Clinical trial NCT04200365
Conditions: Chronic Graft-versus-host-disease
Keywords: Chronic Graft-versus-host-disease Allogeneic hematopoietic stem cell transplant Corticosteroids Immunosuppressive therapies
Sponsor: SCRI Development Innovations, LLC
Start date: 2020-06-05; Completion date: 2023-09-07
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is being done in patients who have been receiving corticosteroids or other immunosuppressive therapies for the treatment of cGVHD for at least 6 months. The purpose of this study is to find out if itacitinib in combination with corticosteroids or other immunosuppressive therapies is safe and effective in people with cGVHD.

Detailed description:
Graft versus host disease remains a major hurdle to improve allogeneic hematopoietic stem cell transplantation outcome, with cGVHD being associated with decreased quality of life. Suppression of the immune system with corticosteroids forms the basis of first-line therapy for management of GVHD, but sustained responses are usually seen in less than 50 percent of patients and there is no standard second- or third-line treatment for steroid refractory cGVHD. Identification of novel therapeutic targets are needed to improve outcomes. Therapeutic potential has been shown by a JAK inhibitor in the treatment of steroid refractory GVHD. Itacitinib is a novel, selective inhibitor of the JAK family of protein tyrosine kinases and will be studied here in patients with steroid refractory cGVHD.

Arms: arm 1: None
Interventions: intervention 1: Itacitinib
Intervention descriptions: intervention 1: Itacitinib will be administered orally once daily for up to 24 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This document is confidential and is the property of the Sarah Cannon Development Innovations, LLC.  No part of 
this document may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from Sarah Cannon Development Innovations, LLC. 
 
BMT 29 
A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid 
Refractory Chronic Graft-Versus-Host Disease 
 
SARAH CANNON DEVELOPMENT 
INNOVATIONS STUDY NUMBER: 
BMT 29 
STUDY DRUG: 
INCB39110 (Itacitinib) 
SPONSOR: 
Sarah Cannon Development Innovations, LLC 
(Innovations) 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
1-844-710-6157 
asksarah@sarahcannon.com 
 
STUDY CHAIR: 
Carlos Bachier, MD 
Program Director, Blood and Marrow Transplant 
Sarah Cannon Center for Blood Cancer 
2410 Patterson Street, Suite 500 
Nashville, TN 37203 
615-342-4914 Office 
210-364-3897 Cell 
 
DATE FINAL: 
11 July 2019 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:      
20 August 2019 
AMENDMENT NUMBER: 
2 
AMENDMENT DATE:      
13 December 2019 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:      
08 June 2021 
AMENDMENT NUMBER: 
4 
AMENDMENT DATE:      
26 October 2021 
 
 


 
 
CONFIDENTIAL 
STUDY DRUG:  INCB039110 (ITACITINIB) 
  
 
INNOVATIONS STUDY NUMBER: BMT 29 
FINAL PROTOCOL DATE:  26 OCTOBER 2021  
 
 
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Clinical Study Statement of Compliance 
A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid 
Refractory Chronic Graft-Versus-Host Disease 
 
 This clinical study shall be conducted in compliance with the protocol, as referenced herein, 
and all applicable local, national, and international regulatory requirements to include, but not 
be limited to: 
• 
International Conference on Harmonisation (ICH) Guidelines on Good Clinical 
Practice (GCP) 
• 
Ethical principles that have their origins in the Declaration of Helsinki 
• 
Food and Drug Administration (FDA) Code of Federal Regulation (CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
o 
Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA) 
 
As the Study Chair and/or Principal Investigator, I understand that my signature on the 
protocol constitutes my agreement and understanding of my responsibilities to conduct the 
clinical study in accordance to the protocol and applicable regulations.  Furthermore, it 
constitutes my understanding and agreement that any changes initiated by myself, without 
prior agreement in writing from the Sponsor, shall be defined as a deviation from the protocol, 
and shall be formally documented as such. 
 


 
 
CONFIDENTIAL 
STUDY DRUG:  INCB039110 (ITACITINIB) 
  
 
INNOVATIONS STUDY NUMBER: BMT 29 
FINAL PROTOCOL DATE:  26 OCTOBER 2021  
 
 
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Clinical Study Protocol Approval Page 
A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid 
Refractory Chronic Graft-Versus-Host Disease 
 
INNOVATIONS STUDY NUMBER: 
BMT 29 
STUDY DRUG: 
INCB39110 (Itacitinib) 
DATE FINAL: 
11 July 2019 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:      
20 August 2019 
AMENDMENT NUMBER: 
2 
AMENDMENT DATE:      
13 December 2019 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:  
08 June 2021 
AMENDMENT NUMBER: 
4 
AMENDMENT DATE:      
26 October 2021 
 
 
Carlos Bachier, MD_________     
__________________________         ______________ 
Study Chair 
Program Director, Blood and Marrow 
Transplant 
Sarah Cannon Center for Blood Cancer 
2410 Patterson Street, Suite 500 
Nashville, TN 37203 
Study Chair Signature 
 
Date 
 
 
 
 
 
Marcy Vallone 
  
__________________________  
  _____________ 
Vice President 
Sarah Cannon Development 
Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
Sarah Cannon Development Innovations, 
LLC Representative Signature 
 
Date 
 
 
 


 
 
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STUDY DRUG:  INCB039110 (ITACITINIB) 
  
 
INNOVATIONS STUDY NUMBER: BMT 29 
FINAL PROTOCOL DATE:  26 OCTOBER 2021  
 
 
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Clinical Study Principal Investigator Signature Form 
A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid 
Refractory Chronic Graft-Versus-Host Disease 
 
INNOVATIONS STUDY NUMBER: 
BMT 29 
DATE FINAL: 
11 July 2019 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:      
20 August 2019 
AMENDMENT NUMBER: 
2 
AMENDMENT DATE:      
13 December 2019 
AMENDMENT NUMBER: 
3 
AMENDMENT DATE:   
08 June 2021 
AMENDMENT NUMBER: 
4 
AMENDMENT DATE:      
26 October 2021 
 
By signing this protocol acceptance page, I confirm I have read, understand, and agree to conduct the 
study in accordance with the current protocol. 
 
 
 
___________________________            _______________________________     _______  
Principal Investigator Name 
(Please Print) 
 
Principal Investigator Signature 
 
Date 
 
Please retain a copy of this page for your study files and return the original signed and dated form to: 
 
Sarah Cannon Development Innovations, LLC 
1100 Dr. Martin L. King Jr. Blvd., Suite 800 
Attention:  BMT 29 Study Team 
Nashville, TN 37203 


 
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STUDY DRUG:  INCB039110 (ITACITINIB) 
  
 
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FINAL PROTOCOL DATE:  26 OCTOBER 2021  
 
 
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CLINICAL PROTOCOL AMENDMENT SUMMARY OF CHANGES 
BMT 29 
 
AMENDMENT NUMBER: 
1 
AMENDMENT DATE:      
20 August 2019 
Additions to the text are bolded and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.   
Section 3.1 
Inclusion Criteria 
Corrected Inclusion Criterion #9 to state that the hematologic function requirements are in 
Inclusion Criterion #5. 
9. 
Adequate hematologic function as defined in Inclusion Criterion #35. 
 
Table 2 
Guidelines for Interruption and Restarting of Itacitinib 
Altered the proposed dose modifications for bilirubin elevations for patients for whom the 
bilirubin is increasing in the presence of GVHD response and cannot be attributed to GVHD or 
concomitant therapy.  The new requirement is that the medication should be held or dose 
reduced immediately and restarted or re-escalated if the repeat value obtained 7 days later 
shows no persistent elevation. 
Table 2 
Guidelines for Interruption and Restarting of Itacitinib 
Adverse Event 
Action Taken 
Chemistry 
Total bilirubin elevations that occur in the 
presence of GVHD response that cannot 
be attributed to new liver GVHD or 
concomitant therapy. 
 
Total bilirubin is 3.0 to 5.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Immediately hold or rReduce dose by 1 level until 
bilirubin ≤1.5 x ULN 
- Re-escalate or Rresume previous dose if the repeat 
value obtained 7 days later shows no persistent 
elevation. resolved in 14 days; if >14 days, maintain 
reduced dose. 
Total bilirubin is >5.0 to 10.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Immediately Iinterrupt until bilirubin is ≤1.5 x 
ULN. 
- Monitor liver function tests weekly or more 
frequently as appropriate. 
- Re-escalate or Rresume previous dose if the repeat 


 
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Table 2 
Guidelines for Interruption and Restarting of Itacitinib 
Adverse Event 
Action Taken 
value obtained 7 days later shows no persistent 
elevation.resolved in 14 days; if >14 days, resume 
at reduced dose. 
Total bilirubin is >10.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Interrupt until bilirubin is ≤1.5 x ULN. 
- Re-escalate or Rresume at reduced dose if the 
repeat value obtained 7 days later shows no 
persistent elevation.resolved in 14 days; if 
>714 days, discontinue treatment and monitor as 
appropriate. 
 


 
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FINAL PROTOCOL DATE:  26 OCTOBER 2021  
 
 
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AMENDMENT NUMBER: 
2 
AMENDMENT DATE:      
13 December 2019 
Additions to the text are bolded and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.   
 
Section 3.2 
Exclusion Criteria 
Exclusion criteria #2 was revised to exclude patients on JAK therapy for chronic GVHD, but 
permit prior JAK therapy for acute GVHD. 
2. 
Prior treatment with aReceiving concomitant JAK inhibitor for cGVHD; prior 
treatment with a JAK inhibitor for aGVHD is permitted 
 
Section 5.1.1 Primary Efficacy Period (Cycle 1 Through End of Cycle 6) 
Updated study drug dispension schedule to Day 1 for all cycles. 
The primary efficacy period is defined as Cycle 1 through the end of Cycle 6.  A cycle is 28 
days.  Study treatment will begin on Cycle 1 Day 1 and study drug will be dispensed on Day 1 of 
each cycle.per the following schedule: 
• 
Cycle 1: Days 1, 8, 15, and 22 
• 
Cycles 2 to 6: Day 1 of each cycle (±7 days) 
 
Section 6.3.1 Day 1 of Each Cycle 
Updated study drug dispension schedule to Day 1 for all cycles. 
• 
Dispense study drug & Dosing Diary Cycle 1 and dDispense study drug, collect unused 
drug from previous cycle, and check compliance on Day 1 of all other cycles. 
 
Section 6.7.12 Study Drug Diary and Appendix D: BMT 29 Schedule of Assessments 
Removed requirement for patient diaries. 
6.7.12 Study Drug Diary 
Patients will be given a study drug diary to record the details of each dose of study drug.  Diaries 
will be dispensed/collected on Day 1 of each cycle.  Compliance with oral dosing will be 
confirmed by counting returned tablets and cross-checking with the dosing diaries, which will be 
examined at these visits. 
Dispense/Collect Study Drug & Dosing Diary 


 
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AMENDMENT NUMBER: 
3 
AMENDMENT DATE:      
08 June 2021 
Additions to the text are bolded and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary. 
Section 3.1 
Inclusion Criteria 
Inclusion criterion #2 was revised to the following: 
2. Male and female patients 18 years-of-age or older who have undergone one allo-HSCT(s) 
from any donor HLA type (related or unrelated donor with any degree of HLA matching) 
using any graft source (bone marrow, peripheral blood stem cells, or cord blood).  
Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are 
eligible. 
Section 3.2 
Exclusion Criteria 
Exclusion criterion #1 was deleted. 
1. Has received >1 prior allo-HCT or donor lymphocyte infusion (DLI) 
Sections 5, 5.3 Treatment Duration, Synopsis, and Study Assessment Table Footnote a 
While patients are expected to receive study treatment for approximately 1 year, patients seeing 
clinical benefit may stay on treatment for an additional year. 
Patients will be followed for survival for 1 year after the last dose of study drug.  The total 
duration of the study is planned to be at leastapproximately 3½ years. 
Section 5.4.2 Restricted Concomitant Medications 
The following medications have restrictions on use during the treatment period of the study: 
• 
Medications that interfere with coagulation or platelet function including, but not limited 
to, aspirin in doses exceeding 81 mg/day and related drugs such as heparin and warfarin sodium 
(Coumadin®) are not permitted.  Low-dose aspirin (≤81 mg per day) is permitted, unless 
clinically contraindicated, as is the use of low molecular weight heparin.  If concomitant 
administration of an anticoagulant/antiplatelet medication is indicated, then caution and 
enhanced monitoring is required; it is suggested that CBCs be checked every 1 to 2 weeks for 
the first 2 cycles of administration.  History of thrombocytopenia should be a factor in the 
choice of anticoagulant and dose. 
Section 6.3 
Study Assessment Timing and Study Assessment Table Footnotes 
Clarification was added in each subsection that all lipid panel tests will be done in the fasted 
state. 
Section 6.7.7 Laboratory Assessments 
Laboratory samples (hematology, lipids [fasting], clinical chemistry, urinalysis, and virology 
[screening and as clinically indicated]) are to be collected as outlined in Appendix D.  Safety 


 
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laboratory analyses will be performed.  Laboratory results will be graded using NCI CTCAE 
Version 5. 
Details are presented in the Laboratory Manual. 
Section 7.1 
Itacitinib 
Itacitinib will be administered orally at a starting dose of 200 mg once QD (2 x 100 mg tablets), 
and may be taken with or without food. 
Section 7.1.3 Instructions for Patients for Handling Itacitinib 
Patients must be instructed on the handling of itacitinib as follows: 
• To refrain from taking study medication on the dOn days of clinic visits, tablets can to 
taken before the visit or at the clinic until after blood samples are collected. 


 
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AMENDMENT NUMBER: 
4 
AMENDMENT DATE:      
26 October 2021 
Additions to the text are bolded and deletions from the text are crossed-off.  Only the parts of 
sections with changes are presented.  Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary. 
 
Section 3.2 
Exclusion Criteria 
Exclusion Criterion #1 was revised to the following: 
1. Receiving concomitant JAK inhibitor for chronic GVHD; prior treatment with a JAK 
inhibitor for acute GVHD is permitted if treatment was stopped more than 60 days prior 
to study start.  Patients are eligible if JAK inhibitors for treatment of cGVHD are 
stopped due to side effects and not due to refractoriness. 
 


 
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BMT 29 PROTOCOL SYNOPSIS 
Title of Study: 
A Pilot Study of INCB039110 (Itacitinib) for the Treatment of Steroid Refractory Chronic 
Graft-Versus-Host Disease 
Innovations Study 
Number: 
BMT 29 
Sponsor: 
Sarah Cannon Development Innovations, LLC 
Study Duration: 
The total duration of the study is planned to be at least 3½ 
years. 
Phase of Study:  II 
Study Centers: 
This study will be conducted at approximately 10 sites in the United States. 
Number of 
Patients: 
Up to 40 patients are planned to be enrolled in this study. 
Objectives: 
Primary Objective 
The primary objective of this study is to determine: 
• 
The overall GVHD response rate defined as the proportion of patients demonstrating a 
complete response or partial response after 6 months of treatment with itacitinib as 
defined by National Institute of Health Consensus Criteria (Lee et al. 2015) in patients 
with steroid-refractory chronic graft-versus-host disease. 
 
