Phase IIa Study of Addition of Itacitinib With Tacrolimus/Sirolimus Regimen for GVHD Prophylaxis in Fludarabine and Melphalan Non-Myeloablative Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, MDS or MF
Phase: PHASE2
Conditions: Acute Leukemia, Hematologic and Lymphocytic Disorder, Myelodysplastic Syndrome, Primary Myelofibrosis, Secondary Myelofibrosis
Sponsor: City of Hope Medical Center

 
IRB #19576 
 
11/29/2022 
Packet: 12 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGIC MALIGNANCIES AND STEM CELL TRANSPLANTATION 
 
TITLE:  Phase IIa Study of Addition of Itacitinib with Tacrolimus/Sirolimus Regimen for GVHD 
Prophylaxis in Fludarabine and Melphalan Non-Myeloablative Conditioning Hematopoietic Cell 
Transplantation for Acute Leukemias, MDS or MF 
 
 
 
CITY OF HOPE PROTOCOL NUMBER/VERSION: IRB # 19576  
PROTOCOL DATE: 11/29/2022  
 
Initial Submission 
 
 
 
Protocol dated 02/24/2020  
 
 
 
Version: 00 
COH Amendment 01  
 
 
Protocol dated 04/10/2020 
 
 
 
Version: 01 
COH Amendment 02  
 
 
Protocol dated 07/09/2020 
 
 
 
Version: 02 
COH Amendment 03  
 
 
Protocol dated 09/17/2020 
 
 
 
 Packet: 03 
COH Amendment 04  
 
 
Protocol dated 01/15/2021 
 
 
 
 Packet: 04 
COH Amendment 05  
 
 
Protocol dated 01/15/2021 (tp) 
 
 
 Packet: 05 
COH Amendment 06  
 
 
Protocol dated 02/24/2021  
 
 
 
 Packet: 06 
COH Amendment 07  
 
 
Protocol dated 04/09/2021  
 
 
 
 Packet: 07 
COH Amendment 08  
 
 
Protocol dated 05/06/2021  
 
 
 
 Packet: 08 
COH Amendment 09 at Continuation 
Protocol dated 05/06/2021 (TP) 
 
 
 Packet: 09 
COH Amendment 10   
 
 
Protocol dated 04/04/2022                   
 
 Packet: 10 
COH Amendment 11  
 
 
Protocol dated 11/29/2022 
 
 
 
 Packet: 11 
COH Amendment 12 at Continuation 
Protocol dated 11/29/2022 (TP) 
 
 
 Packet: 12 
 
 
DISEASE SITE: 
 
 
 
 
Hematopoietic Stem Cell Transplant (HSCT) 
 
STAGE: 
 
 
 
 
 
 
 
MODALITY(IES): 
 
TYPE:  
 
 
 
 
 
Phase IIa 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Haris Ali, M.D.  
 
COLLABORATING INVESTIGATOR: 
 
Monzr Al Malki, M.D.  
 
PARTICIPATING CLINICIANS: 
 
 
Ibrahim Aldoss, M.D., Ahmed Aribi, M.D., Shukaib Arslan, 
M.D., Andrew Artz, M.D., Elizabeth Budde, M.D., Len 
Farol, M.D., Stephen Forman, M.D., Joshua Mansour, 
M.D., Guido Marcucci, M.D.,  Matthew Mei, M.D., Ryotaro 
Nakamura, M.D., Vinod Pullarkat, M.D., Michael 
Rosenzweig, M.D., Amandeep Salhotra, M.D., Ricardo 
Spielberger, M.D., Anthony Stein, M.D., Idoroenyi 
Amanam, M.D., Geoffrey Shouse, M.D., Salman Otoukesh, 
M.D., Peter Curtin, M.D., Brian Ball, M.D., Paul Koller, MD  
 
BIOSTATISTICIAN:  
 
 
 
Dongyun Yang, Ph.D. 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as 
authorized.  
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
Phase IIa Study of Addition of Itacitinib with Tacrolimus/Sirolimus Regimen for GVHD 
Prophylaxis in Fludarabine and Melphalan Non-Myeloablative Conditioning 
Hematopoietic Cell Transplantation for Acute Leukemias, MDS or MF 
 
Version Date: 11/29/2022 
Protocol Version: 09  
 
City of Hope #: 19576 
Agents: Itacitinib 
IND Number: 148028  
IND Holder: City of Hope 
Funding Support: Incyte 
Industry Partner: Incyte 
NCT Number: NCT04339101 
Participating Sites: City of Hope (Duarte)  
Short Title Itacitinib as acute GVHD prophylaxis after HCT with FLU/Mel 
regimen 
 
 
Principal Investigator 
Haris Ali, MD  
City of Hope National Medical Center 
Dept. of Hematologic Malignancies and Stem Cell Transplantation 
T: 626-218-2405 
Email: harisali@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
T: (626)-218-7904 
Email: DCC@coh.org 
. 
 

