.  Participants will be 
instructed to bring all unused study drugs with them to the study visits in order for site personnel 
to conduct tablet counts to assess study drug accountability.  The drug accountability 
documentation will be used by the sponsor to calculate treatment compliance. 
6.5. 
Dose-Limiting Toxicity and Determination of Recommended Phase 2 
Dose 
6.5.1. 
Definition of a Dose-Limiting Toxicity 
Dose-limiting toxicity will be defined as the occurrence of any of the toxicities in Table 13 
(except those with a clear alternative explanation) occurring up to and including Day 28.  All 
DLTs will be assessed for severity by the investigator with CTCAE Version 5.0.  All participants 
who received at least 42 of 56 doses of study drug at the assigned dose level or who experienced 
a DLT during the first 28 days will be considered evaluable for determining tolerability of the 
dose. 


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Individual participant dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the RP2D of itacitinib IR, decisions will be made 
based on events that are observed from the first day of study drug administration through and 
including Day 28.   
Table 13: 
Definition of Dose-Limiting Toxicity 
Toxicity 
Definition 
Nonhematologic 
Any ≥ Grade 3 nonhematologic toxicity EXCEPT: 
• Grade 3 fatigue, asthenia, fever, anorexia, or constipation. 
• Grade 3 nausea, vomiting, or diarrhea not requiring tube feeding, total parental 
nutrition, or hospitalization/prolongation of hospitalization. 
• Grade 3 AST or ALT that resolves to < Grade 2 within 7 days. 
• Grade 3 or 4 isolated electrolyte abnormalities that resolve, with or without 
intervention, to < Grade 2 levels in < 72 hours. 
Hematologic 
Any of the following: 
• Grade 3 thrombocytopenia with bleeding. 
• Any Grade 4 thrombocytopenia lasting > 7 days. 
• Grade 4 decrease in neutrophil count lasting > 7 days. 
• Grade 3 or 4 febrile neutropenia of any duration. 
6.5.2. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific safety data, adjudicate individual high grade AEs and DLTs, determine 
agreement with respect to dose escalation or dose elimination, and guide other major study 
decisions. 
If 600 mg BID (Dose Level 2) is declared as the RP2D, any participants enrolled at the first dose 
level in Part 1 of the study will have the option of escalating to the RP2D, if they have not 
experienced a DLT.  The participant will be required to provide consent for Part 2.  Once a 
participant is escalated to the RP2D, the Part 2 SoA should be followed. 
6.6. 
Dose Modifications 
Selections and modifications to the study treatment regimen are planned for Part 1.  Dose 
interruptions and modifications also may occur for individual study participants.  The 
identification of DLTs will define the doses used in planned cohorts.  Further, the occurrence of 
DLTs and other toxicities (related or unrelated to study drug) will guide decisions for treatment 
interruptions and discontinuation for individual participants. 
Individual decisions regarding dose modifications of itacitinib IR should be made using clinical 
judgment in consultation with the medical monitor (whenever possible), taking into account 
relatedness of the AE to the study treatment and the participant's underlying condition.  Adverse 
events that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory 


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values without associated clinically significant signs or symptoms may be exempt from 
dose-reduction rules. 
The decision to proceed to the next dose level (either an increase or a decrease) will be made by 
the study team and the investigator based on safety, tolerability, and preliminary 
 data 
obtained from at least 3 participants at the prior dose level. 
6.6.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
Investigators may employ any measures or concomitant medications necessary to optimally treat 
the participant after discussion with the sponsor (whenever possible). 
6.6.2. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be monitored until it resolves to baseline or appears to have stabilized for a 
minimum of 2 weeks.  During follow-up, participants should be seen as often as medically 
indicated to assure safety. 
6.6.3. 
Criteria and Procedures for Dose Interruptions and Modifications of Study 
Drug 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the participant should continue or discontinue study treatment. 
Guidelines for interruption and restarting of itacitinib IR are provided in Table 14. 
6.6.3.1. 
Part 1 
In Part 1, dose interruptions are permitted for individual study participants; dose modifications 
will not be permitted during the DLT evaluation period.  The occurrence of DLTs and other 
toxicities (related or unrelated to study drug) will guide decisions for treatment interruptions and 
discontinuation for individual participants.  In order to be considered evaluable in Part 1, 
participants must receive at least 42 of the 56 doses of study drug at the assigned dose level 
during the 28-day DLT evaluation period or have experienced a DLT during the first 28 days. 


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6.6.3.2. 
Part 2  
Table 14: 
Guidelines for Interruption and Restarting of Study Drug 
Adverse Event 
Action Taken 
Chemistry 
Grade 4 increase in ALT and/or 
AST 
Step 1:  Interrupt study drug.  Assess ALT or AST every 7 days 
until the toxicity has resolved to ≤ Grade 1. 
Step 2:  If assessed as not related to study drug, restart study drug 
at same dose.  If assessed as related to study drug, restart study 
drug at a dose 100 mg BID less than the previous dose.   
Note:  If liver tests indicate a potential Hy's Law case 
(ALT > 3.0 × ULN, ALP < 2 × ULN, and bilirubin ≥ 2.0 × ULN), 
interrupt study treatment, conduct a full work-up (including 
imaging if clinically indicated) to evaluate other immediately 
apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including but not limited to, viral hepatitis, 
pre-existing chronic or acute liver disease, or the administration of 
other drug(s) known to be hepatotoxic.  If Hy's Law can’t be 
unequivocally ruled out, permanently discontinue study treatment. 
Hematology 
Grade 4 thrombocytopenia or 
Grade ≥ 3 thrombocytopenia 
with bleeding 
Interrupt dose and assess platelet count every 7 days until toxicity 
resolves to ≤ Grade 1 or to baseline platelet count; restart study 
drug at 100 mg BID less than the previous dose. 
Grade 4 thrombocytopenia and 
clinically significant bleeding 
event 
Permanently discontinue study drug. 
Grade 4 neutropenia 
Interrupt dose until resolved to ≤ Grade 2 or to baseline ANC.  
Restart dose at 100 mg BID less than the previous dose. 
Grade 3 anemia 
If hemoglobin ≥ 8.0 g/dL not achievable with transfusion of 
PRBC, interrupt dose until resolved ≤ Grade 2.  Restart dose at 
100 mg BID less than the previous dose. 
Other toxicities 
Any Grade 1 or Grade 2 toxicity 
Continue study drug treatment and treat the toxicity; monitor as 
clinically indicated. 
Any other Grade 3 toxicity 
Step 1:  Interrupt study drug.  Assess relevant laboratory every 
7 days until the toxicity has resolved to ≤ Grade 1. 
Step 2:  If assessed as not related to study drug, restart study drug 
at same dose.  If assessed as related to study drug, restart study 
drug at a dose 100 mg BID less than the previous dose. 


