Clinical trial NCT03139604
Conditions: Graft-versus-host Disease (GVHD)
Keywords: Acute graft-versus-host disease Janus kinase (JAK) inhibitor itacitinib corticosteroids allogeneic hematopoietic stem cell transplant (allo-HSCT)
Sponsor: Incyte Corporation
Start date: 2017-07-19; Completion date: 2020-07-13
Enrollment: 439 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate itacitinib or placebo in combination with corticosteroids as first-line treatment of participants with Grade II to IV acute graft-versus-host disease (aGVHD).

Detailed description:

Arms: arm 1: Itacitinib plus corticosteroids arm 2: Matching placebo plus corticosteroids
Interventions: intervention 1: Itacitinib intervention 2: Placebo intervention 3: Prednisone intervention 4: Methylprednisolone
Intervention descriptions: intervention 1: Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids. intervention 2: Matching placebo tablets administered orally once daily (QD) plus corticosteroids. intervention 3: Oral prednisone may be used to begin standard corticosteroid background treatment at the investigator's discretion, at a dose equivalent to methylprednisolone 2 mg/kg per day. intervention 4: Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.

Protocol documents:
Prot_000.pdf: 
Incyte Corporation 
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Protocol INCB 39110-301 Am 4 
Version 4 
13 AUG 2018 
 
Clinical Study Protocol 
 
INCB 39110-301 
GRAVITAS-301:  A Randomized, Double-Blind, 
Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in 
Combination With Corticosteroids for the Treatment of First-Line 
Acute Graft-Versus-Host Disease 
 
 
Product: 
Itacitinib (INCB039110) 
IND Number: 
113,428 
EudraCT Number 
2017-000538-78 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
28 FEB 2017 
Amendment (Version) 1: 
31 MAY 2017 
Amendment (Version) 2: 
16 JUN 2017 
Amendment (Version) 3:  
07 MAY 2018 
Amendment (Version) 4: 
13 AUG 2018 
 
 
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, Good Clinical Practices as defined in Title 21 of the US Code of 
Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and applicable 
regulatory requirements. 
 
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 the prior 
written consent of Incyte Corporation. 
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Protocol INCB 39110-301 Am 4 
Version 4 
13 AUG 2018 
INVESTIGATOR'S AGREEMENT 
I have read the INCB 39110-301 Protocol Amendment 4 (Version 4 dated 13 AUG 2018) 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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Protocol INCB 39110-301 Am 4 
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SYNOPSIS 
Name of Investigational Product:  Itacitinib (INCB039110) 
Title of Study:  GRAVITAS-301:  A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of 
Itacitinib or Placebo in Combination With Corticosteroids for the Treatment of First-Line Acute 
Graft-Versus-Host Disease 
Protocol Number:  INCB 39110-301 
Study Phase:  3 
Indication:  Acute graft-versus-host disease 
Primary Objective 
Primary Endpoint 
Compare the efficacy of itacitinib in combination 
with corticosteroids versus placebo in 
combination with corticosteroids in terms of 
overall response rate (ORR) at Day 28 in 
subjects with acute graft-versus-host disease 
(aGVHD). 
ORR at Day 28, defined as the proportion of subjects 
demonstrating a complete response (CR), very good partial 
response (VGPR), or partial response (PR). 
Key Secondary Objective 
Key Secondary Endpoint 
Compare the efficacy between treatment cohorts 
at a subsequent key clinical landmark. 
Nonrelapse mortality (NRM) at Month 6, defined as the 
proportion of subjects who died due to causes other than 
malignancy relapse at Month 6. 
Secondary Objectives 
Secondary Endpoints 
Compare additional response and longer-term 
efficacy outcomes between treatment cohorts. 
ORR, defined as the proportion of subjects demonstrating a 
CR, VGPR, or PR at Days 14, 56, and 100. 
NRM at Months 9, 12, and 24. 
DOR for responders will be calculated.  The DoR is defined 
from the time of the onset of response to loss of response.  
Subjects who died or discontinued will be censored at the 
death date or the previous assessment. 
Time to response, defined as the interval from treatment 
initiation to first response. 
Relapse rate of malignant and nonmalignant hematologic 
diseases, defined as the proportion of subjects whose 
underlying hematologic disease relapses. 
Malignancy relapse-related mortality rate, defined as the 
proportion of subjects whose malignancy relapses and has a 
fatal outcome. 
Failure-free survival, defined as the proportion of subjects 
who are still alive, have not relapsed, have not required 
additional therapy for aGVHD, and have not demonstrated 
signs or symptoms of chronic graft-versus-host disease 
(cGVHD), at Month 6. 
Overall survival (OS), defined as the interval from study 
enrollment to death due to any cause. 
Assess the incidence and severity of adverse 
events (AEs) and serious adverse events. 
Clinical safety data (eg, AEs, infections) will be tabulated 
and listed. 
Evaluate the pharmacokinetics of itacitinib when 
administered in combination with corticosteroids. 
Cmax, Cmin, tmax, AUC, and CL/F. 
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Evaluate the incidence of secondary graft failure. 
Incidence rate of secondary graft failure, defined as > 95% 
recipient cells any time after engraftment with no signs of 
relapse, OR retransplantation because of secondary 
neutropenia (< 0.5 × 109/L) and/or thrombocytopenia 
(< 20 × 109/L) within 2 months of transplant. 
Evaluate the use and discontinuation of 
corticosteroids. 
Average and cumulative corticosteroid dose at Days 28, 56, 
100, and 180; proportion of subjects who discontinue 
corticosteroids at Days 56 and 100. 
Evaluate the use and discontinuation of 
immunosuppressive medications. 
Proportion of subjects who discontinue immunosuppressive 
medications at Days 56 and 100. 
Evaluate the incidence of aGVHD flares. 
Incidence rate of aGVHD flares through Day 100. 
Evaluate the incidence of cGVHD. 
Incidence rate of cGVHD at Days 180 and 365. 
Overall Study Design: 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of itacitinib or placebo 
in combination with corticosteroids as first-line treatment of subjects with Grade II to IV aGVHD.  
Subjects will be randomized 1:1 to itacitinib 200 mg once daily (QD) plus corticosteroids or matching 
placebo plus corticosteroids.  Randomization will be stratified by GVHD risk status (standard risk vs high 
risk).  Subjects will receive randomized study treatment until treatment failure (progression of disease, no 
response, or requiring additional systemic therapy), unacceptable toxicity, completion of taper, or death.  
Transfusion support and continued use of anti-infective medications, GVHD prophylaxis medications 
(including calcineurin inhibitors), and topical steroid therapy is permitted. 
GVHD staging and grading will be assessed for efficacy as per Mount Sinai Acute GVHD International 
Consortium (MAGIC) criteria; safety and tolerability will be assessed as per NCI CTCAE v4.03. 
An independent data monitoring committee will perform the first interim analysis for the primary efficacy 
analysis (futility only) once 112 subjects (56 per cohort) have completed the Day 28 visit or withdrew 
early.  If the futility boundary is crossed at interim 1 (ie, if conditional power < 20%), the study may be 
terminated for futility.  A second interim analysis for the primary efficacy analysis (both efficacy and 
futility) will be performed once 240 subjects have completed the Day 180 visit or withdrew early from the 
study. 
The primary analysis (ie, final primary analysis) will be conducted once the last subject completes the 
Day 180 visit or withdraws from the study.  The study will end once 75% of subjects have achieved 
2-year transplant-related mortality, have died, or have been lost to follow-up. 
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Study Population: 
Subjects who have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) and have 
developed Grade II to IV aGVHD may be eligible candidates for this study. 
Key Inclusion Criteria: 
• Male or female, 18 years of age or older; outside the European Union, an older limit could apply 
depending on local regulation (eg, 20 years and older for Taiwan and Japan).  
• Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of HLA matching) 
and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic 
malignancy or disorder.  Recipients of myeloablative and reduced-intensity conditioning regimens are 
eligible. 
• Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any 
GVHD prophylaxis regimen.  Biopsies should be obtained to pathologically confirm aGVHD; in cases 
where a biopsy is negative, is unable to be obtained, or is clinically contraindicated, clinical suspicion of 
aGVHD by the treating physician is sufficient, provided that alternative diagnoses of drug effects or 
infection are adequately ruled out. 
• Evidence of myeloid engraftment (eg, absolute neutrophil count ≥ 0.5 × 109/L for 3 consecutive 
assessments if ablative therapy was previously used).  Use of growth factor supplementation is allowed. 
• Be willing to avoid pregnancy or fathering children based on 1 of the following criteria: 
- Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral 
oophorectomy OR ≥ 12 months of amenorrhea). 
- Woman of childbearing potential who has a negative serum pregnancy test at screening and who 
agrees 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 
should be communicated to the subject and their understanding confirmed. 
- Man who agrees to take appropriate precautions to avoid fathering children (with at least 99% 
certainty) from screening through safety follow-up.  Permitted methods that are at least 99% effective 
in preventing pregnancy should be communicated to the subject and their understanding confirmed. 
• Able to give written informed consent and comply with all study visits and procedures. 
• Able to swallow and retain oral medication. 
Key Exclusion Criteria: 
• Has received more than 1 allo-HSCT. 
• Has received more than 2 days of systemic corticosteroids for acute-GVHD. 
• Presence of GVHD overlap syndrome. 
• Presence of an active uncontrolled infection.  An active uncontrolled infection is defined as 
hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or 
radiographic findings attributable to infection.  Persisting fever without signs or symptoms will not be 
interpreted as an active uncontrolled infection. 
• Known human immunodeficiency virus infection. 
• Active hepatitis B virus (HBV) or hepatitis B virus (HCV) infection that requires treatment, or at risk 
for HBV reactivation (ie, positive hepatitis B surface antigen [HbsAg]).  Subjects with negative HbsAg 
and positive total HB core antibody may be included if HBV DNA is undetectable at the time of 
screening.  Subjects who are positive for HCV antibody are eligible only if polymerase chain reaction 
test is negative for HCV RNA.  Subjects whose immune status is unknown or uncertain must have 
results confirming immune status before enrollment.  Prior serology results are acceptable for 
determining eligibility. 
 
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• Subjects with evidence of relapsed primary disease, or subjects who have been treated for relapse after 
the allo-HSCT was performed. 
• Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg per day 
methylprednisolone (or prednisone equivalent) within 7 days of randomization. 
• Severe organ dysfunction unrelated to underlying GVHD, including: 
- Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as persistent bilirubin 
abnormalities not attributable to GVHD and ongoing organ dysfunction). 
- Clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months of enrollment, New York Heart Association Class III or IV congestive 
heart failure, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia that 
requires therapy. 
- Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen. 
• Serum creatinine > 2.0 mg/dL or creatinine clearance < 40 mL/min measured or calculated by 
Cockroft-Gault equation. 
• Currently breast feeding. 
• Receipt of live (including attenuated) vaccines or anticipation of need for such a vaccine during the 
study. 
• Received Janus kinase (JAK) inhibitor therapy after allo-HSCT for any indication.  Treatment with a 
JAK inhibitor before allo-HSCT is permitted. 
• Treatment with any other investigational agent, device, or procedure, within 21 days (or 5 half-lives, 
whichever is greater) of enrollment.  Subjects participating in a GVHD prophylaxis study or 
conditioning regimen should be discussed with the sponsor's medical monitor before enrollment. 
• Any medical complications or conditions that would, in the investigator's judgment, interfere with full 
participation in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 
• Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar 
compounds. 
Study Drug, Dosage, and Mode of Administration: 
Subjects will begin treatment with itacitinib or placebo at a dose level of 200 mg (2 × 100 mg tablets) 
taken by mouth (PO) QD.  Subjects may have dose reductions and interruptions during the course of 
treatment based on safety and laboratory assessments.  Tapering of itacitinib or placebo is permitted 
provided that the subject has reached the Day 180 visit, achieved a CR or VGPR, and discontinued 
corticosteroid therapy for at least 8 weeks.  The dose of itacitinib or placebo may be escalated if GVHD 
flares during the course of a taper.  Subjects who experience worsening GVHD during itacitinib or 
placebo dose escalation and require additional therapy will be considered as having progressive disease 
and be withdrawn from treatment. 
Reference Therapy, Dosage, and Mode of Administration: 
Corticosteroids are the current standard care for aGVHD and will therefore be used as background 
treatment in this study.  All subjects will begin treatment with methylprednisolone 2 mg/kg per day (or 
prednisone equivalent) or at a dose that is appropriate for the severity of disease as outlined per local 
treatment guidelines.  Subjects who previously began corticosteroid therapy at a different dose may 
remain on that dose if considered clinically appropriate by the treating physician.  Corticosteroids should 
be tapered as tolerated according to institutional guidelines at a rate that is commensurate with resolution 
of GVHD manifestations. 
If GVHD flares during the tapering of corticosteroids, the dose may be re-escalated at the investigator's 
discretion and will not be considered treatment failure, as long as the dose does not exceed the initial 
starting dose.  If the dose required exceeds this threshold, or if the flare is unresponsive to increased 
corticosteroids or multiple flares are observed, then the subject will be considered to have experienced 
treatment failure. 
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Estimated Duration of Participation:  Subject participation is expected to average 12 months, which 
includes the following: 
• A screening period lasting up to 28 days. 
• A treatment period lasting as long as the subject is benefiting from treatment. 
• A safety follow-up period lasting 30 to 35 days after treatment ends. 
• A survival follow-up period lasting until death or study withdrawal. 
Estimated Number of Subjects:  Approximately 436 subjects. 
Principal Coordinating Investigator:  TBD 
Statistical Methods: 
An absolute improvement of 16% in the primary endpoint of ORR at Day 28 would be considered a 
clinically meaningful improvement over standard first-line systemic treatment for aGVHD (standard care 
ORR at Day 28: P0 = 0.56; itacitinib ORR at Day 28: P1  = 0.72).  A 40% improvement in the key 
secondary endpoint of NRM at Month 6 (0.33 vs 0.198) would also be considered clinically meaningful.  
A sample size of 436 subjects (218 per treatment cohort) provides approximately 90% power to detect the 
overall treatment difference of 0.16 in the primary endpoint and 83% power to detect the overall 
treatment difference of 0.132 in the key secondary endpoint.  This sample size also compensates for an 
assumed 5% early withdrawal rate. 
The first interim analysis (futility only) is for the primary efficacy analysis on ORR at Day 28, which will 
be performed once 112 subjects (56 per cohort) have completed the Day 28 visit or withdrew early from 
the study.  If the (nonbinding) futility boundary is crossed (ie, conditional power < 20%), the sponsor will 
consider stopping the study. 
A second interim analysis (for both efficacy and futility) will be performed once 240 subjects have 
completed the Day 180 visit or withdrew early from the study.  The primary efficacy analysis on ORR at 
Day 28 will be conducted first; the sponsor will consider stopping the study if conditional power is 
< 20%.  If the efficacy boundary is crossed, the primary efficacy objective is considered achieved, and the 
key secondary analysis on NRM at Day 180 will be conducted. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
INTRODUCTION ......................................................................................................17 
1.1. 
Overview of Acute Graft-Versus-Host Disease .........................................................17 
1.2. 
First-Line Treatment of Acute GVHD .......................................................................18 
1.3. 
Itacitinib Background .................................................................................................18 
1.3.1. 
Pharmacology .............................................................................................................19 
1.3.2. 
Clinical Studies ...........................................................................................................19 
1.4. 
Study Rationale ...........................................................................................................19 
1.4.1. 
Animal Studies in Acute GVHD Models ...................................................................19 
1.4.2. 
Clinical Experience With JAK Inhibitors for the Treatment of GVHD .....................22 
1.4.3. 
Rationale for Chosen Endpoints .................................................................................23 
1.5. 
Potential Risks and Benefits of the Treatment Regimen ............................................23 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
3. 
SUBJECT ELIGIBILITY ...........................................................................................26 
3.1. 
Subject Inclusion Criteria ...........................................................................................26 
3.2. 
Subject Exclusion Criteria ..........................................................................................27 
3.3. 
Lifestyle Considerations .............................................................................................28 
3.3.1. 
Meals and Dietary Restrictions ...................................................................................28 
3.3.2. 
Activity .......................................................................................................................28 
4. 
INVESTIGATIONAL PLAN .....................................................................................28 
4.1. 
Overall Study Design ..................................................................................................28 
4.2. 
Measures Taken to Avoid Bias ...................................................................................29 
4.3. 
Number of Subjects ....................................................................................................29 
4.3.1. 
Planned Number of Subjects ......................................................................................29 
4.3.2. 
Replacement of Subjects .............................................................................................29 
4.4. 
Duration of Treatment and Subject Participation .......................................................29 
4.5. 
Overall Study Duration ...............................................................................................29 
4.6. 
Study Termination ......................................................................................................30 
5. 
TREATMENT ............................................................................................................30 
5.1. 
Study Drug and Treatment Assignment .....................................................................30 
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5.1.1. 
Subject Numbering and Treatment Assignment .........................................................30 
5.1.2. 
Randomization and Blinding ......................................................................................30 
5.2. 
Study Drugs ................................................................................................................31 
5.2.1. 
Itacitinib/Placebo ........................................................................................................31 
5.2.1.1. 
Description and Administration ..................................................................................31 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................31 
5.2.1.3. 
Storage ........................................................................................................................31 
5.2.1.4. 
Instruction to Subjects for Handling Itacitinib or Placebo .........................................31 
5.2.2. 
Corticosteroids ............................................................................................................32 
5.2.2.1. 
Prednisone ...................................................................................................................32 
5.2.2.2. 
Methylprednisolone ....................................................................................................32 
5.2.3. 
Starting Dose and Administration of Corticosteroids .................................................33 
5.2.4. 
Prophylactic and Supportive Care Medications .........................................................33 
5.3. 
Treatment Compliance ................................................................................................33 
5.4. 
Treatment Interruptions and Adjustments ..................................................................34 
5.4.1. 
Dose Modifications .....................................................................................................34 
5.4.2. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................34 
5.4.3. 
Tapering of Itacitinib/Placebo ....................................................................................36 
5.4.4. 
Criteria for Permanent Discontinuation of Study Drug ..............................................37 
5.4.5. 
Criteria and Procedures for Dose Interruptions or Adjustments of  
Corticosteroids ............................................................................................................37 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................37 
5.5.1. 
Withdrawal Criteria ....................................................................................................37 
5.5.2. 
Withdrawal Procedures ...............................................................................................38 
5.5.3. 
Study Completion .......................................................................................................38 
5.5.4. 
Concomitant Medications ...........................................................................................39 
5.5.4.1. 
Permitted Medications ................................................................................................39 
5.5.4.2. 
Restricted Medications ...............................................................................................39 
5.5.4.3. 
Prohibited Medications ...............................................................................................39 
6. 
STUDY ASSESSMENTS ..........................................................................................40 
6.1. 
Screening ....................................................................................................................43 
6.2. 
Treatment ....................................................................................................................44 
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6.3. 
End of Treatment ........................................................................................................44 
6.4. 
Re-Treatment ..............................................................................................................44 
6.5. 
Follow-Up ...................................................................................................................44 
6.5.1. 
Safety Follow-Up ........................................................................................................44 
6.5.2. 
Post-Treatment GVHD Follow-Up .............................................................................45 
6.5.3. 
Survival Follow-Up ....................................................................................................45 
6.6. 
Unscheduled Visits .....................................................................................................45 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................46 
7.1. 
Administration of Informed Consent Form ................................................................46 
7.2. 
Interactive Response Technology Procedure ..............................................................46 
7.3. 
Demography and Medical History ..............................................................................46 
7.3.1. 
Demographics and General Medical History .............................................................46 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................46 
7.4. 
Prior and Concomitant Medications ...........................................................................46 
7.5. 
Safety Assessments .....................................................................................................47 
7.5.1. 
Adverse Events ...........................................................................................................47 
7.5.2. 
Physical Examination .................................................................................................47 
7.5.3. 
Vital Signs ..................................................................................................................47 
7.5.4. 
ECOG Performance Status .........................................................................................47 
7.5.5. 
Twelve-Lead Electrocardiograms ...............................................................................48 
7.5.6. 
Laboratory Assessments .............................................................................................48 
7.5.6.1. 
Chemistry ....................................................................................................................48 
7.5.6.2. 
Hematology .................................................................................................................48 
7.5.6.3. 
Pregnancy Testing ......................................................................................................48 
7.5.6.4. 
Hepatitis Screening .....................................................................................................49 
7.5.6.5. 
HIV Screening ............................................................................................................49 
7.6. 
Efficacy Assessments .................................................................................................49 
7.6.1. 
GVHD Staging and Grading .......................................................................................49 
7.6.2. 
Chronic GVHD Assessment .......................................................................................50 
7.6.3. 
Graft Failure and Donor Chimerism ...........................................................................51 
7.6.4. 
Post-Transplant Lymphoproliferative Disorder Assessment ......................................51 
7.6.5. 
Relapse/Recurrence of Underlying Hematologic Disease ..........................................51 
 
 
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7.7. 
Pharmacokinetic Assessments ....................................................................................51 
7.7.1. 
Blood Sample Collection ............................................................................................51 
7.7.2. 
Bioanalytical Methodology and Analysis ...................................................................52 
 
 
7.9. 
Other Study Procedures ..............................................................................................53 
7.9.1. 
Distribution of Subject Reminder Cards .....................................................................53 
8. 
SAFETY MONITORING AND REPORTING .........................................................53 
8.1. 
Adverse Events ...........................................................................................................53 
8.1.1. 
Definitions ..................................................................................................................53 
8.1.2. 
Reporting ....................................................................................................................53 
8.2. 
Laboratory Test Abnormalities ...................................................................................55 
8.3. 
Serious Adverse Events ..............................................................................................55 
8.3.1. 
Definitions ..................................................................................................................55 
8.3.2. 
Reporting ....................................................................................................................56 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................57 
8.5. 
Pregnancy ...................................................................................................................57 
8.6. 
Warnings and Precautions ..........................................................................................58 
8.7. 
Data Monitoring Committee .......................................................................................58 
8.8. 
Product Complaints ....................................................................................................58 
9. 
STATISTICS ..............................................................................................................59 
9.1. 
Study Populations .......................................................................................................59 
9.2. 
Selection of Sample Size ............................................................................................59 
9.2.1. 
Interim Analysis 1 .......................................................................................................60 
9.2.2. 
Interim Analysis 2 .......................................................................................................61 
9.2.3. 
Final Analysis of the Primary Analysis ......................................................................61 
9.3. 
Level of Significance ..................................................................................................62 
9.4. 
Statistical Analyses .....................................................................................................62 
9.4.1. 
Primary Analyses ........................................................................................................62 
9.4.2. 
Secondary Analyses ....................................................................................................62 
 
 
9.4.4. 
Safety Analyses ..........................................................................................................64 
9.4.4.1. 
Adverse Events ...........................................................................................................64 
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9.4.4.2. 
Clinical Laboratory Tests ...........................................................................................64 
9.4.4.3. 
Vital Signs ..................................................................................................................64 
9.4.4.4. 
Electrocardiograms .....................................................................................................65 
9.4.5. 
Pharmacokinetic Analysis ..........................................................................................65 
 
 
9.5. 
Analyses for the Data Monitoring Committee ............................................................66 
9.6. 
Interim Analyses .........................................................................................................66 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................67 
10.1. 
Investigator Responsibilities .......................................................................................67 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................68 
10.3. 
Data Management .......................................................................................................69 
10.4. 
Data Privacy and Confidentiality of Study Records ...................................................69 
10.5. 
Financial Disclosure ...................................................................................................70 
10.6. 
Publication Policy .......................................................................................................70 
11. 
REFERENCES ...........................................................................................................71 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................75 
APPENDIX B. MAGIC CRITERIA FOR STAGING AND GRADING FOR ACUTE 
GVHD .........................................................................................................................76 
APPENDIX C. GVHD ORGAN STAGING CATEGORIES ....................................................78 
APPENDIX D. CYTOCHROME P450 3A INHIBITORS AND INDUCERS ..........................79 
APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................86 
 
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LIST OF TABLES 
Table 1: 
Guidelines for Interruption and Restarting of Itacitinib/Placebo ...............................35 
Table 2: 
Dose Reduction Levels for Itacitinib ..........................................................................36 
Table 3: 
Schedule of Assessments ............................................................................................41 
Table 4: 
Laboratory Assessments .............................................................................................42 
Table 5: 
Clinical Laboratory Analytes ......................................................................................43 
Table 6: 
ECOG Performance Status Grades .............................................................................47 
Table 7: 
Pharmacokinetic Sample Collection Time and Windows (Subjects 1-112) ...............52 
Table 8: 
Operation Characteristics Using Hwang-Shih-DeCani Alpha Spending 
Function with Shape Parameter -4 ..............................................................................61 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................65 
Table 10: Criteria for Clinically Notable ECG Abnormalities ...................................................65 
 