Secondary Objectives 
The secondary objectives of this study are to determine the: 
• 
Ability to either withdraw or decrease steroids to <0.5 mg/kg of methylprednisolone or 
equivalent 
• 
Overall survival 
• 
Safety and tolerability of itacitinib in patients with steroid-refractory chronic graft-
versus-host disease. 
• 
Quality of life impact using the Lee Symptom Scale from screening until the end-of-
treatment visit. 
• 
Recurrence or progression of chronic GVHD (cGVHD)  
• 
Relapse rate of underlying malignancy. 
Study Design: 
This is an open-label, multi-center, single-arm pilot study in patients who have been 
receiving immunosuppressive therapy for the treatment of cGVHD for a duration of 
>6 months prior to starting daily itacitinib treatment in this study.  While patient 
participation is expected to be approximately 12 months, patients seeing clinical benefit may 
stay on treatment for an additional year. 
Patients will continue to receive their systemic immunosuppressive regimen of 
corticosteroids for steroid-refractory chronic graft-versus-host disease per standard of care 
by the Investigator during the screening and treatment periods.  In addition, transfusion 
support, continued use of anti-infective medications, and topical steroid therapy is permitted. 
Chronic GVHD staging and grading will be assessed for efficacy as per NIH Consensus 
Criteria (Jagasia et al. 2015).  Safety and tolerability will be assessed as per National Cancer 
Institute Common Terminology Criteria for Adverse Events Version 5. 
Study Drug, Dose, 
and Mode of 
Administration: 
Itacitinib 200 mg will be administered orally once daily for up to 24 months.  For patients 
with no GVHD response/stable GVHD after 2 months of therapy at 200 mg a day, the dose 
will increase to 300 mg once daily. 
If a patient has achieved a complete GVHD response or partial GVHD response after 
6 months of treatment, Investigators may begin to taper the dose of itacitinib by 1 dose level 
provided corticosteroids have been discontinued for at least 8 weeks following institutional 
guidelines. 


 
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Main Inclusion 
Criteria: 
1. Eligible male and female patients 18 years-of-age or older who have undergone 
allogeneic hematopoietic stem cell transplant(s) from any donor HLA type (related or 
unrelated donor with any degree of HLA matching) using any graft source (bone 
marrow, peripheral blood stem cells, or cord blood).  Recipients of non-myeloablative, 
myeloablative, and reduced intensity conditioning are eligible. 
2. Active, clinically diagnosed, moderate or severe cGVHD per NIH Consensus (Jagasia et 
al. 2015; Appendix G) 
a) Moderate cGVHD: At least 1 organ (except lung) with a score of 2, ≥3 organs 
involved with a score of 1, or lung score of 1.  
b) Severe cGVHD: At least 1 organ with a score of 3, or lung score of 2 or 3  
3. cGVHD must be refractory to steroids defined by at least one of the criteria below: 
a) Patient is refractory to glucocorticoid therapy at screening, defined as ongoing 
treatment with prednisone or equivalent ≥0.20 mg/kg/day x 4 weeks at screening 
and organ progression documented 4 weeks after the initiation of this regimen.   
b) Patient is dependent on glucocorticoid therapy at screening, defined as treatment 
with a prednisone equivalent mean dose ≥0.20 mg/kg/day received for 12 weeks 
at screening. 
c) Patient is intolerant to glucocorticoids at screening, defined as ongoing treatment 
with prednisone equivalent ≥0.20 mg/kg/day x 4 weeks at screening and presence 
of at least one documented glucocorticoid toxicity. 
4. Evidence of myeloid and platelet engraftment (absolute neutrophil count [ANC] 
>1,000/mm3 AND platelet count >25,000/mm3).  Use of growth factors or platelet 
transfusions is not allowed within 7 days before screening laboratory assessment. 
5. Patients must currently be receiving systemic corticosteroids or other 
immunosuppressive therapies for the treatment of cGVHD for a duration of >6 months 
prior to start of study treatment.  
6. Patients must be able to swallow and retain oral medication. 
7. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. 
Main Exclusion 
Criteria: 
 
1. Receiving concomitant JAK inhibitor for chronic GVHD; prior treatment with a JAK 
inhibitor for acute GVHD is permitted if treatment was stopped more than 60 days prior 
to study start.  Patients are eligible if JAK inhibitors for treatment of cGVHD are 
stopped due to side effects and not due to refractoriness. 
2. Treatment with any other investigational agent, device, or procedure, within 28 days (or 
5 half-lives, whichever is longer) of enrollment.  For previous study drugs where 5 half-
lives is <28 days, a minimum of 10 days between termination of that study drug and 
administration of itacitinib is required. 
3. Pregnant or nursing (lactating) women 
4. Patients with relapsed primary malignancy, or who have been treated for relapse after 
the allogeneic hematopoietic stem cell transplant was performed 
5. History of progressive multifocal leuko-encephalopathy. 
Statistical 
Methodology: 
No formal hypothesis testing is planned for this exploratory study.  In order to estimate the 
overall response rate in this population, a 95% exact two-sided confidence interval will be 
calculated.  A sample size of 40 produces a two-sided 95% CI with a width equal to 0.266 
when the sample proportion is 0.200. 


 
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BMT 29 CONTACT INFORMATION 
Sarah Cannon Development Innovations 
Contact Information: 
Sarah Cannon Development Innovations 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
1-844-710-6157 
asksarah@sarahcannon.com 
 
Study Chair: 
Carlos Bachier, MD 
Program Director, Blood and Marrow Transplant 
Sarah Cannon Center for Blood Cancer 
2410 Patterson Street, Suite 500 
Nashville, TN 37203 
615-342-4914 Office 
210-364-3897 Cell 
Carlos.Bachier@hcahealthcare.com 
 
Safety Dept. Fax #: 
Safety Dept. Email: 
1-866-807-4325 
CANN.SAE@scri-innovations.com 
Medical Support Center Phone # 
Regulatory Department Email: 
1-844-710-6157 
SCRIRegulatory@SCRI-Innovations.com 
Innovations Enrollment Fax #: 
Innovations Enrollment Email #: 
1-866-346-1062 or 615-524-4012 
CANN.SCRIInnovationsEnr@scri-innovations.com 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
Allo-HSCT 
Allogeneic hematopoietic stem cell transplant 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Complete response/remission 
ECOG  
Eastern Cooperative Oncology Group  
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GVHD 
Graft-versus-host disease (a [acute], c [chronic]) 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
Innovations 
Sarah Cannon Development Innovations 
IRB 
Institutional Review Board 
JAK 
Janus kinase 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIH 
National Institute of Health 
NR 
No response 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PHI 
Protected health information 
PR 
Partial response/remission 
QD 
Quaque die (each day) 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SD 
Stable disease 
SR-cGVHD 
Steroid-refractory chronic graft-versus-host disease 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 


 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................. 19 
1.1 
Background and Study Rationale .......................................................................... 19 
1.1.1 
Inhibition of JAKs as a Target for Graft-Versus-Host Disease............................. 19 
1.1.2 
Itacitinib in Subjects with Acute Graft-Versus-Host Disease ............................... 20 
1.2 
Potential Risks and Benefits of the Treatment Regimen ....................................... 20 
2. 
STUDY OBJECTIVES ......................................................................................... 21 
2.1 
Primary Objective.................................................................................................. 21 
2.2 
Secondary Objectives ............................................................................................ 21 
3. 
STUDY PATIENT POPULATION AND DISCONTINUATION ...................... 22 
3.1 
Inclusion Criteria ................................................................................................... 22 
3.2 
Exclusion Criteria .................................................................................................. 23 
3.3 
Discontinuation from Study Treatment ................................................................. 25 
4. 
STUDY REGISTRATION.................................................................................... 25 
5. 
STUDY DESIGN .................................................................................................. 26 
5.1 
Main Treatment Periods ........................................................................................ 26 
5.1.1 
Primary Efficacy Period (Cycle 1 Through End of Cycle 6) ................................ 26 
5.1.2 
Extension Period (Cycle 8 to Cycle 12) ................................................................ 26 
5.2 
Treatments ............................................................................................................. 27 
5.2.1 
Itacitinib................................................................................................................. 27 
5.2.2 
Dietary Restrictions ............................................................................................... 27 
5.2.3 
Corticosteroids....................................................................................................... 27 
5.3 
Treatment Duration ............................................................................................... 27 
5.4 
Concomitant Medications...................................................................................... 27 
5.4.1 
Permitted Concomitant Medications ..................................................................... 27 
5.4.2 
Restricted Concomitant Medications .................................................................... 28 
5.4.3 
Prohibited Concomitant Medications .................................................................... 28 
6. 
STUDY ASSESSMENTS AND EVALUATIONS .............................................. 29 
6.1 
Overview ............................................................................................................... 29 
6.2 
Baseline Study Assessments ................................................................................. 29 
6.3 
Study Assessment Timing ..................................................................................... 30 
6.3.1 
Day 1 of Each Cycle .............................................................................................. 30 
6.3.2 
Days 8, 15, and 22 of Cycle 1 Only ...................................................................... 31 
6.4 
Response Assessments .......................................................................................... 31 
6.5 
End-of-Treatment Visit ......................................................................................... 31 


 
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6.6 
Follow-up .............................................................................................................. 32 
6.6.1 
Safety Follow-Up (30 [±7] Days Following Last Dose of Study Treatment) ....... 32 
6.6.2 
Survival Follow Up (Every 3 Months [±30 Days]) ............................................... 33 
6.7 
Study Treatment Assessments ............................................................................... 33 
6.7.1 
Informed Consent .................................................................................................. 33 
6.7.2 
Medical History and Demographics ...................................................................... 33 
6.7.3 
Physical Examinations (Including Performance Scale and Vital Signs) ............... 33 
6.7.4 
Pulmonary Function Test ...................................................................................... 33 
6.7.5 
12-Lead Electrocardiogram ................................................................................... 33 
6.7.6 
Pregnancy Testing ................................................................................................. 34 
6.7.7 
Laboratory Assessments ........................................................................................ 34 
6.7.8 
Chimerism Testing ................................................................................................ 34 
6.7.9 
Response and Activity Assessments ..................................................................... 34 
6.7.10 
Prior and Concomitant Medications ...................................................................... 34 
6.7.11 
Adverse Event Assessments .................................................................................. 34 
7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION ............................................................................... 34 
7.1 
Itacitinib................................................................................................................. 34 
7.1.1 
Labeling, Packaging, and Supply .......................................................................... 35 
7.1.2 
Preparation and Administration of Itacitinib ......................................................... 35 
7.1.3 
Instructions for Patients for Handling Itacitinib .................................................... 35 
7.2 
Corticosteroids....................................................................................................... 36 
7.2.1 
Prednisone ............................................................................................................. 36 
7.2.2 
Methylprednisolone ............................................................................................... 36 
7.3 
Accountability for All Study Drugs ...................................................................... 37 
8. 
DOSE MODIFICATIONS .................................................................................... 37 
8.1 
Criteria and Procedures for Dose Interruptions and Adjustments of Itacitinib ..... 37 
8.2 
Adjustments of Corticosteroids ............................................................................. 40 
8.3 
Tapering of Itacitinib ............................................................................................. 40 
8.4 
Criteria for Permanent Discontinuation of Itacitinib ............................................. 40 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS .................................. 40 
9.1 
2014 NIH Consensus Development Project on Clinical Trials in cGVHD .......... 40 
9.2 
Clinician-Reported and Patient-Reported Global cGVHD Activity 
Assessments........................................................................................................... 41 
9.3 
Corticosteroid Use ................................................................................................. 41 
9.4 
Quality-of-Life Impact .......................................................................................... 41 
10. 
STATISTICAL CONSIDERATIONS .................................................................. 41 


 
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10.1 
Statistical Design ................................................................................................... 41 
10.2 
Sample Size Considerations .................................................................................. 41 
10.3 
Analysis Population ............................................................................................... 41 
10.4 
Data Analysis ........................................................................................................ 41 
10.4.1 
Demographics and Baseline Characteristics ......................................................... 42 
10.4.2 
Efficacy Analysis .................................................................................................. 42 
10.4.3 
Safety Analysis ...................................................................................................... 42 
10.5 
Analysis Time Points............................................................................................. 42 
10.5.1 
Final Analysis ........................................................................................................ 42 
10.5.2 
Safety Review........................................................................................................ 43 
10.5.3 
Efficacy Analysis .................................................................................................. 43 
11. 
SAFETY REPORTING AND ANALYSES ......................................................... 43 
11.1 
Definitions ............................................................................................................. 43 
11.1.1 
Adverse Events ...................................................................................................... 43 
11.1.2 
Serious Adverse Events ......................................................................................... 43 
11.1.3 
Adverse Reaction .................................................................................................. 44 
11.1.4 
Suspected Adverse Reaction ................................................................................. 44 
11.1.5 
Recording and Reporting of Adverse Events ........................................................ 44 
11.1.6 
Assessment of Adverse Events.............................................................................. 45 
11.2 
Serious Adverse Event Reporting by Investigators ............................................... 46 
11.3 
Recording of Adverse Events and Serious Adverse Events .................................. 46 
11.3.1 
Diagnosis Versus Signs and Symptoms ................................................................ 46 
11.3.2 
Persistent or Recurrent Adverse Events ................................................................ 46 
11.3.3 
Abnormal Laboratory Values ................................................................................ 47 
11.3.4 
Deaths .................................................................................................................... 47 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ........................................ 47 
11.3.6 
Pre-Existing Medical Conditions .......................................................................... 48 
11.3.7 
New Cancers.......................................................................................................... 48 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ................................. 48 
11.3.9 
Itacitinib Overdose ................................................................................................ 48 
11.4 
Incyte Corporation Serious Adverse Event Reporting Requirements ................... 49 
11.4.1 
Sponsor Assessment of Unexpected Events .......................................................... 49 
11.4.2 
Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application ................................................................................................... 50 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL .................................... 50 
12.1 
Study Monitoring, Auditing, and Inspecting ......................................................... 50 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ............ 50 
13.1 
Institutional Review Board Approval.................................................................... 50 


 
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13.2 
Regulatory Approval ............................................................................................. 51 
13.3 
Informed Consent .................................................................................................. 51 
13.3.1 
Confidentiality ....................................................................................................... 51 
13.4 
Financial Information ............................................................................................ 52 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY ........ 52 
14.1 
Amendments to the Protocol ................................................................................. 52 
14.2 
Documentation Required to Initiate the Study ...................................................... 53 
14.3 
Study Documentation and Storage ........................................................................ 54 
14.4 
Data Collection ...................................................................................................... 55 
14.5 
Disclosure and Publication Policy ......................................................................... 55 
15. 
REFERENCES ...................................................................................................... 57 
16. 
APPENDICES ....................................................................................................... 59 
LIST OF TABLES 
Table 1 
Dose Levels of Itacitinib .......................................................................... 38 
Table 2 
Guidelines for Interrupting and Restarting of Itacitinib .......................... 38 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria ......................................................... 59 
Appendix B: 
New York Heart Association (NYHA) Classification of Cardiac 
Disease ..................................................................................................... 60 
Appendix C: 
Guidelines for Female Patients of Childbearing Potential and Fertile 
Male Patients ............................................................................................ 61 
Appendix D: 
BMT 29 Schedule of Assessments .......................................................... 63 
Appendix E: 
Clinician-Reported Global cGVHD Activity Assessment Form ............. 67 
Appendix F 
Patient-Reported Global cGVHD Activity Assessment Form................. 71 
Appendix G: 
Staging of cGVHD (NIH Criteria) ........................................................... 72 
Appendix H 
Response Assessment for cGVHD (NIH Criteria) .................................. 76 
Appendix I 
Lee cGVHD Symptom Score................................................................... 78 
Appendix J: 
Cytochrome P450 3A4 Inhibitors and Inducers....................................... 79 