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Table 14: 
Guidelines for Interruption and Restarting of Study Drug (Continued) 
Adverse Event 
Action Taken 
Other toxicities (continued) 
Any recurrent Grade 3 toxicity 
after 1 dose reduction 
Interrupt study drug.  Assess relevant laboratory every 7 days until 
the toxicity has resolved to ≤ Grade 2.  Restart dose at 100 mg BID 
less than the previous dose administration unless that lower dose is 
less than 200 mg BID. 
Any other Grade 4 toxicity 
Discontinue study drug administration and follow up per Protocol.  
When the toxicity is an isolated, unrelated, Grade 4 laboratory 
event that is transient and manageable with appropriate care, the 
investigator may choose to continue treatment at a reduced dose or 
after a short interruption. 
6.6.4. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
itacitinib IR be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• The occurrence of an AE that is related to itacitinib IR that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
• An AE requiring more than 2 dose reductions, if below the RP2D of itacitinib IR. 
• A persistent AE requiring a delay of therapy for more than 3 weeks unless a greater 
delay has been approved by the sponsor. 
See Section 7 for discontinuation procedures. 
6.6.5. 
Permitted Medications and Procedures 
Concomitant treatments and/or procedures that are required to manage a participant's medical 
condition during the study will also be recorded in the eCRF. 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 30 days before the first dose of study treatment and 30 days after 
the last dose of study treatment will be recorded in the eCRF.  Any addition, deletion, or change 
in the dose of these medications will also be recorded.  Concomitant medications administered 
up to 30 days after the last dose of study treatment for an SAE should be recorded for SAEs as 
defined in Section 9.4. 


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6.6.6. 
Restricted Medications and Procedures 
The following medications have restrictions on use during the treatment period of the study: 
• Aspirin in doses exceeding 125 mg per day is not permitted.  Low-dose aspirin 
(≤ 125 mg per day) is permitted unless clinically contraindicated. 
• If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
then caution and enhanced monitoring is required.  History of thrombocytopenia 
should be a factor in the choice of anticoagulant and dose. 
6.6.7. 
Prohibited Medications and Procedures 
The following medications are prohibited during the treatment period of the study: 
• Use of any medications used to treat MF (eg HU, interferon, thalidomide, busulfan, 
lenalidomide, anagrelide, other cytotoxics or immune modulators, other JAK 
inhibitors, or any investigational agent) is not permitted at any time beginning at 
Day 1 until the time that itacitinib IR therapy is permanently discontinued.  
Investigators must determine that the participant is able to withdraw current therapy 
without it being likely to lead to significant deterioration of the participant’s condition 
in order for the participant to qualify for the study.  
• Coadministration with strong CYP3A4 inducers.  The FDA DDI website provides the 
a list of examples of strong CYP3A4 inducers (see Appendix C). 
• Coadministration with strong CYP3A inhibitors.  The FDA DDI website provides the 
a list of examples of strong CYP3A inhibitors (see Appendix C). 
6.7. 
Treatment After the End of the Study 
Participants may continue to receive itacitinib IR in the extension period (Section 8.6), if they are 
continuing to receive benefit from the treatment. 


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• Progression of MF, lack of response, or if additional systemic therapy is required. 
• The participant becomes pregnant. 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that 
he/she does not want to be followed any longer; in this case no further data, except 
data in public domain, may be solicited from or collected on the participant.   
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity as noted in Section 6.6. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
• Prohibited medication is required. 
A participant may be discontinued from study treatment as follows: 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted.  Reasonable efforts should be made to have the participant return for a 
follow-up visit.  These visits are described in the SoA.  The last date of the last dose of itacitinib 
IR and the reason for discontinuation of itacitinib IR will be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for discontinuation must be documented in the participant's medical 
record and the primary reason for discontinuation must be included in the eCRF. 
• The EOT visit should be performed and date recorded. 


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• The status of the participant should be updated to EOT in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
itacitinib–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety/efficacy assessments.   
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See SoA for data to be collected at the time of study withdrawal and follow-up and for any 
further evaluations that need to be completed. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF must contain all required elements and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the applicable requirements and regulations for the countries in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date. 


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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is enrolled in the 
study.  Screening may not exceed 35 days.  Assessments that are required to demonstrate 
eligibility may be performed over the course of 1 or more days during the screening process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of the ICF may be used for screening or baseline 
purposes provided the procedure meets the Protocol-defined criteria and has been performed in 
the timeframe of the study (ie, within 35 days of Day 1).  For participants who are enrolled in the 
study, information associated with eligibility requirements must be entered into the appropriate 
eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm eligibility, before 
enrollment or the administration of study treatment.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
enrollment will be used to determine eligibility.   
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site staff should contact the IRT to obtain the 
participant ID number during screening.  Additionally, the IRT will be contacted at each regular 
study visit to update the study drug supply.  Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Reminder Cards and Diaries 
Participants will be provided with a reminder card at each visit.  The reminder card will indicate 
the date/time of the next visit and will also remind the participant that they should not take their 
morning dose of study drug/treatment on Day 1 or Week 4, as they will take it after blood draws 
have been completed.  The reminder cards for these visits will have an area on which the date 
and time of the last dose taken (from the previous evening) and the time and contents of their last 
meal before the visit should be recorded. 
Participants will be provided with the MFSAF v4.0 diary to be completed each night.  See 
Section 8.2.3.1 for additional information regarding the MFSAF. 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 20 years that are considered to be clinically significant by the investigator. 


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8.1.5.2. 
Disease Characteristics and Treatment History 
Documentation of disease history including details of MF diagnosis, and prior bone marrow 
biopsy data with respect to fibrosis stage will be recorded.  All treatments for MF, phlebotomy 
history, and all transfusions of RBC products or platelets from at least 12 weeks before the 
screening visit will also be collected. 
8.2. 
Efficacy Assessments 
8.2.1. 
Spleen Palpation 
Spleen size should be evaluated at timepoints indicated in the SoA.  The participant should be in 
the recumbent position.  The edge of the spleen will be determined by palpation, measured in 
centimeters, using a soft ruler, from the costal margin to the point of greatest splenic length.  The 
measurements should be noted and the site at which it was determined (eg, anterior axillary line, 
midclavicular line, and/or subxiphoid). 
8.2.2. 
Imaging 
An MRI/CT of the upper and lower abdomen and pelvis, for spleen volume will be performed as 
outlined in the SoA.  An MRI is the preferred method for obtaining spleen volume data.  
However, CT scans may be performed if the participant is not a candidate for MRI or if MRI is 
not readily available.  The MRIs will be read initially by local radiologist who will assess the 
scan for quality and send all scans (MRI or CT) to the central imaging laboratory the same day, 
if possible.  The scans from an individual participant will be read by a central reader.  Spleen 
volume will be obtained by outlining the circumference of the organ and determining the volume 
using the validated technique of least squares. 
8.2.3. 
Patient-Reported Outcomes 
8.2.3.1. 
Myelofibrosis Symptom Assessment Form Electronic Symptom Diary 
Myelofibrosis-associated symptoms will be assessed with a symptom diary (MFSAF v4.0 diary, 
24-hour recall format).  Participants will be issued a hand-held electronic device to record 
symptom severity.  The MFSAF v4.0 assesses 7 symptoms including fatigue, night sweats, 
itching (pruritus), abdominal discomfort, pain under the left ribs, feeling of fullness (early 
satiety), and bone pain; the TSS is the sum of the 7 symptoms.  Participants will rate the severity 
of their symptoms on a numeric rating scale of 0 (Absent) to 10 (Worst Imaginable) during the 
past 24 hours (Gwaltney et al 2017). 
The MFSAF v4.0 diary will be completed by participants as indicated in the SoA. 
8.2.3.2. 
Patient Global Impression of Change 
Participant overall status will be assessed with the PGIC (Guy 1976).  This form will be 
administered at timepoints indicated in the SoA.  The PGIC consists of a single question 
pertaining to participant overall status since the start of the study.  The questionnaire gives 
participants 7 options to describe their overall status including:  Very much improved, Much 
improved, Minimally improved, No change, Minimally worse, Much worse, and Very much 
worse.  The PGIC and instructions will be provided to the sites.  