LIST OF FIGURES 
Figure 1: 
Effect of Ruxolitinib on Survival in Mice After Allo-HSCT .....................................20 
Figure 2: 
Ruxolitinib Maintains a Beneficial GVT Effect as Determined by 
Bioluminescence Imaging in the A20 Leukemia Model ............................................20 
Figure 3: 
Effect of Itacitinib on Survival (Top Panel) and GVHD Score (Bottom 
Panel) in Mice After Allo-HSCT ................................................................................21 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
AE 
adverse event 
aGVHD 
acute graft-versus-host disease 
allo-HSCT 
allogeneic hematopoietic stem cell transplantation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice daily 
BMT CTN 
Bone Marrow Transplant Clinical Trials Network 
CI 
confidence interval 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft-versus-host disease 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CMH 
Cochran-Mantel-Haenszel 
CMV 
cytomegalovirus 
CR 
complete response 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FFS 
failure-free survival 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GVH 
graft versus host 
GVHD 
graft-versus-host disease 
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Abbreviation 
Definition 
GVT 
graft versus tumor  
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HLA 
human leukocyte antigen 
HSCT 
hematopoietic stem cell transplant 
IB 
Investigator's Brochure 
IC50 
half-maximal inhibitory concentration 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IFN-γ 
interferon-γ 
IFN-γR 
interferon-γ receptor 
IL 
interleukin 
IL-2R 
interleukin 2 receptor 
IN 
Investigator Notification 
IRB 
institutional review board 
IUD 
intrauterine devices 
IUS 
intrauterine hormone-releasing system 
IVRS 
interactive voice response system 
JAK 
Janus kinase  
MAGIC 
Mount Sinai Acute GVHD International Consortium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
myelofibrosis 
MHC 
major histocompatibility 
MPN 
myeloproliferative neoplasm 
NIH 
National Institutes of Health 
NK 
natural killer 
NRM 
nonrelapse mortality 
ORR 
overall response rate 
OS 
overall survival 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PTLD 
post-transplant lymphoproliferative disorder 
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Abbreviation 
Definition 
QD 
once daily 
RA 
rheumatoid arthritis 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SR 
steroid-refractory 
STAT 
signal transducers and activators of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
Treg 
regulatory T cell 
TTR 
time to response 
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
VGPR 
very good partial response 
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1. 
INTRODUCTION 
1.1. 
Overview of Acute Graft-Versus-Host Disease 
Allogeneic HSCT is an effective immunotherapy for human cancer (Appelbaum 2007).  More 
than 32,000 allo-HSCTs are performed each year worldwide, primarily for the treatment of 
hematologic malignancies (Niederwieser et al 2016).  Acute GVHD and cGVHD remain major 
contributors to transplantation-related deaths and the most significant barrier to successful 
allo-HSCT.  GVHD occurs when donor-derived immune cells recognize the transplant recipient 
(the host) as foreign, thereby initiating an immune reaction and subsequent inflammatory 
cascade that results in varying degrees of tissue damage and potential organ failure in the 
transplant recipient.  Despite prophylactic treatments with immunosuppressive agents, 
approximately 50% of transplantation recipients develop GVHD.  Risk factors associated with 
aGVHD include donor/recipient HLA mismatch, increased age (donor or recipient), sex, 
intensity of the pretransplant conditioning regimen, and donor source (Jagasia et al 2012, 
Flowers et al 2011).  Most GVH reactions are undesirable and affect multiple organs; however, 
GVH reactions against hematopoietic tissue targets are desirable and critical for the cure of 
hematologic malignancies (ie, the GVT effect) and for donor immune-hematopoietic system 
engraftment.  These disparate effects of GVH reactions are difficult to separate, and any 
strategies directed against GVHD may adversely affect survival by increasing malignancy 
relapse, graft rejection, and the frequency and severity of infections (Pavletic and Fowler 2012). 
There are few therapeutic studies for aGVHD, and currently no agents are approved by the FDA 
for either prevention or treatment of aGVHD (Martin et al 2009).  At diagnosis, the extent of 
individual organ involvement and overall grade of aGVHD should be documented, taking into 
account all organ involvement, as this has prognostic significance.  Acute GVHD diagnosis 
should be confirmed by biopsy of an affected organ if possible; in addition, other non-GVHD 
complications involving the skin, liver, and GI tract should be ruled out.  Although diagnostic 
biopsies are highly specific if current histopathology criteria are used, the sensitivity of these 
biopsies is only approximately 60%; therefore, the ultimate aGVHD diagnosis and decision to 
treat systemically is based on careful integration of all available clinical information 
(Weisdorf et al 2003). 
The classic target organs for aGVHD are the skin (severity ranging from maculopapular rash to 
erythroderma and bullae formation), the GI tract (resulting in nausea, vomiting, abdominal 
cramps, or diarrhea), and the liver (resulting in hyperbilirubinemia, jaundice, or elevated 
transaminases).  The hematopoietic system can also be targeted, resulting in complete donor 
lymphohematopoietic chimerism and the GVT response against hematologic malignancies.  
Endothelium, lungs, and other organs can also be targeted, although skin, gut, and liver 
involvement are the only organs scored in the current grading system. 
The severity of aGVHD is graded according to the degree of involvement of the skin, liver, and 
GI tract.  Two of the more traditionally-used grading systems are the Glucksberg system (I-IV, 
Glucksberg et al 1974) and the International Bone Marrow Transplant Research system (A-D; 
Rowlings et al 1997).  These grading systems have evolved over time through the efforts of NIH 
working groups to reflect the inclusion of persistent nausea with histologic evidence of GVHD as 
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Stage 1 upper GI aGVHD (Przepiorka et al 1995) and standardization of collecting of complex 
clinical data from multiple organ systems (Harris et al 2016). 
It has been well-established that patients with severe (clinical Grades III-IV) aGVHD are less 
responsive to steroids, leading to poorer survival and higher transplant-related mortality than 
patients with Grade I to II disease.  However, clinical observations suggest there is a subset of 
moderately severe (Grade II) patients who are at higher risk of treatment-related mortality 
compared with patients with standard-risk aGVHD (MacMillan et al 2015).  The limited efficacy 
observed with current therapeutic options highlights the need to identify more effective treatment 
for these patients. 
1.2. 
First-Line Treatment of Acute GVHD 
Current guidelines from the American Society for Bone Marrow Transplant and the European 
Group for Blood and Marrow Transplantation recommend the use of methylprednisolone 
2 mg/kg per day (or an equivalent dose of prednisone) as the starting dose for patients with 
Grades II to IV aGVHD; lower doses may be appropriate for patients with Grade II disease 
depending on risk status.  Corticosteroids are therefore considered the current standard care for 
aGVHD and will be used as background treatment in this study.  Tapering of corticosteroids 
should begin as soon as the manifestations of GVHD begin to show substantial improvement 
(Martin et al 2012, Ruutu et al 2014). 
Because only approximately 50% of aGVHD patients respond to systemic steroids and many of 
these responses are not durable, attempts have been made to evaluate the addition of other agents 
to corticosteroids, including antibodies directed against IL-2R, high-dose steroids, horse 
antithymocyte globulin, anti–tumor necrosis factor drugs, mycophenolate mofetil, pentostatin, 
and sirolimus (Cahn et al 1995, Lee et al 2004, Cragg et al 2000, Couriel et al 2009, Levine et al 
2008, Alousi et al 2009, Pidala et al 2009).  In most cases, the second agent yielded modest 
benefit; a study of daclizumab found the additional intervention to be detrimental.  Thus, the use 
of methylprednisolone or prednisone remains the standard first-line treatment for the initial 
treatment of aGVHD, but new treatment options that provide more durable responses and less 
immunosuppression-related toxicities are needed. 
1.3. 
Itacitinib Background 
Itacitinib adipate is a novel, potent, and selective inhibitor of the JAK family of protein TYKs 
with selectivity for JAK1.  Itacitinib is an investigational product that is proposed for 
development for treatment of MPNs, including MF; inflammatory diseases, including RA and 
psoriasis; GVHD; solid tumors; and B-cell malignancies.  Janus kinases play an important role in 
signal transduction following cytokine and growth factor binding to their receptors.  Aberrant 
production of cytokines and growth factors has been associated with MPNs and a number of 
chronic inflammatory conditions, and JAK1 has been shown to cooperate with other JAKs to 
mediate the signaling of a number of inflammatory cytokines.  Therefore, JAK inhibitors 
represent potential therapeutic agents for these disease states (refer to the IB). 
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1.3.1. 
Pharmacology 
Itacitinib potently inhibits JAK1 (IC50 = 3.6 nM at 1 mM adenosine triphosphate concentration), 
with 22- to > 500-fold selectivity over the other JAK family members, JAK2, JAK3, and TYK2.  
It does not significantly inhibit (< 30% inhibition) a broad panel of approximately 60 other 
kinases.  Itacitinib is also potent (IC50 values of approximately 10 nM to 350 nM) in 
cytokine-driven cell-based assays.  This effect is not due to general cytotoxicity.  Itacitinib also 
inhibits the growth of the cytokine-dependent cell line INA-6.  Itacitinib potently inhibits the 
phosphorylation of STAT proteins and the production of proinflammatory factors induced by 
other cytokines, such as IL-23 and IL-6 with IC50 values of approximately 30 nM to 100 nM.  In 
contrast, itacitinib shows less inhibition in cell-based assays dependent on JAK2 with IC50 values 
of approximately 1 μM or greater, suggesting that itacitinib is JAK2 sparing in cells.  In in vivo 
models of JAK dependent malignancy, itacitinib impedes subcutaneous tumor growth of INA-6 
cells expressing wild-type JAKs when administered by continuous infusion, achieving plasma 
concentrations well below those necessary to inhibit JAK2.  Oral itacitinib also reduced 
splenomegaly in a model of JAK2 V617F–driven neoplasia relevant to MF. 
Additional details on pharmacology and toxicology may be found in the IB. 
1.3.2. 
Clinical Studies 
As of 13 DEC 2017, 9 clinical studies with itacitinib have been completed: 4 studies in healthy 
subjects; 2 monotherapy proof-of-concept studies in subjects with active rheumatoid arthritis  
and stable, chronic plaque psoriasis; and 3 combination studies (itacitinib + gemcitabine and 
nab-paclitaxel in subjects with advanced or metastatic solid tumors; itacitinib + docetaxel in 
subjects with previously treated Stage IIIB, Stage IV, or recurrent NSCLC; and itacitinib + 
INCB040093 in subjects with relapsed or refractory Hodgkin lymphoma).  Additional details 
regarding the design and results of these studies are summarized in the IB. 
As of the clinical data cutoff date, 967 unique subjects have been exposed to itacitinib; this does 
not include 9 subjects enrolled in an ongoing, blinded, placebo-controlled study.  The most 
frequently reported TEAEs (≥ 20%) for itacitinib monotherapy in subjects with underlying 
disease and in various treatment combinations are presented in the IB. 
1.4. 
Study Rationale 
1.4.1. 
Animal Studies in Acute GVHD Models 
To determine the role of JAK/STAT signaling in GVHD, MHC-mismatched allo-HSCT was 
performed in mice [B6 (H-2b) to Balb/c(H-2d)].  In this model, IFN-γR signaling was shown to 
play a major role in T-cell trafficking to GVHD target organs via CXCR3.  Mice transplanted 
with IFN-γR -/- T cells had improved survival and less clinical GVHD compared with mice 
transplanted with wild-type T cells.  Furthermore, pharmacologic inhibition of interferon 
signaling with a JAK/STAT signaling inhibitor, ruxolitinib, for 20 days resulted in the decreased 
expression of CXCR3, reduced GVHD, and improved survival after allo-HSCT in mice 
(Figure 1; Choi et al 2012). 
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In a separate study, in vivo JAK/STAT signaling inhibition improved survival of mice 
developing aGVHD and reduced histopathological GVHD grading, serum levels of 
proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells 
(Choi et al 2012). 
It was shown that the JAK1/2 inhibitor ruxolitinib impaired differentiation of CD4+ T cells into 
IFN-γ and IL-17A–producing cells and that both T-cell phenotypes are linked to GVHD.  
Additionally, ruxolitinib treatment in allo-HSCT recipients increased FoxP3+ Tregs, which are 
linked to immunologic tolerance. 
When tested in the same preclinical model of GVHD as described above for ruxolitinib, 
preliminary results with itacitinib showed similar pharmacologic inhibition of interferon 
signaling, resulting in the decreased expression of CXCR3, reduced GVHD, and improved 
survival after allo-HSCT in mice when dosed for 30 days (Figure 3).  
 
 
Figure 3: 
Effect of Itacitinib on Survival (Top Panel) and GVHD Score (Bottom Panel) 
in Mice After Allo-HSCT 
 
 
5% DMAC = vehicle control; TCD BM = T-cell–depleted bone marrow. 
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1.4.2. 
Clinical Experience With JAK Inhibitors for the Treatment of GVHD 
Clinical experience with ruxolitinib in patients with steroid-refractory GVHD was initially 
reported in 6 patients based on a prospective protocol (Spoerl et al 2014).  Results were updated 
in a retrospective analysis of 95 patients with steroid-refractory aGVHD (n = 54, all Grade III or 
IV) or steroid-refractory cGVHD (n = 41, all moderate or severe) who were treated with 
ruxolitinib at a dose of 5 to 10 mg BID (Zeiser et al 2015).  Of the 54 patients with aGVHD (all 
of whom with Grade 3 or 4 disease), an ORR of 81.5% was reported, including 25 CRs (46.3%).  
The median TTR was 1.5 weeks (range 1-11) after initiation of ruxolitinib therapy.  In addition, a 
6-month survival estimate of 79% (67.3%-90.7%, 95% CI) was reported, with a median follow-
up time of 26.5 weeks.  GVHD relapses were reported in 6.8% (3/44) of patients.  A significant 
decline in levels of IL-6 and soluble IL-2 receptor were observed in 12 of 25 evaluable patients 
treated at one center.  Cytomegalovirus reactivation was observed in 33.3% (18/54) of aGVHD 
patients and was controlled using antiviral therapy, while ruxolitinib treatment continued.  
Cytopenias were also observed during treatment with ruxolitinib in 55.5% (30/54) of patients; 
however, cytopenias were reported before treatment with ruxolitinib in 51.7% (28/54).  
Malignancy relapse was reported in 9.3% (5/54).  After additional follow-up (median follow-up 
of 19 and 24 months for patients with aGVHD and cGVHD, respectively), 1-year OS rates of 
62.4% (CI:  49.4%-75.4%) and 92.7% (CI:  84.7%-100%) were reported for SR-aGVHD and 
SR-cGVHD, respectively.  The median duration of ruxolitinib treatment was 5 and 10 months for 
patients with SR-aGVHD and SR-cGVHD, respectively reflecting the different biology of the 
diseases (Zeiser et al 2016). 
In a Phase 1 study that assessed the safety and tolerability of itacitinib in combination with 
corticosteroids, 30 aGVHD subjects were randomized to 1 of 2 treatment cohorts (200 mg 
cohort, n = 14; 300 mg cohort, n = 16).  One subject was randomized to the 300 mg cohort but 
withdrew from the study before starting treatment.  One DLT of Grade 3 thrombocytopenia was 
reported in 1 subject with pre-existing thrombocytopenia who was randomized to the 300 mg 
cohort.  Adverse events reported in greater than 20% of all subjects include diarrhea, 
hypokalemia, peripheral edema, hyperglycemia, abdominal pain, hypophosphatemia, fatigue, 
headache, hypomagnesemia, and sepsis.  Thrombocytopenia and platelet count decreases were 
observed in 24.2% and 20.7% of subjects, respectively, with a higher proportion of these events 
occurring in the 300 mg cohort, although a higher incidence of pre-existing thrombocytopenia 
was also observed in this group.  The Day 28 ORR in first-line aGVHD subjects in both 
treatment cohorts was 83.3%; for subjects with SR-aGVHD, the overall Day 28 ORR was 64.7% 
(200 mg cohort, 62.5%; 300 mg cohort, 66.7%).  Most responses occurred within the first 
14 days of treatment, and responses were durable, with a median DOR of 130 days and 136 days 
in the 200 mg cohort and 300 mg cohort, respectively.  Complete response rates of 66.7% and 
17.6% were reported for first-line and SR-aGVHD cohorts, respectively.  Pharmacokinetics of 
itacitinib were evaluated using plasma samples collected predose and at 1 hour, 2 hours, and 4 to 
8 hours postdose on Study Days 1 and 7.  Although intersubject variability was found to be high, 
PK exposure (Cmax and AUC) was consistent with historical data, and a large overlap in 
steady-state exposure was observed between the 200 mg and 300 mg cohorts.  The higher 
incidence of thrombocytopenia and DLT of thrombocytopenia in the 300 mg cohort, as well as 
similarities in PK and efficacy between dose groups, led to the identification of the 200 mg dose 
of itacitinib as the recommended phase 2 dose for future GVHD studies (Schroeder et al 2016).  
The treatment compliance rate and median duration of treatment were also higher in the 200 mg 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
Primary Objective 
Primary Endpoint 
Compare the efficacy of itacitinib in combination 
with corticosteroids versus placebo in 
combination with corticosteroids in terms of ORR 
at Day 28 in subjects with aGVHD. 
ORR at Day 28, defined as the proportion of subjects 
demonstrating a CR, VGPR, or PR. 
 
Key Secondary Objective 
Key Secondary Endpoint 
Compare the efficacy between treatment cohorts 
at a subsequent key clinical landmark. 
NRM at Month 6, defined as the proportion of subjects who 
died due to causes other than malignancy relapse at Month 6. 
Secondary Objectives 
Secondary Endpoints 
Compare additional response and longer-term 
efficacy outcomes between treatment cohorts. 
ORR, defined as the proportion of subjects demonstrating a 
CR, VGPR, or PR at Days 14, 56, and 100. 
NRM at Months 9, 12, and 24. 
DOR for responders will be calculated.  The DoR is defined 
from the time of the onset of response to loss of response.  
Subjects who died or discontinued will be censored at the death 
date or the previous assessment. 
TTR, defined as the interval from treatment initiation to first 
response. 
Relapse rate of malignant and nonmalignant hematologic 
diseases, defined as the proportion of subjects whose 
underlying hematologic disease relapses.  
Malignancy relapse-related mortality rate, defined as the 
proportion of subjects whose malignancy relapses and has a 
fatal outcome. 
FFS, defined as the proportion of subjects who are still alive, 
have not relapsed, have not required additional therapy for 
aGVHD, and have not demonstrated signs or symptoms of 
cGVHD, at Month 6. 
OS, defined as the interval from study enrollment to death due 
to any cause. 
Assess the incidence and severity of AEs and 
SAEs. 
Clinical safety data (eg, AEs, infections) will be tabulated and 
listed. 
Evaluate the PK of itacitinib when administered 
in combination with corticosteroids. 
Cmax, Cmin, tmax, AUC, and CL/F. 
Evaluate the incidence of secondary graft failure. 
Incidence rate of secondary graft failure, defined as > 95% 
recipient cells any time after engraftment with no signs of 
relapse, OR retransplantation because of secondary neutropenia 
(< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 
2 months of transplant. 
Evaluate the use and discontinuation of 
corticosteroids. 
Average and cumulative corticosteroid dose at Days 28, 56, 
100, and 180; proportion of subjects who discontinue 
corticosteroids at Days 56 and 100. 
Evaluate the use and discontinuation of 
immunosuppressive medications. 
Proportion of subjects who discontinue immunosuppressive 
medications at Days 56 and 100. 
Evaluate the incidence of aGVHD flares. 
Incidence rate of aGVHD flares through Day 100. 
Evaluate the incidence of cGVHD. 
Incidence rate of cGVHD at Days 180 and 365. 
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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed, because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Male or female, 18 years of age or older; outside the European Union, an older limit 
could apply depending on local regulation (eg, 20 years and older for Taiwan and Japan). 
2. Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of 
HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord 
blood) for a hematologic malignancy or disorder.  Recipients of myeloablative and 
reduced-intensity conditioning regimens are eligible. 
3. Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after 
allo-HSCT and any GVHD prophylaxis regimen.  Biopsies should be obtained to 
pathologically confirm aGVHD; in cases where a biopsy is negative, is unable to be 
obtained, or is clinically contraindicated, clinical suspicion of aGVHD by the treating 
physician is sufficient, provided that alternative diagnoses of drug effects or infection are 
adequately ruled out. 
4. Evidence of myeloid engraftment (eg, ANC ≥ 0.5 × 109/L for 3 consecutive assessments 
if ablative therapy was previously used).  Use of growth factor supplementation is 
allowed. 
5. Be willing to avoid pregnancy or fathering children based on 1 of the following criteria: 
a. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and who agrees 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 subject and their understanding confirmed. 
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c. Man who agrees to take appropriate precautions to avoid fathering children (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 subject and their understanding confirmed. 
6. Able to give written informed consent and comply with all study visits and procedures. 
7. Able to swallow and retain oral medication. 
3.2. 
Subject Exclusion Criteria 
1. Has received more than 1 allo-HSCT. 
2. Has received more than 2 days of systemic corticosteroids for acute-GVHD. 
3. Presence of GVHD overlap syndrome. 
4. Presence of an active uncontrolled infection.  An active uncontrolled infection is defined 
as hemodynamic instability attributable to sepsis or new symptoms, worsening physical 
signs, or radiographic findings attributable to infection.  Persisting fever without signs or 
symptoms will not be interpreted as an active uncontrolled infection. 
5. Known human immunodeficiency virus infection. 
6. Active HBV or HCV infection that requires treatment, or at risk for HBV reactivation (ie, 
positive HBsAg).  Subjects with negative HbsAg and positive total HB core antibody 
may be included if HBV DNA is undetectable at the time of screening.  Subjects who are 
positive for HCV antibody are eligible only if polymerase chain reaction test is negative 
for HCV RNA.  Subjects whose immune status is unknown or uncertain must have 
results confirming immune status before enrollment.  Prior serology results are acceptable 
for determining eligibility. 
7. Subjects with evidence of relapsed primary disease, or subjects who have been treated for 
relapse after the allo-HSCT was performed. 
8. Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg per day 
methylprednisolone (or prednisone equivalent) within 7 days of randomization. 
9. Severe organ dysfunction unrelated to underlying GVHD, including: 
a. Cholestatic disorders or unresolved veno-occlusive disease of the liver (defined as 
persistent bilirubin abnormalities not attributable to GVHD and ongoing organ 
dysfunction). 
b. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months of enrollment, New York Heart Association 
Class III or IV congestive heart failure, circulatory collapse requiring vasopressor or 
inotropic support, or arrhythmia that requires therapy. 
c. Clinically significant respiratory disease that requires mechanical ventilation support 
or 50% oxygen. 
10. Serum creatinine > 2.0 mg/dL or creatinine clearance < 40 mL/min measured or 
calculated by Cockroft-Gault equation. 
11. Currently breast feeding. 
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12. Receipt of live (including attenuated) vaccines or anticipation of need for such a vaccine 
during the study. 
13. Received JAK inhibitor therapy after allo-HSCT for any indication.  Treatment with a 
JAK inhibitor before allo-HSCT is permitted. 
14. Treatment with any other investigational agent, device, or procedure, within 21 days (or 
5 half-lives, whichever is greater) of enrollment.  Subjects participating in a GVHD 
prophylaxis study or conditioning regimen should be discussed with the sponsor's 
medical monitor before enrollment. 
15. Any medical complications or conditions that would, in the investigator's judgment, 
interfere with full participation in the study, including administration of study drug and 
attending required study visits; pose a significant risk to the subject; or interfere with 
interpretation of study data. 
16. Known allergies, hypersensitivity, or intolerance to any of the study medications, 
excipients, or similar compounds. 
3.3. 
Lifestyle Considerations 
3.3.1. 
Meals and Dietary Restrictions 
Subjects 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 the exposure to itacitinib. 
3.3.2. 
Activity 
No restrictions are required. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of itacitinib or 
placebo in combination with corticosteroids as first-line treatment of subjects with Grade II to IV 
aGVHD.  Subjects will be randomized 1:1 to itacitinib 200 mg plus corticosteroids or matching 
placebo plus corticosteroids.  Randomization will be stratified by GVHD risk status (ie, standard 
risk vs high risk; MacMillan et al 2015; Appendix C).  Subjects will receive randomized study 
treatment until treatment failure (progression of disease, no response, or requiring additional 
systemic therapy), unacceptable toxicity, or death.  Transfusion support and continued use of 
anti-infective medications, GVHD prophylaxis medications (including calcineurin inhibitors), 
and topical steroid therapy are permitted. 
GVHD staging and grading will be assessed for efficacy as per MAGIC criteria (Harris et al 
2016); safety and tolerability will be assessed as per NCI CTCAE v4.03 (NCI 2009). 
An independent DMC will perform a futility-only interim analysis for primary analysis on ORR 
at Day 28 once 112 subjects (56 per cohort) have completed the Day 28 visit or withdrew early 
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from the study.  If the futility boundary is crossed, the sponsor will consider stopping the study 
for futility.  Otherwise, a second interim analysis on ORR at Day 28 for primary analysis will be 
conducted for both efficacy and futility once 240 subjects have completed the Day 180 visit or 
withdrew early from the study.  If neither the futility nor efficacy boundary is crossed, the study 
will continue to accrue approximately 436 subjects and then the final analysis for the primary 
analysis will be conducted using CMH test.  The study will end once 75% of subjects have 
achieved 2-year transplant-related mortality, have died, or have been lost to follow-up.  
4.2. 
Measures Taken to Avoid Bias 
Subjects will be randomized in a 1:1 ratio to receive itacitinib plus corticosteroids or matching 
placebo plus corticosteroids and will be stratified by GVHD risk status (ie, standard-risk versus 
high-risk; MacMillan et al 2015; Appendix C).  Centralized randomization numbers within each 
stratum will be created for treatment assignment.  Subjects, investigators, and the study team will 
be blinded to treatment assignment.  A sponsor statistician who is not part of the study team will 
be unblinded and may provide summary aggregated data by treatment cohort to the sponsor 
and/or the DMC, but individual subject data will remain blinded. 
Disease assessments and safety assessments will be performed in accordance with standardized 
criteria. 
4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
This study will enroll approximately 218 subjects with clinically or pathologically confirmed 
Grade II to IV aGVHD per treatment cohort, for a total of 436 subjects at approximately 85 study 
sites. 
4.3.2. 
Replacement of Subjects 
Not applicable. 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Each subject enrolled in the study may continue to receive study treatment as long as benefit is 
being observed and/or treatment withdrawal criteria are not met.  If the subject discontinues 
study treatment, the treatment period will end, and the subject will enter the follow-up period 
(see Section 6.4).  The safety follow-up period will last 30 to 35 days, and the survival follow-up 
period will last until death or study withdrawal.  Study participation is expected to average 
approximately 12 months per individual subject but may vary based on clinical outcomes. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the informed consent.  Subjects who are still 
on-study at the time of the primary endpoint analysis will continue to receive study treatment 
until treatment withdrawal criteria are met (Section 5.5).  All subjects will be followed for 
survival until death, withdrawal of consent, or the end of the study, whichever occurs first.  The 
study will end once 75% of subjects have died or are lost to follow-up.  Provisions will be made 
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to ensure access to treatment for subjects who are continuing to benefit from study treatment at 
the time of study completion. 
4.6. 
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 institutional review board 
(IRB)/independent ethics committee (IEC) in writing 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 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 8.7. 
5. 
TREATMENT 
5.1. 
Study Drug and Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site staff should contact the IVRS to obtain the subject ID 
number during screening. 
Site staff will contact the IVRS to randomize the subject and obtain the initial study drug 
assignment.  The investigator or designee will select the assigned bottles of study drug from their 
stock that correspond to the number provided by the IVRS, record the bottle numbers in the 
eCRF, and dispense the study drug to the subject.  All subsequent dispensing of study drug 
should follow this process.  Full details will be provided in the IVRS manual. 
All subject numbers will be 6 digits; the first 3 digits will be the site number and the last 3 digits 
will be the subject's number.  This subject number will be maintained throughout the study and 
will not be reassigned.  Subjects who withdraw consent or discontinue from the study after being 
assigned a subject number will retain their initial number. 
If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IVRS, 
then the IVRS help desk must be notified immediately.  The reason for the misallocation of the 
study drug must be documented by the study site. 
For subjects who signed an ICF but are not allocated and for subjects who are allocated but were 
not treated, refer to the eCRF Completion Guidelines for instruction on which eCRFs to 
complete. 
5.1.2. 
Randomization and Blinding 
Randomization will occur centrally by IVRS.  Full instructions will be provided in the IVRS 
manual.  Randomization will be stratified by standard risk and high risk (MacMillan et al 2015; 
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Appendix C) at a ratio of 1:1.  As this is a randomized, double-blind, placebo-controlled study, 
neither investigators, nor the sponsor will be aware of the treatment cohort to which the subject 
is randomized. 
5.2. 
Study Drugs 
5.2.1. 
Itacitinib/Placebo 
5.2.1.1. 
Description and Administration 
Itacitinib 100 mg (free base equivalent) sustained-release tablets contain the active ingredient, 
hypromellose, microcrystalline cellulose, lactose monohydrate, and magnesium stearate.   
Placebo tablets developed to match the itacitinib 100 mg sustained-release tablets are similar in 
appearance to active drug product tablets with regard to color, size, and shape and contain 
hypromellose, microcrystalline cellulose, and magnesium stearate. 
Itacitinib or placebo will be administered PO at a starting dose of 200 mg QD (2 × 100 mg 
tablets). 
Subjects may have dose reductions or modifications of itacitinib or placebo during the course of 
treatment based on AEs, clinical evaluation, and laboratory assessments.  See Section 5.4 for 
dose modifications of study drug. 
Subjects are permitted to remain on itacitinib or placebo treatment until withdrawal from study 
treatment is considered necessary as per Section 5.5. 
5.2.1.2. 
Supply, Packaging, and Labeling 
Itacitinib or placebo tablets will be provided to sites in high-density polyethylene bottles as 
applicable by Incyte.  No preparation is required. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.3. 
Storage 
Itacitinib or placebo should be stored at ambient conditions (15°C to 30°C, or 59°F to 86°F) as 
per the IB. 
5.2.1.4. 
Instruction to Subjects for Handling Itacitinib or Placebo 
The subject must be instructed in the handling of itacitinib or placebo as follows: 
• To store the bottles at room temperature, in a safe place and out of the reach of 
children. 
• To only remove the number of tablets needed at the time of administration. 
• Not to remove tablets in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
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• To take tablets with a glass of water. 
• Not to take another dose if vomiting occurs after taking study medication. 
• To refrain from taking study medication on the day of clinic visits until after blood 
samples are collected. 
• To fast on PK assessment days (Days 1, 7, and 28). 
• To bring all used and unused bottles of study medication to the site at each visit. 
5.2.2. 
Corticosteroids 
Either oral prednisone or intravenous methylprednisolone may be used to begin standard 
corticosteroid background treatment at the investigator's discretion. 
5.2.2.1. 
Prednisone 
5.2.2.1.1. Description 
Prednisone is a white to off-white, odorless, crystalline powder.  Tablets are typically white in 
color and contain lactose monohydrate, magnesium stearate, microcrystalline cellulose, 
pregelatinized starch, and sodium starch glycolate.  Commonly available dose strengths include 
1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg tablets. 
5.2.2.1.2. Supply, Packaging, and Labeling  
Investigators are responsible for ensuring that subjects receive commercially available supplies 
of prednisone for the duration of the study treatment period.  Incyte may provide prednisone 
where required by applicable law or regulation. 
5.2.2.1.3. Storage 
Prednisone tablets should be stored in accordance with local prescribing information 
requirements. 
5.2.2.2. 
Methylprednisolone 
5.2.2.2.1. Description 
Methylprednisolone sterile powder is an anti-inflammatory glucocorticoid, which contains 
methylprednisolone sodium succinate as the active ingredient.  Methylprednisolone sodium 
succinate, USP, is the sodium succinate ester of methylprednisolone, and it occurs as a white, or 
nearly white, odorless hygroscopic, amorphous solid.  It is very soluble in water and in alcohol; 
it is insoluble in chloroform and is very slightly soluble in acetone. 
5.2.2.2.2. Supply, Packaging, and Labeling  
Investigators are responsible for ensuring that subjects receive commercially available supplies 
of methylprednisolone for the duration of the study treatment period.  Incyte may provide 
methylprednisolone where required by applicable law or regulation. 
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5.2.2.2.3. Storage 
Methylprednisolone (unreconstituted product or solution) should be stored in accordance with 
local prescribing information. 
5.2.3. 
Starting Dose and Administration of Corticosteroids 
All subjects will receive methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at  a 
dose that is appropriate for the severity of disease as outlined per local treatment guidelines 
(Martin et al 2012, Ruutu et al 2014) as background treatment.  Subjects who previously began 
corticosteroid therapy at a different dose may remain on that dose if considered clinically 
appropriate by the treating physician.  Corticosteroids should be tapered as per institutional 
guidelines at a rate that is commensurate with resolution of GVHD manifestations. 
If GVHD flares during the taper of prednisone or methylprednisolone, the dose may be 
re-escalated at the investigator's discretion and will not be considered treatment failure, as long 
as the dose does not exceed the initial starting dose.  If the dose required exceeds this threshold, 
or if the flare is not responsive to increased corticosteroids or multiple flares are observed, then 
the subject will be considered to have experienced treatment failure and be withdrawn from 
study treatment. 
5.2.4. 
Prophylactic and Supportive Care Medications 
Patients who undergo allo-HSCT are at risk for a variety of infections based on the degree of 
immunosuppression induced by the conditioning regimen before transplant.  As such, it is 
considered routine practice to use antibiotics, anti-infectives, and immunizations as prophylactic 
therapies (Tomblyn et al 2009).  In cases where post-transplant anti-infective prophylaxis 
measures are necessary, ongoing therapy may continue at the investigator's discretion per 
institutional guidelines. 
Systemic and topical GVHD prophylaxis medications (eg, cyclosporine, methotrexate, and 
tacrolimus) may be continued at therapeutic doses as appropriate based on stage and sites of 
disease. 
Additional supportive care measures (eg, use of antimotility agents for diarrhea management, 
topical steroids, beclomethasone, budesonide, ursodiol) are permitted at the investigator's 
discretion. 
See Section 5.5.4 for additional details. 
5.3. 
Treatment Compliance 
Treatment compliance with all study-related medications should be emphasized to the subject by 
the site personnel, and appropriate steps should be taken to optimize compliance during the 
study.  Itacitinib or placebo compliance will be calculated, by the sponsor, based on the drug 
accountability documented by the site staff and monitored by the sponsor/designee (tablet 
counts).  Subjects will be instructed to bring all study-related medications with them to each 
study visit 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. 
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Although commercial supplies of corticosteroids will be used, dose changes and interruptions 
will also be documented in the medical record and monitored by the sponsor or its designee.  As 
corticosteroid dose strengths and administration types will vary, compliance with corticosteroids 
will not be calculated. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Dose interruptions and modifications may occur for individual study subjects based on the 
emergence or resolution of toxicity. 
5.4.2. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
Treatment with itacitinib/placebo may be delayed up to 14 days to allow for resolution of 
toxicity.  After interruption, subjects should be evaluated on a weekly basis until 
resolution/improvement of the AE.  Subjects may resume treatment if no medical condition or 
other circumstance exists that, in the opinion of the investigator, would make the subject 
unsuitable for further participation in the study.  The investigator should contact the medical 
monitor to discuss cases where treatment has been delayed for more than 14 days before 
restarting treatment. 
Because subjects may enter the study with compromised bone marrow function, these dose 
reductions are provided as guidelines (see Table 1 and Table 2); individual decisions regarding 
dose reduction should be made using clinical judgment and an individual benefit/risk assessment, 
taking into account relatedness of the AE to the study drug and the subject's underlying 
condition.  Adverse events that have a clear alternative explanation or transient (≤ 72 hours) 
abnormal laboratory values without associated clinically significant signs or symptoms may be 
exempt from dose-reduction rules.  The sponsor's medical monitor may be consulted for advice. 
Subjects receiving itacitinib/placebo at a dose of 200 mg QD may have their dose reduced to 
100 mg QD.  Subjects who are unable to tolerate itacitinib/placebo at a dose of 100 mg QD 
should be withdrawn from study treatment. 
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would be withdrawn from study treatment.  A physiologic dose of 6 to 8 mg/day of 
methylprednisolone (ie, 7.5-10 mg/day of prednisone) during itacitinib/placebo taper is allowed 
and will not be considered treatment failure. 
If subjects completely taper off itacitinib/placebo and GVHD signs/symptoms reappear at a later 
time, subjects may enter the re-treatment phase at the investigator’s discretion (Section 6.4). 
Assessments would be performed as per the re-treatment assessment schedule listed in Table 3. 
5.4.4. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying disease or malignancy will 
be presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
subject's ability to continue study-specific procedures or is considered to not be in the 
subject's best interest. 
• Persistent AE requiring a delay of therapy for more than 14 days, unless a greater 
delay has been approved by the sponsor. 
5.4.5. 
Criteria and Procedures for Dose Interruptions or Adjustments of  
Corticosteroids 
Adjustments to the dose of corticosteroids should be made at the treating investigator's 
discretion. 
5.5. 
Withdrawal of Subjects From Study Treatment 
The decision to discontinue study treatment will not constitute study completion (see 
Section 5.5.3).  In the event that the decision is made to discontinue study treatment, the 
treatment period will be considered complete, and the follow-up period will begin. 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject has experienced an unacceptable toxicity. 
• Relapse of underlying malignancy. 
• The subject is unable to tolerate itacitinib/placebo at a dose of 100 mg QD. 
• Additional systemic therapy is required for GVHD progression or lack of response, 
including corticosteroid doses greater than those used on Study Day 1. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The subject becomes pregnant. 
• Consent is withdrawn. 
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• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be withdrawn from study treatment as follows: 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, the sponsor should be consulted for instruction on handling the 
subject. 
5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study and the EOT visit should be conducted.  Reasonable efforts should 
be made to have the subject return for a follow-up visit as described in Section 6.  The last date 
of the last dose of study drug and the reason for subject withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be registered in the IVRS. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the subject 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, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.5.3. 
Study Completion 
A subject will be considered as completing the study if they meet any of the following criteria: 
• Subject dies and a date of death is available. 
• Subject is known to have died; however, the date of death cannot be obtained.  
(NOTE:  Every effort must be made to obtain the date of death.) 
• Subject has discontinued study treatment and has withdrawn consent for collection of 
follow-up anticancer and survival data. 
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5.5.4. 
Concomitant Medications 
5.5.4.1. 
Permitted Medications 
Concomitant treatments and/or procedures that are required to manage a subject's medical 
condition (including prophylactic and/or supportive care medications as described in 
Section 5.2.3) during the study will also be recorded in the eCRF. 
5.5.4.2. 
Restricted Medications 
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. 
• Coadministration with the following potent CYP3A4 inhibitors:  itraconazole, 
voriconazole, mibefradil, and clarithromycin; if the subject's medical condition 
requires treatment with any of these drugs, dose reduction of itacitinib to 100 mg QD 
is recommended, as more potent inhibitors have been shown to increase exposure to 
itacitinib.  The sponsor's medical monitor may be consulted for advice when using 
these agents.  
No dose adjustment is recommended for concomitant administration of other 
CYP3A4 inhibitors  (Appendix D). 
• Coadministration with CYP3A4 inducers (Appendix D). 
• 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. 
5.5.4.3. 
Prohibited Medications 
The following medications are prohibited during the treatment period of the study: 
• Any concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy) intended to treat malignancy relapse or recurrence.  
Maintenance therapy with tyrosine kinase inhibitors for high-risk Philadelphia 
chromosome−positive leukemia and FLT3 inhibitors for FLT3+ acute myeloid 
leukemia may be used with sponsor approval. 
• Any secondary GVHD therapy due to insufficient response/progression on study 
treatment.  
• Concomitant use of targeted therapies with anti-GVHD activity, including but not 
limited to tumor necrosis factor alpha inhibitors and IL-6 receptor inhibitors. 
• Concomitant use of a JAK inhibitor. 
• Initiating therapy with an investigational medication unless otherwise approved by 
the medical monitor. 
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6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (see 
Table 3) and all laboratory assessments will be performed as indicated in Table 4.  Table 5 
presents a summary of clinical laboratory analytes to be assessed.  The order of assessments is 
suggested by the order of mention within the schedule.  See Section 7 for instructions on each 
assessment.  Further details of study procedures and assessments can be found in the study 
reference manual. 
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Table 3: 
Schedule of Assessments 
Visit Day 
Item 
Section 
Screening  
Treatment
a 
 