 
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1. 
INTRODUCTION 
1.1 
Background and Study Rationale 
During the last 2 decades, the number of patients undergoing allogeneic hematopoietic stem cell 
transplantation (allo-HSCT) has more than doubled worldwide.  Graft-versus-host disease 
(GVHD) remains the major hurdle to improve allo-HSCT outcome.  High mortality rates are 
seen for patients suffering from steroid-refractory (SR) acute GVHD (aGVHD), while chronic 
GVHD (cGVHD) is associated with a decreased quality of life (Zeiser et al. 2015). 
Depending on a number of patient- and transplant-related variables, the incidence of aGVHD 
ranges from 10% to 80% with symptoms usually developing 2 to 3 weeks post-transplant.  It is 
estimated that cGVHD affects 30% to 70% of allo-HSCT recipients surviving beyond 100 days, 
with a median onset of 4 to 6 months following HSCT.  Although cGVHD is associated with 
reduced relapse rates in patients transplanted for leukemia, cGVHD remains the leading cause of 
late death in HSCT survivors (Garnett et al. 2013). 
Management of GVHD is challenging.  Immunosuppression with corticosteroids forms the basis 
of first-line therapy in both aGVHD and cGVHD, but sustained responses are usually seen in 
<50% of patients and there remains no standard 2nd- and 3rd-line treatment for SR-cGVHD.  
While evaluation of further therapeutic options is complicated, alternative systematic therapy 
strategies and the identification of novel therapeutic targets are needed to improve outcomes. 
A retrospective survey of 95 patients treated for SR-aGVHD and SR-cGVHD with a Janus 
kinase (JAK) 1/2 inhibitor, ruxolitinib, in 19 European and US transplant centers highlighted the 
therapeutic potential of JAK-inhibitors in the treatment of SR-GVHD.  Treatment with 
ruxolitinib was considered safe and well tolerated in the heavily pre-treated patient population.  
An overall response rate (ORR) above 80% was reported for both SR-aGVHD and SR-cGVHD 
with median time to response being rapid (<2 weeks).  Additional follow-up for patients with 
SR-aGVHD and SR-cGVHD reported 1-year ORRs of 62.4% and 92.7%, respectively (Zeiser et 
al. 2015). 
A novel, potent, and selective inhibitor of the JAK family of protein tyrosine kinases (TYKs) 
with selectivity for JAK1, itacitinib (INCB039110 adipate), is the investigational product in this 
study.  Itacitinib is being developed by Incyte Corporation for the treatment of GVHD, solid 
tumors, B-cell malignancies, myeloproliferative neoplasms, and inflammatory diseases. 
1.1.1 
Inhibition of JAKs as a Target for Graft-Versus-Host Disease 
Pharmacologic inhibition of JAK and signal transducer and activator of transcription (STAT) 
signaling is anticipated to be a promising therapeutic approach for GVHD.  This will achieve the 
beneficial antileukemia effect and overcome human leukocyte antigen barriers in allo-HSCT 
(Choi et al. 2012, Choi et al. 2014). 
In vivo JAK/STAT-signaling inhibition improved survival of mice developing aGVHD and 
reduced histopathological GVHD grading, serum levels of pro-inflammatory cytokines, and 
expansion of allo-reactive luc-transgenic T cells (Spoerl et al. 2014).  Ruxolitinib impaired 
differentiation of CD4+ T cells into IFN-γ and IL-17A–producing cells, both being T-cell 


 
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phenotypes linked to GVHD.  Additionally, ruxolitinib treatment in allo-HSCT recipients 
increased FoxP3+ regulatory T cells, which are linked to immunologic tolerance.  Itacitinib 
showed similar pharmacologic inhibition of interferon signaling, resulting in the decreased 
expression of CXCR3, reduced GVHD, and improved survival when administered for 30 days 
after allo-HSCT in mice. 
Promising preliminary clinical efficacy results with 200 or 300 mg itacitinib monotherapy once 
each daily (QD) are presented in Section 1.1.2. 
1.1.2 
Itacitinib in Subjects with Acute Graft-Versus-Host Disease 
Itacitinib is currently being studied in several indications including in patients with aGVHD.  
This pilot study will be the first in patients with SR-cGVHD. 
The Itacitinib Investigator’s Brochure Version 11 presents preliminary data from Study 
INCB 39110-108 in which 29 patients with aGVHD had received itacitinib (as of the cut-off date 
of 13 December 2018) in combination with corticosteroids (prednisone or methylprednisolone).  
The most frequently reported treatment-emergent adverse events (TEAEs) (≥30%) were 
consistent with expectations for patients with aGVHD and included peripheral edema (44.8%), 
diarrhea and thrombocytopenia/platelet count decreased (48.3% each), hyperglycemia (34.5%), 
anemia, abdominal pain and hypokalemia (37.9% each) and fatigue (31.0%).  The most 
frequently reported treatment-related SAEs was sepsis (6 patients; 20.7%).  Other serious TEAEs 
included acute kidney injury, diarrhea, gastrointestinal hemorrhage, multiple organ dysfunction 
syndrome and respiratory failure (3 patients each, 10.3%), and abdominal pain, staphylococcal 
infection and thrombocytopenia (2 patients each; 6.9%).  Nine patients (31.0%) had fatal TEAEs.  
Preliminary pharmacokinetic (PK) analyses indicated that exposures appeared similar in patients 
with aGVHD, healthy volunteers, and subjects with plaque psoriasis, rheumatoid arthritis, and 
solid tumors. 
Preliminary efficacy results showed ORRs (defined as a complete responses [CRs], very good 
partial responses, and partial responses [PRs]) at Day 28 of 83.3% for first-line aGVHD subjects 
treated with 200 or 300 mg itacitinib once QD, and 62.5% and 66.7% were reported at Day 28 
for subjects with SR-aGVHD treated with 200 or 300 mg itacitinib once QD, respectively 
(Itacitinib Investigator’s Brochure). 
1.2 
Potential Risks and Benefits of the Treatment Regimen 
Adverse events (AEs) that have been most frequently reported in at least 10% of all subjects 
receiving itacitinib monotherapy include constipation, anemia, thrombocytopenia, diarrhea, 
nausea, fatigue, and upper respiratory tract infection. 
As a result of itacitinib-mediated immunomodulation, an increased incidence of infections could 
possibly occur with itacitinib therapy.  Strict clinical monitoring is indicated to identify and treat 
infections in study subjects should they occur. 
Because of the potential for myelosuppression, patients will have hematologic parameters closely 
monitored during clinical studies.  If there are clinically relevant declines in hematology 
parameters, therapy may be interrupted until resolution or discontinuation.  Since itacitinib also 
has the potential to cause white blood cell (WBC) margination (i.e., a transient decrease in 


 
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absolute neutrophil count [ANC]), assessment of hematology parameters should be performed 
before study drug administration and at all applicable study visits. 
As described previously, murine models of JAK/STAT inhibition using both ruxolitinib and 
itacitinib have demonstrated a decrease in the expression of CXCR3, reduction of GVHD, 
preservation of the beneficial graft-versus-tumor effect, and improvement in survival.  To the 
extent that the thrombocytopenia and anemia observed with ruxolitinib are due to the inhibition 
of JAK2-mediated erythropoiesis and thrombopoiesis, a selective JAK1 inhibitor would likely be 
associated with a lower incidence of thrombocytopenia and anemia, while still resulting in a 
significant reduction in the production and the signaling of inflammatory and immune cytokines.  
It is therefore of interest to evaluate a selective JAK1 inhibitor in this setting given the 
hematologic complications associated with GVHD. 
In INCB 39110-108, treatment interruptions and stepwise 100 mg dose reductions were used to 
manage toxicity.  In an analysis of the data, efficacy was not affected in patients who 
demonstrated a Day 28 response and had a dose reduction for any reason.  Dose reductions also 
facilitated platelet recovery in patients receiving treatment.  Interestingly, platelet recovery was 
also observed in patients who did not have a dose reduction.  Thus, the proposed itacitinib 
tapering schedule (see Section 8.3) is not expected to negatively impact efficacy in responding 
patients, and clinicians are permitted to re-escalate the dose of itacitinib in patients who initiate a 
taper but subsequently begin to demonstrate signs or symptoms of GVHD progression. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine the ORR defined as the proportion of patients 
demonstrating a cGVHD response of CR or PR after 6 months of treatment with itacitinib as 
defined by National Institute of Health (NIH) Consensus Criteria (Lee et al. 2015) in patients 
with SR-cGVHD. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to determine the: 
• Ability to either withdraw or decrease steroids to <0.5 mg/kg of methylprednisolone or 
equivalent 
• Overall survival 
• Safety and tolerability of itacitinib in patients with SR-cGVHD 
• Quality of life impact using the Lee Symptom Scale from screening until the end-of-
treatment (EOT) visit 
• Recurrence or progression of cGVHD and  
• Relapse rate of underlying malignancy. 


 
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3. 
STUDY PATIENT POPULATION AND DISCONTINUATION 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in this research study: 
1. Written informed consent, according to local guidelines, signed by the patient or by a 
legal guardian prior to the performance of any study-related screening procedures. 
2. Male and female patients 18 years-of-age or older who have undergone allo-HSCT(s) 
from any donor HLA type (related or unrelated donor with any degree of HLA matching) 
using any graft source (bone marrow, peripheral blood stem cells, or cord blood).  
Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are 
eligible. 
3. Active, clinically diagnosed, moderate or severe cGVHD per NIH Consensus Criteria 
(Jagasia et al. 2015), Appendix G): 
a) Moderate cGVHD: At least 1 organ (except lung) with a score of 2, ≥3 organs 
involved with a score of 1 in each organ, or lung score of 1. 
b) Severe cGVHD: At least 1 organ with a score of 3, or lung score of 2 or 3. 
4. cGVHD must be refractory to steroids defined by at least one of the criteria below: 
a) Patient is refractory to glucocorticoid therapy at screening, defined as ongoing 
treatment with prednisone equivalent ≥0.20 mg/kg/day x 4 weeks at screening and 
organ progression documented 4 weeks after the initiation of this regimen. 
b) Patient is dependent on glucocorticoid therapy at screening, defined as treatment 
with a prednisone equivalent mean dose ≥0.20 mg/kg/day received for 12 weeks at 
screening. 
c) Patient is intolerant to glucocorticoids at screening, defined as ongoing treatment 
with prednisone equivalent ≥0.20 mg/kg/day x 4 weeks at screening and presence of 
at least one documented glucocorticoid toxicity. 
5. Evidence of myeloid and platelet engraftment (absolute neutrophil count [ANC] 
>1,000/mm3 AND platelet count >25,000/mm3.  Use of growth factors or platelet 
transfusions is not allowed within 7 days before screening laboratory assessment. 
6. Patients must currently be receiving systemic or other immunosuppressive therapies for 
the treatment of cGVHD for a duration of >6 months prior to start of study treatment. 
7. Patients must be able to swallow and retain oral medication. 
8. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2 
(Appendix A). 
9. Adequate hematologic function as defined in Inclusion Criterion #5. 
10. Adequate renal function defined as creatinine clearance ≥30 mL/min measured or 
calculated by Cockcroft-Gault equation. 


 
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11. Patients willing to avoid pregnancy or father children based on 1 of the following criteria: 
- Women of non-childbearing potential (i.e., surgically sterile by hysterectomy 
and/or bilateral oophorectomy OR ≥12 months of amenorrhea) 
- Women of childbearing potential who have a negative serum pregnancy test at 
screening and who agree to take appropriate precautions to avoid pregnancy (with 
at least 99% certainty) from screening through the safety follow-up.  Permitted 
methods that are at least 99% effective in preventing pregnancy (see Appendix C) 
should be communicated to the patient and their understanding confirmed. 
- Men who agree to take appropriate precautions to avoid fathering children (with 
at least 99% certainty) from screening through the safety follow-up.  Permitted 
methods that are at least 99% effective in preventing pregnancy (see Appendix C) 
should be communicated to the patient and their understanding confirmed.  Male 
patients must also refrain from donating sperm during their participation in the 
study and for at least 3 months after completing the study. 
12. Ability to understand the nature of this study and to comply with study and follow-up 
procedures. 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
1. Receiving concomitant JAK inhibitor for cGVHD; prior treatment with a JAK inhibitor 
for aGVHD is permitted if treatment was stopped more than 60 days prior to study start.  
Patients are eligible if JAK inhibitors for treatment of cGVHD are stopped due to side 
effects and not due to refractoriness. 
2. Treatment with any other investigational agent, device, or procedure, within 28 days (or 
5 half-lives, whichever is longer) of enrollment.  For previous study drugs where 5 half-
lives is ≤28 days, a minimum of 10 days between termination of that study drug and 
administration of itacitinib is required. 
3. Presence of current secondary malignancies with the exception of previously treated 
in situ carcinoma (i.e., noninvasive), cervical carcinoma Stage 1B or less, and 
noninvasive basal cell or squamous cell skin carcinoma. 
4. Pregnant or nursing (lactating) women 
5. Patients with relapsed primary malignancy, or who have been treated for relapse after the 
allo-HSCT was performed 
6. History of progressive multifocal leukoencephalopathy 
7. Evidence of the following infections: 
- Active uncontrolled bacterial, fungal, parasitic, or viral infection.  Infections are 
considered controlled if appropriate therapy has been instituted and, at the time of 
screening, no signs of infection progression are present.  Progression of infection 


 
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is defined as hemodynamic instability attributable to sepsis, new symptoms, 
worsening physical signs or radiographic findings attributable to infection.  
Persisting fever without other signs or symptoms will not be interpreted as 
progressing infection. 
- Known human immunodeficiency virus (HIV) infection 
- Active tuberculosis infection that developed after allo-HSCT 
- Active viral infection confirmed by polymerase chain reaction (PCR) for the BK 
virus (a polyoma virus), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and 
human herpes virus 6 (HHV-6). 
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires 
treatment, or at risk for HBV reactivation (i.e., positive HBsAg). 
8. 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) 
- Impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of oral itacitinib (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
- 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 (Appendix B), circulatory 
collapse requiring vasopressor or inotropic support, or arrhythmia that requires 
therapy 
- Significant respiratory disease that requires mechanical ventilation support or a 
resting O2 saturation <90% by pulse oximetry or FEV1 <30%. 
9. Patients requiring platelet transfusions to maintain a platelet count >25,000/mm3 
10. Any corticosteroid therapy for indications other than cGVHD at doses >1 mg/kg/day 
methylprednisolone or equivalent within 7 days of study start 
11. Patients receiving treatment with medications that interfere with coagulation or platelet 
function including, but not limited to, aspirin dose exceeding 81 mg/day and related 
drugs such as heparin or warfarin sodium (Coumadin®).  Use of low molecular weight 
heparin is allowed. 
12. Known allergies, hypersensitivity, or intolerance to itacitinib or any of its excipients 
13. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol. 