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8.2.3.3. 
EORTC QLQ-C30 
Health-related quality of life will be assessed with the EORTC QLQ-C30 Version 3.0 (Aaronson 
et al 1993).  This form will be administered at timepoints indicated in the SoA.  The QLQ-C30 
contains questions pertaining to function, symptoms, and global health status/ quality of life.  
The EORTC QLQ-C30 and instructions will be provided to the sites.  
8.2.4. 
Health Economics  
Health Economics parameters are not being evaluated in this study. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
See Section 6.6 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
30 days after the last dose of study drug or until the start of new MF therapy, whichever occurs 
first.  Adverse events that begin or worsen after informed consent should be recorded on the 
Adverse Events Form in the eCRF regardless of the assumption of a causal relationship with the 
study drug.  Conditions that were already present at the time of informed consent should be 
recorded on the Medical History Form in the eCRF.  Adverse events (including laboratory 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible 
rather than by individual underlying signs and symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study drug or procedures, or that caused the participant to discontinue 
the study drug.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 


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8.3.1.1. 
Surveillance and Management of Infections 
During the study, investigators should be mindful that participants with myelofibrosis are at 
increased risk for infections.  Itacitinib has the potential to further increase the risk of infection in 
these participants. 
The use of prophylactic antimicrobial agents, including antivirals and anti-PJP medications, is 
permitted (strong CYP3A inhibitors or strong CYP3A4 inducers are prohibited, as outlined in 
Section 6.6.7).  During safety assessments and other interactions with participants, particular 
attention should be directed at identifying signs and symptoms of infections in order to ensure 
prompt and comprehensive evaluation and management. 
8.3.2. 
Physical Examinations 
At the screening visit, a comprehensive physical examination should be conducted.  The 
comprehensive physical examination will include height and body weight, and assessment(s) of 
the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination. 
During the study, the physical exam may be a targeted physical exam.  These assessments should 
be an evaluation as indicated by participant symptoms, AEs, or other findings and should be 
documented on the AE eCRF. 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Abnormalities identified after the first dose of study treatment constitute an AE if they 
are considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study drug.  Investigators should pay special attention to clinical 
signs related to previous serious illnesses. 
8.3.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests), include blood 
pressure, pulse, respiratory rate, and body temperature.  If vital signs cannot be taken before 
blood collection for laboratory tests, there must be a minimum of 30 minutes from the 
completion of the blood collection procedures to the beginning of the vital signs collection.  
Blood pressure and pulse will be taken with the participant in the recumbent, semirecumbent, or 
sitting position after 5 minutes of rest.  Weight will also be assessed at the visits indicated in the 
SoA.  Vital sign results identified after the first dose of study drug constitute an AE if they are 
considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study drug. 
8.3.4. 
Electrocardiograms 
12-lead ECGs will be obtained as outlined in the SoA using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  All 12-lead ECGs will 
be performed with the participant in a recumbent or semirecumbent position after 5 minutes of 
rest. 


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The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
participant management.  Additional 12-lead ECGs may be performed as clinically indicated to 
manage participant safety.  The decision to include or exclude a participant or discontinue study 
treatment based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor as appropriate.  Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs.  In the event that a single QTc is > 470 milliseconds at screening, the 
ECG may be repeated and the participant may be enrolled if the average QTc for 2 ECGs is 
≤ 470 milliseconds or with approval from the medical monitor.  For participants with an 
intraventricular conduction delay (QRS interval > 120 milliseconds) at screening, the JTc 
interval may be used in place of the QTc with medical monitor approval.  In addition, the JTc 
interval should be used for all subsequent assessments. 
8.3.5. 
Laboratory Assessments 
8.3.5.1. 
Local Laboratory Assessments 
See Table 15 for the list of clinical laboratory tests to be performed.  The timing and frequency 
of laboratory tests are outlined in Table 4 for Part 1 and in Table 6 for Part 2.  A certified 
laboratory local to the investigative site will perform all clinical laboratory assessments for 
safety (ie, blood chemistries, hematology assessments, coagulation tests, endocrine function, and 
urinalysis).  The investigative site will enter the laboratory results and laboratory normal ranges 
into the eCRF.  Additional testing may be required by the sponsor based on emerging safety data.  
Additional tests may also be performed if clinically indicated. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor. 
Laboratory sample collection on Day 1 must be performed before study treatment administration.  
After Day 1, predose laboratory procedures can be conducted up to 72 hours before study 
treatment administration. 


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Table 15: 
Required Laboratory Analytes 
Serum Chemistries 
Hematology 
Serology 
Coagulation 
Comprehensive metabolic panel: 
• Albumin 
• Alkaline phosphatase 
• ALT 
• AST 
• Bicarbonate or CO2 
• Blood urea nitrogen  
• Calcium 
• Chloride 
• Creatinine 
• Glucosea 
• Potassium 
• Sodium 
• Total bilirubin 
• Total protein 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Lactate dehydrogenase 
Lipase 
Amylase 
 
C-reactive protein 
Complete blood count with 
differential, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be 
provided for: 
• WBC differential laboratory 
results 
 
Peripheral blood smear to 
assess for blasts 
Hepatitis B surface antigen 
Hepatitis B surface antigen 
antibody 
Hepatitis B core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
HIV 
PT 
PTT or aPTT 
INR 
Fasting Lipid Panel 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Female participants of childbearing potential 
only require a serum test at screening and EOT 
and a urine pregnancy test before the first dose 
on Cycle 1 Day 1. 
Pregnancy tests (serum or urine) should be 
repeated if required by local regulations. 
a Fasting glucose should be obtained on visit days when the participant is fasting, according to the SoA 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data. 