 
Follow-Up 
-28 to -1 
D1 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56
b D100 
D180 
D365
c 
EOT
d 
Re-
Treatmentde 
Safety
f 
GVHD
g 
Survival
h 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IVRS 
7.2 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
Demography/disease history 
7.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
X 
 
 
Supportive care medications 
5.2.4  
X 
X 
X 
X 
X 
 
 
AE assessment 
7.5.1 
X 
X 
X 
X 
X 
 
 
Physical examination 
7.5.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Vital signs 
7.5.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
ECOG PS 
7.5.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
12-lead ECG 
7.5.5 
X 
As indicated 
X 
 
 
 
 
aGVHD grading and 
response 
 6.5.2  
7.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
 
cGVHD assessment 
6.5.2 
7.6.2 
X 
As indicated 
X 
X 
X 
X 
 
Chimerism/graft failure 
assessment 
7.6.3 
X 
As indicated 
 
PTLD assessment 
7.6.4 
 
As indicated 
X 
X 
X 
X 
 
Underlying disease relapse 
assessment 
7.6.5 
 
As indicated 
X 
X 
X 
X 
X 
Dispense study drug 
5.1.1 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Study drug compliance 
5.3 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
Steroid dose monitoring 
5.2.2 
X 
X 
X 
X 
 
 
 
Survival follow-up 
 6.5.3  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
New aGVHD therapies 
6.5.3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG = electrocardiogram; I/E = inclusion/exclusion; PS = performance status; PTLD = post-transplant lymphoproliferative disorder. 
Error! Reference source not found.a A ± 3-day window is permitted to facilitate scheduling during the treatment phase. 
b After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
c The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
d A second EOT should occur if the subject restarts itacitinib and subsequently discontinues treatment. 
e Re-treatment assessments occur every 28 days ± 3 days.  
f 30 to 35 days after EOT. 
g Every 28 days ± 7 days, for participants who completed study treatment or discontinued early for reasons other than GVHD progression. 
h Every 8 weeks ± 7 days. 
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Table 4: 
Laboratory Assessments 
Visit Day 
Item 
Section 
Screening 
Treatment
a 
 
 
 
 
-28 to -1 
D1
b 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56
c 
D100 
D180 
D365
d 
EOT
e 
Re-
Treatment
f 
GVHD 
Follow-Up 
Safety 
Follow-Up
g 
Chemistry panel 
7.5.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X
h 
X 
Hematology 
7.5.6.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Hepatitis screening 
7.5.6.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening 
7.5.6.5  
X 
 
 
 
 
 
Serum pregnancy test 
(childbearing females 
only) 
7.5.6.3 
X 
 
X 
 
 
 
Urine pregnancy test
i
(childbearing females 
only) 
7.5.6.3 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
PK assessment
j 
7.7 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
a A ± 3-day window is permitted to facilitate scheduling during the treatment period. 
b Day 1 laboratory assessments do not need to be repeated if screening assessments were performed within the preceding 7 days. 
c After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
d The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
e A second EOT should occur if the subject restarts itacitinib and subsequently discontinues treatment. 
f Re-treatment assessments occur every 28 days. 
g 30 to 35 days after EOT. 
h Liver testing including total bilirubin data 
i Urine pregnancy tests are required at Day 28 and every 28 days. 
j Subjects 1-112:  samples collected on Days 1, 7, and 28 at predose and at 1 hour ± 15 minutes, 2 hours ± 30 minutes, and 5 hours ± 60 minutes postdose.  Subjects 113-436:  Day 7 and 28 at predose 
only. 
k Day 56 only. 
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Table 5: 
Clinical Laboratory Analytes 
Serum Chemistries 
Hematology
a 
Other 
Albumin 
ALP 
ALT 
AST 
Bicarbonate or CO2 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipid profile (total cholesterol, 
HDL, LDL, and triglycerides) 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Reticulocytes 
Platelet count 
Red blood cell count 
White blood cell count 
White blood cell differential (5 parts): 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Serum pregnancy test 
Urine pregnancy test 
Hepatitis Screening Tests 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis B core antibody 
HCV antibody 
HCV-RNA 
HBV-DNA 
ALP = alkaline phosphatase; AST = aspartate aminotransferase; HDL=high-density lipoprotein; LDL=low-density 
lipoprotein. 
a Hematology and chemistry assessments will be performed locally. 
6.1. 
Screening 
The screening period is the interval between signing the ICF and the day the subject is 
randomized in the study (Day 1).  The screening period may not exceed 28 days.  Informed 
consent must be obtained before performing any study-specific procedures that are not 
considered standard of care.  Assessments that are required to demonstrate eligibility may be 
performed over the course of 1 or more days during this period. 
Procedures conducted as part of the subject's routine clinical management (eg, complete blood 
count) and obtained before signing of informed consent may be used for screening or baseline 
purposes, provided that the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study.  Results from the screening visit evaluations will be 
reviewed to confirm subject eligibility before randomization or the administration of study drug.  
Tests with results that fail eligibility requirements may be repeated once during the screening 
period if the investigator believes the results to be in error or believes there has been a change in 
eligibility status (eg, following recovery from an infection).  For screening assessments that are 
repeated, the most recent available result before randomization will be used to determine subject 
eligibility.  Treatment should start as soon as possible but within 2 days after the date of 
randomization. 
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6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study drug through 
the point at which the principal investigator determines the subject will be permanently 
discontinued from study drug.  Dates for subsequent study visits will be determined based upon 
this day and should occur within ± 3 days of the scheduled date unless delayed for safety 
reasons.  During the Day 1 visit, results from screening visit evaluations should be reviewed to 
determine whether the subject continues to meet the eligibility requirements as specified in the 
Protocol. 
6.3. 
End of Treatment 
If a decision is made that the subject will permanently discontinue study treatment, 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 subject should be encouraged to return for the follow-up visit. 
6.4. 
Re-Treatment 
For subjects who experience aGVHD recurrence after taper of randomized treatment is 
completed, investigators have the option to use open-label itacitinib plus corticosteroids for the 
treatment of recurrent aGVHD irrespective of initial randomized treatment.  For the purpose of 
this Protocol, treatment of recurrent aGVHD with open-label itacitinib plus corticosteroids will 
be called the re-treatment phase.  Subjects entering the re-treatment phase will be required to 
follow the assessment schedule as outlined in Table 3.  Corticosteroid tapering will be performed 
at the investigator's discretion.  Investigators wishing to initiate a taper of itacitinib earlier than 
Day 180 may do so upon consultation with and approval from the sponsor's medical monitor.  
Subjects may be re-treated with itacitinib only once.  Subjects ending the re-treatment phase will 
repeat the EOT visit and subsequent safety and survival follow-up visits. 
6.5. 
Follow-Up 
6.5.1. 
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 35 days after the EOT visit (or after the last dose of study drug if 
the EOT visit was not performed).  Adverse events and SAEs must be reported up until at least 
30 days after the last dose of study drug, the date of the follow-up visit, or until toxicities 
resolve, return to baseline, or are deemed irreversible, whichever is longer. 
If a subject withdrew from treatment due to reasons other than disease progression, GVHD 
staging and grading will be repeated at the safety follow-up visit. 
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6.5.2. 
Post-Treatment GVHD Follow-Up 
Subjects who completed study treatment or discontinued treatment for reasons other than GVHD 
progression will be followed every 28 days (± 7 days) after the safety follow-up visit until any of 
the following occurs: 
• GVHD progression. 
• Initiation of a new anti-GVHD therapy. 
• Relapse/recurrence of underlying hematologic disease. 
• A maximum of 12 months from EOT or a maximum of 24 months from Day 1 is 
reached, whichever occurs first. 
6.5.3. 
Survival Follow-Up 
Subjects who complete post-treatment follow-up or experience GVHD progression or require a 
new anti-GVHD therapy should be contacted by telephone, email, or visit at least every 8 weeks 
(± 7 days) to assess for new GVHD therapy and survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
6.6. 
Unscheduled Visits 
Unscheduled visits may be held at any time at the investigator's discretion, and appropriate 
clinical and laboratory measurements performed based on AEs or other findings. 
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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation.  
Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in 
order to participate in the study (see Appendix A). 
7.2. 
Interactive Response Technology Procedure 
The IVRS will be contacted to obtain a subject ID number when a subject enters the screening 
period.  Upon determining that the subject is eligible for study entry, the IVRS will be contacted 
to obtain study drug assignment.  Additionally, the IVRS will be contacted every 28 days to 
update study drug supply.  See Section 5.1.1 for additional information.  
7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and a complete medical and medication history will be collected at screening. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history including hematologic malignancy type, 
current GVHD staging, date of diagnosis, sites of disease, prior anticancer therapy, ablation 
therapy, prophylaxis therapy, donor type, and other details related to the disease under study will 
be collected at screening. 
7.4. 
Prior and Concomitant Medications  
Prior and concomitant medications will be reviewed to determine subject eligibility.  All 
concomitant medications and measures must be recorded in the eCRF, and any medication 
received or procedure performed within 30 days before randomization and up to the safety 
follow-up visit will be recorded in the eCRF.  The medication record will be maintained after 
signing the ICF to document concomitant medications, including any changes to the dose or 
regimen.  Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF. 
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7.5. 
Safety Assessments 
7.5.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.5.2. 
Physical Examination 
The targeted physical examination will be a symptom-directed evaluation conducted by the 
investigator or a medically qualified designee.  The targeted physical examination will include 
height (screening only) and assessment(s) of the body systems or organs, as indicated by subject 
symptoms, AEs, or other findings.  Clinically notable abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs. 
7.5.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, and 
body weight.  Blood pressure and pulse will be taken with the subject in the recumbent, 
semirecumbent, or sitting position.  Clinically notable abnormalities that are considered 
clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.4. 
ECOG Performance Status 
ECOG performance status (Oken et al 1982; Table 6) will be assessed at screening and other 
study visits per Table 3.  Performance status must be assessed by a medically qualified individual 
and recorded in the eCRF. 
Table 6: 
ECOG Performance Status Grades 
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. 
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7.5.5. 
Twelve-Lead Electrocardiograms 
A 12-lead ECG will be performed during screening with the subject in a recumbent or 
semirecumbent position after 5 minutes of rest.  
The 12-lead ECG will be interpreted by the investigator at the site and will be used for 
immediate subject management.  The decision to include or exclude a subject or withdraw a 
subject from the study 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.  
Electrocardiograms that are identified as abnormal and clinically meaningful compared with the 
screening assessment should be reported as AEs.  For such AEs, the findings of the abnormal 
ECGs and the corresponding baseline ECG findings must be reported in the eCRF.  
An additional ECG will be performed at the EOT visit; additional ECGs may be performed at the 
investigator's discretion as clinically indicated. 
7.5.6. 
Laboratory Assessments 
Blood draws for laboratory assessments will occur at study visits indicated in Table 4.  Blood 
draws will be completed before the subject receives the morning dose of study drug.  Specific 
laboratory assessments are listed in Table 5.   
All laboratory assessments will be performed at a local (site) laboratory using institutional best 
practices.  Results and normal reference ranges will be entered into the eCRF.  
7.5.6.1. 
Chemistry 
All chemistry panel assessments will be performed at a local (site) laboratory from blood 
samples collected using institutional best practices before administration of study drug.  Results 
and normal reference ranges will be entered into the eCRF.  
7.5.6.2. 
Hematology 
Hematology assessments, including complete blood count with differential, will be performed at 
a local (site) laboratory using institutional best practices before administration of study drug.  
Results and normal reference ranges will be entered into the eCRF. 
7.5.6.3. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the EOT visit.  Urine pregnancy tests will be conducted every 28 days.  Urine pregnancy 
tests will be performed locally.  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 subject and determine whether it is in the subject's best interest to 
resume study drug and continue participation in the study. 
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7.5.6.4. 
Hepatitis Screening 
Subjects with active HBV or HCV infection that requires treatment or who are at risk for HBV 
reactivation are excluded from the study.  At risk for HBV reactivation is defined as hepatitis B 
surface antigen positive or anti–hepatitis B core antibody positive.  Prior test results obtained as 
part of standard of care before allo-HSCT confirming that a subject is immune and not at risk for 
reactivation (ie, hepatitis B surface antigen negative, surface antibody positive) may be used for 
purposes of eligibility, and tests do not need to be repeated.  Subjects with prior positive serology 
results must have negative polymerase chain reaction results.  Subjects whose immune status is 
unknown or uncertain must have results confirming immune status before enrollment. 
7.5.6.5. 
HIV Screening 
Subjects with an active HIV infection are excluded from the study.  Prior HIV screening results 
obtained as standard of care for allo-HSCT confirming the subject is HIV-negative may be used 
for determining eligibility, and tests do not need to be repeated.  Subjects whose HIV status is 
unknown must have results confirming negative status before enrollment.  
7.6. 
Efficacy Assessments 
7.6.1. 
GVHD Staging and Grading 
Acute GVHD grading will be performed by the investigator on a weekly basis for the first 
8 weeks after randomization, then every 28 days thereafter.  GVHD staging and grading will also 
occur on Days 100, 180, and 365 and at the EOT visit. 
On-treatment aGVHD grading should be performed relative to the Day 1 assessment. 
If subjects withdrew due to reasons other than GVHD progression, then GVHD staging and 
grading will be assessed at the safety follow-up visit and every 28 days thereafter during survival 
follow-up until progression of GVHD, start of new anti-GVHD therapy, or death.  
Data regarding the quantification of aGVHD symptoms (extent of skin rash, total bilirubin level, 
volume of diarrhea) should be reported using MAGIC guidelines (Harris et al 2016); response 
will be assessed as per CIBMTR modifications to the IBMTR response index as indicated in 
Appendix B (CIBMTR 2009). 
• Skin: 
− Only areas involved with active erythema should be used for determination of 
body surface area staging based on the rule of nines. 
− A portion of a body area segment may be used for the quantification. 
− Desquamation or fluid-filled bullae should be reported if present, as these findings 
are the hallmark of Stage 4 skin GVHD. 
• Liver: 
− Liver GVHD staging is based solely on total (not conjugated/direct) serum 
bilirubin levels. 
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− Liver GVHD manifesting as transaminitis without concomitant elevation in serum 
bilirubin should be diagnosed when the presence of GVHD is confirmed by liver 
biopsy (where appropriate) and score it as Stage 0.  
− If bilirubin levels were elevated before the diagnosis of GVHD in another target 
organ and do not increase further, liver GVHD should not be diagnosed in the 
absence of biopsy confirmation.  However, if hyperbilirubinemia develops at the 
same time or after the onset of GVHD in another target organ, liver GVHD is 
presumed to be present in the absence of an identified alternative cause. 
• Upper GI: 
− Symptoms of concern for upper GI GVHD include anorexia, nausea, vomiting, 
and dyspepsia, and assessment depends on close attention to caloric intake and 
symptom reporting. 
− An upper GI endoscopy should be performed whenever possible to confirm upper 
GI GVHD; however, the diagnosis may be made without biopsy confirmation. 
− GVHD is typically not considered as a possible etiology when nausea lasts fewer 
than 3 days, or with fewer than 2 vomiting episodes per day for at least 2 days, or 
anorexia without weight loss. 
• Lower GI: 
− Staging of lower GI GVHD relies on accurate measurement of daily stool 
volumes and documentation of the presence of hematochezia or severe abdominal 
pain. 
− In cases where stool volume cannot be closely measured, volume should be 
calculated based on average of 200 mL per episode multiplied by the number of 
episodes in a 24-hour period. 
− At the time of GVHD onset, staging should be based on the highest daily volume 
during the 3 days before diagnosis (excluding volumes attributable to procedures 
such as bowel preps or endoscopy). 
− After the initiation of treatment, lower GVHD staging should be based on the 
diarrhea volume using the following measurements (in the order of preference):  
1) average of 3 consecutive days, 2) average of 2 consecutive days, or 3) the 
volume on day of assessment. 
− Severe abdominal pain, ileus, and/or grossly bloody stool should be documented 
when present because Stage 4 lower GI GVHD is staged based on the presence of 
these symptoms and is independent of volume of diarrhea. 
7.6.2. 
Chronic GVHD Assessment 
Subjects will be assessed for signs and symptoms of cGVHD according to local institutional 
practice at screening, during the treatment phase, at the end of treatment, and during re-treatment 
(if applicable) as indicated in Table 3.  Definitive and possible manifestations of cGVHD should 
be assessed as per NIH consensus guidelines for cGVHD (Jagasia et al 2015). 
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The severity of AEs will be assessed using CTCAE v4.03 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. 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention 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 intervention indicated. 
Grade 5 
Death due to AE 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed 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. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an 
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AE, that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be 
reported as an AE with a start date equal to the day the event met the Grade 1 AE definition and 
a stop date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The 
Grade 3 event will also be reported as an AE, with the start date equal to the day the event 
changed in intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved.  For analysis purposes, this will be considered 1 AE 
for this subject, and the highest reported severity will be used. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets the definition of 
serious, as defined in Section 8.3.1, and/or per the investigator's discretion.  A dose modification 
for the laboratory abnormality may be required (see Section 5.4.2) and should not contribute to 
the designation of a laboratory test abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective or preplanned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
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• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based upon appropriate medical judgment, the event 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
To ensure subject safety, every SAE, regardless of suspected causality (including events that 
may not be associated with the study drug[s] but may be associated with a study procedure or 
disease progression), unless otherwise specified by the Protocol, occurring after the subject has 
signed the ICF and up to the last study visit, or up to 30 days after the subject has stopped study 
treatment, whichever is later, must be reported to the sponsor (or designee) within 24 hours of 
learning of its occurrence.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor, or its designee, only if the investigator suspects a causal 
relationship to the study drug.  An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported SAE should be reported separately as a 
new event.  Previously planned (ie, before providing informed consent) surgeries should not be 
reported as SAEs unless the underlying medical condition worsens over the course of the study. 
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to each specific 
study drug (itacitinib/placebo and the corticosteroid during the time it is given).  
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE 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 
SAE 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 subject 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. 
If the SAE is not documented in the IB for itacitinib (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 
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may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
The procedure for emergency unblinding is provided in the study reference manual.  This option 
may be used ONLY if the subject's well-being requires the investigator to be aware of the 
subject's treatment assignment. 
The investigator should make every effort to contact the sponsor's medical monitor before 
unblinding a subject's treatment assignment; however, this is not mandatory.  If a subject's 
treatment assignment is unblinded, the sponsor or its designee must be notified immediately by 
telephone. 
If an investigator, site personnel performing assessments, or subject is unblinded, the subject 
must be withdrawn from the study treatment.  In cases where there are ethical reasons to have the 
subject remain in the study, the investigator must obtain specific approval from the sponsor's (or 
its designee's) clinical research physician or medical monitor for the subject to continue in the 
study. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.4 for the maximum permitted duration of study drug interruption). 
• 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 and breastfeeding 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 must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
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8.6. 
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 (INs).  Any 
important new safety information should be discussed with the subject during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
8.7. 
Data Monitoring Committee 
An external DMC will be formed to monitor the study.  The DMC will consist of external 
investigators who will function autonomously from all other individuals associated with the 
conduct of the trial, including investigators and sponsor personnel.  The DMC will be 
responsible for reviewing results from the prespecified interim analysis and recommending an 
appropriate course of action based on these data.  Details on the composition and responsibilities 
of the DMC can be found in the DMC charter. 
8.8. 
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. 
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 reported as described in Section 8.1.2 of this Protocol. 
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. 
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9. 
STATISTICS 
9.1. 
Study Populations 
Subject enrollment, disposition, demographics, and medical history will be summarized at 
baseline.  Dose exposure will be calculated for each dose level.  Safety and disease response data 
will be compared over time to assess change from baseline, during treatment, and follow-up. 
The populations to be analyzed include the following: 
• Efficacy evaluable population:  Subjects randomized into the study. 
• Per-Protocol population:  A subset of subjects in the efficacy evaluable population 
who are compliant with requirements of the clinical study Protocol, including: 
− Continued to meet all eligibility criteria on Study Day 1. 
− Initiated correct randomized therapy within the Protocol-specified window. 
− Did not significantly deviate from the Protocol in terms of missed study visits, 
noncompliance with randomized therapy, or prohibited concomitant medications. 
• Safety evaluable population:  Subjects randomized into the study who received at 
least 1 dose of study drug. 
• Pharmacokinetic and translational research evaluable population:  Subjects who 
receive at least 1 dose of study drug and provide at least 1 plasma sample 
(1 corresponding PK or translational research measurement) after study drug 
administration will be considered as potential PK evaluable subjects.  The study 
pharmacokineticist will review data listings of study drug administration and sample 
records to identify subjects to be excluded from analyses of PK data. 
9.2. 
Selection of Sample Size 
A sample size of 414 subjects with 1:1 randomization (itacitinib vs placebo) and stratification 
based on aGVHD risk status (standard risk vs high risk) provides approximately 90% power to 
test for the primary endpoint (ORR at Day 28) and 83% power to test for the key secondary 
endpoint (NRM at Month 6).  The family-wise α-level will be controlled at 0.025 overall for the 
two comparisons.  Specifically, this study will claim to have achieved the efficacy objective 
when the primary endpoint ORR at Day 28 shows a significant treatment effect at 1-sided α = 
 0.025.  Conditional on significance of the primary endpoint, the key secondary endpoint (NRM 
at Month 6) will be tested at 1-sided α = 0.025. 
An absolute improvement of 16% in the primary endpoint of ORR at Day 28 would be 
considered a clinically meaningful improvement over standard first-line systemic treatment for 
aGVHD (standard care ORR at Day 28:  P0 = 0.56; itacitinib ORR at Day 28:  P1 = 0.72).  A 
sample size of 414 subjects (207 subjects per treatment arm) will provide approximately 90% 
power to detect a 16% overall difference (72% vs 56%) between treatment cohorts for the 
primary endpoint (ORR at Day 28) at a 1-sided alpha level of 0.025.  A CMH test with 2-strata 
will be used. 
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The assumed Day 28 ORR of 56% is based on MacMillan et al (2015).  The stratum-specific 
response rates (standard risk, 68%; high risk, 44%) assume a standard risk:high risk ratio of 
0.50:0.50.  It is expected that treatment with itacitinib will result in a 16% increase in the ORR, 
that is, an expected odds ratio of 2.02 (which corresponds to an overall increase in ORR to 72%), 
with stratum-specific response rates of 81% and 61% for standard-risk and high-risk aGVHD 
cohorts, respectively.  Power for the CMH test with stratification based on GVHD risk score was 
calculated using software N-Query 5.0. 
Given its clinical significance, NRM at Month 6 will be assessed as the key secondary endpoint.  
Based on MacMillan et al (2015), the overall NRM at Month 6 in the BAT arm is 33%, with a 
stratum-specific NRM of 22% for standard risk and 44% for high risk (assuming a standard 
risk:high risk ratio of 0.50:0.50).  A 40% relative reduction in NRM rate will be considered a 
clinically meaningful improvement.  A sample size of 414 subjects (207 subjects per treatment 
cohort) will provide 83% power to detect a relative reduction of 40% (or absolute difference of 
13.2%, ie, 19.8% vs 33% at Day 180) between treatment cohorts at a 1-sided α level of 0.025 
with an odds ratio of 0.50.  A CMH test with 2-strata will be used.  Stratum-specific NRM rates 
of 12.4% and 28.2% are expected for standard-risk and high-risk cohorts, respectively.  Power 
for the CMH test with stratification based on GVHD risk score was calculated using software 
N-Query 5.0. 
In order to compensate for an anticipated early withdrawal rate of up to 5% (ie, subjects who do 
not have any response data before Day 28), a total of 436 subjects (218 per treatment arm) will 
be randomized into the study to ensure a sample size of 414 evaluable subjects. 
If the Day 180 NRM rate difference between 2 groups is tested using a Kaplan–Meier estimator 
of the cumulative distribution function at Day 180, with the rates being 19.8% and 33%, 
respectively, simulations (with sample size of 436 subjects) have shown that the power of 
detecting treatment difference is 0.811. 
9.2.1. 
Interim Analysis 1 
The first interim analysis for futility only will be performed when 112 subjects (25.7% of the 
planned 436 subjects) have completed the Day 28 visit or withdrew early from the study.  No 
alpha will be spent during the first interim analysis.  The stopping rule is nonbinding.  When the 
conditional power is <20%, the sponsor may consider terminating the study if the totality of 
evidence is warranted.  The conditional power is calculated assuming that the estimated 
treatment effect at the interim analysis is the true effect using the following formula 
(Jennison and Turnbull 2000): 
 
where Φ is the cumulative distribution function of the observed normalized test statistic z, and 
t is the information fraction (ie, observed sample at interim divided by total sample, which is the 
planned total sample size 436); t = 0.257 at interim 1 and 
 1.96. 
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9.2.2. 
Interim Analysis 2 
The second interim analysis for both futility and efficacy will be performed when 240 subjects 
(55% of the targeted 436 subjects) have completed the Day 180 visit or withdrew early from the 
study. 
The Hwang-Shih-DeCani alpha spending function with shape parameter -4 (O’Brien-Fleming 
like boundary) will be used to define the upper efficacy boundary  for the primary analysis of 
ORR at Day 28 when approximately 240 subjects reach Day 180 (Hwang et al 1990).  Based on 
enrollment projection, there will be approximately 360 subjects who have completed Day 28. 
Table 8 lists the efficacy boundary when information fraction (ie, the percentage of subjects) is 
0.826 (360 subjects complete Day 28) at interim 2; if ORR tested at Day 28 crosses the 
boundary, the key secondary endpoint, 6-month NRM, will be tested by passing the allocated 
alpha in this interim analysis to NRM.  By simulation, without considering early stopping for 
futility, the power of testing 6-month NRM at Interim 2 (with 240 subjects complete Day 180) is 
about 0.608. 
As in interim 1, conditional power based on test statistic of ORR at Day 28 will be recalculated 
using its observed information fraction and observed normalized test statistic at interim 2.  The 
sponsor will consider stopping the study for futility if the conditional power is less than 20%.  If 
neither the efficacy nor the futility boundary for testing ORR at Day 28 is crossed, the study will 
continue. 
Table 8: 
Operation Characteristics Using Hwang-Shih-DeCani Alpha Spending 
Function with Shape Parameter -4 
 