 
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3.3 
Discontinuation from Study Treatment 
Patients will be discontinued from study treatment for any of the following reasons: 
• 
Relapse of underlying malignancy 
• 
Irreversible or intolerable toxicity or abnormal laboratory values thought to be related to 
drug toxicity 
• 
The patient is unable to tolerate itacitinib 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. 
• 
Conditions requiring therapeutic intervention not permitted by the protocol 
• 
Intercurrent illness (this will be at the Investigator’s discretion) 
• 
Inability of the patient to comply with study requirements 
• 
Patient requests to discontinue treatment, but agrees to finish study procedures 
• 
Patient withdraws consent from the study and is discontinued from the study 
• 
Non-compliance/lost to follow-up 
• 
Pregnancy 
• 
Further participation would be injurious to the patient's health or well-being, in the 
Investigator's medical judgment. 
• 
The study is terminated by the Sponsor or the Institutional Review Board (IRB). 
After discontinuation from protocol treatment, patients must be followed for AEs for 30 days 
after their last dose of study drug.  All new AEs occurring during this period must be reported 
and followed until resolution, unless, in the opinion of the Investigator, these values are not 
likely to improve, because of the underlying disease.  In this case, the Investigator must record 
his or her reasoning for this decision in the patients’ medical records. 
All patients who have Grade 3 or 4 laboratory abnormalities (per National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5) at the time of 
discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the Investigator, not likely that these values will improve.  In this 
case, the Investigator must record his or her reasoning for making this decision in the patients’ 
medical records. 
4. 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, treatment alternatives, risks, and 
discomforts.  Human protection committee (IRB) approvals of this protocol and any associated 
ICFs is required.  Eligible patients who wish to participate in the study will be enrolled into the 
study. 


 
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Registration must occur prior to the initiation of protocol therapy.  Patients eligible to participate 
in the study may be enrolled by each site following the patient registration instructions provided 
by the Sarah Cannon Development Innovations (Innovations) study contact.  Patient registration 
follow-up and/or confirmation will be provided via email within approximately 24 hours or by 
the next business day. 
5. 
STUDY DESIGN 
This is an open-label, multi-center, single-arm pilot study in patients who have been receiving 
immunosuppressive therapy for the treatment of cGVHD for a duration of >6 months prior to 
starting daily itacitinib treatment in this study.  The planned enrollment for this study is 
40 patients, and patient treatment is expected to be approximately 12 months, although patients 
seeing clinical benefit may stay on treatment for an additional year. 
Patients will continue to receive their systemic immunosuppressive regimen for SR-cGVHD per 
standard of care as determined by the Investigator during the screening and treatment periods.  In 
addition, transfusion support, continued use of anti-infective medications, and topical steroid 
therapy is permitted. 
Chronic GVHD staging and grading will be assessed for efficacy as per NIH Consensus Criteria 
(Jagasia et al. 2015).  Safety and tolerability will be assessed as per NCI CTCAE Version 5. 
5.1 
Main Treatment Periods 
Patients who taper off study treatment and all immunosuppressive therapy due to achieving a 
cGVHD status of CR or PR will continue to be followed according to the Schedule of 
Assessments (Appendix D), including all safety and efficacy assessments, and will be monitored 
for cGVHD recurrence. 
5.1.1 
Primary Efficacy Period (Cycle 1 through End of Cycle 6) 
The primary efficacy period is defined as Cycle 1 through the end of Cycle 6.  A cycle is 
28 days.  Study treatment will begin on Cycle 1 Day 1 and study drug will be dispensed on Day 
1 of each cycle. 
Patients will be treated for a minimum of 6 cycles, unless they meet the discontinuation criteria 
listed in Section 3.3). 
Primary efficacy assessments will be performed on Cycle 7 Day 1, after completion of 6 cycles 
of treatment. 
5.1.2 
Extension Period (Cycle 8 to Cycle 12) 
Patients will continue treatment and will be monitored on Day 1 of each cycle until the end-of-
treatment (EOT) visit, according to the assessments outlined in Appendix D. 
Patients undergoing dose tapering should be monitored for cGVHD flare occurrences, which 
must be reported in the database. 


 
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5.2 
Treatments 
5.2.1 
Itacitinib 
Itacitinib will be administered orally at a starting dose of 200 mg once QD (2 x 100 mg tablets), 
and may be taken with or without food. 
Itacitinib dose will be increased to 300 mg QD (3 x 100 mg tablets) for patients with no response 
(NR)/stable disease (SD) after 2 months of therapy at 200 mg QD. 
Patients may have dose reductions or interruptions of itacitinib during the course of treatment 
based on AEs, clinical evaluation, and laboratory assessments.  See Section 8.1 for dose 
modifications of study drug. 
5.2.2 
Dietary Restrictions 
Patients should be instructed to refrain from the consumption of pomegranates or pomegranate 
juice, and grapefruit or grapefruit juice, as these are known to inhibit cytochrome CYP3A 
enzymes and may increase exposure to itacitinib. 
5.2.3 
Corticosteroids 
Patients will join this study after receiving immunosuppressive regimens for SR-cGVHD for at 
least 6 months and will remain on the dose at which they started if considered clinically 
appropriate by the Investigator. 
Corticosteroids should be tapered 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 patient will be considered to have experienced treatment 
failure and will be withdrawn from study treatment. 
5.3 
Treatment Duration 
While patients are expected to receive study treatment for approximately 1 year, those seeing 
clinical benefit may stay on treatment for an additional year. 
Patients will be followed for survival for 1 year after the last dose of study drug.  The total 
duration of the study is planned to be at least 3½ years.  
5.4 
Concomitant Medications 
Patients will be instructed not to take any additional medications during the course of the study 
without prior consultation with the research team.  At each visit, the patient will be asked about 
any new medications he/she is taking or has taken after the start of the study drug. 
5.4.1 
Permitted Concomitant 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 


 
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measures are necessary, ongoing therapy may continue at the Investigator's discretion per 
institutional guidelines. 
Additional supportive care measures (e.g., use of antimotility agents for diarrhea management, 
topical steroids) are permitted at the Investigator's discretion.  Concomitant treatments and/or 
procedures that are required to manage a patient's medical condition during the study will be 
recorded in the eCRF. 
5.4.2 
Restricted Concomitant Medications 
The following medications have restrictions on use during the treatment period of the study: 
• Medications that interfere with coagulation or platelet function including, but not limited 
to, aspirin in doses exceeding 81 mg/day and related drugs such as heparin and warfarin 
sodium (Coumadin®) are not permitted.  Low-dose aspirin (≤81 mg per day) is 
permitted, unless clinically contraindicated, as is the use of low molecular weight 
heparin.  If concomitant administration of an anticoagulant/antiplatelet medication is 
indicated, then caution and enhanced monitoring is required; it is suggested that CBCs be 
checked every 1 to 2 weeks for the first 2 cycles of administration.  History of 
thrombocytopenia should be a factor in the choice of anticoagulant and dose. 
• For coadministration with potent CYP3A inhibitors; consider alternative agents with less 
CYP3A inhibition (Appendix J).  Differences in individual sensitivity and varied CYP 
enzyme inhibition may result in the need for dose reduction of itacitinib and/or 
corticosteroids, as appropriate. Note: If the participant’s medical condition requires 
treatment with any of these drugs, a dose reduction of itacitinib to 100 mg QD is 
recommended, as more potent inhibitors have been shown to increase exposure to 
itacitinib.  No dose adjustment is recommended for concomitant administration of other 
CYP3A4 inhibitors. 
• Coadministration with CYP3A4 inducers (Appendix J). 
5.4.3 
Prohibited Concomitant Medications 
The following treatments are prohibited during the treatment period of the study: 
• No other investigational therapy (e.g., chemotherapy, radiation therapy, surgery, 
immunotherapy [including other JAK inhibitors], biologic therapy, hormonal therapy, or 
tumor embolization) should be given to patients to treat a suspected malignancy relapse.  If 
such agents are required for a patient, then the patient must first be withdrawn from the 
study. 
• Herbal preparations/medications are not allowed throughout the study.  These herbal 
medications include, but are not limited to: St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.  
Patients should stop using these herbal medications 7 days prior to first dose of study drug. 


 
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6. 
STUDY ASSESSMENTS AND EVALUATIONS 
6.1 
Overview 
All patients should visit the study center on the days specified within this protocol.  The 
complete Schedule of Assessments for this study is presented in Appendix D. 
Safety laboratory assessments including hematology, serum biochemistry, pregnancy test, and 
urinalysis will be performed locally. 
6.2 
Baseline Study Assessments 
The following information will be collected and procedures will be performed for each patient at 
screening. Screening should take place within 28 days of start of study treatment and safety 
laboratory assessments should be done within ≤14 days prior to initiation of treatment: 
• Written informed consent prior to any other study-related procedures (see Section 13.3) 
• Medical history and demographics 
• Physical examination (including height and weight) 
• ECOG performance status (see Appendix A) 
• Vital signs (pulse rate, blood pressure [BP], and body temperature) 
• Blood transfusion review 
• 12-lead electrocardiogram (ECG) 
• Pulmonary function tests (FEV1, FVC, DLCO, TLC, RV) 
• Urine pregnancy test for women of child-bearing potential (must be performed within 72 
hours prior to the start of treatment).  Positive urine pregnancy test should be confirmed 
with a serum beta human chorionic gonadotropin (β-hCG) test. 
• Hematology panel (hematocrit, hemoglobin, mean corpuscular volume, platelet count, 
red blood cell count, white blood cell [WBC] count, WBC 5-part differential) 
• Clinical chemistry panel (sodium, potassium, phosphorus, chloride, creatinine, calcium, 
venous bicarbonate, albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate 
dehydrogenase, serum glucose, and blood urea nitrogen) 
• Lipid panel (fasting) (high-density lipoprotein [HDL] cholesterol, low-density lipoprotein 
[LDL] cholesterol, total cholesterol, and triglycerides)  
• Urinalysis 
• Virology tests (HIV, Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis 
B core antibody, Hepatitis C antibody, HBV-DNA [if required], HCV-RNA [if required]) 
• Concomitant medication review 


 
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• AE and infection monitoring.  Patients with either pre-transplant positive serology results 
or unknown viral testing results prior to transplant must have viral load results 
confirming no evidence of active viral infection within 28 days prior to study treatment. 
• cGVHD diagnosis and staging (see Appendix G) 
• Chimerism assessment as per institutional standards 
• Lee Symptom Scale (see Appendix I) 
• Document corticosteroid dosage (total dose/kg and type of corticosteroids) 
• Document concomitant cGVHD therapy 
6.3 
Study Assessment Timing 
The treatment period begins on the day the patient receives the first dose of study drug through 
the point at which the Investigator determines the patient will be permanently discontinued from 
study drug.  Dates for subsequent study visits will be determined based upon this day and should 
occur as close to the scheduled day as possible taking into consideration the windows of time 
included in the assessments table.  During the Day 1 visit, results from screening visit 
evaluations should be reviewed to determine whether the patient continues to meet the eligibility 
requirements as specified in the protocol. 
6.3.1 
Day 1 of Each Cycle 
• Physical examination 
• ECOG performance status 
• Vital signs (blood pressure, body temperature, and pulse rate after about 5 minutes of 
rest) 
• Blood transfusion review 
• Hematology, lipid (fasting), and clinical chemistry panels 
• Urinalysis 
• Pulmonary function tests at Cycle 4 Day 1 and Cycle 7 Day 1 only (FEV1, FVC, DLCO, 
TLC, RV) 
• Urine pregnancy test for women of child-bearing potential (testing is not required if done 
within 72 hours prior to the start of treatment on Cycle 1 Day 1). Positive urine 
pregnancy test should be confirmed with a β-hCG serum test. 
• Concomitant medication review 
• AE and infection monitoring 
• Global cGVHD activity assessments (clinician-reported [Appendix E] and patient-
reported [Appendix F]) 
• cGVHD response assessment (Appendix H) (starting at Cycle 2 through 7, and then every 
odd-numbered cycle thereafter starting with Cycle 9)  


 
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• Lee Symptom Scale (Day 1 of Cycles 1 and 7 only; Appendix I) 
• Document corticosteroid dosage (total dose/kg and type of corticosteroids) 
• Assess relapse of underlying malignancy (at the Investigator’s discretion; formal re-
staging not required) 
• Document concomitant cGVHD therapy 
• Dispense study drug, collect unused drug from previous cycle, and check compliance. 
6.3.2 
Days 8, 15, and 22 of Cycle 1 Only 
• Physical examination 
• Vital signs (blood pressure, body temperature, and pulse rate after about 5 minutes of 
rest) 
• Hematology, lipid (fasting), and clinical chemistry panels 
• Urinalysis 
• Concomitant medication review 
• AE and infection monitoring 
• Document corticosteroid dosage (total dose/kg and type of corticosteroids) 
• Document concomitant cGVHD therapy 
6.4 
Response Assessments 
Response criteria (CR, PR, or other [unchanged, mixed response, progression]) based on the 
2014 NIH Consensus Development Project on Clinical Trials in cGVHD (see Appendix H for 
criteria) will be assessed on Day 1 of Cycles 2 through 7; and then every odd-numbered cycle 
thereafter starting on Day 1 of Cycle 9, as well as the EOT visit.   
Patients with GVHD progression, progression of the underlying malignancy, or unacceptable 
toxicity should be discontinued from the study; patients with stable GVHD or a GVHD response 
to therapy will continue treatment. 
6.5 
End-of-Treatment Visit 
The follow-up evaluations required after treatment ends (due to the completion of the planned 
study treatment period, GVHD progression, progression of underlying malignancy, or once the 
patient is discontinued due to unacceptable toxicity or the decision to discontinue treatment by 
the patient or the study physician) are specified in Appendix D.  This visit should be performed 
within 7 days and no later than 14 days after discontinuation of study treatment.  If treatment is 
discontinued because of toxicity or any other reason(s) and no study treatment is administered, 
that visit may fulfill the EOT visit. 
The following assessments will be performed at the EOT visit: 
• Physical examination 


 
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• ECOG performance status 
• Vital signs (blood pressure, body temperature, and pulse rate after about 5 minutes of 
rest) 
• Urine pregnancy test for women of child-bearing potential 
• Blood transfusion review 
• Electrocardiogram 
• Hematology, lipid (fasting), and clinical chemistry panels 
• Urinalysis 
• Concomitant medication review 
• AE and infection monitoring 
• Global cGVHD activity assessment (clinician-reported [Appendix E] and patient-reported 
[Appendix F]) 
• cGVHD response assessment (Appendix H) 
• Assess relapse of underlying malignancy with Lee Symptom Scale (Appendix I) 
• Document corticosteroid dosage (total dose/kg and type of corticosteroids) 
• Document concomitant cGVHD therapy 
6.6 
Follow-up 
6.6.1 
Safety Follow-Up (30 [±7] Days Following Last Dose of Study Treatment) 
A 30-day safety follow-up assessment will be performed after the last dose of itacitinib. 
The following assessments will be performed at this visit: 
• Physical examination 
• ECOG performance status 
• Vital signs (blood pressure, body temperature, and pulse rate after about 5 minutes of 
rest) 
• Hematology, lipid (fasting), and clinical chemistry panels 
• Urinalysis 
• Urine pregnancy test for women of child-bearing potential 
• Concomitant medication review 
• AE and infection monitoring 
• Discuss new GVHD therapies 