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8.3.5.2. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the follow-up visit (30 to 37 days after last dose).  Urine pregnancy tests will be 
performed locally as outlined in Table 4 for Part 1 and Table 6 for Part 2, as medically indicated 
(eg, in case of loss of menstrual cycle, when pregnancy is suspected), or per country-specific 
requirement (note that country-required urine pregnancy testing will be outlined and 
communicated to investigational sites under separate cover).  If a urine pregnancy test is positive, 
the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study drug and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.6 for reporting 
requirements. 
8.3.5.3. 
Serology 
Hepatitis screening assessments will be performed at the screening visit to rule out hepatitis 
infection; required analytes are shown in Table 15.  Generally, hepatitis tests should be 
performed early in the screening process due to the length of time needed to obtain the results.  
Additional tests may be performed if clinically indicated. 


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8.6. 
Extension Period 
The extension period is the interval between Week 24 and the EOT visit.  Participants will 
remain on itacitinib IR and return to the clinic every 8 weeks, as outlined in the SoA.  


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Participants may remain on treatment as long as they are receiving clinical benefit and have not 
met any criteria for study withdrawal. 
8.7. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (eg, laboratory or clinical assessments) at those visits should be recorded in the eCRF. 
8.8. 
End of Treatment and/or Early Termination 
When the participant permanently discontinues itacitinib IR, whether the participant is 
terminating the study early or the participant has completed the study, the EOT visit should be 
conducted.  If the EOT visit coincides with a regular study visit, the EOT evaluations will 
supersede those of that scheduled visit, and the data should be entered in the EOT visit in the 
eCRF.  The participant should be encouraged to return for the follow-up visit. 
8.9. 
Follow-Up 
8.9.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 37 days after the EOT visit (or after the last dose of itacitinib IR 
if the EOT visit was not performed.  Adverse events and SAEs must be reported up until 1) at 
least 28 days after the last dose of itacitinib IR or 2) until toxicities resolve, return to baseline, or 
are deemed irreversible, whichever is longer.  Reasonable efforts should be made to have the 
participant return for the follow-up visit and report any AEs that may occur during this period.  If 
the participant cannot return to the site for the safety follow-up visit, the participant should be 
contacted by telephone for assessment of AEs and SAEs. 


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9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not it is considered drug-related. 
• An AE can therefore be any unfavorable or unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Additional Guidance for Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease) are to be reported as an AE. 
• Abnormal laboratory test results are to be reported as an AE if they are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes in 
study treatment.  Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded 
in the eCRF rather than the abnormal laboratory test result (eg, low hemoglobin, platelet count 
decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition/disease, including either an increase 
in the frequency and/or intensity of the condition, is to be reported as an AE. 
• New conditions detected or diagnosed after the start of study treatment administration are to be 
reported as an AE. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction are to be reported as 
an AE. 
• Signs and/or symptoms from dosing errors of a study treatment (eg, overdose) or a concomitant 
medication are to be reported as an AE. 
• "Lack of efficacy," "disease progression," or "failure of expected pharmacological action" will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments. 
• A condition that leads to a medical or surgical procedure (eg, endoscopy, appendectomy) will be 
reported as an AE if it occurs after informed consent is obtained.  If the condition is present before 
entering the study, then it should be captured as medical history. 
• Pre-existing diseases or conditions with expected fluctuations in signs or symptoms should be 
reported as an AE only if the investigator judges the fluctuation to have worsened more than 
expected during study participation. 


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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term "life-threatening" in the definition of "serious" refers to an adverse drug experience that 
places the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurs.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) are not considered SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term "disability" means a substantial disruption of a person's ability to conduct normal life 
functions.  This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle), that may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Is an important medical event 
An important medical event is an event that may not result in death, be immediately life-threatening, or 
require hospitalization but may be considered serious when, based on appropriate medical judgment, 
the event may jeopardize the participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in the above definition.  Examples of such events include new invasive or 
malignant cancers, intensive treatment in an emergency department or at home for allergic 
bronchospasm, blood dyscrasias, or seizures that do not result in hospitalization, or development of 
drug dependency or drug abuse, or suspected transmission of an infectious agent via a medicinal 
product.  Secondary malignancies should always be considered SAEs. 


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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after the study treatment is given, should be recorded on the 
Adverse Event Form in the eCRF.  (AE/SAEs that occur after informed consent should be recorded 
on the Medical History Form in the eCRF until the study drug is given, with the exception of 
AEs/SAEs associated with study procedures).  Conditions that were present at the time informed 
consent was obtained should be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostic reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records 
in lieu of completing the Adverse Event Form in the eCRF. 
• There may be rare instances when copies of medical records for certain cases are requested.  In this 
case, all participant identifiers, with the exception of the participant number, will be redacted by the 
site staff on the copies of the medical records before submission.  These records can be submitted to 
Incyte Pharmacovigilance by email/fax per the contact information listed in the Study Reference 
Manual or as per SAE completing guidelines. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine the following: 
• The severity grade (CTCAE v5.0 Grade 1 to 5).  See below for further instructions on the assessment 
of intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study drug:  suspected 
(yes) or not suspected (no).  See below for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at the final safety follow-up visit. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication 
or nondrug therapy, this action should be recorded on the Adverse Event Form and the treatment 
should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Non-Drug Therapy). 


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Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to estimate the 
grade of severity. 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate 
activities of daily living. 
• Grade 3:  Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study drug and each occurrence of 
each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are medical facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the possibility of a relationship. 
• The investigator will also consult the RSI in the IB or Product Information for study drug, or 
marketed products, respectively, in making his/her assessment. 
• Alternative causes, such as underlying or concurrent disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration, will be 
considered and investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report.  However, the causality assessment is one of the criteria 
used when determining regulatory reporting requirements.  Therefore, it is very important that 
the investigator always make an assessment of causality based on the available information 
for every event before the initial transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and 
submit the updated causality assessment. 


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Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature 
and/or causality of the AE or SAE as fully as possible.  This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
• Once an AE is detected, it should be followed in the AE eCRFs until it has resolved or until it is 
judged to be permanent; assessment should be made at each visit (or more frequently if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
• If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the sponsor with a copy of any postmortem findings, including 
histopathology. 
• Updated SAE information will be recorded in the originally completed eCRF and reported to Incyte 
Pharmacovigilance via the SAE EDC CRF until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up. 
• Any updated SAE data (including SAEs being downgraded to nonserious) will be submitted to the 
sponsor (or designee) within 24 hours of receipt of the information. 
See Appendix E for the management of potential Hy's Law cases. 
9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug, or study procedure), all SAEs 
occurring after the participant has signed the ICF through 30 days after the last dose of study 
treatment, must be reported to the sponsor (or designee) within 24 hours of learning of its 
occurrence, unless otherwise specified by the Protocol.  The investigator will submit any updated 
SAE data to the sponsor (or designee) within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study treatment or study participation, the investigator must notify the sponsor (or 
designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected unexpected serious adverse 
reactions will be collected and reported to the competent authorities and relevant ethics 