 
No. of Subjects 
(%) 
Alpha Spent / 
Cumulative 
Efficacy Boundary or Critical 
Value (as Compared With 
Observed Normalized Test 
Statistic z) 
ORR at 
Day 28 
Interim 1 
112 (25.7) 
− 
− 
Interim 2 
360 (82.6) 
0.0122/0.0122 
2.249810 
Final 
436 (100) 
0.0128/0.025 
2.015483 
The interim analyses will be performed by an independent statistician and programmer not 
involved with the conduct of the study as described in the DMC charter. 
9.2.3. 
Final Analysis of the Primary Analysis 
Final analysis will be conducted when approximately 436 subjects have completed Day 180 or 
withdrew from the study.  If the observed normalized test statistic crosses the efficacy boundary, 
then superiority of itacitinib plus corticosteroids over placebo plus corticosteroids will be 
claimed.  Again, ORR at Day 28 will be tested first, and if positive, NRM mortality at Day 180 
will be tested. 
Note that if there is substantial over-running at the end of the study (ie, total number of subjects 
is greater than 446), the method to adjust the final critical value will be provided in order to 
control overall Type I error rate.  In such a scenario, details in implementation the rules will be 
specified in the Statistical Analysis Plan. 
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9.3. 
Level of Significance 
The 1-sided significance level for the primary and key secondary endpoint analysis is 0.025.  The 
2-sided significance level for other analyses is 0.05.  All CIs will be 95%. 
9.4. 
Statistical Analyses 
9.4.1. 
Primary Analyses 
The primary endpoint is ORR at Day 28, defined as the proportion of subjects demonstrating a 
CR, VGPR, or PR, as per standard criteria (Harris et al 2016, CIBMTR 2009).  The comparison 
of ORR at Day 28 between treatment cohorts will be conducted once the last subject completes 
the Day 28 visit or withdraws from the study.  A CMH test with normal approximation will be 
used.  Summary statistics and 95% CI will be provided. 
Subjects who are missing Day 28 aGVHD response assessment data will be considered to be 
nonresponders. 
 
 
9.4.2. 
Secondary Analyses 
The key secondary endpoint is NRM at Month 6, defined as the proportion of subjects who died 
due to causes other than malignancy relapse at Month 6.  The comparison of NRM at Month 6 
between treatment cohorts will be conducted using a 2-sample proportion test with normal 
approximation.  Summary statistics and 95% CI will be provided. 
Additional secondary endpoints will be analyzed as follows:  
• ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at 
Days 14, 56, and 100.  The comparison between treatment cohorts will be conducted 
using a 2-sample proportion test with normal approximation.  Summary statistics and 
applicable 95% CI will be provided. 
• NRM, defined as the proportion of subjects who died due to causes other than 
malignancy relapse at Months 9, 12, and 24.  The comparison between treatment 
cohorts will be conducted using a 2-sample proportion test with normal 
approximation.  Cumulative incidence rates will be provided.  Summary statistics and 
applicable 95% CI will be provided. 
• DOR, defined as the time from first response until GVHD progression or death.  The 
comparison between treatment cohorts will be conducted using the log-rank test.  The 
Kaplan-Meier method will be used.  Summary statistics will be provided. 
• TTR, defined as the interval from treatment initiation to first response. 
• Relapse rate of malignant and nonmalignant hematologic diseases, defined as the 
proportion of subjects whose underlying disease relapses.  The comparison between 
treatment cohorts will be conducted using a 2-sample proportion test with normal 
approximation.  The cumulative incidence rate and summary statistics will be 
provided. 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• 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 
subject 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 subjects. 
− 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. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− 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 subject.  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 subject records. 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• 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 subjects 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. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
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 study drug to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects were provided the specified 
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study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
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 study drug 
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 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  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 study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of 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. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor, or its designee, must adhere to applicable data privacy laws 
and regulations.  The investigator and the sponsor, or its designee, are responsible for ensuring 
that sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject'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 local data protection laws.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
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records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 Code of Federal Regulations (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 subjects, 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. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), 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. 
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11. 
REFERENCES 
Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or 
pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial 
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Appelbaum FR. Hematopoietic-cell transplantation at 50. N Engl J Med 2007;357:1472-1475. 
Cahn JY, Bordigoni P, Tiberghien P, et al. Treatment of acute graft-versus-host disease with 
methylprednisolone and cyclosporine with or without an anti-interleukin-2 receptor monoclonal 
antibody: a multicenter phase III study. Transplantation 1995;60:939-942. 
Center for International Blood & Marrow Transplant Research (CIBMTR). Clinical trial 
endpoints for patients with acute GVHD. 2009. 
https://www.cibmtr.org/Meetings/Materials/GVHDworkshop/pages/index.aspx. Accessed 
February 5, 2015. 
Choi J, Cooper, ML, Alahmari B, et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD 
and preserves the graft-versus-leukemia effect. PloS One 2014;9:e109799. 
Choi J, Ziga ED, Ritchey J, et al. IFNγR signaling mediates alloreactive T-cell trafficking and 
GVHD. Blood 2012;8:4093-4103. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. 2014. http://www.hma.eu/ctfg.html. Accessed July 15, 2015. 
Couriel DR, Saliba R, de Lima M, et al. A phase III study of infliximab and corticosteroids for 
the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant 
2009;15:1555-1562. 
Cragg L, Blazar BR, Defor T, et al. A randomized trial comparing prednisone with 
antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute 
graft-versus-host disease. Biol Blood Marrow Transplant 2000;6:441-447. 
Flowers MED, Inamoto Y, Carpenter PA, et al. Comparative analysis of risk factors for acute 
graft-versus-host disease and for chronic graft-versus-host disease according to National 
Institutes of Health consensus criteria. Blood 2011;117:3214-3219. 
Glucksberg H, Storb R, Fefer A, et al. Clinical manifestations of graft-versus-host disease in 
human recipients of marrow from HLA-matched sibling donors. Transplantation 
1974;18:295-304. 
Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute 
graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD 
International Consortium. Biol Blood Marrow Transplant 2016;22:4-10. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med 1990;9:1439-1445. 
Itacitinib Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after 
hematopoietic stem cell transplantation. Blood 2012;119:296-307. 
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Jagasia MH, Greinix HT, Williams KM, et al. National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 
2014 Diagnosis and Staging Working Group Report.  Biol Blood Marrow Transplant 
2015;21:389-401. 
Jennison C, Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. Boca 
Raton, FL: Chapman and Hall; 2000, page 211. 
Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids 
for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood 
2004;104:1559-1564. 
Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of survival. Biol 
Blood Marrow Transplant 2010;16:1693-1699. 
Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy 
for acute graft-versus-host disease. Blood 2008;111:2470-2475. 
MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment trials. 
Blood 2010;115:5412-5417. 
MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host 
disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol 
Blood Marrow Transplant 2015;21:761-767. 
Maecker HT, McCoy JP, Nussenblatt R. Standardizing immunophenotyping for the Human 
Immunology Project. Nat Rev Immunol 2012;12:191-200. 
Magenau JM, Qin X, Tawara I, et al. Frequency of CD4(+)CD25(hi)FOXP3(+) regulatory T 
cells has diagnostic and prognostic value as a biomarker for acute graft-versus-host-disease. Biol 
Blood Marrow Transplant 2010;16:907-914. 
Martin PJ. Study design and endpoints in graft-versus-host disease. Best Pract Res Clin 
Haematol 2008;21:357-372. 
Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for clinical trials testing treatment of 
acute graft-versus-host disease: a joint statement. Biol Blood Marrow Transplant 
2009;15:777-784. 
Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute 
graft-versus-host disease: recommendations of the American Society of Blood and Marrow 
Transplantation. Biol Blood Marrow Transplant 2012;18:1150-1163. 
Matsuda K, Yamauchi K, Tozuka M, et al. Monitoring of hematopoietic chimerism by short 
tandem repeats, and the effect of CD selection on its sensitivity. Clin Chem 2004;50:2411-2414. 
Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of 
human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03. 2009. http://ctep.cancer.gov/reporting/ctc.html. Accessed July 8, 2015. 
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Zeiser R, Lengerke C, Spoerl S, et al. High responses rates in patients treated with ruxolitinib for 
corticosteroid-refractory graft-versus-host disease: analysis including 13 transplant centers. 
Presented at: 41st Annual Meeting of the European Society for Blood and Marrow 
Transplantation; March 22-25, 2015; Istanbul, Turkey. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating 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.  Such 
methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2  
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2  
• Vasectomised partner2,3 
• Sexual abstinence4 
Source:  CTFG 2014. 
For Subjects Participating in the Study in Canada: 
In order to conform to Health Canada guidance5, subjects participating in this clinical trial in 
Canada are to use 2 forms of contraception, including at least 1 form of highly effective and 
1 effective method of contraception.  Subjects who are using combined hormonal contraception 
or progestogen-only hormonal contraception will be required to include a barrier method as well. 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical 
success. 
4 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 trial and the preferred 
and usual lifestyle of the subject. 
5 http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/womct_femec-eng.php (accessed 
May 26, 2017) 
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APPENDIX B. MAGIC CRITERIA FOR STAGING AND GRADING FOR 
ACUTE GVHD 
Acute GVHD Staging and Grading, MAGIC Guidelines 
Stage 
Skin 
(Active Erythema Only) 
Liver 
(Bilirubin) 
Upper GI 
Lower GI 
(Stool Output/Day) 
0 
No active (erythematous) 
GVHD rash 
< 2 mg/dL 
No or intermittent 
nausea, vomiting, or 
anorexia 
Adult:  < 500 mL/day or 
< 3 episodes/day. 
Child:  < 10 mL/kg per day 
or < 4 episodes/day.  
1 
Maculopapular rash 
< 25% BSA 
2-3 mg/dL 
Persistent nausea, 
vomiting, or anorexia 
Adult:  500-999 mL/day or 
3-4 episodes/day. 
Child:  10-19.9 mL/kg per 
day or 4-6 episodes/day. 
2 
Maculopapular rash 
25%-50% BSA 
3.1-6 mg/dL 
− 
Adult:  1000-1500mL/day or 
5-7 episodes/day. 
Child:  20-30 mL/kg per day 
or 7-10 episodes/day. 
3 
Maculopapular rash 
> 50% BSA 
6.1-15 mg/dL 
− 
Adult:  > 1500 mL/day or 
> 7 episodes/day. 
Child:  > 30 mL/kg per day 
or > 10 episodes/day. 
4 
Generalized erythroderma 
(> 50% BSA) plus bullous 
formation and desquamation 
> 5% BSA 
> 15 mg/dL 
− 
Severe abdominal pain with 
or without ileus or grossly 
bloody stool (regardless of 
stool volume). 
Overall clinical grade (based on most severe target organ involvement): 
Grade 0:  No Stage 1-4 of any organ. 
Grade I:  Stage 1-2 skin without liver, upper GI, or lower GI involvement. 
Grade II:  Stage 3 rash and/or Stage 1 liver and/or Stage 1 upper GI and/or Stage 1 lower GI. 
Grade III:  Stage 2-3 liver and/or Stage 2-3 lower GI, with Stage 0-3 skin and/or Stage 0-1 upper GI. 
Grade IV:  Stage 4 skin, liver, or lower GI involvement, with Stage 0-1 upper GI. 
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Response Definitions: 
• CR is defined as CIBMTR score of 0 for the GVHD grading in all evaluable organs. 
For a response to be scored as CR at day 28 or later, the participant must still be in 
CR on that day and have had no intervening additional therapy for an earlier 
progression, partial response (PR) or no response (NR). 
• VGPR is defined as: 
− Skin:  No rash, or residual erythematous rash involving < 25% of the body 
surface, without bullae (residual faint erythema and hyperpigmentation do not 
count) 
− Liver:  Total serum bilirubin concentration <2 mg/dL or <25% of baseline at 
enrollment 
− Gut: 
o Tolerating food or enteral feeding 
o Predominantly formed stools 
o No overt gastrointestinal bleeding or abdominal cramping 
o No more than occasional nausea or vomiting 
• Partial response (PR) is defined as improvement in one or more organs involved with 
GVHD symptoms without progression in others.  For a response to be scored as PR at 
Day 28 or later, the participant must still be in PR on that day and have had no 
intervening additional therapy for an earlier progression, PR or NR. 
• Mixed response (MR) is defined as improvement in one or more organs with 
deterioration in another organ manifesting symptoms of GVHD or development of 
symptoms of GVHD in a new organ. 
• Progression of disease (PD) is defined as deterioration in at least one organ without 
any improvement in others. 
• No response (NR) is defined as absence of any improvement or progression as 
defined. Patients receiving secondary therapy (including need to re-escalate steroid 
dose to ≥ 2.5 mg/kg/day of prednisone or methylprednisolone equivalent of 
2mg/kg/day), will be classified as nonresponders. 
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APPENDIX C. GVHD ORGAN STAGING CATEGORIES 
Standard Risk aGHVD: 
1. Stage 1-3 skin only 
2. Upper GI only 
3. Stage 1-2 lower GI only  
4. Stage 1-3 skin + upper GI 
5. Stage 1-3 skin + Stage 1 lower GI  
6. Stage 1 lower GI + upper GI  
7. Stage 1-3 skin  + Stage 1-4 liver  
8. Stage 1-3 skin + Stage 1 lower GI + upper GI 
High Risk aGHVD: 
9. Stage 1-2 lower GI + Stage 1-3 liver 
10. Stage 1-3 skin + (Stage 1-2 lower GI or upper GI) + Stage 1-3 liver 
11. Stage 3 lower GI only 
12. Stage 1-3 skin + Stage 2 lower GI 
13. Stage 3-4 lower GI + (Stage 1-3 skin or liver Stage 1-4) 
14. Stage 1-4 liver alone 
15. Stage 1-3 skin + Stage 3-4 lower GI + Stage 1-4 liver 
16. Stage 4 skin only 
17. Stage 4 lower GI only 
 
Adapted from MacMillan et al 2015. 
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APPENDIX D. CYTOCHROME P450 3A INHIBITORS AND INDUCERS 
A list of CYP3A4 inhibitors and inducers is provided below.  Highlighted rows indicated recent 
additions to the list.  
Source:  University of Washington School of Pharmaceutics: Drug Interaction Database 
Program. 2002. http://www.druginteractioninfo.org. Accessed October 2016. 
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In Vivo CYP3A Inducers 
 
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APPENDIX E. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
31 MAY 2017 
Amendment (Version) 2: 
16 JUN 2017 
Amendment (Version) 3: 
07 MAY 2018 
Amendment (Version) 4: 
13 AUG 2018 
Amendment 4 (13 AUG 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to clarify the population and procedural requirements 
for study subjects to enter the re-treatment phase.  Additional clarification on study procedures 
has been included as well. 
1. Synopsis; Section 2, Study Objectives and Endpoints; Section 9.4.2, Secondary 
Analyses 
Description of change: Modified malignancy relapse endpoint to include reporting of 
relapses observed in malignant and nonmalignant diseases.  
Rationale for change:  To address regulatory feedback and align the endpoint with the 
patient population. 
2. Synopsis; Section 3.2, Subject Exclusion Criteria 
Description of change:  Clarified requirements for hepatitis screening (criterion 6). 
Rationale for change:  Editorial clarification. 
3. Section 1.5, Potential Risks and Benefits of the Treatment Regimen; Section 9.4, 
Statistical Analyses 
Description of change:  Included reference to exploratory subgroup analyses that will be 
performed to assess outcomes based on baseline disease and transplant characteristics. 
Rationale for change:  To address regulatory feedback. 
4. Section 5.4.3, Tapering of Itacitinib/Placebo 
Description of change:  Clarified requirements for additional tapering of randomized 
treatment; clarified physiologic doses of corticosteroids are acceptable, and clarified 
requirements and procedures for subjects who enter the re-treatment phase.  
Rationale for change:  Procedural and editorial clarification. 
5. Section 1.5, Potential Risks and Benefits of the Treatment Regimen; Section 5.5.4.2, 
Restricted Medications 
Description of change:  Added emerging data from study INCB 39110-108 and updated 
recommendations for concomitant administration of potent CYP3A4 inhibitors.   
Rationale for change:  To reflect emerging data that have been added in Section 1.5. 
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6. Section 5.5.4.3, Prohibited Medications 
Description of change:  Updated to clarify that concurrent anticancer therapy intended to 
treat malignancy relapse or recurrence is prohibited, and that maintenance therapy with 
tyrosine kinase inhibitors for high-risk Philadelphia chromosome−positive leukemia and 
FLT3 inhibitors for FLT3+ acute myeloid leukemia may be used with sponsor approval. 
Rationale for change:  To clarify concomitant medication used for the treatment of 
underlying malignancy. 
7. Section 5.5.4.3, Prohibited Medications 
Description of change: Updated to clarify that concomitant administration of targeted 
agents as supportive care is not permitted due to potential to confound outcomes. 
Rationale for change:  Clarification to address frequently asked question. 
8. Section 6, Study Assessments (Table 3) 
Description of change:  PTLD assessment was updated to include the EOT, 
re-treatment, and safety and GVHD follow-up visits. 
Rationale for change:  To assess PTLD for a longer period of time (through the 
follow-up visits). 
9. Section 6, Study Assessments (Table 3 and Table 4); Section 6.5.2, Post-Treatment 
GVHD Follow-Up 
Description of change:  A post-treatment GVHD follow-up visit was added to highlight 
requirements for assessing GVHD status for subjects who end treatment due to reasons 
other than GVHD progression. 
Rationale for change:  Clarification to address frequently asked question. 
10. Section 6, Study Assessments (Table 3); Section 6.5.3, Survival Follow-Up 
Description of change:  Revised to indicate which subjects will be followed for survival 
and that new GVHD therapies and relapse of underlying hematology disease will be 
assessed in addition to survival status. 
Rationale for change:  For clarification. 
11. Section 6, Study Assessments (Table 3); Section 7.6.5, Relapse/Recurrence of 
Underlying Hematologic Disease 
Description of change:  Added underlying disease relapse assessment. 
Rationale for change:  To clarify assessment of the underlying disease relapse. 
12. Section 6, Study Assessments (Table 3); Section 7.6.3, Graft Failure and Donor 
Chimerism 
Description of change:  Updated to include information on graft failure. 
Rationale for change:  To ensure consistency between the study assessments table and 
Section 7.6.3 of the Protocol. 
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13. Section 6.4, Re-Treatment 
Description of change:  Clarified scope of the re-treatment phase of the study.  
Rationale for change:  Procedural clarification. 
14. Section 9.2, Selection of Sample Size 
Description of change:  Updated statistical calculations to reflect updated simulations 
for Interim 2. 
Rationale for change:  Clarification. 
15. 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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Amendment 3 (07 MAY 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to include an additional interim analysis for efficacy, 
reduce PK sampling schedule after the first interim analysis, provide clarification on eligibility 
requirements and study procedures, and align with clinical background and updated guidance 
from the most recent IB. 
1. Section 1.3.2, Clinical Studies 
Description of change:  Updated language on itacitinib clinical background as per the 
most recent IB (v10). 
Rationale for change:  New information. 
2. Synopsis, Section 3.1, Subject Inclusion Criteria 
Description of change:  In Criterion 4, clarified that ANC requirements are based on 
3 consecutive assessments, not days. 
Rationale for change:   Procedural clarification. 
3. Section 3.3, Lifestyle Considerations 
Description of change:  New section added to ensure study participants are instructed to 
avoid consumption of foods that may increase exposure to itacitinib. 
Rationale for change:   New guidance per IB v10.  
4. Section 5.2.1.1, Description and Administration 
Description of change:  Removed text regarding study treatment administration and 
fasting requirements. 
Rationale for change:   Editorial; redundant with Section 7.7.1. 
5. Section 5.2.3, Starting Dose and Administration of Corticosteroids 
Description of change:  Removed text regarding corticosteroid treatment administration 
and fasting requirements. 
Rationale for change:   Editorial; no fasting or administration requirements are 
necessary with respect to corticosteroid administration. 
6. Section 5.4.2, Criteria and Procedures for Dose Interruptions and Adjustments of 
Study Drugs (Table 1, Guidelines for Interruption and Restarting of 
Itacitinib/Placebo) 
Description of change:   Added clarification around platelet recovery requirements.   
Rationale for change:   No requirements were present for subjects who had experienced 
a ≥ 50% decrease from baseline that was outside the current absolute parameters. 
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7. Section 6, Study Assessments (Table 3, Schedule of Assessments); Section 7.6.1, 
GVHD Staging and Grading 
Description of change:  Clarified that subjects who are withdrawn from treatment due to 
reasons other than progression of GVHD must continue to have GVHD assessments 
performed during the follow-up period. 
Rationale for change:  Clarification. 
8. Section 6, Study Assessments (Table 4, Laboratory Assessments); Section 7.7, 
Pharmacokinetic Assessments 
Description of change:  Reduced PK sample collection for subjects enrolled after the 
first interim analysis.  
Rationale for change:  Reduced blood sample collection requirements. 
9. Section 6, Study Assessments (Table 5, Clinical Laboratory Analytes) 
Description of change:  Added option to collect CO2 instead of bicarbonate levels. 
Rationale for change:  To align with clinical practice at certain institutions. 
10. Section 7.5.6.1, Chemistry 
Description of change:  Removed text regarding local assessment of coagulation 
parameters. 
Rationale for change:  Editorial; coagulation data are not being collected in this study. 
11. Synopsis; Section 9.2.1, Interim Analysis 1; Section 9.2.2, Interim Analysis 2; 
Section 9.6, Interim Analyses 
Description of change:  Added language regarding interim analysis 1 and interim 
analysis 2. 
Rationale for change:  To provide more information regarding the interim analyses. 
12. 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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Amendment 2 (16 JUN 2017) 
The primary purpose of this amendment is to address regulatory feedback provided after 
finalization of the original Protocol that aligns eligibility and study conduct to Voluntary 
Harmonisation Procedure (VHP) recommendations and additional feedback from other agencies. 
1. Synopsis; Section 3, Subject Eligibility 
Description of change:  Modified inclusion criterion 1 to reflect lower age limit of 
20 years based on local regulation; clarified exclusion of potential subjects with renal 
dysfunction  (ie, moved serum creatinine and creatinine clearance requirements from 
inclusion to exclusion criteria); excluded potential subjects who may require live or 
attenuated vaccines during the study.  
Rationale for change:  To address regulatory feedback. 
2. Section 4.5, Overall Study Duration 
Description of change:  Clarified intention to allow subjects who are continuing to 
benefit from study treatment to have continued access to treatment after the study ends.   
Rationale for change:  To address regulatory feedback.  
3. Section 6, Study Assessments (Table 4); Section 7.5.6.5, HIV Screening 
Description of change:  Clarified subjects whose HIV status is unknown will need to 
have screening performed before enrollment. 
Rationale for change:  To address regulatory feedback. 
4. Synopsis; Section 6, Study Assessments (Tables 4 and 5); Section 7.5.6.3, Pregnancy 
Testing 
Description of change:  Added requirement for subjects who are of childbearing 
potential to have urine pregnancy tests every 28 days while on treatment. 
Rationale for change:  To address regulatory feedback  
5. Section 6, Study Assessments (Table 5) 
Description of change:  Added assessment of lipid profiles to the serum chemistry panel. 
Rationale for change:  To address regulatory feedback. 
6. Appendix B, MAGIC Criteria for Staging and Grading for Acute GVHD 
Description of change:  Clarified definition of Stage 4 skin GVHD to include 
desquamation > 5% BSA. 
Rationale for change:  Editorial clarification. 
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Amendment 1 (31 MAY 2017) 
The primary purpose of this amendment is to address regulatory feedback provided after 
finalization of the original Protocol that relates to appropriate birth control measures that are 
aligned with Health Canada guidelines. 
1. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Added the following text: 
For Subjects Participating in the Study in Canada: 
In order to conform to Health Canada guidance, subjects participating in this clinical trial 
in Canada are to use 2 forms of contraception, including at least 1 form of highly 
effective and 1 effective method of contraception.  Subjects who are using combined 
hormonal contraception or progestogen-only hormonal contraception will be required to 
include a barrier method as well.   
Rationale for change:  To address regulatory feedback. 
 