 
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6.6.2 
Survival Follow Up (Every 3 Months [±30 Days]) 
Patients who permanently discontinue the study treatment for reasons other than achieving a 
GVHD status of CR or PR will be followed for survival, relapse of underlying malignancy, and 
reporting of new cGVHD therapies approximately every 3 months for 1-year after completion of 
study drug, and can be contacted by telephone, email, or by a site visit. 
6.7 
Study Treatment Assessments 
6.7.1 
Informed Consent 
All subjects must take part in the informed consent process.  Adequate time must be allowed for 
the subject to ask questions and make a voluntary decision.  No protocol-specific procedures, 
including screening procedures are to be performed until the subject has signed and dated an 
IRB-approved informed consent form (ICF).  For more details, please see Section 13.3. 
6.7.2 
Medical History and Demographics 
A complete medical history and demographics will be taken at screening.  Information to be 
documented includes, prior medical illnesses and conditions, conditioning regimen, stem cell 
source, GVHD prophylaxis therapy, disease status at transplant, prior lines of GHVD therapy 
and surgical procedures. 
6.7.3 
Physical Examinations (Including Performance Scale and Vital Signs) 
A complete physical examination will be done at screening, on Days 1, 8, 15, and 22 of Cycle 1, 
on Day 1 of each subsequent treatment cycle, at the end-of-treatment (EOT) and 30-day safety 
follow-up (FU) visits, and at the discretion of the Investigator.  They will include documentation 
of height (screening only), weight, and vital signs collected after the patient has been sitting for 
at least 5 minutes (blood pressure, body temperature, and pulse rate).  Blood transfusions will be 
reviewed at screening, Day 1 of each cycle and at the EOT visit.  The ECOG performance status 
(see Appendix A) will be done at all visits with a physical exam with the exception of Days 8, 
15, and 22 of Cycle 1.  Any abnormal or clinically significant findings from the physical 
examination must be recorded on the appropriate electronic case report form (eCRF) page. 
If these assessments are performed within 72 hours of initiation of treatment at the screening 
visit, an abbreviated physical examination can be done on Day 1 of Cycle 1.  Vital signs 
assessments and ECOG performance status are still required prior to first study drug dose. 
6.7.4 
Pulmonary Function Test 
Pulmonary function test will be performed at screening (within 14 days of Cycle 1 Day 1), Day 1 
of Cycle 4 and Cycle 7 and include FEV1, FVC, DLCO (corrected for Hb), TLC and RV. 
6.7.5 
12-Lead Electrocardiogram 
Electrocardiograms will be done at screening, at the EOT visit, and at the discretion of the 
Investigator.  Each will be performed with the patient in a supine position having rested in this 
position for at least 5 minutes before the reading. 
ECG should to be performed immediately prior to any blood sample collections, if possible. 


 
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6.7.6 
Pregnancy Testing 
Women of child-bearing potential will have a urine pregnancy test at screening (3 days prior to 
initiation of treatment), on Day 1 of each cycle, the EOT visit, and during the 30-day follow-up 
visit.  Additional urine pregnancy testing is at the Investigator’s discretion. Positive results are to 
be confirmed with serum beta human chorionic gonadotropin testing. 
6.7.7 
Laboratory Assessments 
Laboratory samples (hematology, lipids [fasting], clinical chemistry, urinalysis, and virology 
[screening and as clinically indicated]) are to be collected as outlined in Appendix D.  Safety 
laboratory analyses will be performed.  Laboratory results will be graded using NCI CTCAE 
Version 5. 
6.7.8  
Chimerism Testing 
Chimerism will be tested at screening according to institutional standards. 
6.7.9 
Response and Activity Assessments 
Please see Section 9. 
6.7.10 
Prior and Concomitant Medications 
All concomitant medications are to be collected and recorded in the eCRF from the time the 
patient signs the ICF throughout the patient’s participation in the study. 
6.7.11 
Adverse Event Assessments 
Information regarding the occurrence of AEs (including infections) will be collected from the 
time the patient signs the ICF throughout their participation in the study, including a period of 
30 days after the last dose of study drug.  Adverse event severity will be determined using the 
CTCAE Version 5 grading scale.  Please see Section 11 for more details. 
7. 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION, AND 
TOXICITY INFORMATION 
7.1 
Itacitinib 
Investigational Product 
Dosage Form and Strength 
Manufacturer 
Itacitinib 
100 mg 
Incyte 
Itacitinib 100 mg (free base equivalent) sustained-release tablets contain the active ingredients 
hypromellose, microcrystalline cellulose, lactose monohydrate, and magnesium stearate. 
Itacitinib will be administered orally at a starting dose of 200 mg once QD (2 x 100 mg tablets), 
and may be taken with or without food. 
Itacitinib dose will be increased to 300 mg QD (3 x 100 mg tablets) for patients with NR/SD 
after 2 months of therapy at 200 mg QD. 


 
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Patients may have dose reductions or interruptions of itacitinib during the course of treatment 
based on AEs, clinical evaluation, and laboratory assessments.  See Section 8.1 for dose 
modifications of study drug. 
Patients are permitted to remain on itacitinib treatment until withdrawal from study treatment is 
considered necessary as per Section 3.3. 
7.1.1 
Labeling, Packaging, and Supply 
Incyte Corporation will provide itacitinib tablets to the sites in high-density polyethylene bottles.  
All Incyte Corporation investigational product labels will be in the local language and will 
comply with legal requirements. 
At each visit, patients will be dispensed sufficient supplies until the next visit.  Study drug 
compliance will be assessed at each patient visit.  The research staff will count and document the 
amount of study drug taken and returned by the patient.  The batch number of the study drug 
dispensed to the patient should be entered on the CRF, if applicable. 
The immediate packaging will contain a statement to conform with U.S. Food and Drug 
Administration (FDA) Investigational New Drug (IND) requirements as follows: Caution: New 
Drug - Limited by Federal (or United States) law to investigational use. 
All study drugs must be kept in a secure place under appropriate storage conditions. 
Itacitinib should be stored at ambient conditions (15°C to 30°C, or 59°F to 86°F) per the IB. 
Sarah Cannon Development Innovations (Innovations) representatives must be granted access on 
reasonable request to check drug storage, dispensing procedures, and accountability records. 
7.1.2 
Preparation and Administration of Itacitinib 
Itacitinib is administered orally.  No preparation is required. 
7.1.3 
Instructions for Patients for Handling Itacitinib 
Patients must be instructed in the handling of itacitinib 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 
• To take tablets with a glass of water 
• Not to take another dose if vomiting occurs after taking the study medication, but rather 
wait for the next scheduled dose. 
• On days of clinic visits, tablets can be taken before the visit or at the clinic after blood 
samples are collected. 
• To bring all used and unused bottles of study medication to the site at each visit. 


 
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If the patient misses a dose of study drug, the patient should take the dose as soon as possible.  If 
the next dose is due in less than 12 hours, however, the patient should skip the missed dose and 
take the next dose as scheduled. 
If vomiting is persistent, the patient should contact the Investigator. 
Study drug will be dispensed and compliance will be assessed by pill counts on Day 1 of each 
cycle.  The research staff will count and document the amount of study drug taken and returned 
by the patient. 
7.2 
Corticosteroids 
Patients will join this study after receiving immunosuppressive regimens of corticosteroids for 
SR-cGVHD for at least 6 months and will remain on the dose at which they started if considered 
clinically appropriate by the Investigator. 
Corticosteroids should be tapered 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 patient will be considered to have experienced treatment 
failure and will be withdrawn from study treatment. 
Corticosteroids may be taken or administered without food. 
7.2.1 
Prednisone 
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, 2.5, 5, 10, 20, and 50 mg tablets.  Prednisone tablets should be stored in accordance with local 
prescribing information requirements. 
Investigators are responsible for ensuring that patients receive commercially available supplies 
of prednisone for the duration of the study treatment period, if applicable. 
7.2.2 
Methylprednisolone 
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.  
Methylprednisolone (unreconstituted product or solution) should be stored in accordance with 
local prescribing information. 
Investigators are responsible for ensuring that patients receive commercially available supplies 
of methylprednisolone for the duration of the study treatment period, if applicable. 


 
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7.3 
Accountability for All Study Drugs 
The Principal Investigator (or designee) is responsible for accountability of all used and unused 
study drug supplies at the site. 
All study drug inventories must be made available for inspection by the Sponsor (Innovations) or 
its representatives and regulatory agency inspectors upon request. 
At the end of the study, all Innovations Drug Accountability Record Form(s) will be completed 
by the site and sent to the Innovations Regulatory Department.  Study drug supplies must not be 
destroyed unless prior approval has been granted by Innovations or its representative.  Please 
contact Innovations regarding disposal of any study drug reserves. 
8. 
DOSE MODIFICATIONS 
Patients receiving itacitinib at a dose of 200 mg QD may have their dose reduced to 100 mg QD.  
Patients who are unable to tolerate itacitinib at a dose of 100 mg QD should be withdrawn from 
study treatment (see Table 1). 
8.1 
Criteria and Procedures for Dose Interruptions and Adjustments of Itacitinib 
If toxicity occurs, the toxicity will be graded utilizing the NCI CTCAE Version 5 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE), and appropriate supportive care treatment will be 
administered to decrease the signs and symptoms thereof.  Dose interruptions and modifications 
may occur for individual study patients based on the emergence or resolution of toxicity. 
Treatment with itacitinib may be delayed up to 14 days to allow for resolution of toxicity.  
Subjects may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the Investigator, would make the patient unsuitable for further participation in the 
study.  The Investigator should contact the Study Chair to discuss cases where treatment has 
been delayed for more than 14 days before restarting treatment. 
Because patients may enter the study with compromised bone marrow function, these dose 
reductions are provided as guidelines (see Table 2).  Individual decisions regarding dose 
reduction should be made using clinical judgment and in consultation with the Study Chair, 
taking into account relatedness of the AE to the study drug and the patient'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. 


 
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Table 1 
Dose Levels of Itacitinib 
Dose Level 
Itacitinib 
Dose Level +1a 
300 mg QD 
Starting Dose  
200 mg QD 
Dose Level -1 
100 mg QD 
Dose Level -2 
Discontinue 
a 
Itacitinib dose will be increased to 300 mg QD (3 x 100 mg tablets) for patients with NR/SD after 2 months of 
therapy at 200 mg QD 
NR = no response; QD = once daily; SD = stable disease 
 
Table 2 
Guidelines for Interrupting and Restarting of Itacitinib 
Adverse Event 
Action Taken 
Chemistry 
AST and/or ALT >3.0 × ULN in patients 
with normal ALT/AST at baseline 
• 
Interrupt for up to 14 days until the toxicity has 
resolved to ≤ Grade 1.  Exceptions require Sponsor 
approval. 
• 
Restart at previous dose.  If assessed as related to 
itacitinib, restart at next lower dose and monitor as 
clinically indicated. 
NOTE: In patients with GVHD-related chemistry 
elevations at baseline, contact the Study Chair to discuss 
clinical management and possible dose reductions. 
Total bilirubin elevations that occur in the 
presence of GVHD response that cannot 
be attributed to new liver GVHD or 
concomitant therapy 
 
Total bilirubin is 3.0 to 5.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Immediately hold or reduce dose by 1 level until 
bilirubin ≤1.5 x ULN 
- Re-escalate or resume previous dose if the repeat 
value obtained 7 days later shows no persistent 
elevation. 
Total bilirubin is >5.0 to 10.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Immediately interrupt until bilirubin is ≤1.5 x 
ULN. 
- Monitor liver function tests weekly or more 
frequently as appropriate. 
- Re-escalate or resume previous dose if the repeat 
value obtained 7 days later shows no persistent 
elevation. 
Total bilirubin is >10.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 


 
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Table 2 
Guidelines for Interrupting and Restarting of Itacitinib 
Adverse Event 
Action Taken 
- Interrupt until bilirubin is ≤1.5 x ULN. 
- Re-escalate or resume at reduced dose if the repeat 
value obtained 7 days later shows no persistent 
elevation; if >7 days, discontinue treatment and 
monitor as appropriate. 
Total bilirubin elevations that occur in 
patients with Stage 1/2 liver GVHD that 
cannot be attributed to worsening liver 
GVHD or concomitant therapy 
 
Total bilirubin is >3.0 x ULN: 
• 
Repeat assessment within 7 days.  If elevation persists: 
- Reduce dose by 1 dose level. 
- Resume previous dose if bilirubin is ≤3.0 x ULN. 
Hematology 
ANC is <0.5 x 109/L, suspected as 
unrelated to study treatment (e.g., GVHD, 
active cytomegalovirus viremia) 
• 
Reduce dose by 1 dose level. 
• 
Monitor ANC count as clinically indicated. 
• 
Resume previous dose if ANC count is ≥0.5 x 109/L for 
more than 7 days. 
ANC is <0.5 x 109/L, suspected as related 
to study treatment 
 
• 
Interrupt for up to 14 days. 
• 
Monitor ANC count as clinically indicated. 
• 
Resume at a reduced dose if ANC count is ≥0.5 x 109/L 
for more than 7 days.  If the patient's ANC count 
remains at ≥0.5 x 109/L for more than 7 days after 
resuming treatment at a lower dose, the previous dose 
may be resumed. 
Platelet count is <10 x 109/L, or platelet 
count has decreased by ≥50% from 
baseline, suspected as unrelated to study 
treatment 
 
• 
Reduce dose by 1 dose level. 
• 
Monitor platelet count as clinically indicated. 
• 
Resume at previous dose if platelet count returns to 
≥20 x 109/L for more than 7 days. 
Platelet count is <10 x 109/L, or platelet 
count has decreased by ≥50% from 
baseline, suspected as related to study 
treatment 
 
• 
Interrupt for up to 14 days. 
• 
Monitor platelet count as clinically indicated. 
• 
Resume at a reduced dose if platelet count returns to 
≥20 x 109/L for more than 7 days.  If the patient's 
platelet count remains at ≥20 x 109/L for an additional 
7 days, the previous dose of may be resumed. 
Other Toxicities 
Any Grade 1 or Grade 2 toxicity 
 
• 
Continue treatment and manage the toxicity. 
• 
Monitor as clinically indicated. 
Any Grade 3 toxicity, if clinically 
significant and not manageable by 
supportive care 
 
• 
Interrupt up to 14 days until toxicity resolves to 
≤ Grade 1. 
• 
Restart at same dose; if assessed as related to itacitinib, 
restart at next lower dose and monitor as clinically 
indicated. 
Any recurrent Grade 3 toxicity at 100 mg 
• 
Discontinue study treatment; follow-up per protocol.  