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committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE via the EDC 
system (primary method) or by completing the Serious Adverse Event Report Form in English (only 
if the EDC system is not available).  The contact information for Incyte Pharmacovigilance by email 
is listed in the Study Reference Manual. 
• In circumstances where the EDC system is not accessible for reporting SAE information (initial 
and/or follow-up SAE information) to the sponsor within 24 hours, refer to the Incyte Reference 
Guide for Completing the Serious Adverse Report Form.  Once the EDC system is functional, the 
SAE report should be retrospectively added to the EDC system and follow-up should be completed 
through the EDC.  The original copy of the Serious Adverse Event Report Form and the email must 
be kept at the study site (refer to the Incyte Reference Guide for Completing the Serious Adverse 
Report Form for details and for the email address). 
• Follow-up information is also recorded in the eCRF and transmitted to Incyte Pharmacovigilance via 
the EDC system.  The follow-up report should include information that was not provided previously, 
such as the outcome of the event, treatment provided, action taken with study drug because of the 
SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation).  Each recurrence, complication, or progression of the original 
event should be reported as follow-up to that event, regardless of when it occurs. 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE by completing 
the Serious Adverse Event Report Form in English. 
• Follow-up information is also recorded and transmitted to Incyte Pharmacovigilance on an amended 
or new Serious Adverse Event Report Form, with an indication that it is follow-up to the previously 
reported SAE and the date of the original report.  The follow-up report should include information 
that was not provided on the previous Serious Adverse Event Report Form, such as the outcome of 
the event (eg, resolved or ongoing), treatment provided, action taken with study drug because of the 
SAE (eg, dose reduced, interrupted, or discontinued), or participant disposition (eg, continued or 
withdrew from study participation).  Each recurrence, complication, or progression of the original 
event should be reported as a follow-up to that event, regardless of when it occurs. 
• Contacts for SAE reporting can be found in Study Procedures Manual. 


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9.5. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
9.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that the study drug 
may have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately (female participants only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
9.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 


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All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9.9. 
Treatment of Overdose 
For this study, any dose of itacitinib IR greater than 600 mg BID within a 24-hour time period 
will be considered an overdose. 
In the event of an overdose, the investigator/treating physician should: 
• Contact the medical monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
itacitinib IR can no longer be detected systemically (at least 3 days). 
• Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
There has been no clinical experience with overdose of itacitinib IR.  Treatment of overdose 
should consist of general supportive measures. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
This study is divided into 2 parts.  In Part 1, participants will participate in a dose-escalation 
period aimed at identifying the RP2D.  The sample size for Part 1 will vary depending on the 
number of DLTs observed; it is anticipated that 12 to 18 participants will be enrolled in this part 
of the study. 
In Part 2, in anticipation of a 10% drop-out rate, 55 participants will be enrolled in order to have 
a sample size of 50 participants.  In COMFORT-1, the proportion of participants who had a 
≥ 35% reduction in spleen volume (SRR) at Week 24 compared with baseline was 42%; this 
SRR was in first-line treatment with ruxolitinib.  In participants already treated with ruxolitinib, 
and/or fedratinib monotherapy, a lower response rate would be anticipated.  For the sample size 
calculation, a response rate of 5% is assumed as the null hypothesis.  Based on a 1-sided Type I 
error (alpha-level) value of 5%, power values are calculated for 3 different sample sizes and 
provided in Figure 3.  A 10% percentage point improvement over the null hypothesis value of 
5% (ie, a response rate of 15%) will provide approximately 84% power, when n = 50, based on a 
test for a single proportion using normal approximation. 
Figure 3: 
Power Curves for Values of n = 30, 40, and 50 
 


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10.2. 
Populations for Analysis 
The populations for analysis are provided in Table 18. 
Table 18: 
Populations for Analysis 
Population 
Description 
FAS 
All participants enrolled in the study who received at least 1 dose of study 
treatment. 
DLT evaluable 
All participants who receive at least 42 of 56 doses for the 28-day cycle 
regimen (representing ≥ 75% of the dose planned) or who have a DLT. 
10.3. 
Level of Significance 
This is an exploratory study, and no formal statistical tests will be performed.  All CIs will be 
95%. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
10.4.1.1. Part 1 
The primary objective of Part 1 of this study is to evaluate the safety and tolerability of itacitinib 
IR, to characterize the DLTs of increasing dose levels and to select a RP2D for Part 2 of the 
study.  Dose-limiting toxicities during Days 1 to 28 will be used to determine the RP2D.  During 
the remainder of the study, supportive data including the frequency, severity, and duration of 
AEs will be used to confirm the safety and tolerability of the RP2D. 
10.4.1.2. Part 2 
The primary endpoint is the proportion of participants achieving a ≥ 35% spleen volume 
reduction from baseline to Week 24.  Summary statistics and hypothesis testing with a 1-sided 
Type I error rate of 5% will be carried out for this primary endpoint.  In addition, 95% CIs will 
be provided. 
In support of the primary analysis, a Bayesian beta-binomial analysis is proposed for the primary 
endpoint SRR.  With proportions treated as a binomial random variable, prior beliefs (~ prior 
distribution) on the proportion (of participants achieving a ≥ 35% improvement in splenic 
response) will be used to calculate the posterior distribution of the proportion of responders.  For 
this primary analysis, a flat Uniform (0,1) prior will be used.   Ninety percent Bayesian credible 
intervals will then be presented in addition to the actual proportion. 


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10.4.2. 
Secondary Analysis 
Secondary endpoints include the following: 
• TSS response rate at Week 24 where TSS is response defined as the proportion of 
participants who achieve at least a 50% reduction in TSS over the 28 days 
immediately prior to the end of Week 24 compared with the 7 days immediately prior 
to initiation of itacitinib IR (baseline).  
• PGIC will be evaluated based on the percentage of participants categorized as 
improved on the week 24 PGIC. 
• ERORTC QLQ-C30 questionnaire pertaining to function, symptoms, and global 
health status/quality of life will be summarized. 
TSS response rate will be summarized descriptively by visit.  The proportion of participants with 
any reduction from baseline in MFSAF TSS will also be estimated with 95% CI.  Number of 
responders at each visit will also be presented.  PGIC will be summarized descriptively by visit. 
10.4.3. 
Safety Analyses 
10.4.3.1. Adverse Events 
A TEAE is any AE that emerges after the first dose of study drug, or worsens after the first dose 
of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include all AEs.  
All AEs will be tabulated by the MedDRA preferred term and system organ class.  The severity 
of AEs will be based on the NCI CTCAE v5 using Grades 1 through 5. 
The subset of TEAEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related.  If the investigator does not specify the relationship of the AE 
to study drug, then the AE will be considered treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  
10.4.3.2. Clinical Laboratory Tests 
The normal ranges for the clinical reference laboratory will be used when assessing the severity 
of abnormal laboratory results.  The incidence of abnormal laboratory values will be reported 
and changes in laboratory values from baseline will be reported in shift tables.   
Laboratory data will be classified into Grades 1 through 5 according to CTCAE v5.  The 
following summaries will be produced for the laboratory data: 
• Number and percentage of participants with postbaseline CTCAE grades (regardless 
of the baseline value).  Only the worst grade will be reported for each participant. 
• Shift tables from baseline to the worst postbaseline value according to CTCAE grade.  
For laboratory parameters where CTCAE grades are not defined, the shift tables will 
include low/normal/high categorizations base on laboratory reference ranges. 