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
INCB 39110-301 
GRAVITAS-301:  A Randomized, Double-Blind, 
Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in 
Combination With Corticosteroids for the Treatment of First-Line 
Acute Graft-Versus-Host Disease 
 
 
 
 
 
IND Number: 
113,428 
EudraCT Number: 
2017-000538-78 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment (Version) 4 dated 13 AUG 2018 
CRF Approval Date: 
12 MAR 2019 
SAP Version: 
Amendment 1 
SAP Author: 
 
Executive Director, Biostatistics 
Date of Plan: 
23 JUL 2019 
 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives and Endpoints ...................................................................................9 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Randomization ............................................................................................................12 
3.2. 
Control of Type I Error ...............................................................................................12 
3.3. 
Sample Size Considerations........................................................................................13 
3.4. 
Interim and Final Analyses .........................................................................................14 
3.4.1. 
Interim Analysis 1.......................................................................................................15 
3.4.2. 
Interim Analysis 2.......................................................................................................15 
3.4.3. 
Final Analysis .............................................................................................................17 
3.5. 
Schedule of Assessments ............................................................................................17 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................21 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................21 
4.1.1. 
Day 1 ...........................................................................................................................21 
4.1.2. 
Study Day ...................................................................................................................21 
4.1.3. 
Baseline Value ............................................................................................................21 
4.1.4. 
Retreatment Day 1 ......................................................................................................21 
4.1.5. 
Analysis Visit Definition ............................................................................................21 
4.1.6. 
Last Available Value ..................................................................................................22 
4.1.7. 
Date of Last Contact ...................................................................................................22 
4.1.8. 
Handling of Missing and Incomplete Data .................................................................22 
4.2. 
Variable Definitions....................................................................................................22 
4.2.1. 
Age ..............................................................................................................................22 
4.2.2. 
Body Mass Index ........................................................................................................22 
4.2.3. 
Body Surface Area ......................................................................................................22 
4.2.4. 
Prior and Concomitant Medication .............................................................................23 
5. 
STATISTICAL METHODOLOGY ...........................................................................24 
5.1. 
General Methodology .................................................................................................24 


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5.2. 
Treatment Groups .......................................................................................................24 
5.3. 
Analysis Sets ...............................................................................................................24 
5.3.1. 
Interim Analysis 1.......................................................................................................24 
5.3.1.1. 
Interim 1 Analysis Set.................................................................................................24 
5.3.2. 
Interim Analysis 2.......................................................................................................24 
5.3.2.1. 
Interim 2 Efficacy Analysis Set ..................................................................................24 
5.3.2.2. 
Interim 2 Safety Analysis Set .....................................................................................25 
5.3.3. 
Final Analysis .............................................................................................................25 
5.3.3.1. 
Full Analysis Set .........................................................................................................25 
5.3.3.2. 
Per Protocol Analysis Set ...........................................................................................25 
5.3.4. 
Safety Analysis Set .....................................................................................................25 
5.3.5. 
Pharmacokinetic and Translational Research Evaluable Analysis Set .......................25 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES................................................................................................................26 
6.1. 
Demographics and Baseline Characteristics, Disease History, Transplant 
History, Medical History, and Prior Therapies ...........................................................26 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................26 
6.1.2. 
Hematologic Disease History .....................................................................................26 
6.1.3. 
Allogeneic Hematopoietic Stem Cell Transplant History ..........................................26 
6.1.4. 
Medical History ..........................................................................................................27 
6.1.5. 
Prior Anticancer Therapy or Radiotherapy.................................................................27 
6.2. 
Disposition of Subjects ...............................................................................................27 
6.3. 
Protocol Deviations.....................................................................................................27 
6.4. 
Transfusions Performed On Study or Within 30 Days Before Enrollment ................27 
6.5. 
Exposure .....................................................................................................................27 
6.6. 
Study Drug Compliance..............................................................................................28 
6.7. 
Prior and Concomitant Medication .............................................................................28 
7. 
EFFICACY .................................................................................................................29 
7.1. 
General Considerations ...............................................................................................29 
7.2. 
Efficacy Hypotheses ...................................................................................................29 
7.3. 
Analysis of the Primary Efficacy Endpoint ................................................................30 
7.3.1. 
Primary Efficacy Analysis ..........................................................................................30 
7.3.1.1. 
Day 28 Overall Response Rate ...................................................................................30 


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7.3.1.2. 
Sensitivity Analyses for Day 28 Overall Response Rate............................................31 
7.3.2. 
Duration of Response for Day 28 Responders............................................................31 
7.3.3. 
Alternative Ways of Calculating Duration of Response for Day 28 
Responders ..................................................................................................................31 
7.3.4. 
Subgroup Analyses for Primary Endpoint ..................................................................31 
7.4. 
Analysis of the Secondary Efficacy Endpoints...........................................................32 
7.4.1. 
Key Secondary Endpoint Analysis .............................................................................32 
7.4.1.1. 
Primary Analysis of Nonrelapse Mortality Rate at Month 6 (Day 180).....................33 
7.4.1.2. 
Sensitivity Analysis of Nonrelapse Mortality Rate at Month 6 (Day 180) 
Using Kaplan-Meier Approach...................................................................................34 
7.4.1.3. 
Nonrelapse Mortality Rate Using Kaplan-Meier Approach .......................................35 
7.4.2. 
Survival Analyses of Nonrelapse Mortality................................................................35 
7.4.3. 
Competing-Risks Analyses of Nonrelapse Mortality .................................................35 
7.4.4. 
Overall Response Rate at Days 14, 56, 100, and 180 .................................................36 
7.4.5. 
Best Overall Response ................................................................................................36 
7.4.6. 
Time to Response........................................................................................................36 
7.4.7. 
Relapse Rate of Malignant and Nonmalignant Hematologic Diseases ......................37 
7.4.8. 
Malignancy Relapse-Related Mortality Rate..............................................................37 
7.4.9. 
Failure-Free Survival ..................................................................................................37 
7.4.10. 
Overall Survival ..........................................................................................................38 
7.5. 
Other Secondary Efficacy Analyses ...........................................................................38 
7.6. 
Analysis of Exploratory Efficacy Variables ...............................................................39 
7.7. 
Pharmacokinetic Analyses ..........................................................................................39 
 
 
8. 
SAFETY AND TOLERABILITY ..............................................................................40 
8.1. 
General Considerations ...............................................................................................40 
8.2. 
Adverse Events ...........................................................................................................40 
8.2.1. 
Adverse Event Definitions ..........................................................................................40 
8.2.2. 
Adverse Event Summaries ..........................................................................................41 
8.3. 
Clinically Notable Treatment-Emergent Adverse Events Based on 
Customized MedDRA Queries ...................................................................................44 
8.4. 
Clinical Laboratory Tests............................................................................................44 
8.5. 
Vital Signs...................................................................................................................45 


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8.6. 
Electrocardiograms .....................................................................................................45 
9. 
INTERIM ANALYSES AND FINAL ANALYSES..................................................46 
9.1. 
Overview of Interim Analyses ....................................................................................46 
9.1.1. 
Interim Analysis 1.......................................................................................................46 
9.1.2. 
Interim Analysis 2.......................................................................................................46 
9.2. 
Final Analyses.............................................................................................................48 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................48 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................48 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................49 
10.2.1. 
Original to Amendment 1 ...........................................................................................49 
11. 
REFERENCES ...........................................................................................................50 
APPENDIX A. STATISTICAL MODELS FOR EFFICACY ANALYSES .............................51 
APPENDIX B. PLANNED TABLES, FIGURES, AND LISTINGS.........................................53 
APPENDIX C. CLINICALLY NOTABLE EVENTS BASED ON CUSTOMIZED 
MEDDRA QUERIES .................................................................................................62 
APPENDIX D. VARIOUS UPPER EFFICACY BOUNDARIES FOR TESTING DAY 
28 ORR AT BOTH INTERIM 2 AND FINAL ANALYSES USING 
HWANG-SHIH-DECANI ALPHA SPENDING FUNCTION WITH 
SHAPE PARAMETER -4 ..........................................................................................66 
 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints ...........................................................................................10 
Table 2: 
Operation Characteristics Using Hwang-Shih-DeCani Alpha Spending 
Function With Shape Parameter -4 .............................................................................16 
Table 3: 
Schedule of Assessments ............................................................................................18 
Table 4: 
Laboratory Assessments .............................................................................................19 
Table 5: 
Clinical Laboratory Analytes ......................................................................................20 
Table 6:  
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................45 
Table 7: 
Criteria for Clinically Notable ECG Abnormalities ...................................................45 
Table 8: 
Statistical Analysis Plan Versions ..............................................................................48 
 
LIST OF FIGURES 
Figure 1: 
Study Design:  Screening and Randomization ...........................................................11 
Figure 2: 
Study Design:  Study Flowchart .................................................................................12 
Figure 3: 
Upper Efficacy and Lower Futility Boundaries for Day 28 ORR at the 
Interim Analyses and Critical Value at the Final Analysis.........................................14 
Figure 4: 
Recommended Decision Process at Interim 2 ............................................................17 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
aGVHD 
acute graft-versus-host disease 
allo-HSCT 
allogeneic hematopoietic stem cell transplantation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BOR 
best overall response 
BSA 
body surface area 
cGVHD 
chronic graft-versus-host disease 
CI 
confidence interval 
CIBMTR 
Center for International Blood & Marrow Transplant Research 
CL/F 
apparent oral dose clearance 
Cmax 
maximum observed plasma or serum concentration 
CMH 
Cochran-Mantel-Haenszel 
Cmin 
minimum observed plasma or serum concentration over the dose interval 
CMV 
cytomegalovirus 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.03) 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FAS 
full analysis set 
FFS 
failure-free survival 
GI 
gastrointestinal 
GVHD 
graft-versus-host disease 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 


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Abbreviation 
Term 
HLA 
human leukocyte antigen 
IC50 
concentration that results in 50% inhibition 
IVRS 
interactive voice response system 
JAK 
Janus kinase 
KM 
Kaplan-Meier 
LDL 
low-density lipoprotein 
MAGIC 
Mount Sinai Acute GHVD International Consortium 
MedDRA 
Medical Dictionary for Regulatory Activities 
MQ 
MedDRA query 
NCI 
National Cancer Institute 
NRM 
nonrelapse mortality 
ORR 
overall response rate 
OS 
overall survival 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PTLD 
post-transplant lymphoproliferative disorder 
 
 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
 
 
SOC 
system organ class 
STAT 
signal transducer and activator of transcription 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, and listings 
tmax 
time to maximum concentration 
TTR 
time to response 
TYK 
tyrosine kinase 
VGPR 
very good partial response 
WHO 
World Health Organization  


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1. 
INTRODUCTION 
Itacitinib potently inhibits JAK1 (IC50 = 3.6 nM at 1 mM adenosine triphosphate concentration), 
with 22- to > 500-fold selectivity over the other JAK family members, JAK2, JAK3, and TYK2.  
It does not significantly inhibit (< 30% inhibition) a broad panel of approximately 60 other 
kinases.  Itacitinib is also potent (IC50 values of approximately 10 nM to 350 nM) in 
cytokine-driven cell-based assays. 
New treatments for the therapy of aGVHD after allo-HSCT are urgently needed.  
 
 
 
 
 
 
Section 1 of the Protocol provides a detailed description of the investigational products, target 
patient population, and the potential risks and benefits from the combination treatments.  The 
purpose of this document is to provide a detailed SAP. 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 39110-301 Protocol Amendment (Version) 4 dated 13 AUG 2018 
and CRFs approved 12 MAR 2019.  Unless superseded by an amendment, this SAP will be 
effective for all subsequent Protocol amendments and CRFs. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the study objectives and endpoints. 


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Table 1: 
Objectives and Endpoints 
Primary Objective 
Primary Endpoint 
Compare the efficacy of itacitinib in combination with 
corticosteroids versus placebo in combination with 
corticosteroids in terms of ORR at Day 28 in subjects 
with aGVHD. 
ORR at Day 28, defined as the proportion of subjects demonstrating a 
CR, VGPR, or PR. 
Key Secondary Objective 
Key Secondary Endpoint 
Compare the efficacy between treatment cohorts at a 
subsequent key clinical landmark. 
NRM at Month 6, defined as the proportion of subjects who died due 
to causes other than malignancy relapse at Month 6. 
Secondary Objectives 
Secondary Endpoints 
Compare additional response and longer-term efficacy 
outcomes between treatment cohorts. 
ORR, defined as the proportion of subjects demonstrating a CR, 
VGPR, or PR at Days 14, 56, and 100. 
NRM at Months 9, 12, and 24. 
DOR for responders will be calculated.  The DOR is defined from the 
time of the onset of response to loss of response.  Subjects who died or 
discontinued will be censored at the death date or the previous 
assessment. 
TTR, defined as the interval from treatment initiation to first response. 
Relapse rate of malignant and nonmalignant hematologic diseases, 
defined as the proportion of subjects whose underlying hematologic 
disease relapses. 
Malignancy relapse-related mortality rate, defined as the proportion of 
subjects whose malignancy relapses and has a fatal outcome. 
FFS, defined as the proportion of subjects who are still alive, have not 
relapsed, have not required additional therapy for aGVHD, and have 
not demonstrated signs or symptoms of cGVHD, at Month 6. 
OS, defined as the interval from study enrollment to death due to any 
cause. 
Assess the incidence and severity of AEs and SAEs. 
Clinical safety data (eg, AEs, infections) will be tabulated and listed. 
Evaluate the PK of itacitinib when administered in 
combination with corticosteroids. 
Cmax, Cmin, tmax, AUC, and CL/F. 
Evaluate the incidence of secondary graft failure. 
Incidence rate of secondary graft failure, defined as > 95% recipient 
cells any time after engraftment with no signs of relapse, OR 
retransplantation because of secondary neutropenia (< 0.5 × 109/L) 
and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplant. 
Evaluate the use and discontinuation of corticosteroids. 
Average and cumulative corticosteroid dose at Days 28, 56, 100, and 
180; proportion of subjects who discontinue corticosteroids at Days 56 
and 100. 
Evaluate the use and discontinuation of 
immunosuppressive medications. 
Proportion of subjects who discontinue immunosuppressive 
medications at Days 56 and 100. 
Evaluate the incidence of aGVHD flares. 
Incidence rate of aGVHD flares through Day 100. 
Evaluate the incidence of cGVHD. 
Incidence rate of cGVHD at Days 180 and 365. 


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3. 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study of itacitinib or 
placebo in combination with corticosteroids as first-line treatment of subjects with Grade II to IV 
aGVHD.  Subjects will be randomized 1:1 to itacitinib 200 mg plus corticosteroids or matching 
placebo plus corticosteroids.  Randomization will be stratified by GVHD risk status (ie, standard 
risk vs high risk; MacMillan et al 2015).  Subjects will receive randomized study treatment until 
treatment failure (progression of disease, no response, or requiring additional systemic therapy), 
unacceptable toxicity, or death.  Transfusion support and continued use of anti-infective 
medications, GVHD prophylaxis medications (including calcineurin inhibitors), and topical 
steroid therapy are permitted. 
GVHD staging and grading will be assessed for efficacy as per MAGIC criteria 
(Harris et al 2016); safety and tolerability will be assessed as per NCI CTCAE v4.03 (NCI 2010). 
An independent DMC will perform an interim analysis for futility once 112 subjects (around 
56 per cohort) have completed the Day 28 visit or withdrew early from the study.  If the futility 
boundary is crossed at Interim Analysis 1, the sponsor may consider stopping the study.  A 
second interim analysis for the primary endpoint of Day 28 ORR (both efficacy and futility) will 
be performed once 240 eligible subjects have completed the Day 180 visit or withdrew early 
from the study.  If the Day 28 ORR efficacy boundary is crossed, the Day 180 NRM will be 
tested. 
The final analysis will be conducted once the last subject completes the Day 180 visit or 
withdraws from the study. 
Figure 1 below depicts study design at screening and randomization, and Figure 2 summarizes 
study flow after randomization.  
Figure 1: 
Study Design:  Screening and Randomization 
 
R = randomization. 


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Figure 2: 
Study Design:  Study Flowchart 
 
Note:  Methylprednisolone is given at 2 mg/kg per day or at a dose per local treatment guidelines.  Some subjects 
started with 1 mg/kg per day on Day 1, and this is accepted per the Protocol. 
3.1. 
Randomization 
Randomization will occur centrally by the IVRS.  Subjects will be randomized in a 1:1 ratio to 
receive itacitinib plus corticosteroids or matching placebo plus corticosteroids and will be 
stratified by baseline GVHD risk status (ie, standard-risk versus high-risk).  As this is a 
randomized, double-blind, placebo-controlled study, neither the investigators nor the sponsor 
will be aware of the treatment to which a subject is randomized. 
3.2. 
Control of Type I Error 
For the primary and key secondary endpoints, the overall 1-sided Type 1 error is controlled at 
0.025.  Early stopping for positive efficacy is permitted in this study.  Testing of the primary 
endpoint will use an alpha-spending approach to control Type I error.  Subsequent testing of the 
key secondary endpoint will control Type I error using the Bonferroni method.  See Sections 3.4 
and 9 for more details.  
No multiplicity adjustment will be applied to other endpoints.  For estimation purposes, 95% CIs 
will be provided for parameter estimates of other endpoints.   


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3.3. 
Sample Size Considerations 
A sample size of 414 subjects with 1:1 randomization (itacitinib vs placebo) and stratification 
based on baseline aGVHD risk status (standard risk vs high risk) provides approximately 90% 
power to test for the primary endpoint (ORR at Day 28) and approximately 80% power to test for 
the key secondary endpoint (NRM rate at Month 6).  The family-wise α-level will be controlled 
at 0.025 overall for the two comparisons.  Specifically, this study will claim to have achieved the 
efficacy objective when the primary endpoint ORR at Day 28 shows a significant treatment 
effect at 1-sided α = 0.025.  Conditional on significance of the primary endpoint, the key 
secondary endpoint (NRM rate at Month 6) will be tested at 1-sided α = 0.025. 
An absolute improvement of 16% in the primary endpoint of ORR at Day 28 would be 
considered a clinically meaningful improvement over standard first-line systemic treatment for 
aGVHD.  A sample size of 414 subjects (207 subjects per treatment group) will provide 
approximately 90% power to detect a 16% overall difference (72% vs 56%) between treatment 
groups for the primary endpoint (ORR at Day 28) at a 1-sided alpha level of 0.025.   
The assumed Day 28 ORR of 56% is based on MacMillan et al (2015).  The stratum-specific 
response rates (standard risk, 68%; high risk, 44%) assume a standard risk:high risk ratio of 
0.50:0.50.  It is expected that treatment with itacitinib will result in a 16% increase in the ORR, 
that is, an expected odds ratio of 2.02 (which corresponds to an overall increase in ORR to 72%), 
with stratum-specific response rates of 81% and 61% for standard-risk and high-risk aGVHD 
cohorts, respectively.  Power for the CMH test with stratification based on GVHD risk score was 
calculated using software N-Query 5.0. 
Given its clinical significance, NRM rate at Month 6 will be assessed as the key secondary 
endpoint.  The Day 180 NRM rate difference between 2 groups is tested using a KM estimator of 
the cumulative distribution function at Day 180.  Based on MacMillan et al (2015), the overall 
NRM at Month 6 in the best available therapy group is 33%, with a stratum-specific NRM rate of 
22% for standard risk and 44% for high risk (assuming a standard risk:high risk ratio of 
0.50:0.50).  A 40% relative reduction in NRM rate will be considered a clinically meaningful 
improvement.  Based on simulation, a sample size of 414 subjects (207 subjects per treatment 
cohort) will provide approximately 80% power to detect a relative reduction of 40% (or absolute 
difference of 13.2%, ie, 19.8% vs 33% at Day 180) between treatments at a 1-sided α level of 
0.025.  NRM at Month 6 will be tested using a CMH test stratified by risk status (standard-risk 
vs high-risk aGVHD).  Stratum-specific NRM rates of 12.4% and 28.2% are expected for 
standard-risk and high-risk cohorts, respectively.  Power for the CMH test with stratification 
based on GVHD risk score was calculated using software N-Query 5.0. 
In order to compensate for an anticipated early withdrawal rate of up to 5% (ie, subjects who do 
not have any response data before Day 28), a total of 436 subjects (218 per treatment arm) will 
be randomized into the study to ensure a sample size of 414 evaluable subjects. 


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3.4. 
Interim and Final Analyses 
There are 2 interim analyses planned in this study.  Interim Analysis 1 will be conducted at the 
time when 112 subjects have completed the Day 28 visit or withdrawn from the study.  Only a 
futility analysis will be conducted based on test statistic of Day 28 ORR using stratified CMH 
test (see details below).  The observed normalized z statistic will be compared with the futility 
boundary of 0.626 as depicted in Figure 3 (equivalently conditional power equal to 0.2); if the 
normalized z statistic is less than the futility boundary, it is recommended to stop the study early 
for futility.  Interim Analysis 2 will be conducted when approximately 240 subjects have 
completed the Day 180 visit or have withdrawn from the study.  At Interim Analysis 2, both 
futility and efficacy will be tested for Day 28 ORR using stratified CMH test with z-score 
efficacy boundary of 2.25 and futility boundary of 1.46 corresponding to conditional power of 
0.2.  Critical value at final analysis is 2.02.  See details on boundary specifications in 
Sections 3.4.1 and 3.4.2.  Note that boundaries for both the Interim Analysis 2 and the Final 
Analysis are constructed based on a hypothetical example solely for illustration purposes, 
whereas the real boundaries used in the study will based on the observed information fraction at 
Interim Analysis 2.  
Figure 3: 
Upper Efficacy and Lower Futility Boundaries for Day 28 ORR at the 
Interim Analyses and Critical Value at the Final Analysis   
 
In any interim analysis, the sponsor may consider stopping the study for futility if the conditional 
power is less than 20% and stopping for efficacy if both efficacy boundaries are crossed.  If 
neither the efficacy nor the futility boundary for Day 28 ORR is crossed, the study will continue.  
Additionally, if efficacy for Day 28 ORR is crossed but efficacy for Day 180 NRM rate is not 
crossed, the study will continue. 


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3.4.1. 
Interim Analysis 1 
The first interim analysis for futility only will be performed when 112 subjects (25.7% of the 
planned 436 subjects) have completed the Day 28 visit or withdrew early from study.  No alpha 
will be spent during the first interim analysis.  The stopping rule is nonbinding.  When the 
conditional power is < 20%, the sponsor may consider terminating the study if the totality of 
evidence is warranted.  The conditional power is calculated assuming that the estimated 
treatment effect at the interim analysis is the true effect using the formula (Jennison and 
Turnbull 1999): 
  
where Φ is the cumulative distribution function of the observed normalized test statistic z, and 
t is the information fraction (ie, observed sample at interim divided by the planned total sample 
size 436); t = 0.257 at Interim 1 and 
 1.96. 
Since CMH test with only 1 stratification factor, aGVHD risk status (standard vs high risk), will 
be used to test ORR at Day 28, it is thus a chi-square test with degree of freedom equal to 1, that 
is, 
.  Taking the square root of the observed CMH test statistic 
 will result in 
normalized test statistic z. 
3.4.2. 
Interim Analysis 2 
For Interim Analysis 2, the analysis of both efficacy and futility will use a clinical database 
cutoff based on when 240 eligible subjects (55.0% of the targeted 436 subjects) have completed 
the Day 180 visit or withdrew from the study prior to Day 180. 
The Hwang-Shih-DeCani alpha spending function with shape parameter –4 (O’Brian-Fleming 
like boundary) will be used to define upper efficacy boundary for the primary analysis of ORR at 
Day 28 when approximately 240 eligible subjects reach Day 180 (Hwang et al 1990).  Based on 
enrollment projection, there will be approximately 360 subjects who have completed Day 28. 
Table 2 lists efficacy boundary when information fraction (ie, the percentage of subjects) is 
0.826 (360 subjects complete Day 28) at Interim 2; if ORR tested at Day 28 crosses the 
boundary, then the key secondary endpoint, 6-month NRM rate, will be tested by using the 
Bonferroni method for alpha spending (ie, 0.0125 as compared with 1-sided p-value at both 
interim and final analyses).  By simulation, without considering early stopping for futility, the 
power of testing 6-month NRM at Interim 2 (with 240 eligible subjects who have completed 
Day 180) is approximately 0.608. 


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Table 2: 
Operation Characteristics Using Hwang-Shih-DeCani Alpha Spending 
Function With Shape Parameter -4 
 
 
No. of 
Subjects (%) 
Alpha Spent 
/Cumulative 
Efficacy 
Boundary or 
Critical Value (as 
Compared With 
Observed 
Normalized Test 
Statistic z) 
Nominal 
Significance 
/Alpha Level:  
1- 
 
Efficacy 
Boundary or 
Critical Value 
at Chi-Square 
Test Statistic 
With Degree of 
Freedom 1 
ORR at 
Day 28 
Interim 
Analysis 1 
112 (25.7) 
– 
– 
– 
– 
Interim 
Analysis 2 
360 (82.6) 
0.0122/0.0122 
2.249810 
0.0122305 
5.061645 
Final 
436 (100) 
0.0128/0.025 
2.015483 
0.02192703 
4.062172 
If, at Interim Analysis 2, the observed number of subjects who have completed Day 28 is 
different from 360, then the boundaries for efficacy in Table 2 will be recalculated using 
observed information fraction. 
The interim analyses will be performed by an independent statistician and programmer not 
involved with the conduct of the study as described in the DMC charter. 
At the Interim Analysis 2 clinical data cutoff date, the date when the 240th eligible subject 
randomized in the study has reached Day 180, 360 subjects are expected to have been 
randomized.  Testing of Day 28 ORR will be conducted for subjects who have completed the 
Day 28 visit or withdrew from the study by the clinical data cutoff date.  This means that 
subjects who were ongoing but had not yet reached the Day 28 visit by the Interim Analysis 2 
clinical data cutoff date will be excluded from both the Day 28 ORR and NRM efficacy 
analyses. 
Figure 4 depicts the recommended decision process at Interim Analysis 2:  first, testing Day 28 
ORR using stratified CMH and assuming 360 subjects have completed Day 28 or withdrew from 
the study by the cutoff date, if observed normalized test statistic is ≤ 1.46, it is recommended to 
stop the study for futility; if the observed normalized test statistic of Day 28 ORR is ≥ 2.25, then 
the NRM rate at Day 180 will be tested using the Bonferroni method.  If both the primary 
efficacy analysis and the key secondary efficacy analysis pass their corresponding efficacy 
boundary, the superiority of itacitinib over placebo for both the Day 28 ORR and Day 180 NRM 
endpoints can be claimed at Interim Analysis 2. 


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Figure 4: 
Recommended Decision Process at Interim 2 
 
3.4.3. 
Final Analysis 
If the study is not stopped at Interim Analysis 2, the final analysis will be conducted when 
approximately 436 subjects have completed the Day 180 visit or withdrawn from the study.  If 
the observed normalized test statistic crosses the efficacy boundary, then superiority of itacitinib 
plus corticosteroids over placebo plus corticosteroids will be claimed.  Again, ORR at Day 28 
will be tested first, and if positive, NRM mortality at Day 180 will be tested. 
Note that if there is substantial over-running at the end of the study (ie, total number of subjects 
greater than 446), the final critical value will be adjusted upward so that the 1-sided overall 
Type I error rate is controlled at 0.025 level.  Alternatively, a weighted z-statistic combining 
log-rank test statistic from 2 stages will be used to compare with the prespecified upper boundary 
at final analysis in order to control overall Type I error at a 1-sided 0.025 level. 
Final analyses of Day 28 ORR, NRM rate at Day 180, as well as other efficacy and safety 
analyses to be included in the CSR are defined in Sections 7 and 8, and planned TFLs for the 
CSR are presented in Appendix B. 
3.5. 
Schedule of Assessments 
All study assessments will be performed as indicated in the schedule of assessments (see 
Table 3), and all laboratory assessments will be performed as indicated in Table 4.  Table 5 
presents a summary of clinical laboratory analytes to be assessed.  The order of assessments is 
suggested by the order of mention within the schedule. 


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Table 3: 
Schedule of Assessments 
Visit Day 
Item 
Screening  
Treatmenta 
 
 
Follow-Up 
-28 to -1 
D1 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56b D100 
D180 
D365c 
EOTd 
Retreatmentde 
Safetyf 
GVHDg 
Survivalh 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact IVRS 
X 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
Demography/disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
X 
X 
X 
X 
X 
 
 
Supportive care medications 
X 
X 
X 
X 
X 
 
 
AE assessment 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
As indicated 
X 
 
 
 
 
aGVHD grading and 
response 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
 
cGVHD assessment 
X 
As indicated 
X 
X 
X 
X 
 
Chimerism/graft failure 
assessment 
X 
As indicated 
 
PTLD assessment 
 
As indicated 
X 
X 
X 
X 
 
Underlying disease relapse 
assessment 
 
As indicated 
X 
X 
X 
X 
X 
Dispense study drug 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
Study drug compliance 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
 
 
Steroid dose monitoring 
X 
X 
X 
X 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
New aGVHD therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG = electrocardiogram; I/E = inclusion/exclusion; PS = performance status; PTLD = post-transplant lymphoproliferative disorder. 
a A ± 3-day window is permitted to facilitate scheduling during the treatment phase. 
b After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
c The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
d A second EOT should occur if the subject restarts itacitinib and subsequently discontinues treatment. 
e Retreatment assessments occur every 28 days ± 3 days.  
f 30 to 35 days after EOT. 
g Every 28 days ± 7 days, for participants who completed study treatment or discontinued early for reasons other than GVHD progression. 
h Every 8 weeks ± 7 days. 


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Table 4: 
Laboratory Assessments 
Visit Day 
Item 
Screening 
Treatmenta 
 
 
 
 
-28 to -1 
D1b 
D7 
D14 
D21 
D28 
D35 
D42 
D49 
D56c 
D100 
D180 
D365d 
EOTe 
Retreatmentf 
GVHD 
Follow-Up 
Safety 
Follow-Upg 
Chemistry panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Xh 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
Hepatitis screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV screening 
X 
 
 
 
 
 
Serum pregnancy test 
(childbearing females 
only) 
X 
 
X 
 
 
 
Urine pregnancy testi
(childbearing females 
only) 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
PK assessmentj 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
a A ± 3-day window is permitted to facilitate scheduling during the treatment phase. 
b Day 1 laboratory assessments do not need to be repeated if screening assessments were performed within the preceding 7 days. 
c After Day 56, visits will occur every 28 days and will include all Day 56 assessments. 
d The Day 365 visit will also serve as the regularly scheduled visit occurring every 28 days after Day 56 (ie, Day 364). 
e A second EOT should occur if the subject restarts itacitinib and subsequently discontinues treatment. 
f Retreatment assessments occur every 28 days. 
g 30 to 35 days after EOT. 
h Liver testing including total bilirubin data 
i Urine pregnancy tests are required at Day 28 and every 28 days. 
j Subjects 1-112:  samples collected on Days 1, 7, and 28 at predose and at 1 hour ± 15 minutes, 2 hours ± 30 minutes, and 5 hours ± 60 minutes postdose.  Subjects 113-436:  Day 7 and 28 at predose 
only. 
k Day 56 only. 