 
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Table 2 
Guidelines for Interrupting and Restarting of Itacitinib 
Adverse Event 
Action Taken 
QD dose 
 
Exceptions require Study Chair approval. 
Any other Grade 4 toxicity 
 
• 
Discontinue study treatment; follow-up per protocol. 
ALT = alanine aminotransferase; Absolute neutrophil count = ANC; AST = aspartate aminotransferase; GVHD = graft versus 
host disease; LFT = liver function test; ULN = upper limit of normal. 
8.2 
Adjustments of Corticosteroids 
Adjustments or tapering of the dose of corticosteroids should be made at the treating 
Investigator's discretion. 
8.3 
Tapering of Itacitinib 
If a patient has achieved CR or PR after 6 months of treatment, Investigators may begin to taper 
the dose of itacitinib by 1 dose level provided corticosteroids have been discontinued for at least 
8 weeks following institutional guidelines.  Subjects must not be experiencing any Grade 2 or 
higher hematologic toxicity related to study treatment or symptoms of an active infection. 
Investigators wishing to initiate a taper of itacitinib at an earlier time point may do so upon 
consultation with and approval from the Study Chair. 
If GVHD signs/symptoms worsen during the taper of itacitinib, the dose may be escalated by 
1 dose level.  If the patient requires additional systemic therapy (includes restarting of 
corticosteroids), then the patient would be considered as having disease progression (PD) and 
would be withdrawn from study treatment. 
8.4 
Criteria for Permanent Discontinuation of Itacitinib 
A full list of criteria for permanent discontinuation of itacitinib are presented in Section 3.3. 
9. 
RESPONSE EVALUATIONS AND MEASUREMENTS 
Response will be evaluated by determining the ORR after 6 months of treatment with itacitinib 
as defined by NIH Consensus Criteria.  In addition, patients’ ability to either withdraw or 
decrease steroids while receiving itacitinib will be evaluated, as will patients’ personal 
assessment of their quality of life. 
9.1 
2014 NIH Consensus Development Project on Clinical Trials in cGVHD 
Patient response (CR, PR, or other [unchanged, mixed response, progression]) based on the 2014 
NIH Consensus Development Project on Clinical Trials in cGVHD is the primary activity 
endpoint for this study (see Appendix H for criteria).  Response criteria will be assessed on Day 
1 of Cycles 2 through 6, between the end of Cycle 6 and the start of Cycle 7, every odd-
numbered cycle thereafter starting with Cycle 9, and at the EOT visit. 


 
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9.2 
Clinician-Reported and Patient-Reported Global cGVHD Activity Assessments 
Patients will be assessed for severity of cGVHD using the Clinician-Reported Global cGVHD 
Activity Assessment Form (Appendix E) and Patient-reported cGVHD Activity Assessment 
Form (Appendix F).  Chronic GVHD severity will be assessed on Day 1 of each cycle and at the 
EOT visit.   
9.3 
Corticosteroid Use 
Corticosteroid dose will be collected throughout the study according to the Schedule of 
Assessments (Appendix D) and changes will be documented.  Please see Section 7.2 for 
additional details. 
9.4 
Quality-of-Life Impact 
Quality of life impact will be assessed according to the Schedule of Assessments (Appendix D) 
using the Lee Symptom Scale (see Appendix I; Lee et al. 2002). 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Statistical Design 
This is a multi-center, open-label, single-arm pilot study of itacitinib in patients who have been 
receiving immunosuppressive therapy for the treatment of SR-cGVHD for a duration of 
>6 months prior to starting daily itacitinib treatment in this study.  The study is designed to 
determine the ORR after 6 months of treatment with itacitinib. 
10.2 
Sample Size Considerations 
No formal hypothesis testing is planned for this exploratory trial.  In order to estimate the ORR 
in this population, a 95% exact two-sided confidence interval (CI) will be calculated.  A sample 
size of 40 produces a two-sided 95% CI with a width equal to 0.266 when the sample proportion 
is 0.200 (i.e., 20% response rate). 
10.3 
Analysis Population 
The following analysis populations will be used: 
• The Response Evaluable Analysis Set is defined as all patients with cGVHD who 
received at least one cycle of itacitinib and completed at least one post-baseline disease 
assessment. 
• The Safety Analysis Set is defined as all patients who received at least one dose of 
itacitinib. 
10.4 
Data Analysis 
Descriptive statistics, including mean, median, standard deviations and ranges for all continuous 
measures will be tabulated and reported.  Percentages and frequencies for all categorical 
measures will also be presented.  Time-to-event endpoints will be reported using Kaplan-Meier 
estimates, with 95% CIs for median time to event. 


 
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10.4.1 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized using descriptive statistics.  
Data to be tabulated will include demographic features such as age, sex, and race, as well as 
disease-specific characteristics. 
The number and percentages of patients enrolled, treated, completed the treatment/study and 
withdrawn from treatment/study for any reason will be presented. 
10.4.2 
Efficacy Analysis 
All efficacy analyses will be performed using the Response Evaluable Analysis Set. 
• ORR is defined as the proportion of patients with a cGVHD status of CR or PR after 6 
months of treatment according to the NIH Consensus Criteria (Lee et al. 2015. 
 
• Overall Survival (OS) is defined as the time from the first day of study drug 
administration (Day 1) to death on study.  Patients who are alive will be censored at the 
date of last known date alive. 
For ORR, the estimates and the associated 95% CIs (based on the Clopper-Pearson method) will 
be calculated. 
For OS, a Kaplan-Meier curve will be generated and the median time to event and the associated 
95% CIs will be provided. 
10.4.3 
Safety Analysis 
Safety will be assessed through the analysis of the reported incidence of treatment-emergent 
AEs.  Treatment-emergent AEs are those with an onset on or after the initiation of therapy, and 
will be graded according to NCI CTCAE Version 5.  A copy of CTCAE scoring system may be 
downloaded from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_5.0_2010-06-
14_QuickReference_8.5x11.pdf. 
The AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized using system organ class and preferred term for all patients in the Safety Analysis 
Set.  In addition, summaries of SAEs, AEs leading to treatment discontinuation, AEs by 
maximum NCI CTCAE grade, and AEs related to study treatment will also be presented. 
Other safety endpoints including laboratory results, vital signs, ECG findings, and other 
protocol-specified tests will be listed and/or summarized for all patients in the Safety Analysis 
Set. 
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
and they will be listed and summarized. 
10.5 
Analysis Time Points 
10.5.1 
Final Analysis 
The final analysis of the study will occur following the last visit of the last patient. 


 
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10.5.2 
Safety Review 
The clinical trial will be placed on hold if itacitinib is discontinued due to AEs in greater than 
5/10, 10/20, or 15/30 patients. 
10.5.3 
Efficacy Analysis 
The primary efficacy analysis will be done on consolidated data following 6 months of treatment 
(between the end of Cycle 6 and the beginning of Cycle 7). 
11. 
SAFETY REPORTING AND ANALYSES 
Safety assessments will consist of monitoring and recording protocol-defined AEs and serious 
AEs (SAEs), measurement of protocol-specified hematology, clinical chemistry, and urinalysis 
variables, and measurement of protocol-specified vital signs and other protocol-specified tests 
that are deemed critical to the safety evaluation of the study drug. 
The Principal Investigator is responsible for recognizing and reporting AEs to the SC 
Innovations Safety Department (see Section 11.1.5).  It is Innovations’ responsibility to report 
relevant SAEs to the applicable local, national, or international regulatory bodies.  In addition, 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of each IRB. 
The Principal Investigator is also responsible for ensuring that every staff member involved in 
the study is familiar with the content of this section. 
11.1 
Definitions 
11.1.1 
Adverse Events 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related.  An AE (also known as adverse experience) can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporarily associated with the use of a drug, without any judgment about causality.  An 
AE can arise with any use of the drug (e.g., off-label use, use in combination with another drug) 
and with any route of administration, formulation, or dose (including overdose). 
11.1.2 
Serious Adverse Events 
An AE or a suspected adverse reaction (SAR) is considered “serious” if it results in any of 
the following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 


 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in hospitalization, or development of drug dependency or drug 
abuse. 
It is important to distinguish between “serious” and “severe” when describing AEs, as the terms 
are not synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need 
not necessarily be considered serious.  Seriousness serves as the guide for defining regulatory 
reporting obligations.  “Serious” is a regulatory definition and is based on patient/event outcome 
or action usually associated with events that pose a threat to a patient’s life or vital functions.  
For example, nausea which persists for several hours may be considered severe nausea, but may 
not be considered an SAE.  On the other hand, a stroke which results in only a limited degree of 
disability may be considered only a mild stroke, but would be considered an SAE.  Severity and 
seriousness should be independently assessed when recording AEs on the eCRF and SAEs on the 
SAE Report Form. 
11.1.3 
Adverse Reaction 
An adverse reaction means any AE caused by a drug.  Adverse reactions are a subset of all 
suspected adverse reactions where there is a reason to conclude that the drug caused the event. 
11.1.4 
Suspected Adverse Reaction 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE.  Reasonable possibility means that there is evidence to suggest a causal 
relationship between the drug and the AE.  A suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a drug. 
11.1.5 
Recording and Reporting of Adverse Events 
11.1.5.1 Recording of Adverse Events 
All AEs will be recorded in the eCRF for all patients during the course of the research study, and 
the Investigator will give his or her opinion as to the relationship of the AE to the study treatment 
(i.e., whether the event is related or unrelated to study drug administration). 
A description of the event, including its date of onset and resolution, whether it constitutes a 
SAE or not, any action taken (e.g., changes to study treatment), and outcome, should be 
provided, along with the Investigator’s assessment of causality (i.e., the relationship to the study 
treatment).  For an AE to be a suspected treatment-related event there should be at least a 
reasonable possibility of a causal relationship between the protocol treatment and the AE.  
Adverse events will be graded according to the NCI CTCAE Version 5, and changes will be 
documented. 
If the AE is serious, it should be reported immediately to the Innovations Safety Department.  
Other untoward events occurring in the framework of a clinical study are to be recorded as AEs 
(i.e., AEs that occur prior to assignment of study treatment that are related to a protocol-


 
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mandated intervention, including invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant eCRF screen. 
Test findings will be reported as an AE if the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment; and/ or test findings require additional testing or surgical 
intervention; a test result or finding is associated with accompanying symptoms; or a test result is 
considered to be an AE by the Investigator. 
11.1.5.2 Reporting Period for Adverse Events 
All AEs regardless of seriousness or relationship to the study treatment spanning from the 
signing of the informed consent form until 30 calendar days after discontinuation or completion 
of study treatment, as defined by this clinical study protocol, are to be recorded on the 
corresponding screen(s) included in the eCRF. 
All AEs resulting in discontinuation from the study should be followed until resolution or 
stabilization.  All new AEs occurring during this period must be reported and followed until 
resolution unless, in the opinion of the Investigator, the AE or laboratory abnormality/ies are not 
likely to improve because of the underlying disease.  In this case, the Investigator must record his 
or her reasoning for this decision in the patient’s medical record. 
After 30 days of completion of protocol-specific treatment or discontinuation, only AEs, SAEs, 
or deaths assessed by the Investigator as treatment-related are to be reported. 
11.1.6 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means will be 
reported appropriately.  Each reported AE or SAE will be described by its duration (i.e., start and 
end dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug 
(see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, Investigators should apply the 
following general guideline: 
YES:  There is a plausible temporal relationship between the onset of the AE and 
administration of the study medication, and the AE cannot be readily explained by the 
patient’s clinical state, intercurrent illness, or concomitant therapies, and/or the AE 
follows a known pattern of response to the study drug, and/or the AE abates or resolves 
upon discontinuation of the study drug or dose reduction and, if applicable, reappears 
upon re-challenge. 
NO:  Evidence exists that the AE has an etiology other than the study drug (e.g., pre-
existing medical condition, underlying disease, intercurrent illness, or concomitant 
medication), and/or the AE has no plausible temporal relationship to study drug 
administration (e.g., cancer diagnosed 2 days after first dose of study drug). 


 
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11.2 
Serious Adverse Event Reporting by Investigators 
Adverse events classified by the treating Investigator as serious require expeditious handling and 
reporting to the Innovations Safety Department in order to comply with regulatory requirements.  
Determination of life-threatening or serious is based on the opinion of the Investigator. 
Serious AEs may occur at any time from the signing of the informed consent form through the 
30-day follow-up period after the last dose of study drug.  The Innovations Safety Department 
must be notified of all SAEs, regardless of causality, within 24 hours of the first knowledge 
of the event by the treating physician or research personnel. 
To report an SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report should be sent to the Innovations Safety Department via fax or e-mail using the 
using the following contact information (during both business and non-business hours): 
Sarah Cannon Innovations Safety Department 
Safety Dept. Fax #:      1-866-807-4325 
Safety Dept. Email:     CANN.SAE@SCRI-Innovations.com 
Transmission of the SAE report should be confirmed by the site personnel submitting the report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to the Innovations Safety Department as soon as it is available; these reports 
should be submitted using the Innovations SAE Report Form. 
Investigators must report SAEs and follow-up information to their responsible IRB according to 
the policies of the responsible IRB. 
11.3 
Recording of Adverse Events and Serious Adverse Events 
11.3.1 
Diagnosis versus Signs and Symptoms 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Principal Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE eCRF screen).  If a diagnosis is 
subsequently established, it should be reported as follow-up information is available.  If a 
diagnosis is determined subsequent to the reporting of the constellation of symptoms, the 
signs/symptoms should be updated to reflect the diagnosis. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as an 
SAE. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
time points.  Such events should only be recorded once on the SAE Report Form and/or the AE 


 
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eCRF screen.  If a persistent AE becomes more severe or lessens in severity, it should be 
recorded on a separate SAE Report Form and/or AE eCRF screen. 
A recurrent AE is one that occurs and resolves between patient evaluation time points, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or AE 
eCRF screen. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
eCRF screen.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis 
needs to be recorded on the SAE Report Form or AE eCRF screen. 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment and/ or laboratory findings 
require additional testing or surgical intervention, a laboratory result or finding is associated with 
accompanying symptoms; or a laboratory result is considered to be an AE by the Investigator. 
11.3.4 
Deaths 
Deaths that occur during the protocol-specified AE reporting period that are attributed solely to 
progression of disease, as determined by the Investigator, will be recorded on the “End of Study” 
eCRF screen.  All other on-study deaths, regardless of attribution, will be recorded on an SAE 
Report Form and expeditiously reported to the Innovations Safety Department. 
When recording a SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event eCRF screen.  If the cause of death is unknown and cannot be 
ascertained at the time of reporting, record “Death NOS” (death, cause unknown) on the eCRF 
Adverse Event screen.  During post-study survival follow-up, deaths attributed to progression of 
disease will be recorded only on the “Follow-Up Summary” and “Death Page” eCRF screens. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of pre-existing 
hospitalization should be documented and reported as an SAE unless specifically instructed 
otherwise in this protocol.  There are some hospitalizations that do not require reporting as an 
SAE. 
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
• Emergency Department or Emergency Room 
• Outpatient or same-day surgery units 
• Observation or short-stay unit 
• Rehabilitation facility 


 
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• Hospice or skilled nursing facility 
• Nursing homes, Custodial care or Respite care facility 
Hospitalization during the study for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the study), does not require reporting as an SAE to the Innovations 
Safety Department. 
11.3.6 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be recorded on the General Medical History eCRF screen.  A pre-existing medical 
condition should be recorded as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study.  When recording such events on an SAE Report Form and/or 
AE eCRF screen, it is important to convey the concept that the pre-existing condition has 
changed by including applicable descriptors. 
11.3.7 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the seriousness criteria (see Section 11.1.2).  New primary cancers are those that 
are not the primary reason for the administration of the study treatment and have developed after 
the inclusion of the patient into the study.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.3.8 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
If a patient becomes pregnant while enrolled in the study, a Pregnancy Form should be 
completed and faxed to the Innovations Safety Department.  The Innovations Safety Department 
should be notified expeditiously, irrespective of whether or not it meets the criteria for expedited 
reporting.  Abortions (spontaneous, accidental, or therapeutic) must also be reported to the 
Innovations Safety Department. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, this must be reported to the Innovations Safety Department immediately.  Every effort 
should be made to follow the pregnancy for the final pregnancy outcome. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
11.3.9 
Itacitinib Overdose 
Symptomatic and non-symptomatic overdose must be reported in the eCRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to the Innovations Safety Department no greater than 
24 hours from first knowledge of the event using the corresponding screens in the eCRF and 
following the same process described for SAE reporting (see Section 11.2). 