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10.5. 
Interim Analysis 
A futility analysis is planned after half of the participants in Part 2 complete the Week 12 
assessment.  A short summary of the proposed analysis is provided below and further details of 
the interim analysis plan will be developed and reported separately.  
A Bayesian approach for futility analysis is used to calculate posterior probability and predictive 
probability for the SRR with a noninformative flat Uniform (0,1) prior.  For this calculation, a 
21% or lower SRR is considered ineffective for the treatment.  Thus, we expect the itacitinib IR 
arm is promising if the posterior probability of the rate (SRR) greater than 5% is higher than 
0.95 (ie, prob[rate of SRR > 21% | data] > 0.95).  With a total 50 participants in itacitinib IR arm, 
the number of participants with SRR needs to be 10 or more in order to meet the criteria. 
Futility evaluation is implemented in one interim analysis with 25 participants, and 
25 participants in the last stage, for a total of 50 participants.  With an unfavorable rate set at 
21% (null hypothesis) and posterior probability of 0.95 as the threshold, a total of at least 16 of 
the 50 participants must have splenic response to be able to claim treatment efficacy.  Given a 
5% cutoff of the predictive probability (ie, chance to stop the study in the interim analysis), the 
stopping rule will be as follows: 
• The study will be stopped if there are 4 or fewer participants with splenic response in the 
first interim analysis. 
Performance of the design shows that if the true SRR is 21%, the chance to reach at least a total 
of 16 participants with TSS at end of the study is 5% (Type I error); however, the probability to 
stop the study early is 37%.  If true SRR is indeed 40%, then the chance to reach at least 
16 participants with SRR at end of the study is 90% (power), and the corresponding probability 
to stop the treatment early is 1%. 


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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require approval from both Health Authorities 
and IRB/IEC before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 


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11.1.1. 
Identification of the Coordinating Principal Investigator 
A coordinating principal investigator will be appointed by the sponsor medical monitor before 
the end of the study.  As part of his or her responsibilities, the coordinating principal investigator 
will review the final CSR.  Agreement with the final CSR will be documented by the dated 
signature of the coordinating principal investigator. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 
of the Protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors and, as designated by the sponsor, will have their own data flow 
management plans, study charters, 
 as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, 
 photographs, diary data), 
or as otherwise specified in the Protocol. 
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 


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• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator's site. 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, 
depending on the study.  Current applicable medical records must be available. 
• May have responsibility for sending participants' data, either as unique samples, or 
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a 
qualified vendor designated by the sponsor.  
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that sensitive personal information is handled in accordance with local data protection laws 
(including but not limited to HIPAA and GDPR) as applicable.  Appropriate consent for 
collection, use and disclosure and/or transfer (if applicable) of personal information must be 
obtained in accordance with local data protection laws. 


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Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF; if the participant's name appears on any other document 
(eg, laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
appropriate technical and organizational measures as required by local data protection laws. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 2 years after study completion unless local regulations require 
otherwise.  No records may be destroyed during the retention period without the written approval 
of the sponsor.  No records may be transferred to another location or party without written 
notification to the sponsor. 
11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation, for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 


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The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the Protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
REFERENCES 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and 
Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials 
in oncology. J Natl Cancer Inst 1993;85:365-376. 
Cervantes F. How I treat myelofibrosis. Blood 2014;124:2635-2642. 
Clinical Trials Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2014. 
Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department 
of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental 
Health Administration; 1976. 
Gwaltney C, Paty J, Kwitkowski VE. Development of a harmonized patient-reported outcome 
questionnaire to assess myelofibrosis symptoms in clinical trials. Leuk Res 2017;59:26-31. 
Harrison CN, Schaap N, Mesa RA. Management of myelofibrosis after ruxolitinib failure. Ann 
Hematol 2020;99:1177-1191. 
Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. 
Cytokine Growth Factor Rev 2013;24:133-145. 
Itacitinib Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc C 
2015;64:507-523. 
Mascarenhas JO, Talpaz M, Gupta V. Primary analysis of a phase II open-label trial of 
ITACITINIB, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica 
2017;102:327-335. 
Mesa RA, Verstovsek S, Cervantes F, et al. Primary myelofibrosis (PMF), post polycythemia 
vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), 
blast phase PMF (PMF-BP): consensus on terminology by the international working group for 
myelofibrosis research and treatment (IWG-MRT). Leuk Res 2007;31:737-740. 
Oken MM, Creech RH, Tormey DC. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. J Clin Oncol 1982;5:649-655. 
Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with 
myeloproliferative neoplasm-associated myelofibrosis [published online ahead of print July 9, 
2020]. Leukemia. doi: 10.1038/s41375-020-0954-2. 
Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 
2005;23:8520-8530. 
Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and 
JAK2 inhibitor in myelofibrosis. N Engl J Med 2010;363:1117-1127. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom from screening through 90 days after the end of systemic exposure.  
If the male participant has a partner that is of child-bearing potential, the partner should also use 
contraception through 90 days after the end of relevant systemic exposure.  In addition, male participants 
must refrain from donating sperm from screening through 90 days after the end of relevant systemic 
exposure.  Males who have had a verified successful vasectomy qualify as having met the requirement for a 
highly effective birth control method.  
For female participants of childbearing potential in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered as highly effective birth control methods: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition 
of ovulationa 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− 
oral 
− 
injectable 
− 
implantableb 
• 
Intrauterine deviceb 
• 
Intrauterine hormone-releasing systemb 
• 
Bilateral tubal occlusionb 
• 
Vasectomized partnerbc 
• 
Sexual abstinenced 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode 
of action 
• 
Male or female condom with or without spermicidee 
• 
Cap, diaphragm, or sponge with spermicidee 
• 
Tubal ligation 
For participants in the study in Canada: 
In order to conform to Health Canada guidance, participants in this clinical study in Canada are to use 2 
forms of contraception, including at least 1 form of highly effective and 1 effective method of 
contraception.  Participants who are using combined hormonal contraception or progestogen-only 
hormonal contraception will be required to include a barrier method as well. 
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may reduce the 
efficacy of the contraception method. 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
c Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual partner of the 
woman of childbearing potential study participant and that the vasectomized partner has received medical assessment of the 
surgical success. 
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the 
participant. 
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) are also 
considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trials Facilitation and Coordination Group 2014. 


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APPENDIX B. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 


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APPENDIX C. CYTOCHROME P450 AND P-GLYCOPROTEIN 
INHIBITORS AND CYTOCHROME P450 INDUCERS 
The Food and Drug Administration (FDA) Drug Development and Drug Interactions:  Table of 
Substrates, Inhibitors and Inducers.   
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm#table3-3. Accessed July 9, 2019. 