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Table 5: 
Clinical Laboratory Analytes 
Serum Chemistries 
Hematologya 
Other 
Albumin 
ALP 
ALT 
AST 
Bicarbonate or CO2 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipid profile (total cholesterol, 
HDL, LDL, and triglycerides) 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total protein 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Reticulocytes 
Platelet count 
Red blood cell count 
White blood cell count 
White blood cell differential (5 parts): 
 Basophils 
 Eosinophils 
 Lymphocytes 
 Monocytes 
 Neutrophils 
Serum pregnancy test 
Urine pregnancy test 
Hepatitis Screening Tests 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis B core antibody 
HCV antibody 
HCV-RNA 
HBV-DNA 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
HDL = high-density lipoprotein; LDL = low-density lipoprotein. 
a Hematology and chemistry assessments will be performed locally. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date of first dose of itacitinib/placebo in the treatment phase. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date + 1).  
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date).  
A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before or on the first day of itacitinib or 
placebo administration (in terms of date and time, if available).  
4.1.4. 
Retreatment Day 1 
Retreatment Day 1 is the date of first dose of itacitinib in the retreatment phase. 
4.1.5. 
Analysis Visit Definition 
In order to summarize data collected over time (including unscheduled visits and EOT visit), the 
following general rule will be applied in creating analysis visits: 
 Step 1:  The EOT assessment will be assigned to the next available scheduled 
assessment if it is measured within 3 days of the target day of next scheduled visit.  
For example, if a subject has an EOT assessment after scheduled visit Day 21, and the 
next scheduled visit is the Day 28 visit, then the assessment at EOT will be assigned 
to Analysis Visit Day 28 for this subject if they are assessed within 3 days of the 
target day of next scheduled visit.  
 Step 2:  If the scheduled assessment is available (including mapped EOT assessments 
in Step 1), then the scheduled assessment should be used; otherwise, the first 
nonmissing unscheduled assessment should be used. 
Note that laboratory data were not scheduled to be collected per protocol at the Day 180 visit but 
were collected in study execution to support GVHD staging. 


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4.1.6. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting study 
treatment. 
4.1.7. 
Date of Last Contact  
The date of last contact is defined at the subject level as the latest date of discontinuation, 
laboratory assessment, GVHD/ECOG assessment, vital sign, ECG, scheduled or unscheduled 
visit, and any available date in the clinical database showing that the subject is still alive prior to 
or on the clinical data cutoff date. 
4.1.8. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 
Partial disease/cancer diagnosis date will be handled as follows: 
 If only the day is missing, then the imputed day will be the first of the month.  
 If both the month and day are missing, then the imputed day and month will be 
01 JAN.  
 No imputation will be done if the date is completely missing.  
Missing date of last dose in the treatment period will be handled as follows:  
 If the date is completely missing, then the imputed date of the last dose will be date of 
EOS, date of death, date of clinical data cutoff, or retreatment Day 1 – 1, whichever is 
the earliest. 
4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF.  
4.2.1. 
Age 
Subject age was collected before enrollment.  
Age category 1 is defined as < 65 years and ≥ 65 years, and age category 2 is defined as 
< 65 years, 65 to 74 years, 75 to 84 years, and ≥ 85 years. 
4.2.2. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.3. 
Body Surface Area 
Body surface area will be calculated based on the Mosteller (1987) formula as follows: 
BSA (m2) = {[weight (kg)  height (cm)] / 3600}½. 
Sites will also record the BSA calculated per institutional standards. 


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4.2.4. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication taken within 30 days before the first 
dose of study drug. 
Concomitant medication is defined as any nonstudy drug that is started accordingly:  
 Before the date of first administration of study drug and is ongoing throughout the 
study or ends on/after the date of first study drug administration. 
 On/after the date of first administration of study drug and is ongoing or ends during 
the course of study drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of study drug. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant.  
The start/stop dates recorded in the eCRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study.  Unresolved missing 
start dates will be handled as follows: 
 For the starting date, impute as follows: 
 If the day is missing, then impute as the first day of the month. 
 If the month is missing, then impute as the first day of the year. 
 If the year is missing, then the medication will be considered both prior and 
concomitant. 
 For the ending date, impute as follows: 
 If the day is missing, then impute as the last day of the month. 
 If the month is missing, then impute as the last day of the year. 
If the year is missing, then the medication will be considered as ongoing until the end of the 
study. 
Note that the above imputation rules are for the purpose of defining prior and concomitant 
medications in the study.  Imputed start/end dates are not saved in the analysis dataset. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; Version 9.4 or later) will 
be used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries 
for continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
Interim analyses are planned for this study as defined in Section 9. 
5.2. 
Treatment Groups 
This is a randomized, double-blinded, placebo-controlled study with itacitinib or placebo in 
combination with corticosteroids.  There are 2 treatment groups.  Subjects will be randomized 
1:1 to itacitinib 200 mg plus corticosteroids or matching placebo plus corticosteroids.     
5.3. 
Analysis Sets 
5.3.1. 
Interim Analysis 1 
The Interim Analysis 1 clinical data cutoff date was defined as the date when the first 
112 randomized and dosed subjects have either completed the Day 28 visit or withdrawn from 
the study.  This occurred on 25 JUN 2018. 
5.3.1.1. 
Interim 1 Analysis Set 
The Interim 1 analysis set contains all subjects who have been randomized and have received at 
least 1 dose of study drug as of the Interim 1 cutoff date.  The Interim 1 analysis set will be used 
for both planned efficacy and safety analyses at Interim Analysis 1.  Note that subjects 
randomized after the 112th subject in the Interim 1 analysis set are not included in Interim 1 
analyses, even though they might have safety and efficacy data in the clinical database as of the 
Interim 1 cutoff date.  Because Interim Analysis 1 includes limited numbers of analyses, only 
1 analysis set is defined, which is used for both efficacy and safety analyses. 
5.3.2. 
Interim Analysis 2 
The Interim Analysis 2 cutoff date is when the 240th eligible subject randomized in the study 
reaches Day 180 in the treatment phase.  This occurred on 17 APR 2019.   
5.3.2.1. 
Interim 2 Efficacy Analysis Set  
The Interim 2 efficacy analysis set contains all subjects who have been randomized as of the 
Interim Analysis 2 clinical data cutoff date but excludes subjects who are ongoing at the clinical 
data cutoff date and have not finished the Day 28 visit.  The Interim 2 efficacy analysis set will 
be used for all planned efficacy analyses at Interim Analysis 2. 


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5.3.2.2. 
Interim 2 Safety Analysis Set 
The Interim 2 safety analysis set contains all subjects who have been randomized and have 
received at least 1 dose of study drug as of the Interim 2 cutoff date.  The Interim 2 Safety 
Analysis Set will be used for all planned safety analyses at Interim 2.  All safety tables, figures, 
and listings will be presented by actual treatment group. 
5.3.3. 
Final Analysis 
All efficacy analyses and demographic and baseline summaries will be presented by planned 
treatment group, that is, by either itacitinib or placebo.  
5.3.3.1. 
Full Analysis Set 
All subjects who are randomized constitute the FAS.   
The FAS will be used for the summary of demographics, baseline characteristics, subject 
disposition, and analyses of all efficacy data according to intent-to-treat principle.  
5.3.3.2. 
Per Protocol Analysis Set 
The per protocol analysis set comprises the subset of subjects in the FAS who are compliant with 
requirements of the clinical study Protocol, excluding the following: 
 Did not receive any dose of itacitinib/placebo after randomization 
 Did not meet eligibility criteria 
 Had significant deviation(s) from the Protocol in terms of missed study visits, 
noncompliance with randomized therapy or prohibited concomitant medications 
 Subjects later considered as not having aGVHD 
 Subjects with MAGIC Criteria Grade 0 or I at Baseline 
5.3.4. 
Safety Analysis Set 
The safety analysis set includes subjects randomized into the study who received at least 1 dose 
of study drug.  All safety tables, figures, and listings will be presented by actual treatment group.   
5.3.5. 
Pharmacokinetic and Translational Research Evaluable Analysis Set 
Pharmacokinetic and translational research evaluable analysis set includes subjects who receive 
at least 1 dose of study drug and provide at least 1 plasma sample (1 corresponding PK or 
translational research measurement) after study drug administration will be considered as 
potential PK evaluable subjects.  The study pharmacokineticist will review data listings of study 
drug administration and sample records to identify subjects to be excluded from analyses of PK 
data. 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix B provides a list of data displays.   
In the event that the study terminates at Interim Analysis 1 or 2, the interim safety set will be 
used in place of the safety analysis set, the interim efficacy set will be used in place of FAS, and 
any per protocol populations will use subsets of the appropriate interim safety or efficacy set. 
6.1. 
Demographics and Baseline Characteristics, Disease History, 
Transplant History, Medical History, and Prior Therapies 
Demographic and baseline characteristics, disease history, transplant history, medical history, 
and prior therapies will be summarized for the FAS and listed. 
6.1.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics include the following:  age, sex, race, ethnicity, 
weight, height, BMI, BSA, and ECOG performance status. 
6.1.2. 
Hematologic Disease History 
Underlying hematologic disease, diagnosis/type of non-malignant and malignant disease, time 
since initial diagnosis of underlying hematologic disease, and disease risk status will be 
summarized. 
Time since diagnosis of underlying hematologic disease will be calculated as follows: 
Time since diagnosis of underlying hematologic disease (days) = Day 1 – date of diagnosis 
of underlying malignancy + 1. 
6.1.3. 
Allogeneic Hematopoietic Stem Cell Transplant History 
Type of allogeneic transplant, time since transplant, donor source, ex vivo T-cell depletion of the 
allograft (Yes/No), CD34+ positive selection of the allograft (Yes/No), donor CMV type, subject 
CMV status, HLA matching, HLA score, best response of hematologic disease at the time of 
transplant, days of diagnosis of aGVHD since transplantation, GVHD organ staging categories, 
and type of conditioning treatment regimens will be summarized in the FAS by treatment group. 
Time since transplant will be calculated as follows: 
Time since transplant (days) = Day 1 – date of transplant + 1. 
Days of diagnosis of aGVHD since transplantation will be calculated as follows: 
Days of diagnosis of aGVHD (days) since transplantation = date of diagnosis of GVHD – 
date of transplantation + 1. 


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6.1.4. 
Medical History 
For subjects in the FAS, medical history will be summarized by treatment group.  This 
summation will include the number and percentage of subjects with significant medical history 
for each body system/organ class as documented on the eCRF. 
6.1.5. 
Prior Anticancer Therapy or Radiotherapy  
Number of subjects who received prior anticancer therapy will be summarized for the FAS.  
Regimen name, component drugs, start and stop dates, purpose of the regimen, best response, 
reason for discontinuation, and date of relapse/progression will be listed. 
Number of subjects who received prior radiation will be summarized for the FAS.  Radiotherapy 
type, body site, start and stop dates, total dose, and best response will be listed. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were randomized, discontinued study treatment with 
a primary reason for discontinuation, and withdrew from the study with a primary reason for 
withdrawal will be summarized for the FAS by treatment group.  Subjects entering and 
discontinuing retreatment will also be summarized.  
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be presented in the subject data listings.  
Incidence of different types of protocol deviations will be summarized by treatment group. 
6.4. 
Transfusions Performed On Study or Within 30 Days Before 
Enrollment 
Within 30 days before enrollment, blood component, time since transfusion, quantity, and unit, 
given AE for transfusion, and the reason for the PRBC/platelet transfusion will be listed.  
Transfusion performed at any time after randomization will be listed together with those 
performed within 30 days before enrollment. 
6.5. 
Exposure 
For subjects in the safety analysis set, exposure to study drug will be summarized descriptively 
as follows: 
 Duration of treatment with study drug: 
Duration of treatment (days) = Date of last dose of study drug – Date of first dose of 
study drug + 1 
 Average daily dose of study drug: 
Average daily dose of study drug (mg/day) = [total actual study drug dose taken 
(mg)] / [duration of treatment with study drug] 
Frequency distribution of itacitinib/placebo duration category (days) will be tabulated by 
concatenated intervals:  Day 1 through Day 28, Day 29 through Day 100, Day 101 through 
Day 180, and > Day 180. 


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Similarly, duration of corticosteroid and average daily dose of corticosteroid before EOT as the 
background therapy will be summarized by treatment group.  Frequency distribution of 
corticosteroid duration category (days) will be tabulated by concatenated intervals. 
Frequency distribution of itacitinib/placebo dose modification in the treatment phase (ie, dose 
decreased due to toxicity, dose increased, dose tapered, dose temporarily interrupted and with 
previous dose resumed) will be tabulated by concatenated intervals:  Day 1 through Day 28, 
Day 29 through Day 56, Day 57 through Day 84, Day 85 through Day 112, Day 112 through 
Day 140, Day 141 through Day 168, Day 169 through Day 196, Day 197 through Day 224, 
Day 225 through Day 252, Day 253 through Day 280, Day 281 through Day 308, Day 381 
through Day 336, Day 337 through Day 365, and > Day 365.  
In order to summarize corticosteroid use over time in the treatment phase, for days of interest  
Day X (ie, X = 14, 28, 56, 100, and 180, separately), average corticosteroid dose (mg/day) 
during the week ending on Day X, relative corticosteroid dose (%) during the week ending on 
Day X will be summarized by treatment group.  Number and percentage of subjects ongoing 
with itacitinib/placebo and ongoing with corticosteroid on Day X respectively will be 
summarized by treatment group. 
6.6. 
Study Drug Compliance 
For subjects in the safety analysis set, overall compliance (%) for study drug will be calculated 
for all subjects as follows: 
Overall compliance (%) = 100  [total dose actually taken (mg)] / [total prescribed 
dose (mg)] 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications.  The total dose actually taken (mg) is derived by sum of daily 
dose taken in a specific duration of treatment. 
6.7. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
For subjects in the safety analysis set, the number and percentage of subjects with prior and 
concomitant medications will be summarized by WHO drug class and WHO drug term.  In the 
data listing, each medication will be recorded as prior, concomitant, or both prior and 
concomitant.  
The number and percentage of subjects receiving prior GVHD prophylaxis medications will be 
summarized by treatment group. 
The number and percentage of subjects who have ever taken immunosuppressive medications at 
baseline will be summarized overall and by treatment group.  Subjects who took 
immunosuppressive medications in the 7 days before or on Days 1, 14, 28, 56, 100, and 180 
during the treatment phase will be summarized by treatment group. 
The number and percentage of subjects undergoing each type of conditioning regimen will be 
summarized by treatment group. 


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7. 
EFFICACY 
Appendix B provides a list of planned data displays. 
7.1. 
General Considerations 
In all efficacy analyses, initiation of new, systemic anti-GVHD therapy includes 2 scenarios:  
1) initiation of new anti-GVHD therapy including a higher dose of corticosteroid than that used 
at Day 1 and 2) initiation of new, systemic anti-GVHD therapy when subjects who were treated 
with placebo in the treatment phase were re-treated with itacitinib in the retreatment phase.  
Initiation of new, systemic anti-GVHD therapy will be considered when defining the following:  
1) onset of response and 2) loss of response.  When defining responder for Day 28 ORR; overall 
response at Days 14, 56, 100, and 180; and BOR, the onset of response will be censored by 
initiation of new, systemic anti-GVHD therapy.  Responders who did not have GVHD 
progression or death after response will be censored at the time of either study withdrawal, 
initiation of new, systemic anti-GVHD therapy, or the date of last assessment of GVHD before 
or on the cutoff date, whichever is earliest.  In the survival analysis of NRM, all subjects in the 
analysis set in question without a death due to causes other than malignancy relapse will be 
censored at either study withdrawal, death due to malignancy relapse, or the date of last contact 
before or on the cutoff date, whichever is earliest. 
Duration of response will be calculated for every subject who has a response in the study; DOR 
will also be summarized for any subgroups of interest. 
7.2. 
Efficacy Hypotheses 
The primary efficacy analysis is the comparison of ORR at Day 28 between the 2 treatment 
groups.  The following statistical hypotheses will be tested to address the primary efficacy 
objective: 
H0:  ORRitacitinib = ORRpbo  versus   H1:  ORRintcitinib > ORRpbo 
where ORRitacitinib and ORRpbo are the ORRs at Day 28 in the itacitinib and placebo groups, 
respectively.  The CMH chi-square test, stratified by the randomization stratification factor 
(ie, standard risk and high risk), will be used to compare ORR between the 2 treatment groups, at 
the 1-sided 2.5% level of significance. 
For the primary efficacy analyses, Day 28 ORR, as well as ORR for scheduled visits at Days 14, 
56, 100, and 180, if available, will be used; if a scheduled assessment is not available but an 
unscheduled visit is available (within 3 days of the scheduled date), then the unscheduled 
assessment closest to the scheduled date will be used. 
For summary analyses over time, analysis visits are defined Section 4.1.5, where analysis visits 
will be used in both tables and figures.  The listings will include all collected data from the eCRF 
regardless of whether the visits are scheduled or unscheduled. 


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7.3. 
Analysis of the Primary Efficacy Endpoint 
For all of the following regression analyses specified, regardless of logistic regression, Cox 
regression, or cause-specific hazard/subdistribution hazard regression in competing-risks 
analyses, the covariates in the final model can differ from what is specified, depending on the 
unblinded data.  
7.3.1. 
Primary Efficacy Analysis 
7.3.1.1. 
Day 28 Overall Response Rate 
The primary efficacy endpoint, ORR at Day 28 (ie, with either a CR, VGPR, or PR at Day 28 
assessment or other response assessments within 3 days of Day 28, before start of new 
anti-GVHD therapy), will be analyzed using a stratified CMH test.  Note that the EOT visit must 
be accounted for in the Day 28 ORR calculation, because when the EOT and Day 28 visits occur 
at the same time, per protocol, EOT will supersede the Day 28 visit.  That is, if the EOT visit 
occurs when the Day 28 visit is planned, data from the EOT visit will be used in lieu of the 
Day 28 visit. 
Responders (CIBMTR 2009, Harris et al 2016; refer to Protocol Appendix B): 
 (CR) Complete response 
 (VGPR) Very good partial response 
 (PR) Partial response 
Non-responders: 
 (MR) Mixed response 
 (PD) Progression of disease 
 (NR) No response 
 (NA) Not applicable 
 Other 
 Missing (primary reason) 
 Death prior to the Day 28 visit 
 Withdrawal from study prior to the Day 28 visit 
 Initiation of new anti-GVHD therapy prior to the Day 28 visit 
 Missing visit 
Day 28 ORR will be summarized using descriptive statistics (N, %) by treatment group with 
2-sided exact binomial 95% CIs.  P-value, mean proportion difference, odds ratio, and 95% Wald 
confidence limits calculated from stratified CMH test will be also presented.  


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7.3.1.2. 
Sensitivity Analyses for Day 28 Overall Response Rate 
Sensitivity analyses for Day 28 ORR will consist of the following: 
 Stratified CMH test for Day 28 ORR in the full and per-protocol analysis sets 
 Logistic regression method with both treatment group and baseline GVHD risk status 
as cofactors in the model for the efficacy population 
 Separate CMH test by baseline GVHD risk status 
7.3.2. 
Duration of Response for Day 28 Responders 
The DOR is defined from the time of the first response to the loss of response (ie, either disease 
progression or death).  Responders who did not progress or die after onset of response will be 
censored, and response will be ended at either study withdrawal, initiation of new anti-GVHD 
therapy, or last response assessment before or on the cut-off date, whichever is earliest. 
Duration of response will be calculated for every responder as well as Day 28 responders. 
The DOR for the Day 28 responders will be assessed using the KM method only for subjects 
who achieve Day 28 response.  The KM curves; medians; 1-, 2-, 6-, 12-, 18- and 24-month 
(equivalently at Days 30, 60, 180, 365, 547, and 730) survival estimates and 95% CIs will be 
estimated (Brookmeyer and Crowley 1982).  The DOR will be assessed for each treatment group 
and also by stratum and Day 28 response status.  
7.3.3. 
Alternative Ways of Calculating Duration of Response for Day 28 Responders 
There are 2 other ways of calculating DOR for Day 28 responders: 
 DOR alternate approach 1 – DOR is defined as the interval from Day 28 to either 
death or initiation of new anti-GVHD therapy, including a higher corticosteroid dose 
than that administered at Day 1, whichever is earlier. 
 DOR alternate approach 2 – DOR is defined as the interval from Day 28 to the 
earliest of death, worsening from best response at or after Day 28 in any organ stage, 
or initiation of new anti-GVHD therapy (including a higher corticosteroid dose than 
that administered at Day 1). 
Summary statistics and KM estimate will be provided by treatment group.  Kaplan-Meier plots 
will also be provided. 
7.3.4. 
Subgroup Analyses for Primary Endpoint 
The primary endpoint will be tabulated and forest plots for odds ratios will be generated for the 
following subgroups: 
 Age group (18-65 vs > 65 years) 
 MacMillan (2015) age group: (18-40 years vs >40 years)  
 Sex 
 Race (White vs non-White) 


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 Region (North America vs Western Europe vs Rest of world) 
 North America:  Canada, United States 
 Western Europe:  Belgium, Denmark, France, Germany, Italy, Netherlands, 
Spain, Sweden, Switzerland, United Kingdom, Austria, Finland, Greece, Portugal, 
Switzerland, Ireland 
 Rest of world:  Australia, Chile, Israel, Japan, South Korea, Mexico, New 
Zealand, Poland, Russia, South Africa, Czech Republic, Hungary, Singapore, 
Taiwan 
 HLA/donor source category (Identical, Matched related, Matched unrelated, 
Mismatched related, Mismatched unrelated, Other, Missing)  
 Type of Allogeneic Transplant (Bone Marrow, Peripheral Blood Stem Cell, Cord 
Blood, Other) 
 Baseline aGVHD grade  
 Skin involvement at Baseline (Yes or No) 
 Lower GI involvement at Baseline (Yes or No) 
 Upper GI involvement at Baseline (Yes or No) 
 Liver involvement at Baseline (Yes or No) 
 Baseline GVHD risk status 
 Underlying hematologic disease (malignant or non-malignant) 
 Days from allo-HSCT to Day 1 (< 28 days and ≥ 28 days) 
 Subjects aGVHD status determined after randomization (had aGVHD, did not have 
aGVHD)  
7.4. 
Analysis of the Secondary Efficacy Endpoints 
7.4.1. 
Key Secondary Endpoint Analysis 
Nonrelapse mortality is defined as death due to causes other than malignancy relapse.  For the 
primary analysis, the NRM rate will be estimated using the proportion of subjects with a death 
due to causes other than malignancy relapse within the subjects who were known alive at 
Day 180 or who had such a death.  Reasons for not including a subject in this proportion include: 
 Subject was alive and had not reached Day 180  
 Death due to malignancy relapse 
 Subject ended study participation prior to Day 180 (summarized by reason for study 
withdrawal) 
A sensitivity analysis will also be conducted estimating the NRM rate using the KM estimator 
for each treatment. 


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7.4.1.1. 
Primary Analysis of Nonrelapse Mortality Rate at Month 6 (Day 180) 
For the primary analysis, NRM will be analyzed using a stratified CMH test.  Month 6 NRM will 
be summarized using descriptive statistics by treatment group with 2-sided exact binomial 95% 
CIs.  P-value, mean proportion difference, odds ratio, and 95% Wald confidence limits 
calculated from stratified CMH test will also be presented.  
Let 
 be the estimated proportion of evaluable subjects in the placebo group in stratum i who 
died due to causes other than malignancy relapse prior to or on Day 180 (ie, excluding those 
subjects who are either ongoing and have not reached Day 180, who withdrew from study prior 
to Day 180, or who died due to relapse) with corresponding variance estimator 
.  Let 
 and 
 be the same for the itacitinib group in stratum i.   
The overall estimate of treatment difference in Day 180 NRM between placebo and itacitinib is 
defined as the following: 
 
Its 95% CI is the above estimate of difference 
 
  
With weight 
 defined by inverse of variance in 2 baseline GVHD risk groups.  That is: 
 


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7.4.1.2. 
Sensitivity Analysis of Nonrelapse Mortality Rate at Month 6 (Day 180) Using 
Kaplan-Meier Approach 
A sensitivity analysis will also be conducted where NRM at Day 180 will be estimated by 1 
minus the survival probability at Day 180 using the KM estimator. 
A stratified test statistic for NRM rate at Day 180 is proposed as: 
 
 
 
 
 and 
 are the cumulative distribution function 
estimate at Day 180 in the placebo group in the jth stratum and its variance, respectively.  
 and 
 are defined similarly in the itacitinib group 
for jth stratum subjects.  
 will be asymptotically distributed as a Chi-square test 
statistic with degree of freedom equal to 1. 
The overall estimate of treatment difference in Day 180 NRM between placebo and itacitinib is 
thus defined as the following: 
 
Its 95% CI is the above estimate of difference 
with weight 
 defined by inverse of variance in two baseline GVHD risk groups.  That is: 
 
In order to conduct above hypothesis testing for NRM at Day 180, time to NRM, defined as the 
interval between randomization and death due to causes other than malignancy relapse, will be 
derived.  All subjects in the FAS without a death due to causes other than malignancy relapse 
will be censored at either study withdrawal, death due to malignancy relapse, or the date of last 
contact before or on the cutoff date, whichever is earliest. 


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7.4.1.3. 
Nonrelapse Mortality Rate Using Kaplan-Meier Approach 
The survival distribution of NRM in each treatment group overall
 
 will be estimated using the KM method, and the KM curves; medians; 
1-, 2-, 3-, 6-, 9-, 12-, 18-, and 24-month survival estimates; and 95% CIs will be presented 
(Brookmeyer and Crowley 1982). 
7.4.2. 
Survival Analyses of Nonrelapse Mortality 
Time to death due to causes other than malignancy relapse (NRM) will be analyzed according to 
the randomized treatment group and strata assigned at randomization. 
The hazard ratio of itacitinib relative to placebo overall 
 will be 
calculated, along with its 95% CI, using a stratified Cox model.  
Stratified log-rank test will also be used to test survival curve of NRM in the treatment group 
relative to placebo group using the FAS.  
Subgroup KM analyses of NRM will also be conducted by Day 28 response status 
 
. 
7.4.3. 
Competing-Risks Analyses of Nonrelapse Mortality 
In the literature, analyzing NRM is normally conducted in the context of a competing-risks 
situation.  Time from randomization to first occurrence of NRM or competing event is observed 
and used for analysis; otherwise, the subject is censored.  Nonrelapse mortality and a 
competing-risk event are mutually exclusive.  This is because a subject either dies due to 
malignancy relapse, dies due to an event other than malignancy relapse, or is censored at last 
follow-up.  There are 2 types of competing-risks analyses: 
 I:  Time to NRM competing with time to malignancy relapse 
Time to first occurrence of either death due to reasons other than malignancy relapse 
(NRM) or malignancy relapse is defined as an event of interest and competing risk 
event, respectively.  Subjects without an event (neither event of interest nor 
competing event) will be censored at the date of study withdrawal or date of last 
contact before or on the cutoff date, whichever is the earlier. 
 II:  Time to NRM competing with time to death due to malignancy relapse 
Time to first occurrence of either death due to reasons other than malignancy relapse 
(NRM) or death due to malignancy relapse is defined as an event of interest and 
competing risk event, respectively.  Subjects without an event (neither event of 
interest nor competing event) will be censored at the date of study withdrawal or date 
of last contact before or on the cutoff date, whichever is the earlier. 
For each of the competing-risks analyses (ie, I and II), there are 2 ways of modeling conducted in 
this study.  The first one is cause-specific hazard modeling and the second one is subdistribution 
hazard modeling. 


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In cause-specific hazard modeling, competing events will be censored, and a stratified log-rank 
test 
 will be used to test 2 KM 
curves with KMC estimate equals 1 minus KM estimate.  In cause-specific hazard modeling, 
stratified Cox regression model 
 
with a cofactor of treatment group will be used to estimate cause-specific hazard ratio (itacitinib 
vs placebo) and 95% CI. 
In subdistribution hazard modeling, competing-risk events will be considered to remain in the 
risk set as described by Gray (1988).  Stratified Gray’s test 
 
 will be used to test equality of 2 cumulative incidence curves.  
Cumulative incidence function at Day 180 (SE) will be estimated.  Stratified subdistribution 
hazard regression (Fine and Gray 1999) with cofactor of treatment group (itacitinib vs placebo) 
will be performed, and subdistribution hazard ratio (95% CI) on treatment effect (itacitinib vs 
placebo) will be estimated. 
Cumulative incidence curve for each competing-risk analysis will be plotted overall by Day 28 
response status 
 
7.4.4. 
Overall Response Rate at Days 14, 56, 100, and 180 
Similar to Day 28 ORR, ORR at Days 14, 56, 100, and 180, respectively, is defined as the 
proportion of subjects demonstrating a CR, VGPR, or PR at a defined analysis visit/window 
(ie, ± 3 days of scheduled visit date). 
The ORR on Days 14, 56, 100, and 180 will be estimated with a 95% CI.  The proportion of 
responders will be estimated with 95% CIs.  Confidence intervals will be calculated based on the 
exact method for binomial distributions.  Summary statistics will be provided. 
7.4.5. 
Best Overall Response 
Best overall response for each subject is defined as best response during the course of the study 
(best in the categories of CR, VGPR, or PR), including responses at unscheduled visits. 
Subjects without a BOR (ie, subjects not achieving a response of either CR, VGPR, or PR) in the 
treatment phase will be considered as nonresponders for BOR in the responder analysis.  Number 
and percentage of subjects in each best response category will be tabulated by treatment group in 
the FAS. 
7.4.6. 
Time to Response 
Time to response is defined as time from randomization to the first response of either CR, 
VGPR, or PR before initiation of new anti-GVHD therapy.  In the TTR analysis, subjects 
without a response after randomization will be censored at either study withdrawal, initiation of 
new, systemic anti-GVHD therapy, death, or last response assessment prior to or on the cutoff 
date, whichever is earliest. 
The KM curves; medians; 1-, 2-, 6-, 12-, 18-, and 24-month (at Days 30, 60, 180, 365, 547, and 
730, respectively) survival estimates, and 95% CIs will be estimated (Brookmeyer and 
Crowley 1982). 