 
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There has been no clinical experience with over dosage of itacitinib.  The highest total daily dose 
evaluated in clinical studies was 1200 mg (600 mg twice daily).  No unexpected TEAEs were 
associated with doses of this level.  Treatment of a suspected overdose with itacitinib should 
consist of general supportive measures, as needed.  
For information on how to manage an overdose of itacitinib, see the IB. 
11.4 
Incyte Corporation Serious Adverse Event Reporting Requirements 
The Innovations Safety Department will forward SAE information to Incyte’s 
Pharmacovigilance (PhV) Department via email (IncytePhVOpsIST@incyte.com) within 
1 business day of the Innovations Safety Department personnel becoming aware of the SAE. 
If necessary, the Incyte PhV representative or designee will query the Innovations Safety 
Department (within 48 hours of receipt) for additional information to ensure a valid case prior to 
distributing the report for internal Incyte review. 
Innovations is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating Investigators, in accordance with 
International Conference on Harmonisation (ICH) guidelines, and FDA regulations. 
Incyte in turn will report relevant events originating from this study to the applicable Incyte 
IND(s) and will distribute Investigator Notifications to Investigators participating in the 
applicable Incyte IND(s). 
11.4.1 
Sponsor Assessment of Unexpected Events 
The Sponsor is responsible for assessing an AE or suspected AE as “unexpected”. 
An AE or suspected adverse reaction is considered “unexpected” when the following conditions 
occur: 
• Event(s) is not mentioned in the IB (or current US Package Insert [USPI]) 
• Event(s) is not listed at the specificity or severity that has been observed 
• An event(s) is not consistent with the General Investigative Plan or in the current 
application 
• Includes AEs or SAR that may be anticipated from the pharmacological properties of the 
study drug, or that occur with members of the drug class, but that have previously been 
observed under investigation. 
Known as Suspected Unexpected Serious Adverse Reactions (SUSAR), these events suspected 
(by the Investigator or Sponsor) to be related to the study drug, are unexpected (not listed in the 
Investigator’s Brochure or USPI), and are serious (as defined by the protocol) and require 
expedient submission to relevant health authorities within 7 days (fatal or life-threatening events) 
or 15 days (all serious events), or as defined by law.  The term SUSAR is used primarily in the 
reporting of events to regulatory authorities. 
Expected AEs are those events that are listed or characterized in the current IB or current IB. 


 
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11.4.2 
Funding Partner Reporting for Clinical Studies Under an Investigational New 
Drug Application 
All written IND Safety Reports submitted to the FDA by the Innovations Safety Department 
must also be sent to the pharmaceutical company that is supporting the study with either funding 
or drug supply: 
Incyte Corporation 
IncytePhVOpsIST@incyte.com 
12. 
QUALITY ASSURANCE AND QUALITY CONTROL 
12.1 
Study Monitoring, Auditing, and Inspecting 
The Investigator will permit study-related monitoring, quality audits, and inspections by Incyte 
Corporation, or its representative(s), government regulatory authorities, and the IRB(s) of all 
study-related documents (e.g., source documents, regulatory documents, data collection 
instruments, case report forms).  The Investigator will ensure the capability for inspections of 
applicable study-related facilities.  The Investigator will ensure that the study monitor or any 
other compliance or Quality Assurance reviewer is given access to all study-related documents 
and study-related facilities. 
At the discretion of Innovations, Source Document Verification (SDV) may be performed on all 
data items or a percentage thereof. 
Participation as an Investigator in this study implies the acceptance of potential inspection by 
government regulatory authorities, the IRB(s), and/or Innovations or its representative(s). 
13. 
ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This research study will be conducted according to the standards of Good Clinical Practice 
outlined in the ICH E6 Tripartite Guideline and the Code of Federal Regulations (CFR) Title 21 
part 312, applicable government regulations, institutional research policies and procedures and 
any other local applicable regulatory requirement(s). 
13.1 
Institutional Review Board Approval 
The clinical study protocol, ICF, IB, available safety information, patient documents, patient 
recruitment procedures (e.g., advertisements), information about payments (i.e., Principal 
Investigator payments) and compensation available to the patients and documentation evidencing 
the Principal Investigator’s qualifications should be submitted to the IRB for ethical review and 
approval prior to the study start. 
The Principal Investigator/Sponsor and/or designee will follow all necessary regulations to 
ensure appropriate, initial, and on-going, IRB study review.  The Principal Investigator/Sponsor 
(as appropriate) must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the ICF document.  Investigators will be 


 
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advised by the Sponsor or designee whether an amendment is considered substantial or non-
substantial and whether it requires submission for approval or notification only to an IRB. 
Safety updates for itacitinib, will be prepared by Incyte Corporation or its representative as 
required, for distribution to the Investigator(s) and submission to the relevant IRB. 
13.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to study initiation.  If required, the 
Sponsor will also ensure that the implementation of substantial amendments to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
13.3 
Informed Consent 
Informed consent is a process by which a patient voluntarily confirms his or her willingness to 
participate in a particular study after having been informed of all aspects of the study that are 
relevant to the patient's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated ICF. 
The ICF will be submitted for approval to the IRB that is responsible for review and approval of 
the study.  Each ICF must include all of the relevant elements currently required by the FDA, as 
well as local country authority or state regulations and national requirements. 
Before recruitment and enrollment into the study, each prospective candidate will be given a full 
explanation of the research study.  Once the essential information has been provided to the 
prospective candidate, and the Investigator is sure that the individual candidate understands the 
implications of participating in this research study, the candidate will be asked to give consent to 
participate in the study by signing an ICF.  A notation that written informed consent has been 
obtained will be made in the patient’s medical record.  A copy of the ICF, which will include the 
patient’s signature, will be provided by the Investigator to the patient. 
If an amendment to the protocol substantially alters the study design or the potential risks to 
patients, the patient’s must re-consent to continue participation in the study. 
13.3.1 
Confidentiality 
13.3.1.1 Patient Confidentiality 
Confidentiality of patients’ personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  HIPAA regulations require that, 
in order to participate in the study, a patient must sign an authorization form for the study that he 
or she has been informed of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws 


 
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• The information collected about the research study will be kept separate from the 
patient’s medical records, but the patient will be able to obtain the research records after 
the conclusion of the study 
• Whether the authorization contains an expiration date 
• The rights of a research patient to revoke his or her authorization 
In the event that a patient revokes authorization to collect or use his or her PHI, the Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization.  For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e., that the patient is alive) at the 
end of their scheduled study period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the Investigator and institution permit authorized representatives of Innovations, the regulatory 
authorities, and the IRB direct access to review the patient’s original medical records at the site 
for verification of study-related procedures and data. 
One measure to protect confidentiality is that only a unique study number will identify patients 
in the eCRF or other documents submitted to Innovations.  This information, together with the 
patient’s year of birth, will be used in the database for patient identification.  Patient names or 
addresses will not be entered in the eCRF.  No material bearing a patient’s name will be kept on 
file by Innovations.  Patients will be informed of their rights within the ICF. 
13.3.1.2 Investigator and Staff Information 
Personal data of the Investigators and sub-Investigators may be included in the Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the Investigator or sub-Investigator, 
Innovations personnel shall take all appropriate measures to safeguard and prevent access to this 
data by any unauthorized party. 
13.4 
Financial Information 
The finances for this clinical study will be subject to a separate written agreement between Sarah 
Cannon Development Innovations, LLC and applicable parties.  Any Investigator financial 
disclosures as applicable to 21CFR Part 54 shall be appropriately provided. 
14. 
RESEARCH RETENTION AND DOCUMENTATION OF THE STUDY 
14.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Study Chair/Sponsor.  All amendments require review and approval of all pharmaceutical 
companies providing funding for the study and the Principal Investigator supporting the study.  


 
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The written amendment must be reviewed and approved by Innovations and submitted to the 
IRB at the Investigator’s facility for the board’s approval. 
Items requiring a protocol amendment approval from the IRB and/or FDA or other regulatory 
authorities includes, but are not limited to, the following: 
• Change to study design 
• Risk to patients 
• Increase to dose or patient exposure to drug 
• Patient number increase 
• Addition or removal of tests and/or procedures 
• Addition/removal of a new Investigator 
The amendment will be submitted formally to the FDA or other regulatory authorities by 
Innovations. 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the patients, the patients’ consent to continue participation in the 
study should be obtained. 
14.2 
Documentation Required to Initiate the Study 
Before the study may begin, certain documentation required by FDA regulations and ICH GCP 
must be provided by the Investigator.  The required documentation should be submitted to: 
Sarah Cannon Development Innovations 
Regulatory Department 
1100 Dr. Martin L. King Jr. Blvd. 
Suite 800 
Nashville, TN 37203 
Documents at a minimum required to begin a study in the US include, but are not limited to the 
following: 
• A signature-authorized protocol and contract 
• A copy of the official IRB approval of the study and the IRB members list 
• Current curricula vitae for the Principal Investigator and any associate Investigator(s) 
who will be involved in the study 
• Indication of appropriate accreditation for laboratories (as required) to be used in the 
study and the normal ranges for tests to be performed by those laboratories 
• Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed 
• A copy of the IRB-approved consent form containing permission for audit by 
representatives of Innovations, the IRB, and the FDA and other regulatory agencies (as 
applicable) 


 
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• Financial disclosure forms for all Investigators listed on Form FDA 1572 (if applicable) 
• Verification of Principal Investigator acceptability from local and/or national debarment 
list(s). 
14.3 
Study Documentation and Storage 
The Principal Investigator must maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties and should ensure that all persons assisting in the conduct of the study 
are informed of their obligations.  All persons authorized to make entries and/or corrections on 
the eCRFs are to be included on this document.  All entries in the patient’s eCRF are to be 
supported by source documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the patient’s eCRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, microfiches, ECG traces, copies 
or transcriptions certified after verification as being accurate and complete, photographic 
negatives, microfilm or magnetic media, X-rays, and correspondence. 
The Principal Investigator and each study staff member is responsible for maintaining a 
comprehensive and centralized filing system (e.g., regulatory binder or Investigator study file 
[ISF]) of all study-related (essential) documentation, suitable for inspection at any time by 
representatives from the Sponsor and/or applicable regulatory authorities.  The ISF must consist 
of those documents that individually or collectively permit evaluation of the conduct of the study 
and the quality of the data produced.  The ISF should contain as a minimum all relevant 
documents and correspondence as outlined in ICH GCP Section 8 and 21 CFR Part 312.57, 
including key documents such as the IB and any amendments, protocol and any amendments, 
signed ICFs, copies of completed eCRFs, IRB approval documents, Financial Disclosure forms, 
patient identification lists, enrollment logs, delegation of authority log, staff qualification 
documents, laboratory normal ranges, records relating to the study drug including accountability 
records.  Drug accountability records should, at a minimum, contain information regarding 
receipt, shipment, and disposition.  Each form of drug accountability record, at a minimum, 
should contain Principal Investigator name, date drug shipped/received, and the date, quantity 
and batch/code, or lot number for identity of each shipment.  In addition, all original source 
documents supporting entries in the eCRF must be maintained and be readily available. 
Innovations shall maintain adequate investigational product records and financial interest records 
as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by the FDA; or, in the event that the marketing application has not 
been approved by the FDA, for no less than 2 years after the last shipment/delivery of the drug 
for investigational use is discontinued and the FDA has been notified of the discontinuation. 
The Investigator shall maintain adequate records of drug disposition, case histories, and any 
other study-related records as per 21 CFR Part 312.62 for no less than 2 years after the last 
marketing application has been approved by the FDA; or, in the event that the marketing 
application has not been approved by the FDA, for no less than 2 years after the last shipment / 
delivery of the drug for investigational use is discontinued and the FDA has been notified of the 
discontinuation. 


 
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To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating patients (sufficient information to link records, e.g., eCRFs, medical records), all 
original, signed ICFs, and copies of all eCRFs, SAE Reporting forms, source documents, 
detailed records of treatment disposition, and related essential regulatory documents.  The 
documents listed above must be retained by the Investigator for as long as needed to comply with 
national and international regulations (generally 2 years after discontinuing clinical development 
or after the last marketing approval).  Sponsor will notify the Investigator(s)/institutions(s) when 
the study-related records are no longer required. 
If the Investigator relocates, retires, or for any reason withdraws from the study, both the 
Sponsor and its representative should be prospectively notified.  The study records must be 
transferred to an acceptable designee, such as another Investigator, another institution, or to 
Innovations.  The Investigator must obtain Innovations’ written permission before disposing of 
any records, even if retention requirements have been met.  All study files will be maintained by 
Innovations at the conclusion of the study. 
14.4 
Data Collection 
The study eCRF is the primary data collection instrument for the study.  Case report forms will 
be completed using the English language and should be kept current to enable Innovations to 
review the patients’ status throughout the course of the study. 
In order to maintain confidentiality, only study number, patient number, and year of birth will 
identify the patient in the eCRF.  If the patient’s name appears on any other document (e.g., 
laboratory report), it must be obliterated on the copy of the document to be supplied to 
Innovations and replaced instead with the patient number and other identifier (i.e. patient’s 
initials) as allowed per institutional policy.  The Investigator will maintain a personal patient 
identification list (patient numbers with corresponding patient identifiers) to enable records to be 
identified and verified as authentic.  Patient data/information will be kept confidential, and will 
be managed according to applicable local, state, and federal regulations. 
All data requested in the eCRF must be supported by and be consistent with the patient’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the eCRF, 
a note should be created verifying that the field was “Not Done” or the result was “Unknown.”  
For any entry errors made, the error(s) must be corrected, and a note explaining the reason for 
change should be provided.   
The Investigator will electronically sign and date the patient eCRF casebook indicating that the 
data in the eCRF has been assessed.  Each completed eCRF will be signed and dated by the 
Principal Investigator, once all data for that patient is final. 
14.5 
Disclosure and Publication Policy 
All information provided regarding the study, as well as all information collected/documented 
during the course of the study, will be regarded as confidential.  The Sponsor reserves the right 
to release literature publications based on the results of the study.  Results from the study will be 
published/presented as per the Sponsor’s publication process. 


 
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Inclusion of the Investigator in the authorship of any multi-center publication will be based upon 
substantial contribution to the design, analysis, interpretation of data, drafting and/or critically 
revising any manuscript(s) derived from the study.  The Investigator acknowledges that the study 
is part of a multi-center study and agrees that any publication by the Investigator of the results of 
the study conducted at research site shall not be made before the first multi-center publication.  
In the event there is no multi-center publication within fifteen (15) months after the study has 
been completed or terminated at all study sites, and all data has been received, the Investigator 
shall have the right to publish its results from the study, subject to the notice requirements 
described herein and subject to acknowledgment of the Sponsor as appropriate.  The Investigator 
shall provide the Sponsor thirty (30) days to review a manuscript or any poster presentation, 
abstract or other written or oral material which describes the results of the study for the purpose 
only of determining if any confidential or patentable information is disclosed thereby.  If the 
Sponsor requests in writing, the Investigator shall withhold any publication or presentation an 
additional sixty (60) days solely to permit the Sponsor to seek patent protection and to remove 
any Innovations Confidential Information from all publications. 