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APPENDIX D. INSTRUCTION TO PARTICIPANTS FOR HANDLING 
ITACITINIB IR 
The participant must be instructed in the handling of itacitinib as follows: 
• Store the itacitinib IR at room temperature, in a safe place, and out of the reach of 
children. 
• Only remove the number of tablets needed at the time of administration. 
• Not to remove tablets in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed tablets and/or doses. 
• To take itacitinib IR with a full glass of water. 
• If the participant vomits after taking itacitinib IR, the participant should not take 
another dose. 
• To keep itacitinib IR in a safe place and out of reach of children. 
• To bring all used and unused itacitinib IR bottles/kits to the site at each visit. 
• To refrain from taking study medication on the day of clinic visits until after blood 
samples are collected. 
• To fast on the day of PK assessments. 
• If an itacitinib IR dose is missed by more than 8 hours, that dose should be skipped 
and the next scheduled dose should be administered at the usual time. 


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APPENDIX E. MANAGEMENT OF POTENTIAL HY'S LAW CASES 
INTRODUCTION 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study. 
The investigator participates, in conjunction with Incyte clinical project and pharmacovigilance 
representatives, in the review and assessment of cases fulfilling PHL criteria to ascertain whether 
there is an alternative explanation for the elevations in liver biochemistry other than 
drug-induced liver injury caused by the study drug. 
The investigator fulfills requirements for the recording of data pertaining to PHL or Hy's law 
cases and AE/SAE reporting according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
DEFINITIONS 
For the purpose of this process, definitions are as follows: 
Potential Hy's Law 
An increase in AST or ALT > 3 × ULN and total bilirubin > 2 × ULN at any point during the 
study.  The elevations do not have to be at the same time or within a specified timeframe. 
Hy's Law 
An increase in AST or ALT ≥ 3 × ULN and total bilirubin > 2 × ULN, where no other reason can 
be found to explain the combination of increases (eg, elevated serum ALP indicating cholestasis, 
viral hepatitis, another drug). 
ACTIONS REQUIRED IN CASES OF AST OR ALT > 3 × ULN OR TOTAL BILIRUBIN 
≥ 2 × ULN 
Identification and Determination of Potential Hy's Law 
To identify cases of AST or ALT > 3 × ULN or total bilirubin > 2 × ULN and consequently 
determine whether the participant meets PHL criteria, please follow the instructions below: 
• Review the laboratory report and if a participant has AST or ALT > 3 × ULN OR 
total bilirubin > 2 × ULN at any visit: 
− Determine without delay whether the participant meets PHL criteria by reviewing 
laboratory reports from all previous visits. 
− Enter the laboratory data into the laboratory eCRF as soon as possible. 


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Potential Hy's Law Criteria Not Met 
If the participant has NOT had AST or ALT ≥ 3 × ULN AND total bilirubin > 2 × ULN at any 
point in the study (the elevations do not have to be at the same time or within a specified 
timeframe), irrespective of ALP, please follow the instruction below: 
• Perform follow-up on subsequent laboratory results according to the guidance 
provided in Section 6.6.3 of the Protocol. 
Potential Hy's Law Criteria Met 
If the participant has had AST or ALT ≥ 3 × ULN AND total bilirubin > 2 × ULN at any point in 
the study (the elevations do not have to be at the same time or within a specified timeframe), 
irrespective of ALP, please follow the instruction below: 
• Have participant interrupt study drug. 
• Notify Incyte study team without delay. 
− The investigator, or designee, should contact the medical monitor to discuss and 
agree upon an approach for the study participant's follow-up and the continuous 
review of data. 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as medically indicated. 
• Investigate the etiology of the event and perform any relevant diagnostic 
investigations as discussed with the medical monitor. 
• Enter the laboratory data into the laboratory CRF as soon as possible. 
• If at any time (in consultation with the medical monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
REVIEW AND ASSESSMENT 
No later than 3 weeks after the biochemistry abnormality is initially detected and the criteria for 
PHL is met, the medical monitor, Incyte pharmacovigilance physician, and investigator will 
discuss and review available data and agree on whether there is an alternative explanation for the 
elevations in liver biochemistry other than drug-induced liver injury caused by the study drug.  
Participant matter experts will be included in the review as appropriate. 
Evaluation of Alternative Causes 
In order to gather additional clinical information to seek other possible causes of the observed 
liver test abnormalities, the following alternative etiologies should be considered, including but 
not limited to: 
• Active viral hepatitis 
• Alcoholic and autoimmune hepatitis 


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• Hepatobiliary disorders 
− Biliary tract disease, such as migration of gallstones or intrahepatic lesions, more 
often causes cholestatic injury initially and should be investigated with gall 
bladder and ductal imaging studies, especially if alkaline phosphatase is 
increased.  Malignant interruption of the biliary tract also should be considered. 
• Concomitant treatment 
• Other causes such as systemic infections (eg, bacterial, fungal, viral), nonalcoholic 
steatohepatitis, and cardiovascular diseases 
Actions After Review and Assessment 
According to outcome of the review and assessment, please follow the instructions below: 
If there is an agreed alternative explanation for the AST or ALT and total bilirubin elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE. 
• If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF if possible. 
• If the alternative explanation is an AE/SAE, record the AE/SAE in the eCRF 
accordingly and follow the standard study processes. 
• Have participant resume study drug as per Protocol guidelines. 
If it is agreed that there is no explanation that would explain the AST or ALT and total bilirubin 
elevations: 
• Have participant permanently discontinue study drug and perform end-of-treatment 
procedures. 
• Report an SAE (report term "Hy's Law"). 
− The 'medically important' serious criterion should be used if no other serious 
criteria apply. 
− As there is no alternative explanation for the Hy's law case, a causality assessment 
of related should be assigned. 
• If there is an unavoidable delay of over 3 weeks in obtaining the information 
necessary to assess whether or not the case meets the criteria for a Hy's law case, then 
it is assumed that there is no alternative explanation until such time as an informed 
decision can be made.  Report an SAE (report term "Potential Hy's Law") applying 
serious criteria and causality assessment as per above. 


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ACTIONS REQUIRED FOR REPEAT EPISODES OF AST OR ALT > 3 × ULN AND/OR 
TOTAL BILIRUBIN > 2 × ULN 
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of PHL 
is based on the nature of the alternative cause identified for the previous occurrence. 
If the alternative cause for the previous occurrence of PHL was not chronic or progressing 
malignant disease, please follow the process for PHL review and assessment as described in this 
appendix. 
If the alternative cause for the previous occurrence of PHL was chronic or progressing malignant 
disease, please follow the instructions below: 
• Determine whether there has been a significant change* in the participant's condition. 
− If there is no significant change, no action is required. 
− If there is a significant change, follow the process described for PHL review and 
assessment as described in this appendix. 
* A 'significant' change in the participant's condition refers to a clinically relevant change in ALT, AST, or total 
bilirubin, or associated symptoms.  The determination of whether there has been a significant change will be at the 
discretion of the investigator; this may be in consultation with the medical monitor if there is any uncertainty. 