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7.4.7. 
Relapse Rate of Malignant and Nonmalignant Hematologic Diseases 
Relapse rate of malignant and nonmalignant hematologic diseases is defined as the proportion of 
subjects whose underlying hematologic diseases relapse.  Incidence of such events will be 
tabulated with summary statistics. 
7.4.8. 
Malignancy Relapse-Related Mortality Rate 
Malignancy relapse-related mortality rate is defined as the proportion of subjects whose 
malignancies relapse and have a fatal outcome.  Incidence of such events will be tabulated with 
summary statistics. 
7.4.9. 
Failure-Free Survival 
Failure-free survival is defined as the proportion of subjects who are still alive, have not relapsed 
of underlying hematologic disease, have not required additional therapy for aGVHD, and have 
not had signs or symptoms of cGVHD.  Subjects without an event of relapse of underlying 
hematologic disease, death due to relapse, death due to causes other than relapse, initiation of 
new anti-GVHD therapy, or signs or symptoms of cGVHD will be censored at the date of study 
withdrawal or the date of last contact before or on the data cutoff date, whichever is earlier.  
After randomization, the FFS event date will be the first occurrence of one of the following: 
 Initiation of anti-GVHD therapy, or 
 Relapse/recurrence of underlying hematologic disease, or 
 Death due to malignancy relapse, or  
 Death due to causes other than malignancy relapse, or 
 Signs or symptoms of cGVHD. 
Failure free survival will be analyzed according to the randomized treatment group and strata 
assigned at randomization. 
The survival distribution of FFS in each treatment group overall 
 will be estimated using the KM method, and the KM curves; medians; 1-, 2-, 6-, 12-, 18-, 
and 24-month (at Days 30, 60, 180, 365, 547, and 730, respectively) survival estimates, and 95% 
CIs will be presented (Brookmeyer and Crowley 1982).  The hazard ratio of treatment relative to 
placebo overall 
 will be calculated, along with its 95% CI, using a 
stratified Cox model.  Stratified log-rank test will also be used to test FFS survival curve in the 
itacitinib group against the placebo group. 
Subgroup KM analyses of FFS will also be conducted by Day 28 response status 
 
 


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7.4.10. 
Overall Survival 
Overall survival is defined as the time from randomization to death due to any cause during the 
study.  The KM method will be used to estimate the survival time distribution and the median 
survival.  Subjects with no observed death or loss to follow-up will be treated as censored at 
either the date of study withdrawal or the date of last contact prior to or on the data cutoff date, 
whichever is later. 
Overall survival will be analyzed according to the randomized treatment group and strata 
assigned at randomization. 
The survival distribution of OS in each treatment group overall
 will be 
estimated using the KM method, and the KM curves; medians; 1-, 2-, 6-, 12-, 18-, and 24-month 
(at Days 30, 60, 180, 365, 547, and 730, respectively) survival estimates, and 95% CIs will be 
presented (Brookmeyer and Crowley 1982).  The hazard ratio of itacitinib relative to placebo 
overall 
 will be calculated, along with its 95% CI, using a stratified 
Cox model.  Stratified log-rank test will also be used to test the OS survival curve in the 
itacitinib group against the placebo group. 
Subgroup KM analyses of OS will also be conducted by Day 28 response status 
 
. 
7.5. 
Other Secondary Efficacy Analyses  
Secondary graft failure will be tabulated with summary statistics. 
Incidence rate of aGVHD flares through Day 100 will be summarized.  Summary statistics will 
be provided. 
Average and cumulative corticosteroid dose during the weeks ending on Days 28, 56, 100, and 
180 will be tabulated.  Proportions of subjects who discontinue corticosteroids will be 
summarized.   
Proportions of subjects who discontinue immunosuppressive medication on Days 56 and 100 
will be tabulated.  Summary statistics will be provided. 
Incidence of cGVHD (Days 180 and 365 and overall) will be estimated.  Summary statistics will 
be provided. 
 
.  
Subgroup analyses will be conducted by underlying hematologic disease (malignant vs 
nonmalignant), as appropriate.  


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7.6. 
Analysis of Exploratory Efficacy Variables 
The following exploratory endpoints will be summarized by treatment group using the FAS: 
 
 
 
 
 
 Summary of primary and contributing causes of death. 
 Summary of donor chimerism. 
 Summary of criteria and action taken for relapse of underlying disease. 
7.7. 
Pharmacokinetic Analyses 
A population PK analysis for itacitinib will be performed.  Pharmacokinetic data from clinical 
Study INCB 39110-105 will be combined with data from this study, INCB 39110-301, and will 
aid in identification of the structural model and improve parameter estimation. 
The population PK data preparation will be performed using SAS version 9.1 or later (SAS 
Institute Inc., Cary, NC).  Exploratory data analyses and presentations of data will be performed 
using R version 3.2.0 or later (www.r-project.org), SPlus version 7.0 or later (Tobco Software 
Inc., Palo Alto, CA), and/or SAS version 9.1 or later.  The PK analyses will use NONMEM 
version 7.1.0 or later (ICON Development Solutions, Dublin, Ireland) or Monolix version 
2018R1 or later (Lixoft, Antony, France).  The individual post hoc PK model parameters (CL/F, 
V/F, if applicable) will be determined and will be used to simulate individual exposures.  
Observed PK parameters such as Cmax, tmax, and Cmin will also be presented and summarized.  
Simulation may be used to evaluate potential dose modifications if any covariates, for example, 
renal or hepatic impairment, are noted to have a clinically significant impact on exposure. 
Additional details regarding this analysis may be found in the data analysis plan 
(DMB-18.155.1). 
 
 
 
 
 
 
 
 


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8. 
SAFETY AND TOLERABILITY 
Appendix B provides a list of data displays. 
8.1. 
General Considerations 
All safety analyses will be conducted using the safety analysis set and summarized by actual 
treatment received on Day 1.  Summary tables may be replaced with listings when appropriate.  
For instance, an AE frequency table may be replaced with a listing if it only contains a few 
unique PTs reported on relatively few subjects. 
For summary analyses over time, analysis visits for laboratory assessments/vital signs/ECGs are 
defined in Section 4.1.5. 
Listings will include all collected visits from the eCRF regardless of whether the visits are 
scheduled or unscheduled. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE in the treatment phase is either an AE reported for the first time or worsening of a 
pre-existing condition after first dose of itacitinib/placebo and before or at 30 days after last dose 
in the treatment phase.  Analysis of AEs will be limited to TEAEs that occur during the treatment 
phase, but data listings will include all AEs, regardless of their timing with regard to study 
treatment administration. 
A TEAE in the retreatment phase is either an AE reported for the first time or worsening of a 
pre-existing condition on or after Day 1 of retreatment with itacitinib.  Treatment-emergent AEs 
in the retreatment phase will be listed. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be described 
and graded using the NCI CTCAE v4.03 (NCI 2010).  The CTCAE reporting guidelines and 
grading details are available on the Cancer Therapy Evaluation Program website. 
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, then it will be rated on a scale of 1 to 5 as follows:  1 = mild, 
2 = moderate, 3 = severe, 4 = life-threatening, and 5 = fatal.  All toxicities will be graded based 
on the worst level reached, not the level they may have reached if they had not been treated.  
When the intensity of an AE changes over time for a reporting period (eg, between visits), then 
each change in intensity will be reported as an AE until the event resolves. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related TEAEs.  If the investigator does not specify the relationship of the AE to 
study drug, then the AE will be considered to be treatment-related.  The incidence of TEAEs and 
treatment-related TEAEs will be tabulated.  Serious TEAEs will also be tabulated. 


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Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing values will be handled according to the following rules: 
 An unresolved missing causality will be considered treatment-related. 
 An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
8.2.2. 
Adverse Event Summaries 
An overall summary of AEs in the treatment phase by treatment group will include the 
following: 
 Number (%) of subjects reporting any TEAEs  
 Number (%) of subjects reporting any serious TEAEs  
 Number (%) of subjects reporting any Grade 3 or higher TEAEs 
 Number (%) of subjects reporting any TEAEs related to itacitinib/placebo 
 Number (%) of subjects reporting any TEAEs related to corticosteroids 
 Number (%) of subjects who temporarily interrupted itacitinib/placebo because of 
TEAEs 
 Number (%) of subjects with itacitinib/placebo dose reduction because of TEAEs 
 Number (%) of subjects who permanently discontinued itacitinib/placebo because of 
TEAEs 
 Number (%) of subjects who permanently discontinued itacitinib/placebo and 
corticosteroids because of TEAE 
 Number (%) of subjects who had a fatal TEAE 
 Number (%) of subjects who withdrew from the study because of a TEAE 
Overall summaries of AEs (as described above) will also be provided by age group, sex, race, 
and region. 
The following summaries will be produced for TEAEs occurring in the treatment phase by 
MedDRA term (if 10 or fewer subjects appear in a table, a listing may be appropriate): 
 Number (%) of subjects reporting TEAEs by SOC and PT 
 Number (%) of subjects reporting TEAEs by PT in decreasing order of frequency  
 Number (%) of subjects reporting TEAEs by SOC, PT, and highest grade 
 Number (%) of subjects reporting Grade 3 or higher TEAEs by SOC and PT 
 Number (%) of subjects reporting Grade 3 or higher TEAEs by PT in decreasing 
order of frequency 


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 Number (%) of subjects reporting itacitinib/placebo treatment-related TEAEs by SOC 
and PT 
 Number (%) of subjects reporting itacitinib/placebo treatment-related TEAEs by PT 
in decreasing order of frequency 
 Number (%) of subjects reporting itacitinib/placebo treatment-related TEAEs by 
SOC, PT, and highest grade 
 Number (%) of subjects reporting Grade 3 or higher itacitinib/placebo treatment-
related TEAEs by SOC and PT 
 Number (%) of subjects reporting fatal TEAEs by SOC and PT 
 Number (%) of subjects reporting serious TEAEs by SOC and PT  
 Number (%) of subjects with serious TEAEs by PT in decreasing order of frequency 
 Number (%) of subjects reporting itacitinib/placebo treatment-related serious TEAEs 
by SOC and PT 
 Number (%) of subjects reporting TEAEs leading to itacitinib/placebo dose 
interruption by SOC and PT 
 Number (%) of subjects reporting TEAEs leading to itacitinib/placebo dose reduction 
by SOC and PT 
 Number (%) of subjects reporting TEAEs leading to discontinuation of 
itacitinib/placebo by SOC and PT 
 Number (%) of subjects reporting corticosteroid treatment-related TEAEs by SOC 
and PT 
 Number (%) of subjects reporting corticosteroid treatment-related TEAEs by PT in 
decreasing order of frequency 
 Number (%) of subjects reporting corticosteroid treatment-related TEAEs by SOC, 
PT, and highest grade 
 Number (%) of subjects reporting corticosteroid treatment-related Grade 3 or higher 
TEAEs by SOC and PT 
 Number (%) of subjects reporting corticosteroid treatment-related serious TEAEs by 
SOC and PT 
 Number (%) of subjects reporting TEAEs leading to corticosteroid dose interruption 
by SOC and PT 
 Number (%) of subjects reporting TEAEs leading to corticosteroid dose reduction by 
SOC and PT 
 Number (%) of subjects reporting TEAEs leading to discontinuation of 
corticosteroids by SOC and PT 
 Number (%) of subjects reporting TEAEs leading to withdrawal from the study by 
SOC and PT 


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The following summaries will be produced for TEAEs occurring in the treatment phase by 
MedDRA term based on baseline hepatic impairment status in combination with postbaseline 
azole usage: 
 Number (%) of subjects reporting serious TEAEs by SOC and PT 
 Number (%) of subjects reporting Grade 3 or higher TEAEs by SOC and PT 
 Number (%) of subjects reporting fatal TEAEs by SOC and PT 
 Number (%) of subjects reporting itacitinib/placebo treatment-related TEAEs by SOC 
and PT 
 Number (%) of subjects reporting Grade 3 or higher thrombocytopenia TEAEs by 
SOC and PT based on customized MQ 
 Number (%) of subjects reporting Grade 3 or higher neutropenia TEAEs by SOC and 
PT based on customized MQ 
 Number (%) of subjects reporting Grade 3 or higher anemia TEAEs by SOC and PT 
based on customized MQ 
Severity of hepatic impairment at baseline is defined as follows: 
 Normal:  Total bilirubin ≤ ULN and AST ≤ ULN 
 Mild:  Total bilirubin > 1.0 to 1.5 × ULN and AST = any value or 
total bilirubin ≤ ULN and AST > ULN 
 Moderate:  Total bilirubin > 1.5 to 3 × ULN and AST = any value 
 Severe:  Total bilirubin > 3.0 × ULN and AST = any value 
If multiple azoles were used postbaseline, the most potent azole will be used for classification 
according to the following potency order (listed from strongest to weakest): 
1. Ketoconazole 
2. Itraconazole 
3. Voriconazole 
4. Posaconazole 
5. Fluconazole 


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8.3. 
Clinically Notable Treatment-Emergent Adverse Events Based on 
Customized MedDRA Queries 
The following categories of clinically notable events will be summarized based on customized 
MQs (see Appendix C): 
 Anemia 
 Neutropenia 
 Thrombocytopenia 
 QT prolongation 
 Hyperlipidemia 
 EBV infection 
 CMV infection 
Within each category, the number and percentage of subjects with at least 1 TEAE occurring 
during the treatment phase tabulated by MedDRA PT will be summarized.  Summaries of 
clinically notable TEAEs based on customized MQs will be provided by treatment group, 
category, PT, and the highest grade or outcome. 
 Overall summary of clinically notable TEAEs in the treatment phase based on 
customized MQs 
 Number (%) of subjects with clinically notable TEAEs in the treatment phase based 
on customized MQs by PT and outcome 
 Number (%) of subjects with clinically notable TEAEs in the treatment phase based 
on customized MQs by PT and highest grade 
8.4. 
Clinical Laboratory Tests 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into CTC grades for AEs (CTCAE v4.03).  The following 
summaries will be produced for the laboratory data: 
 Shift tables using CTC grades to compare baseline with the worst postbaseline value 
will be produced with CTC grade. 
 For laboratory parameters where CTC grades are not defined, shift tables to the worst 
postbaseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs will be provided for platelets, 
neutrophils, cholesterol, and triglycerides over time in the treatment phase, plotted by treatment 
group.   


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8.5. 
Vital Signs 
Descriptive statistics and mean change from baseline will be summarized for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time by treatment 
group.  Vital sign results will be reviewed for clinically notable abnormalities (see Table 6), and 
subjects exhibiting clinically notable vital sign abnormalities will be listed.  A value will be 
considered an "alert" value if it is outside the established range and shows a > 25% change from 
baseline. 
Table 6:  
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
8.6. 
Electrocardiograms 
Electrocardiogram results will be reviewed for clinically notable abnormalities according to 
predefined criteria (see Table 7).  Subjects exhibiting clinically notable ECG abnormalities will 
be listed and summarized by treatment group.  Adverse events will be reported for clinically 
notable abnormalities that are considered clinically significant in the judgment of the 
investigator. 
Descriptive statistics (N, mean [SD], minimum, median, and maximum) at baseline for each 
parameter will be summarized by treatment group.  At EOT, summary statistics of mean change 
(SD) and percentage change will also be tabulated by parameter and treatment group.  
Table 7: 
Criteria for Clinically Notable ECG Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS 
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR 
> 1330 ms 
< 600 ms 
QTcF = Fridericia correction. 


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9. 
INTERIM ANALYSES AND FINAL ANALYSES 
9.1. 
Overview of Interim Analyses 
There are 2 planned interim analyses.  The first interim analysis is for futility checking and 
second interim analysis is for efficacy and futility.  
9.1.1. 
Interim Analysis 1 
The first interim analysis for futility only will be performed when 112 (25.7% of the planned 
436 subjects) have completed the Day 28 visit or withdrew early from study.  No alpha will be 
spent during the first interim analysis.  The stopping rule is nonbinding.  When the conditional 
power is < 20%, the sponsor may consider terminating the trial if the totality of evidence is 
warranted.   
Interim Analysis 1 on ORR at Day 28 will be carried out as follows: 
F1:  Obtain CMH test statistic (chi-square test with degree of freedom 1); 
F2:  Obtain observed normalized test statistic z by taking square root of CMH in F1; 
F3:  Calculate conditional power based on 
 (Jennison and Turnbull 1999), 
where Φ is the cumulative distribution function of the observed normalized test statistic z.  
t is the information fraction and (ie, observed sample at interim divided by planned total 
sample size 436); t = 0.257 at Interim 1 and 
 1.96. 
F4:  If conditional power is less than 20%, the sponsor may consider stopping the study for 
futility; otherwise, the study will continue.   
9.1.2. 
Interim Analysis 2 
For Interim Analysis 2, the analysis of both efficacy and futility will use a clinical database 
cutoff based on when 240 eligible subjects (55.0% of the targeted 436 subjects) have completed 
the Day 180 visit or withdrawn from the study prior to Day 180. 
The Hwang-Shih-DeCani alpha spending function with shape parameter -4 (O'Brian Fleming 
like boundary) will be used to define nonbinding upper efficacy boundary  for the primary 
analysis of ORR at Day 28 when approximately 240 eligible subjects reach Day 180.  Based on 
enrollment projection, there will be approximately 360 subjects who have completed Day 28.   
The futility analysis based on test of ORR at Day 28 at Interim Analysis 2 will be carried out the 
same way as in Interim Analysis 1 (Steps F1-F4) but using the observed information fraction and 
observed normalized test statistic from Interim Analysis 2. 


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Table 2 lists efficacy boundary when information fraction (ie, the percentage of subjects) is 
0.826 (360 subjects complete Day 28 or withdraw from the study) at Interim Analysis 2.  If the 
test on ORR at Day 28 crosses the boundary, then the key secondary endpoint, 6-month NRM 
rate, will be tested using a separate boundary using the Bonferroni method for alpha-spending 
(ie, 0.0125 as compared with 1-sided p-value at both interim and final analyses).  Note that 
Table 2 will be re-derived when the observed information for ORR at Day 28 is not 0.826. 
Therefore, efficacy analysis at Interim 2, assuming information faction being 0.826 (ie, 360/436) 
will be conducted as follows: 
E1:  Obtain CMH test statistic on ORR at Day 28 (chi-square test with degree of freedom 1), 
E2:  CMH test statistic will be compared with the critical value in Column 7 of Table 2 
(Interim 2 chi-square test critical value), 
E3:  If positive on ORR at Day 28, NRM rate at Day 180 will be tested using the Bonferroni 
method, 
E4:  If neither efficacy nor futility on Day 28 ORR is crossed, study will continue. 
Assuming that at the Interim Analysis 2 data cutoff date (Day 180 of the 240th randomized 
eligible subject) there are approximately 360 subjects based on estimation who have been 
randomized, then testing of Day 28 ORR will be conducted for subjects who have completed 
Day 28 or withdrawn from the study upon the cutoff date.  This means that, by the Interim 
Analysis 2 data cutoff date, subjects who were ongoing but had not reached the Day 28 visit will 
be excluded for both the Day 28 ORR and Day 180 NRM analyses. 
Analysis of NRM rate at Day 180 will use the same method as described in Section 7.4.1 for 
final analysis but using the Interim Analysis 2 cutoff data instead.  The decision process is 
described in Figure 4. 
At the Interim Analysis 2 data cutoff date, if the total number of randomized subjects in the 
Interim 2 analysis set is different from the predicted number 360, the efficacy boundaries will be 
recalculated based on the actual observed information fraction at Interim Analysis 2. 
An independent DMC will be charged with evaluating interim results.  The DMC will consist of 
clinicians and an independent statistician.  The sponsor will remain blinded, and DMC decisions 
will be communicated through sponsor management as dictated in the DMC charter.  Additional 
operational details of the interim analyses, including tables, figures, and listings provided to the 
DMC, will be provided in the DMC Charter.  


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9.2. 
Final Analyses 
Final analyses are for efficacy of both ORR at Day 28 and NRM rate at Day 180.  Assuming the 
information fraction at Interim Analysis 2 is 0.826 (360 subjects complete Day 28), efficacy 
boundaries in Table 2 will be used; if not, the efficacy boundaries will be regenerated using 
observed information fraction at Interim Analysis 2. 
The test steps are as follows: 
E1:  Obtain CMH test statistic on ORR at Day 28 (chi-square test with degree of freedom 1), 
E2:  CMH test statistic will be compared with the critical value in Column 7 of Table 2 (final 
analysis chi-square test critical value), 
E3:  If positive on ORR at Day 28, NRM rate at Day 180 will be tested using the Bonferroni 
method. 
Note that if there is substantial over-running at the end of the study (ie, total number of subjects 
is greater than 446), the final critical value will be adjusted in order to control overall Type I 
error rate.   
The final analyses will be conducted by the sponsor. 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 8. 
Table 8: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
14 MAY 2018 
Amendment 1 
23 JUL 2019 
10.1. 
Changes to Protocol-Defined Analyses 
Note that the FAS population is equivalent to the efficacy evaluable population as defined in the 
protocol. 


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10.2. 
Changes to the Statistical Analysis Plan 
10.2.1. 
Original to Amendment 1 
The Type 1 error control approach for the key secondary endpoint tested at Interim Analysis 2 
and the Final Analysis was modified to use the Bonferroni method.  Portions of Sections 3 and 9 
were modified to reflect that change.  In addition, the definition of endpoint for and analysis of 
Month 6 NRM was refined to reflect Health Authority feedback.  
 Section 2 was updated to align with Protocol Amendment 4. 
 Section 3 was revised
 to provide detail on the 
interim and final analyses.  Figures were added to help visualize the study design and 
analyses, and the schedule of assessments tables were updated according to Protocol 
Amendment 4. 
 Section 4 was updated to provide additional clarification and definitions. 
 Section 5.3 was updated to add the analysis sets used at Interim Analyses 1 and 2.  “FAS” 
replaced “efficacy evaluable population,” and the definition of per protocol analysis set 
was refined. 
 Section 6 was updated to provide clarification and more details on analyses.  Disease 
history was updated according to the current approved CRF, and sections were added for 
allo-HSCT history and transfusions. 
 Section 7 was revised to provide additional clarification and details on efficacy analyses.  
Alternative ways of calculating DOR were added.  Subgroup analyses by 
, aGVHD status determined after randomization, 
MacMillan age group, HLA/donor source category, aGVHD status determined after 
randomization, and Day 28 response status were added.  Timing of 12-, 18-, and 
24-month analyses was specified. 
 Section 8 was updated for clarification and to add TEAE in the retreatment phase, AE 
Grade 5, and more AE summaries.  The clinically notable AEs were rewritten based on 
customized MQs.  Analyses for EBV in post-transplant lymphoproliferative disorder 
evaluation were also added. 
 Section 9.1 was edited to correct the conditional power formula and to provide more 
clarification on analyses at Interim Analysis 2.   
 Appendix A was added. 
 Appendix B was updated to redefine TFLs. 
 Appendix C was updated to redefine customized MQs. 
 Appendix D was added for other possible efficacy boundaries for testing Day 28 ORR at 
both the Interim 2 and final analyses. 
In addition, other minor, administrative changes have been incorporated throughout the SAP and 
are noted in the redline version of the amendment. 


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11. 
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one-degree-of-freedom chi-square test and a related rapid procedure. Am J Epidemiol 
1980;112:129-134. 
Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 
National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03. 2010. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed December 1, 2017. 


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APPENDIX A. STATISTICAL MODELS FOR EFFICACY ANALYSES 
Analysis for Overall Response 
Cochran-Mantel-Haenszel test 
The null hypothesis of equality of response rate in the 2 treatment groups will be tested against 
1-sided alternative.  The statistical hypotheses are: 
H0:  ORRtrt ≤ ORRpbo  versus   H1:  ORRtrt > ORRpbo 
where ORRtrt is the probability of response in treatment group and ORRpbo is the probability  of 
response in placebo group.  The CMH chi-square test X2CMH (implemented again via SAS 
procedure FREQ with CMH option in the TABLES statement) will be used to test the difference 
in response rates between the treatment groups.  The p-value corresponding to the CMH test for 
“general association” will be used, which follows a Chi-square distribution with 1 degree of 
freedom. 
If the sampling assumptions for chi-square test is not met, the exact CMH test will be used 
(implemented via SAS procedure MULTTEST).  The test is performed by running a stratified 
version of the Cochran-Armitage permutation test (Armitage et al 1969).  In studies with 
stratified randomization, the chi-square approximation is considered appropriate for the X2CMH 
statistics if the rule of Mantel and Fleiss (1980) is satisfied. 
Logistic Regression  
Odds ratio will be used as a measure of association between treatment and response.  The odds 
ratio will be derived from the logistic regression model (implemented using SAS procedure 
LOGISTIC, with both treatment and stratification factor specified as an explanatory variable in 
the CLASS statement), which allows for including not only the stratification factor but also for 
adjustments for other covariates (both categorical and continuous).  The odds ratio will be 
presented with 95% Wald confidence limits. 
In cases where an exact test has been used to compare response rates, the odds ratio should be 
determined using exact logistic regression, and the odds ratio presented with exact 
95% confidence limits.  In these cases, SAS PROC LOGISTIC with EXACTONLY option will 
be used. 
Analyses for Survival Data 
Analyses for Survival Data in this section use OS as an example. 
Stratified Log-Rank Test 
The null hypothesis stating that OS distributions of the 2 treatment groups are equivalent will be 
tested against 1-sided alternative 
Assuming proportional hazards for OS, the following statistical hypotheses will be tested: 
 


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where 
 is the OS hazard ratio ( treatment versus placebo).  The analysis to test these 
hypotheses will consist of a stratified log-rank test at an overall 1-sided 2.5% level of 
significance.  The stratification will be based on the randomization stratification factors 
(ie, aGVHD high vs standard).  
The stratified log-rank test adjusting for the strata used in the randomization will be implemented 
as follows:  In each of the K strata separately, the LIFETEST procedure with STRATA 
statement including only the treatment group variable and with the TIME statement will be used 
to obtain the rank statistic 
 and variance var(
) where k=1, 2, …, K.  The final test statistics 
will then be reconstructed as follows: 
Z=[S1 +…+ SK]/√ [var(S1) +…+ var(Sk)]. One-sided P-value will be obtained from the 
standard normal distribution using the Z statistic. 
(One-sided will be obtained using Z statistic / Two-sided p-value will be obtained using  
 
statistic.) 
Kaplan-Meier Estimates 
An estimate of the OS survival function in each treatment group at distinct event times will be 
constructed using KM (product-limit) method as implemented in PROC LIFETEST with 
METHOD=KM option. The PROC LIFETEST statement will use the option 
CONFTYPE=LOGLOG.  Stratification factor (high vs standard) will be use in STRATA 
statement to get KM estimates by both treatment group and stratum. 
Median survival for each treatment group will be obtained along with 95% CIs calculated from 
PROC LIFETEST output using the method of (Brookmeyer and Crowley 1982).  Kaplan-Meier 
estimates of the survival function with 95% CIs at specific time points will be summarized.  
The standard error of the KM estimate will be calculated using Greenwood’s formula 
(Collett 1994). 
Hazard Ratio 
Hazard ratio will be estimated by fitting the Cox proportional hazards model using SAS 
procedure PHREG. 
A stratified unadjusted Cox model will be, that is, the MODEL statement will include the 
treatment group variable as the only covariate and the STRATA statement will include 
stratification variable(s). 
Hazard ratio with 2-sided 95% CI will be based on Wald test. 
The above survival analyses (ie, log-rank test, KM method and Cox proportional hazards model) 
do not consider competing risk to be an issue. 