 
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15. 
REFERENCES 
 
Choi et al. 2012 
Choi J, Ziga ED, Ritchey J, Collins L, Prior JL, Cooper ML, et al. IFNγR signaling mediates 
alloreactive T-cell trafficking and GVHD. Blood. 2012;8:4093-103. 
Choi et al. 2014 
Choi J, Cooper ML, Alahmari B, Ritchey J, Collins L, Holt M, et al. Pharmacologic blockade of 
JAK1/JAK2 reduces GVHD and preserves the graft-versus-leukemia effect. PLoS One. 
2014;9:e109799. 
Garnett et al. 2013 
Garnett C, Apperley JF, Pavlů J. Treatment and management of graft-versus-host disease: 
improving response and survival. Ther Adv Hematol. 2013;4(6):366–78. doi: 10.1177/ 
2040620713489842. 
Itacitinib Investigator’s Brochure 
Shukla J. Itacitinib Investigator’s Brochure Version 10. Indication: myeloproliferative 
neoplasms, inflammatory diseases, graft-versus-host disease, solid tumors, and B-cell 
malignancies. 01 February 2019. 
Jagasia et al. 2015 
Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, 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(3):389–01. 
Lee et al. 2002 
Lee SK, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure 
symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8(8):444-
52. 
Lee et al. 2015 
Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia MH, et al. Measuring Therapeutic 
Response in Chronic Graft-Versus-Host Disease: National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: IV. 
The 2014 Response Criteria Working Group Report. Biol Blood Marrow Transplant. 
2015;21:984–99. 
Spoerl et al. 2014 
Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, et al. Activity of 
therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123:3832-42. 


 
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Tomblyn et al. 2009 
Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, et al. Guidelines for 
preventing infectious complications among hematopoietic cell transplantation recipients: a global 
perspective. Biol Blood Marrow Transplant. 2009;15:1143-38. 
Zeiser et al. 2015 
Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et al. Ruxolitinib 
in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a 
multi-center survey. Leukemia. 2015;29:2062–68. 


 
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16. 
APPENDICES 
 
Appendix A: ECOG Performance Status Criteria 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to carry 
on all pre-disease performance without 
restriction. 
 
100 
Normal, no complaints, no evidence of 
disease 
 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory.  Restricted in 
physically strenuous activity, but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
 
80 
Normal activity with effort; some signs or 
symptoms of disease 
 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed <50% of the time.  Ambulatory and 
capable of all self-care, but unable to carry 
out any work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs 
 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed >50% of the time.  Capable of only 
limited self-care, confined to bed or chair 
more than 50% of waking hours. 
 
40 
Disabled, requires special care and 
assistance 
 
30 
Severely disabled, hospitalization 
indicated.  Death no imminent 
4 
100% bedridden.  Completely disabled.  
Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
20 
Very sick, hospitalization indicated.  Death 
not imminent 
 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
 


 
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Appendix B: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of physical 
activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal 
syndrome may be present even at rest.  If any physical activity is undertaken, 
discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 


 
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Appendix C: Guidelines for Female Patients of Childbearing Potential and Fertile Male 
Patients 
 
Acceptable Contraception Methods: 
Women of childbearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly-effective contraception during the study and until after the 30-day 
safety follow-up visit. 
Highly effective contraception is defined as either: 
True Abstinence 
When this is in line with the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Sterilization  
When a woman of childbearing potential has had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 6 
weeks prior to study entry.  In case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment. 
Male Partner Sterilization When the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate. 
Use of a combination of any 2 of the following (one from a + one from b): 
a) Placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
b) Barrier methods of contraception: Condom or Occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/vaginal suppository. 
Fertile male patients, defined as all males physiologically capable of conceiving offspring, 
with female partners of childbearing potential must use condoms plus a spermicidal agent 
during the study treatment period and until after the 30-day safety follow-up visit, and must 
not father a child during this period. 
Male patients must also refrain from donating sperm during their participation in the study and 
for at least 3 months after completing the study. 
The following are acceptable forms of barrier contraception: 
• Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
Unacceptable Contraception Methods: for women of childbearing potential include: 
• IUD progesterone T 
• Female condom 


 
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• Natural family planning (rhythm method) or breastfeeding 
• Fertility awareness 
• Withdrawal 
• Cervical shield. 
Pregnancies 
To ensure patient safety, each pregnancy in a patient on study treatment must be reported to 
the Innovations Safety Department within 24 hours of learning of its occurrence.  The 
pregnancy should be followed up for 3 months after the termination of the 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. 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by the 
Investigator to the Innovations Safety Department.  Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the study 
drug of any pregnancy outcome.  Any SAE experienced during pregnancy must be reported on 
the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study.  Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Women Not Of Childbearing Potential Are Defined As Follows: 
• Women are considered post-menopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms).  
• Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy). 
• Women who are >45 years-of-age, not using hormone-replacement therapy and who 
have experienced total cessation of menses for at least 1 year OR who have a follicle 
stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL 
(140 pmol/L). 
• Women who are >45 years-of-age, using hormone-replacement therapy and who have 
experienced total cessation of menses for at least 1 year OR who have had documented 
evidence of menopause based on FSH >40 mIU/mL and estradiol <40 pg/mL prior to 
initiation of hormone-replacement therapy. 


 
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Appendix D: BMT 29 Schedule of Assessments 
Study Period 
Screening 
Treatment Period 
Follow-Up 
Cyclea 
 
Cycle 1 
Cycles 2 to 6 
Cycle 7 
Cycles 8+ 
EOTk 
30-Day 
Safety 
FUl 
FU for 
Survivalm 
Visit Day 
Day -28 to -1b 
1 
8 
15 
22 
1 (±7 days) 
1 (±7 
days) 
1 (±7 
days) 
 
(±7 days) 
Every 3 
months 
(±1 
month) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Medical history and demographicsc 
X 
 
 
 
 
 
 
 
 
 
 
Physical examinationc,d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance statusc,d 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Vital signsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood transfusion reviewd 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
12-Lead electrocardiogramc 
X 
 
 
 
 
 
 
 
X 
 
 
Pulmonary function testd 
X 
 
 
 
 
X (C4 only) 
X 
 
 
 
 
Urine pregnancy testc,e 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
Safety laboratory (hematology, lipids [fasting], 
and chemistries)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety laboratory (urine)c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Virology testingf 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events and infection monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
cGVHD diagnosis and staging 
X 
 
 
 
 
 
 
 
 
 
 
Clinician-reported global cGVHD activity 
assessmentg 
 
X 
 
 
 
X 
X 
X 
X 
 
 


 
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Study Period 
Screening 
Treatment Period 
Follow-Up 
Cyclea 
 
Cycle 1 
Cycles 2 to 6 
Cycle 7 
Cycles 8+ 
EOTk 
30-Day 
Safety 
FUl 
FU for 
Survivalm 
Visit Day 
Day -28 to -1b 
1 
8 
15 
22 
1 (±7 days) 
1 (±7 
days) 
1 (±7 
days) 
 
(±7 days) 
Every 3 
months 
(±1 
month) 
Patient-reported global cGVHD activity 
assessmentg 
 
X 
 
 
 
X 
X 
X 
X 
 
 
Assessment of cGVHD response (NIH criteria)h 
 
 
 
 
 
X 
X 
Xh 
X 
 
 
Chimerism assessment (institutional standards) 
X 
 
 
 
 
 
 
 
 
 
 
Lee Symptom Scalei 
X 
X 
 
 
 
 
X 
 
X 
 
 
Document corticosteroid dosage (total dose/kg 
and type of corticosteroid) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Document concomitant cGVHD therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess underlying disease relapsej 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
New cGVHD therapies 
 
 
 
 
 
 
 
 
 
X 
X 
Dispense/collect study drug  
 
X 
 
 
 
X 
X 
X 
X 
 
 
Patient status 
 
 
 
 
 
 
 
 
 
 
X 
Itacitinib Schedule of Assessments Footnotes 
a 
Treatment cycles are 28 days (4 weeks). Patients will continue treatment with itacitinib for up to 24 months or until patients discontinue from 
study treatment for any of the following reasons listed in Section 3.3. 
b 
Screening should take place within 28 days of start of study treatment. 
c 
Safety laboratory assessments including hematology, lipids (fasting), clinical chemistry, pregnancy test, and urinalysis will be performed 
locally.  Additional assessments to be performed during the screening period: 
- Blood transfusion review 
- Virology tests (HIV, Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody, Hepatitis C antibody, 
HBV-DNA [if required], HCV-RNA [if required]) 


 
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- Concomitant medication review 
- cGVHD diagnosis and staging  
- Chimerism assessment as per institutional standards 
- Lee Symptom Scale  
- Document corticosteroid dosage (total dose/kg and type of corticosteroids) 
- Document concomitant cGVHD therapy 
The following screening parameters should be done ≤14 days prior to initiation of treatment: 
- Pulmonary function tests (FEV1, FVC, DLCO (corrected for Hb), TLC and RV) 
- medical history and demographics (includes conditioning regimen, stem cell source, GVHD prophylaxis therapy, disease status at 
transplant and prior lines of GHVD therapy), physical examination (including height and weight), Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs, electrocardiogram (ECG)  
- hematology: hematocrit, hemoglobin, mean corpuscular volume, platelet count, red blood cell count, white blood cell (WBC) count, 
WBC 5-part differential 
- clinical chemistry (lipids in a fasting state): sodium, potassium, phosphorus, chloride, creatinine, calcium, venous bicarbonate, 
albumin, total protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total 
bilirubin, lactate dehydrogenase, serum glucose, and blood urea nitrogen, lipids high-density lipoprotein (HD) cholesterol, low-
density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides  
- urinalysis 
- screening pregnancy test (urine) 
 
If these assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 Day 1 with the 
exception of the ECOG performance status, an abbreviated physical examination, and vital signs, which are required prior to first study dose.  
Vital signs (blood pressure, body temperature, and pulse rate) are checked at every visit prior to blood work and study treatment and at the 
discretion of the Investigator (see Section 6.7.3). 
d 
Physical examinations including the measurements of height (screening only) and weight will be done at screening, on Days 1, 8, 15, and 22 
of Cycle 1, on Day 1 of each subsequent treatment cycle, at the end-of-treatment (EOT) and the 30-day safety follow-up (FU) visits, and at 
the discretion of the Investigator.  Blood transfusions will be reviewed at screening, on Day 1 of each cycle, and at the EOT visit.  ECOG 
performance status will be done at the visits noted in the table. Pulmonary function test will be performed at screening (within 14 days of 
C1D1) and on Day1 of Cycle 4 and Cycle 7 and include FEV1, FVC, DLCO (corrected for Hb), TLC and RV (see Section 6.7.3). 
e 
A urine pregnancy test must be done at screening (3 days prior to initiation of treatment) for women with child-bearing potential, Day 1 of 
each cycle, at the EOT visit, and at the 30-day safety follow-up visit.  Additional pregnancy testing is at the Investigator’s discretion. Positive 
results are to be confirmed with serum beta human chorionic gonadotropin testing. 


 
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f 
Virology tests to include: HIV, Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B core antibody, Hepatitis C antibody, 
HBV-DNA (if required), HCV-RNA (if required) 
g 
Patients will be assessed for severity of cGVHD using the Clinician-Reported Global cGVHD Activity Assessment Form (see Appendix E) 
and Patient-reported cGVHD Activity Assessment Form (Appendix F) on Day 1 of each cycle, and at the EOT visit.  If a patient withdraws 
from treatment due to reasons other than PD, GVHD grading will be repeated at this visit. 
h 
Response criteria (CR, PR, or progression) based on the 2014 NIH Consensus Development Project on Clinical Trials in cGVHD (see 
Appendix H for criteria) will be assessed on Day 1 of Cycles 2 through 7; and then every odd-numbered cycle thereafter starting on Day 1 of 
Cycle 9, as well as the EOT visit. 
i 
The Lee Symptom Scale (see Appendix I) will be used to capture changes in health status during the course of treatment relative to screening 
and will be done at screening, on Cycle 1 Day 1, Cycle 7 Day 1, and at the EOT visit.  If a patient stops study drug before 6 months, the form 
should be filled out at that time. 
j 
Participants will be closely monitored for any evidence of underlying disease relapse or recurrence on Day 1 of each cycle, at the EOT, and 
the survival follow-up visit. A formal re-staging is not required.  Re-staging will be done at the Investigator’s discretion.  The date of 
malignant and non-malignant hematologic disease relapse and subsequent management should be collected on the appropriate eCRF. 
k 
An EOT visit should be performed for all patients who permanently discontinue study treatment (preferably within 7 days and no later than 
14 days after the last treatment of study drug).  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 (see Section 6.5). 
l 
A safety follow-up visit will be done 30 days (±7 days) following end of treatment.  Adverse events and SAEs must be reported for least 
30 days after the last dose of study drug, and must be followed until toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer (see Section 6.6.1). 
m 
Follow-up for survival: patients will be followed for survival after treatment has been discontinued.  Patients should be contacted by 
telephone, email, or visit every 3 months for 1-year after their last dose of study treatment to assess for new GVHD therapy, relapse of 
underlying malignancy and survival status until death, withdrawal of consent, or the end of the study, whichever occurs first (see Section 
6.6.2). 
 


 
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Appendix E: Clinician-Reported Global cGVHD Activity Assessment Form 
 


 
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Reference:  Lee et al. 2015 


 
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Reference:  Lee et al. 2015 
 


 
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Appendix F Patient-Reported Global cGVHD Activity Assessment Form 
 
 
 


 
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Appendix G: Staging of cGVHD (NIH Criteria) 
 
 


 
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Appendix H Response Assessment for cGVHD (NIH Criteria) 
 
 


 
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Response Assessment for cGVHD (NIH Criteria, continued) 
 
 


 
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Appendix I 
Lee cGVHD Symptom Score 
 
 


 
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Appendix J: Cytochrome P450 3A4 Inhibitors and Inducers 
Source:  http://www.mayomedicallaboratories.com/it-
mmfiles/Cytochrome_P450_3A4_and_3A5_Known_Drug_Interaction_Chart.pdf 
CYP3A4 Inhibitors 
CYP3A4 Inducers 
Strong Inhibitors 
Barbiturates 
Clarithromycin 
Carbamazepine 
Indinavir 
Efavirenz 
Itraconazole 
Glucocorticoids 
Ketoconazole 
Modafinil 
Nefazodone 
Nevirapine 
Ritonavir 
Oxcarbazepine 
Saquinavir 
Phenobarbital 
Suboxone 
Phenytoin 
Telithromycin 
Pioglitazone 
Intermediate Strength Inhibitors 
Rifabutin 
Aprepitant 
St. John's Wort 
Erythromycin 
Troglitazone 
Fluconazole 
 
Verapamil 
 
Diltiazem 
 
Weak Inhibitors 
 
cimetidine 
 
Other Possible Inhibitors 
 
Amiodarone 
 
Boceprevir 
 
Chloramphenicol 
 
Ciprofloxacin 
 
Delaviridine 
 
Diethyl-dithiocarbamate 
 
Fluvoxamine 
 
Gestodene 
 
Imatinib 
 
Mibefradil 
 
Mifepristone 
 
Norfloxacin 
 
Norfluoxetine 
 
Starfruit 
 
Telaprevir 
 
Voriconazole