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APPENDIX F. COVID-19 PANDEMIC MITIGATION STRATEGIES AND 
INSTRUCTIONS 
The COVID-19 global pandemic presents challenges to the ongoing conduct of clinical trials.  In 
line with regulatory guidance regarding clinical trial execution during the pandemic, the sponsor 
has issued the following Protocol considerations to ensure participant safety is maintained and 
adequate benefit/risk analyses are applied relative to participation in the study and the 
completion of study procedures and objectives while maintaining the investigational product 
supply chain. 
Recognizing the dynamic nature and flexibility required to manage the impact of the pandemic 
on this clinical trial, additional details will be incorporated into respective study manuals and 
site-specific monitoring plans as applicable, with institutional requirements as warranted, and 
communicated and discussed with investigative sites as needed.  Relevant test results will be 
documented in the eCRF, and applicable changes to the ICF will be made and monitored.  
SARS-CoV-2 Infection and Participation in the Study 
During the COVID-19 pandemic, additional risks to participants exist either related to going to a 
healthcare facility or as a result of study-related activities.  It is at the principal investigator's 
discretion to balance the risk/benefit while considering the participant's safety.  In addition, 
country-specific requirements are to be followed with regard to COVID-19 testing. 
A participant who fails screening due to SARS-CoV-2 infection may repeat the screening 
process upon recovery and COVID test normalization. 
Study Site Visits 
If local travel restrictions, isolation requirements, or the investigator's benefit/risk assessment 
determines it to be unsafe for participants to attend study visits at the investigational site, the site 
staff may elect to pursue the following: 
• In order to minimize participant risk, study visits may be conducted via telemedicine 
modalities (phone or video) or as per site institutional guidelines.  At a minimum, a 
review of AEs and concomitant medications must be completed.  On-site visits 
should be conducted whenever feasible and are required for administration of study 
treatment.  The participant may also be asked to undergo additional safety laboratory 
assessments. 
• In order to support investigator oversight of participant safety and disease 
management, the participant may be asked to undergo some laboratory tests or study 
procedures (eg, imaging) at a local laboratory or facility closer to the participant's 
residence rather than at the investigational site.  In this case, the study physician will 
provide the participant with the list of parameters to be checked.  These tests should 
be performed in certified laboratories and the investigator must ensure data can be 
transferred to the investigational site. 


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• Some tests, such as MRI assessments, may require longer windows due to the 
COVID-19 pandemic and may be performed outside the regularly scheduled visit 
window or may be conducted at the next scheduled visit.  It is the investigator's 
responsibility to check with the facility (if performed at a different facility) that the 
data will be obtained and available for evaluation.  General procedures performed 
outside of Protocol time windows will be captured as Protocol deviations due to 
COVID-19 in the eCRF.    
Study Treatment Management in the Event of SARS-CoV-2 Infection 
If a participant develops a SARS-CoV-2 infection, the event should be reported as an SAE (if it 
meets the SAE definition requirements) and appropriate medical intervention provided.  
Postbaseline COVID-19 testing should follow country-specific requirements depending on the 
extent of COVID-19 pandemic, local institutional guidance, or the investigator's clinical 
judgment. 
For participants who are diagnosed with COVID-19 during the study (positive COVID-19 test) 
or presumed (test pending/clinical suspicion) affected by SARS-CoV-2 infection, study 
treatment should be delayed until COVID-19 test normalization and clinical recovery.  Prior to 
restarting treatment, the study medical monitor should be notified with the participant's 
condition, that is, the participant should be afebrile for 72 hours and SARS-CoV-2–related 
symptoms (if any) should have recovered for a minimum of 72 hours.  
Safety monitoring following COVID-19 infection should be implemented as per institutional 
guidance or clinical judgment (eg, coagulation factors).  Concomitant medication administered 
for treatment of SARS-CoV-2 infection should be carefully considered for potential drug-drug 
interactions and recorded in the clinical database (EDC). 
COVID-19 Vaccination 
Participants may receive the COVID-19 vaccine as long as it is not a live vaccine.  COVID-19 
vaccination will be captured in the eCRF as a concomitant medication.  Administration of study 
treatment may be delayed to ensure vaccination is completed and acute AEs (if any) are 
managed.  The medical monitor may be consulted if needed. 
Clinical Trial Monitoring 
Study monitoring visits could be postponed; however, the site monitor and sponsor will continue 
to employ off-site monitoring practices such as routine communication methods (eg, phone calls, 
emails, video visits) with the sites to get information on trial progress, participant status, and 
information on issue resolution.  The study monitor may remotely review data entered into the 
EDC for accuracy and completeness if allowed by the national regulatory body, investigational 
site, and/or in compliance with local authorities.   
Reimbursement of Additional Expenses 
The sponsor will reimburse for any extraordinary expenses, keeping appropriate documentation 
as evidence (eg, travel expenses for the local laboratory visit[s], the costs of local [proximate] 
laboratory tests). 


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APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Protocol Amendment 1 
19 JAN 2022 
Protocol Amendment 1 (19 JAN 2022) 
Overall Rationale for the Amendment:  The study sponsor has decided not to proceed with the 
study any further; the primary purpose of this amendment is to update the Schedule of Activities 
for study participants ongoing as of the date of this decision to simplify and minimize the 
required assessments. 
1. Section 1, Protocol Summary (Figure 1:  Study Design Schema:  Part 1; Table 3:  
Schedule of Activities [Part 1]); 
 
 
Description of change:  Study assessments were updated to reduce participant burden. 
Rationale for change:  The study has been terminated to further enrollment; however, 
ongoing participants will move to the extension period and continue on itacitinib until 
withdrawal criteria are met.  As the study will not be completed, the assessment schedule 
was updated to minimize data collection while continuing to monitor safety. 
2. Section 1, Protocol Summary; Section 2.2, Study Rationale; Section 4.1, Overall 
Design 
Description of change:  Text was added to indicate the study is closed to enrollment, no 
additional participants will be treated, and Part 2 is no longer applicable. 
Rationale for change:  The sponsor has decided not to proceed with the study.  Sections 
and text pertaining to Part 2 were not changed; however, Part 2 is no longer relevant. 
3. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; 
Table 3:  Schedule of Activities [Part 1]; Table 5:  Schedule of Activities [Part 2]); 
Section 4.2, Overall Study Duration; Section 6.7, Treatment After the End of the 
Study; Section 8.6, Extension Period 
Description of change:  Reference to the itacitinib rollover protocol was removed. 
Rationale for change:  Participants will remain on study and will not be transitioned to a 
rollover protocol. 
4. Section 7.1.1, Reasons for Discontinuation 
Description of change:  The list was updated to include prohibited medications. 
Rationale for change:  If a prohibited medication is required, the participant must be 
discontinued from study treatment. 
5. Section 8.3.1.1, Surveillance and Management of Infections 
Description of change:  Section was added to describe how to manage infections during 
the course of the study. 
Rationale for change:  To provide guidance for the management of infections. 


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6. Appendix F, COVID-19 Pandemic Mitigation Strategies and Instructions 
Description of change:  Appendix added to describe the process for managing 
participants who may test positive for COVID-19. 
Rationale for change:  To provide guidance during the COVID pandemic. 
7. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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