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APPENDIX B. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings.  Standard tables will 
follow the conventions in the Standard Safety Tables current version, if necessary.  In-text tables 
are identical in structure and content as appendix tables, but follow a Rich Text Format.  In the 
event that the study terminates at Interim Analysis 1 or 2, the interim safety set will be used in 
place of the safety analysis set, the interim efficacy set will be used in place of FAS, and any per 
protocol populations will use subsets of the appropriate interim safety or efficacy set. 
Tables 
Table No. 
Title 
Population Standard 
In-
Text 
Demographics and Disposition 
1.1.1 
Analysis Populations 
FAS 
X 
X 
1.1.2 
Summary of Subject Disposition 
FAS 
X 
X 
1.1.3 
Summary of Number of Subjects Enrolled by Country and Site 
FAS 
X 
 
1.2.1 
Summary of Demographics and Baseline Characteristics  
FAS 
X 
X 
1.3.1 
Summary of Baseline GVHD Characteristics 
FAS 
X 
X 
1.3.2 
Summary of Hematologic Disease History 
FAS 
 
X 
1.3.3 
Summary of Allogeneic Hematopoietic Stem Cell Transplant 
FAS 
 
X 
1.3.4 
Summary of Prior Anticancer Therapy 
FAS 
 
X 
1.3.5 
Summary of Prior Radiotherapy 
FAS 
X 
X 
1.3.6 
Summary of Medical History 
FAS 
X 
X 
1.4.1 
Summary of Prior Medications 
FAS 
X 
X 
1.4.2 
Summary of Prophylaxis Medications  
FAS 
X 
X 
1.4.3 
Summary of Concomitant Medications 
FAS 
X 
X 
1.4.4 
Summary of Conditioning Regimens 
FAS 
X 
X 
1.5.1 
Summary of Protocol Deviations 
FAS 
X 
X 
1.6.1 
PRBC/Platelet Transfusions On Study or Performed Within 30 Days 
Before Enrollment 
FAS 
 
X 
1.7.1  
Summary of Donor Chimerism 
FAS 
 
X 
Efficacy, Exposure, and Dosage 
2.1.1 
Summary Statistics and CMH Analysis of Overall Response Rate at 
Day 28 
FAS 
 
X 
2.1.2 
Summary Statistics and CMH Analysis of Overall Response Rate at 
Day 28 
PP 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.5 
Logistic Regression Analysis of Overall Response Rate at Day 28 
FAS 
 
X 
2.1.6 
Summary of Overall Response Rate at Days 14, 56, 100, and 180 
FAS 
 
X 
2.1.7 
Subgroup Analyses of Overall Response Rate at Day 28 
FAS 
 
X 
2.2.1 
Summary of Best Overall Response 
FAS 
 
X 
2.2.2 
Summary Statistics and Kaplan-Meier Estimate of Time to Response 
FAS 
 
X 


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Table No. 
Title 
Population Standard 
In-
Text 
2.2.3 
Summary Statistics and Kaplan-Meier Estimate of Duration of 
Response 
FAS 
 
X 
2.2.4 
Summary Statistics and Kaplan-Meier Estimate Duration of Response 
by Day 28 Response Status 
FAS 
 
X 
2.2.5 
Summary Statistics and Kaplan-Meier Estimate of Duration of 
Response by Baseline GVHD Risk Status 
FAS 
 
X 
2.2.6 
Summary Statistics and Kaplan-Meier Estimate of Duration of 
Response Using Alternate Approach 1  
FAS 
 
X 
2.2.7 
Summary Statistics and Kaplan-Meier Estimate of Duration of 
Response Using Alternate Approach 2 
FAS 
 
X 
2.2.8 
Kaplan-Meier Estimate and Log-Rank Analysis of Nonrelapse 
Mortality 
FAS 
 
X 
2.2.9 
Kaplan-Meier Estimate and Log-Rank Analysis of Nonrelapse 
Mortality by Baseline GVHD Risk Status  
FAS 
 
X 
2.2.10 
Kaplan-Meier Estimate and Log-Rank Analysis of Nonrelapse 
Mortality by Day 28 Response Status 
FAS 
 
X 
2.2.11 
Summary Statistics and CMH Analysis of Day 180 Nonrelapse 
Mortality Rate 
FAS 
 
X 
2.2.12 
Summary Statistics and CMH Analysis of Day 180 Nonrelapse 
Mortality Rate by Baseline GVHD Risk Status 
FAS 
 
X 
2.2.13 
Analysis of Nonrelapse Mortality Rate at Day 180 Using Kaplan-
Meier Estimate 
FAS 
 
X 
2.2.14 
Cox Regression Analysis of Nonrelapse Mortality 
FAS 
 
X 
2.2.15 
Competing-Risks Analysis of Nonrelapse Mortality Considering 
Competing With Malignancy Relapse 
FAS 
 
X 
2.2.16 
Competing-Risks Analysis of Nonrelapse Mortality Considering 
Competing With Death Due to Malignancy Relapse 
FAS 
 
X 
2.2.17 
Relapse Rate of Malignant and Nonmalignant Hematologic Diseases 
FAS 
 
X 
2.2.18 
Summary of Mortality Rate Due to Malignancy Relapse 
FAS 
 
X 
2.2.19 
Summary of Incidence of Secondary Graft Failure 
FAS 
 
X 
2.2.20 
Summary of Incidence of Acute GVHD Flares Through Day 100 
FAS 
 
X 
2.2.21 
Summary of Immunosuppressive Medication Usage on Days 1, 14, 28, 
56, 100, and 180 During the Treatment Phase 
FAS 
 
X 
2.2.22 
Summary of Stages of GVHD by Organ and Visit 
FAS 
 
X 
2.2.23 
Summary of Incidence of Chronic GVHD  
FAS 
 
X 
2.2.24 
Kaplan-Meier Estimate and Log-Rank Analysis of Failure-Free 
Survival 
FAS 
 
X 
 
 
 
 
 
 
2.2.26 
Kaplan-Meier Estimate and Log-Rank Analysis of Failure-Free 
Survival by Day 28 Response Status 
FAS 
 
X 
2.2.27 
Cox Regression Analysis of Failure-Free Survival 
FAS 
 
X 
2.2.28 
Kaplan-Meier Estimate and Log-Rank Analysis of Overall Survival 
FAS 
 
X 
 
 
 
 
 
 
2.2.30 
Kaplan-Meier Estimate and Log-Rank Analysis of Overall Survival by 
Day 28 Response Status 
FAS 
 
X 


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Table No. 
Title 
Population Standard 
In-
Text 
2.2.31 
Cox Regression Analysis of Overall Survival 
FAS 
 
X 
 
 
 
 
 
 
 
 
 
 
2.2.34 
Summary of Post-Transplant Lymphoproliferative Disorder 
Assessment  
FAS 
 
X 
2.2.35 
Summary of ECOG Status in the Treatment Phase 
FAS 
 
X 
2.2.36 
Summary of Death 
FAS 
 
X 
2.2.37 
Summary of Relapse of Underlying Hematologic Disease 
FAS 
 
X 
Exposure 
3.1.1 
Summary of Itacitinib Dose Modifications in the Treatment Phase 
Safety 
 
X 
3.1.2 
Summary of Corticosteroid Exposure Prior to Day 1 
Safety 
 
X 
3.1.3 
Summary of Corticosteroid Exposure in the Treatment Phase  
Safety 
 
X 
3.1.4 
Summary of Corticosteroid Exposure Between Day 1 and Start of New 
Anti-GVHD Therapy 
Safety 
 
X 
3.1.5 
Summary of Corticosteroid Use Over Time in the Treatment Phase 
Safety 
 
X 
3.1.4.1 
Summary of Itacitinib/Placebo Exposure and Compliance in the 
Treatment Phase 
Safety 
 
X 
3.1.4.2 
Summary of Itacitinib/Placebo Exposure and Compliance in the 
Treatment Phase by Age Group 
Safety 
 
X 
3.1.4.3 
Summary of Itacitinib/Placebo Exposure and Compliance in the 
Treatment Phase by Sex 
Safety 
 
X 
3.1.4.4 
Summary of Itacitinib/Placebo Exposure and Compliance in the 
Treatment Phase by Race  
Safety 
 
X 
3.1.4.5 
Summary of Itacitinib/Placebo Exposure and Compliance in the 
Treatment Phase by Region 
Safety 
 
X 
Adverse Events 
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events in the 
Treatment Phase 
Safety 
X 
X 
3.2.1.2 
Overall Summary of Treatment-Emergent Adverse Events in the 
Treatment Phase by Age Group 
Safety 
X 
X 
3.2.1.3 
Overall Summary of Treatment-Emergent Adverse Events in the 
Treatment Phase by Sex 
Safety 
X 
X 
3.2.1.4 
Overall Summary of Treatment-Emergent Adverse Events in the 
Treatment Phase by Race  
Safety 
X 
X 
3.2.1.5 
Overall Summary of Treatment-Emergent Adverse Events in the 
Treatment Phase by Region 
Safety 
X 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events in the Treatment 
Phase by MedDRA System Organ Class and Preferred Term  
Safety 
X 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events in the Treatment 
Phase by MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events in the Treatment 
Phase by MedDRA System Organ Class, Preferred Term, and Highest 
Grade 
Safety 
X 
X 
3.2.5.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
in the Treatment Phase by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
X 


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Table No. 
Title 
Population Standard 
In-
Text 
3.2.5.2 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
in the Treatment Phase by MedDRA Preferred Term in Decreasing 
Order of Frequency 
Safety 
X 
X 
3.2.6 
Summary of Itacitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA System Organ Class and Preferred Term  
Safety 
X 
X 
3.2.7 
Summary of Itacitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
X 
3.2.8 
Summary of Itacitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA System Organ Class, Preferred Term, and Highest Grade 
Safety 
X 
X 
3.2.9 
Summary of Grade 3 or Higher Itacitinib/Placebo Treatment-Related 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
X 
X 
3.2.10 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome in the Treatment Phase by MedDRA System Organ Class 
and Preferred Term 
Safety 
X 
X 
3.2.11 
Summary of Serious Treatment-Emergent Adverse Events in the 
Treatment Phase by MedDRA System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.12 
Summary of Serious Treatment-Emergent Adverse Events in the 
Treatment Phase by MedDRA Preferred Term and in Decreasing Order 
of Frequency 
Safety 
X 
X 
3.2.13 
Summary of Itacitinib/Placebo Treatment-Related Serious 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA System Organ Class and Preferred Term  
Safety 
X 
X 
3.2.14 
Summary of Treatment-Emergent Adverse Events Leading to 
Itacitinib/Placebo Dose Interruption in the Treatment Phase by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.15 
Summary of Treatment-Emergent Adverse Events Leading to 
Itacitinib/Placebo Dose Reduction in the Treatment Phase by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.16 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Itacitinib/Placebo in the Treatment Phase by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.17 
Summary of Corticosteroid Treatment-Related Treatment-Emergent 
Adverse Events in the Treatment Phase by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
 
3.2.18 
Summary of Corticosteroid Treatment-Related Treatment-Emergent 
Adverse Events in the Treatment Phase by MedDRA Preferred Term 
in Decreasing Order of Frequency 
Safety 
X 
 
3.2.19 
Summary of Corticosteroid Treatment-Related Treatment-Emergent 
Adverse Events in the Treatment Phase by MedDRA System Organ 
Class, Preferred Term, and Highest Grade 
Safety 
X 
 
3.2.20 
Summary of Corticosteroid Treatment-Related Grade 3 or Higher 
Treatment-Emergent Adverse Events in the Treatment Phase by 
MedDRA System Organ Class, Preferred Term, and Highest Grade 
Safety 
X 
 


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Table No. 
Title 
Population Standard 
In-
Text 
3.2.21 
Summary of Corticosteroid Treatment-Related Serious Treatment-
Emergent Adverse Events in the Treatment Phase by MedDRA System 
Organ Class and Preferred Term  
Safety 
X 
 
3.2.22 
Summary of Treatment-Emergent Adverse Events Leading to 
Corticosteroid Dose Interruption in the Treatment Phase by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.23 
Summary of Treatment-Emergent Adverse Events Leading to 
Corticosteroid Dose Reduction in the Treatment Phase by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.24 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of Corticosteroid in the Treatment Phase by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.25 
Summary of Treatment-Emergent Adverse Events Leading to 
Withdrawal From the Study in the Treatment Phase by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
X 
3.2.26 
Overall Summary of Clinical Notable Treatment-Emergent Adverse 
Events in the Treatment Phase Based on Customized MQs  
Safety 
X 
X 
3.2.27 
Summary of Clinically Notable Treatment-Emergent Adverse Events 
in the Treatment Phase Based on Customized MQs by MedDRA 
Preferred Term and Outcome 
Safety 
X 
X 
3.2.28 
Summary of Clinically Notable Treatment-Emergent Adverse Events 
in the Treatment Phase Based on Customized MQs by MedDRA 
Preferred Term and Highest Grade 
Safety 
X 
X 
3.2.29 
Summary of Serious Treatment-Emergent Adverse Events in the 
Treatment Phase by MedDRA System Organ Class, Preferred Term, 
Hepatic Impairment Status at Baseline, and Postbaseline Azole Usage 
Safety 
X 
X 
3.2.30 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
in the Treatment Phase by MedDRA System Organ Class, Preferred 
Term, Hepatic Impairment Status at Baseline, and Postbaseline Azole 
Usage 
Safety 
X 
X 
3.2.31 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome in the Treatment Phase by MedDRA System Organ Class, 
Preferred Term, Hepatic Impairment Status at Baseline, and 
Postbaseline Azole Usage 
Safety 
X 
X 
3.2.32 
Summary of Itacitinib/Placebo Treatment-Related Treatment-
Emergent Adverse Events in the Treatment Phase by MedDRA System 
Organ Class, Preferred Term, Hepatic Impairment Status at Baseline, 
and Postbaseline Azole Usage 
Safety 
X 
X 
3.2.33 
Summary of Grades 3 or Higher Thrombocytopenia Treatment-
Emergent Adverse Events in the Treatment Phase by MedDRA System 
Organ Class, Preferred Term, Hepatic Impairment Status at Baseline, 
and Postbaseline Azole Usage 
Safety 
X 
X 
3.2.34 
Summary of Grades 3 or Higher Neutropenia Treatment-Emergent 
Adverse Events in the Treatment Phase by MedDRA System Organ 
Class, Preferred Term, Hepatic Impairment Status at Baseline, and 
Postbaseline Azole Usage 
Safety 
X 
X 
3.2.35 
Summary of Grades 3 or Higher Anemia Treatment-Emergent Adverse 
Events in the Treatment Phase by MedDRA System Organ Class, 
Preferred Term, Hepatic Impairment Status at Baseline, and 
Postbaseline Azole Usage 
Safety 
X 
X 


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Table No. 
Title 
Population Standard 
In-
Text 
Labs, Vital Signs, and ECGs 
3.3.1 
Summary of Laboratory Values – Hematology 
Safety 
X 
X 
3.3.2 
Shift Summary of Hematology Values – to the Worst Abnormal Value 
Safety 
X 
X 
3.3.3 
Shift Summary of Hematology Laboratory Values in CTC Grade – to 
the Worst Abnormal Value 
Safety 
X 
X 
3.3.4 
Summary of Laboratory Values – Chemistry 
Safety 
X 
X 
3.3.5 
Shift Summary of Chemistry Values – to the Worst Abnormal Value 
Safety 
X 
X 
3.3.6 
Shift Summary of Chemistry Laboratory Values in CTC Grade – to the 
Worst Abnormal Value 
Safety 
X 
X 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
X 
 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
X 
 
3.4.3 
Summary of Pulse 
Safety 
X 
 
3.4.4 
Summary of Respiratory Rate 
Safety 
X 
 
3.4.5 
Summary of Body Temperature 
Safety 
X 
 
3.4.6 
Summary of Body Weight 
Safety 
X 
 
3.4.7 
Summary of QRS Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.8 
Summary of QT Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.9 
Summary of QTcB Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.10 
Summary of QTcF Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.11 
Summary of RR Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.12 
Summary of PR Interval (ms) From 12-Lead ECG 
Safety 
X 
 
3.4.13 
Summary of Clinically Significant ECG Abnormalities 
Safety 
X 
 


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Figures 
Figure 
No. 
Title 
Analysis Set 
4.1.1 
Kaplan-Meier Plot of Time to Response 
FAS 
4.1.2 
Kaplan-Meier Plot of Duration of Response  
FAS 
4.1.3 
Kaplan-Meier Plot of Duration of Response by Day 28 Response Status 
FAS 
 
 
 
4.1.5 
Kaplan-Meier Plot of Duration of Response Using Alternate Approach 1 
FAS 
4.1.6 
Kaplan-Meier Plot of Duration of Response Using Alternate Approach 2 
FAS 
4.1.7 
Forest Plot of Odds Ratio and 95% CIs for Overall Response Rate at Day 28 
FAS 
4.1.8 
Time to Response and Duration of Response by Treatment Group 
FAS 
4.2.1 
Kaplan-Meier Plot of Time to Death Due to Causes Other Than Malignancy Relapse 
FAS 
4.2.2 
Kaplan-Meier Plot of Time to Death Due to Causes Other Than Malignancy Relapse by 
Day 28 Response Status 
FAS 
 
 
 
 
4.2.4 
Cumulative Incidence Function of Nonrelapse Mortality Considering Competing With 
Malignancy Relapse 
FAS 
4.2.5 
Cumulative Incidence Function of Nonrelapse Mortality Considering Competing With 
Malignancy Relapse by Day 28 Response Status 
FAS 
 
 
 
 
4.2.7 
Cumulative Incidence Function of Nonrelapse Mortality Considering Competing With 
Death Due to Malignancy Relapse 
FAS 
4.2.8 
Cumulative Incidence Function of Nonrelapse Mortality Considering Competing With 
Death Due to Malignancy Relapse by Day 28 Response Status 
FAS 
 
 
 
 
4.2.10 
Kaplan-Meier Plot of Time to Failure-Free Survival  
FAS 
4.2.11 
Kaplan-Meier Plot of Time to Failure-Free Survival by Day 28 Response Status 
FAS 
 
 
 
4.2.13 
Kaplan-Meier Plot of Overall Survival 
FAS 
4.2.14 
Kaplan-Meier Plot of Overall Survival by Day 28 Response Status 
FAS 
 
 
 
4.3.1 
Plot of Corticosteroid Daily Dose During Screening and Treatment Phase Over Time 
Safety 
4.3.2 
Plot of Body Weight Over Time 
Safety 
4.3.3 
Plot of Platelets Over Time 
Safety 
4.3.4 
Plot of Neutrophils Over Time 
Safety 
4.3.5 
Plot of Cholesterol Over Time 
Safety 
4.3.6 
Plot of Triglycerides Over Time 
Safety 


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Listings 
Listing No. 
Title 
2.1.1 
Subject Disposition Status 
2.1.2 
Subject Enrollment and Site Information 
2.1.3 
Subject Retreatment Disposition Status 
2.2.1 
Protocol Deviations 
2.2.2 
Randomized Subjects With Inclusion/Exclusion Criteria Violations 
2.3 
Analysis Populations 
2.4.4 
Demographic and Baseline Characteristics 
2.4.5 
Medical History 
2.4.6 
Hematologic Disease History 
2.4.7 
Prior Anticancer Therapy 
2.4.8 
Prior Radiotherapy 
2.4.9 
Prior and Concomitant Medications 
2.4.10 
Prophylaxis Medications 
2.4.11 
Conditioning Regimens 
2.4.12 
PRBC/Platelet Transfusions Performed Within 30 Days Before Enrollment or On Study  
2.4.13 
Allogeneic Hematopoietic Stem Cell Transplant History 
2.5.1 
Itacitinib Exposure and Compliance 
2.5.2 
Corticosteroid Exposure in the Treatment Phase 
2.5.3 
Corticosteroid Usage After End-of-Treatment 
2.6.1 
aGVHD Symptoms and Response Assessment  
2.6.2 
cGVHD Symptoms and Response Assessment 
2.6.3 
Relapse of Malignant and Nonmalignant Hematologic Diseases 
2.6.4 
Failure-Free Survival Events and Assessment 
2.6.5 
Secondary Graft Failure 
2.6.6 
Acute GVHD Flares 
2.6.7 
Discontinuation of Immunosuppressive Medication 
2.6.8 
Post-Transplant Lymphoproliferative Disorder Assessment 
 
  
 
 
2.6.11 
Deaths 
2.6.12 
ECOG Status 
2.6.13 
PK Blood Sampling Times 
2.7.1 
Adverse Events  
2.7.2 
Serious Adverse Events 
2.7.3 
Grade 3 and Higher Adverse Events 
2.7.4 
Fatal Adverse Events 
2.7.5 
Itacitinib/Placebo Treatment-Related Adverse Events 
2.7.6 
Corticosteroids Treatment-Related Adverse Events 
2.7.8 
Adverse Events Leading to Itacitinib/Placebo Dose Interruption 
2.7.9 
Adverse Events Leading to Corticosteroid Dose Interruption 
2.7.10 
Adverse Events Leading to Itacitinib/Placebo Dose Reduction 
2.7.11 
Adverse Events Leading to Corticosteroid Dose Reduction 
2.7.12 
Adverse Events Leading to Discontinuation of Itacitinib/Placebo 


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Listing No. 
Title 
2.7.13 
Adverse Events Leading to Discontinuation of Corticosteroids 
2.7.14 
Adverse Events Occurring in the Retreatment Phase 
2.8.1 
Abnormal Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Hematology 
2.8.3 
Abnormal Clinical Laboratory Values – Chemistry 
2.8.4 
Clinical Laboratory Values – Chemistry 
2.9.1 
Abnormal Vital Sign Values 
2.9.2 
Vital Sign Values 
2.10.1 
Abnormal 12-Lead ECG Values 
2.10.2 
12-Lead ECG Values 


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APPENDIX C. CLINICALLY NOTABLE EVENTS BASED ON 
CUSTOMIZED MEDDRA QUERIES 
This appendix provides the categories of clinically notable events based on customized MQs. 
Clinically Notable Hematological Events 
Category 
Preferred Term 
Anemia 
Anaemia macrocytic 
Anemia 
Aplasia pure red cell 
Anemia 
Aplastic anaemia 
Anemia 
Erythroblast count decreased 
Anemia 
Erythropenia 
Anemia 
Hypoplastic anaemia 
Anemia 
Microcytic anaemia 
Anemia 
Red blood cell count decreased 
Anemia 
Anaemia 
Anemia 
Haematocrit decreased 
Anemia 
Haemoglobin decreased 
Anemia 
Leukoerythroblastic anaemia 
Neutropenia 
Agranulocytosis 
Neutropenia 
Band neutrophil count decreased 
Neutropenia 
Febrile neutropenia 
Neutropenia 
Granulocyte count decreased 
Neutropenia 
Granulocytopenia 
Neutropenia 
Neutropenia 
Neutropenia 
Neutropenic infection 
Neutropenia 
Neutropenic sepsis 
Neutropenia 
Neutrophil count decreased 
Thrombocytopenia 
Acquired amegakaryocytic thrombocytopenia 
Thrombocytopenia 
Platelet count decreased 
Thrombocytopenia 
Thrombocytopenia 
Thrombocytopenia 
Plateletcrit decreased 


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Hematological Infection 
Category 
Preferred Term 
EBV infection 
Epstein Barr virus positive mucocutaneous ulcer 
EBV infection 
Epstein-Barr viraemia 
EBV infection 
Epstein-Barr virus associated lymphoma 
EBV infection 
Epstein-Barr virus associated lymphoproliferative disorder 
EBV infection 
Epstein-Barr virus infection 
EBV infection 
Hepatitis infectious mononucleosis 
EBV infection 
Infectious mononucleosis 
EBV infection 
Oral hairy leukoplakia 
EBV infection 
Post transplant lymphoproliferative disorder 
EBV infection 
X-linked lymphoproliferative syndrome 
EBV infection 
Epstein-Barr virus test positive 
EBV infection 
Epstein-Barr virus antibody positive 
Cytomegaloviral infections 
Congenital cytomegalovirus infection 
Cytomegaloviral infections 
Cytomegalovirus chorioretinitis 
Cytomegaloviral infections 
Cytomegalovirus colitis 
Cytomegaloviral infections 
Cytomegalovirus duodenitis 
Cytomegaloviral infections 
Cytomegalovirus enteritis 
Cytomegaloviral infections 
Cytomegalovirus enterocolitis 
Cytomegaloviral infections 
Cytomegalovirus gastritis 
Cytomegaloviral infections 
Cytomegalovirus gastroenteritis 
Cytomegaloviral infections 
Cytomegalovirus gastrointestinal infection 
Cytomegaloviral infections 
Cytomegalovirus gastrointestinal ulcer 
Cytomegaloviral infections 
Cytomegalovirus hepatitis 
Cytomegaloviral infections 
Cytomegalovirus infection 
Cytomegaloviral infections 
Cytomegalovirus mononucleosis 
Cytomegaloviral infections 
Cytomegalovirus mucocutaneous ulcer 
Cytomegaloviral infections 
Cytomegalovirus myelomeningoradiculitis 
Cytomegaloviral infections 
Cytomegalovirus myocarditis 
Cytomegaloviral infections 
Cytomegalovirus nephritis 
Cytomegaloviral infections 
Cytomegalovirus oesophagitis 
Cytomegaloviral infections 
Cytomegalovirus pancreatitis 
Cytomegaloviral infections 
Cytomegalovirus pericarditis 
Cytomegaloviral infections 
Cytomegalovirus syndrome 
Cytomegaloviral infections 
Cytomegalovirus urinary tract infection 
Cytomegaloviral infections 
Cytomegalovirus viraemia 
Cytomegaloviral infections 
Encephalitis cytomegalovirus 
Cytomegaloviral infections 
Disseminated cytomegaloviral infection 
Cytomegaloviral infections 
Pneumonia cytomegaloviral 
Cytomegaloviral infections 
Cytomegalovirus test positive 


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Hypderlipidemia 
Category 
Preferred Term 
Hyperlipidemia 
Acquired lipoatrophic diabetes 
Hyperlipidemia 
Acquired mixed hyperlipidaemia 
Hyperlipidemia 
Apolipoprotein B/Apolipoprotein A-1 ratio increased 
Hyperlipidemia 
Autoimmune hyperlipidaemia 
Hyperlipidemia 
Blood cholesterol abnormal 
Hyperlipidemia 
Blood cholesterol esterase increased 
Hyperlipidemia 
Blood cholesterol increased 
Hyperlipidemia 
Blood triglycerides abnormal 
Hyperlipidemia 
Blood triglycerides increased 
Hyperlipidemia 
Diabetic dyslipidaemia 
Hyperlipidemia 
Dyslipidaemia 
Hyperlipidemia 
High density lipoprotein abnormal 
Hyperlipidemia 
High density lipoprotein decreased 
Hyperlipidemia 
Hypercholesterolaemia 
Hyperlipidemia 
Hyperlipidaemia 
Hyperlipidemia 
Hypertriglyceridaemia 
Hyperlipidemia 
Hypo HDL cholesterolaemia 
Hyperlipidemia 
Intermediate density lipoprotein increased 
Hyperlipidemia 
LDL/HDL ratio increased 
Hyperlipidemia 
Lipids abnormal 
Hyperlipidemia 
Lipids increased 
Hyperlipidemia 
Lipoprotein (a) abnormal 
Hyperlipidemia 
Lipoprotein (a) increased 
Hyperlipidemia 
Lipoprotein abnormal 
Hyperlipidemia 
Lipoprotein increased 
Hyperlipidemia 
Low density lipoprotein abnormal 
Hyperlipidemia 
Low density lipoprotein increased 
Hyperlipidemia 
Non-high-density lipoprotein cholesterol increased 
Hyperlipidemia 
Remnant-like lipoprotein particles increased 
Hyperlipidemia 
Total cholesterol/HDL ratio abnormal 
Hyperlipidemia 
Total cholesterol/HDL ratio increased 
Hyperlipidemia 
Very low density lipoprotein abnormal 
Hyperlipidemia 
Very low density lipoprotein increased 


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QT Prolongation 
Category 
Preferred Term 
QT prolongation 
Electrocardiogram QT interval abnormal 
QT prolongation 
Electrocardiogram QT prolonged 
QT prolongation 
Long QT syndrome 
QT prolongation 
Long QT syndrome congenital 
QT prolongation 
Torsade de pointes 
QT prolongation 
Ventricular tachycardia 


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APPENDIX D. VARIOUS UPPER EFFICACY BOUNDARIES FOR 
TESTING DAY 28 ORR AT BOTH INTERIM 2 AND 
FINAL ANALYSES USING HWANG-SHIH-DECANI 
ALPHA SPENDING FUNCTION WITH SHAPE 
PARAMETER -4 
No. of Subjects 
in the Interim 
2 Efficacy 
Analysis Set 
Information Fraction at IA2 
(Column 1/436) 
Efficacy Boundary/Critical 
Value at Interim 2 (as 
Compared With Observed 
Normalized Test Statistic z) 
Final Critical Value 
410 
0.940367 
2.062174 
2.036718 
411 
0.942661 
2.058304 
2.037092 
412 
0.944954 
2.054429 
2.037452 
413 
0.947248 
2.050549 
2.037794 
414 
0.949541 
2.046665 
2.038117 
415 
0.951835 
2.042776 
2.038417 
416 
0.954128 
2.038882 
2.038691 
417 
0.956422 
2.034984 
2.038935 
418 
0.958716 
2.03108 
2.039144 
419 
0.961009 
2.027172 
2.039312 
420 
0.963303 
2.023259 
2.039433 
421 
0.965596 
2.019341 
2.039498 
422 
0.96789 
2.015418 
2.039497 
423 
0.970183 
2.01149 
2.039418 
424 
0.972477 
2.007557 
2.039247 
425 
0.974771 
2.003619 
2.038963 
426 
0.977064 
1.999677 
2.038541 
427 
0.979358 
1.995729 
2.037951 
428 
0.981651 
1.991776 
2.037147 
429 
0.983945 
1.987817 
2.036068 
430 
0.986239 
1.983854 
2.034627 
431 
0.988532 
1.979885 
2.03269 
431 
0.990826 
1.975912 
2.030039 
433 
0.993119 
1.971933 
2.026284 
434 
0.995413 
1.967948 
2.020608 
435 
0.997706 
1.963959 
2.010698