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PROTOCOL TEAM 
 
Biostatistician 
Dongyun Yang, PhD 
City of Hope National Medical Center 
Dept. of Computational and 
Quantitative Medicine 
T: 626-218-4891 
Email: donyang@coh.org 
Protocol Development Scientist 
Sally Mokhtari, PhD 
City of Hope National Medical Center 
Dept. of Clinical Translational 
Protocol Development 
T: 626-218-9170 
Email: smokhtari@coh.org 
 
Co-Investigator 
Ryotaro Nakamura, MD 
City of Hope National Medical Center 
Dept. of Hematologic Malignancies 
and Stem Cell Transplantation 
T: 626-218-2405 
Email: rnakamura@coh.org 
 
Co-Investigator 
Monzr M. Al Malki, MD 
City of Hope National Medical Center 
Dept. of Hematologic Malignancies 
and Stem Cell Transplantation 
T: 626-218-2405 
Email: malamalki@coh.org 
 
 
 
 
 
 
 

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STUDY SCHEMA 
 
Figure 1. Study Schema 
Note: For patients older than 70 years of age: 
1. Melphalan will be administered at 100 mg/m2 or per treating physician discretion.  
2. Tacrolimus will be administered at the flat dose of 1 mg/day or per treating physician discretion.  
3. Sirolimus loading dose is 8 mg or per treating physician discretion. 
Patients with myelofibrosis who have been stable on Jak inhibitors (i.e., ruxolitinib, fedaritinib) can continue the 
medication until the day before starting the conditioning. 
 
 

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PROTOCOL SYNOPSIS 
 
Protocol Title 
 Itacitinib as acute GVHD prophylaxis after HCT with FLU/Mel regimen 
Study Detail 
Population/Indication(s): 
acute leukemia, MDS/MPN, chronic phase of CMML, and first chronic phase of 
CML who are undergoing reduced intensity conditioning allogeneic HCT 
Phase: 
Phase IIa 
Sample Size: 
59-65 patients 
Estimated Accrual Duration: 
2 years 
Estimated Study Duration 
4 years 
Participant Duration: 
2 years 
Participating Sites: 
 City of Hope Duarte, CA 
Study Agents: 
Itacitinib 
Sponsor: 
Incyte. 
Industry Partner:  Incyte 
 
 
Rationale for this Study 
Allogeneic hematopoietic stem cell transplantation (HCT) is a curative treatment option for various hematologic 
malignant conditions. However, allogeneic HCT can be associated with significant morbidity and mortality due to relapse 
and acute and chronic graft-versus-host disease (GVHD). Current GvHD preventive strategies include combinations of 
calcineurin inhibitors, mTOR inhibitors, anti-thymocyte globulins and chemotherapeutic agent. Despite these preventive 
measures the incidence of acute GVHD remains high, 30-50% in patients with related donors and 50-70% in those with 
an unrelated donor.  
Itacitinib adipate is a novel, potent, and selective inhibitor of JAK family of protein TYKs with selectivity for JAK1. 
Itacitinib is an investigational product that is proposed for development for treatment of MPNs, including MF; 
inflammatory disease, including rheumatoid arthritis and psoriasis; GVHD; solid tumors; and B cell malignancies. Janus 
kinases play an important role in signal transduction following cytokine and growth factor binding to their receptors. 
Aberrant production of chronic inflammatory conditions, and JAK1 has been shown to cooperate with other JAKs to 
mediate the signaling of a number of inflammatory cytokines. 
In addition, due to the high morbidity and mortality related to GVHD, as explained above, there is a great interest in 
reducing GVHD to improve overall outcome and survival in alloHCT patients.  Therefore, JAK inhibitors represent 
potential therapeutic agents for these disease states. 
Treatment Description 
This study will be done as single center phase IIa trial to estimate GRFS at 1-year after administration of Itacitinib at 200 
mg (PO QD) pre- and post-alloHCT, in patients receiving alloHCT with reduced intensity conditioning for treatment of 
acute leukemias, MDS / MPN, chronic phase of CMML and 1st chronic phase of CML.  All subjects will be followed-up for 
24 months. Treatment on study will be in both outpatient and inpatient setting and will consist of daily treatment with 
Itacitinib (200 mg once a day) from day -3 (pre-transplant) until day +100 post-alloHCT.  
Objectives 
Primary Objective 
 Following a patient safety lead-in, estimate graft-versus-host disease free relapse free (GRFS) survival at 1- year post 
allogeneic stem cell transplantation (alloHCT). 
Secondary Objective 
 Estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality (NRM) at 
100-days post-transplant, 

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 Assess feasibility, defined as ability of patient to receive at least 80% of planned doses of itacidinib from Day -3 to 
100, 
 Estimate the cumulative incidence of chronic GVHD at 1- and 2-years post-transplant, 
 Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant,  
 Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 
2-years post-transplant, and 
 Assess patients quality of life (QOL), Optional quastionaire. 
Exploratory Objective 
 Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and 
flow cytometry of lymphocyte subsets, and 
 Characterize changes in aGVHD biomarkers (Reg-3α, sTNF RI, ) and a composite biomarker panel (IL2Rα , TNF-R1, IL-8, 
and hepatocyte growth factor), JAK-regulated pro-inflammatory cytokines (i.e., IL-6, TNFα, CRP, β2Microglubuolin, 
and IFNγ) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade. 
Study Design 
This is a single center single arm phase IIa trial of adding itacitinib with tacrolimus/sirolimus regimen for GVHD 
prophylaxis for patients with hematologic malignancy who undergo fludarabine melphalan non-myeloablative 
conditioning followed by a matched (8/8) related or unrelated donor hematopoietic cell transplantation (HCT). A patient 
safety lead-in will be conducted to ensure there are no unexpected toxicities. Ultimately a total of 59 patients will be 
treated at the itacitinib dose level considered safe as determined during the patient safety lead-in segment of this study. 
The first six patients enrolled on this study will be part of a patient safety lead-in. At the initial itacitoinib dose of 200 mg, 
a group of up to 3 patients can be enrolled. Note: No more than 3 patients can be at <30 days post stem cell infusion at 
any time during the patient safety lead-in. During the safety lead-in, if >1/6 patients experience unacceptable toxicity 
within 30 days after stem cell infusion, subsequent patients will receive a de-escalated dose of itacitinib to 100 mg. 
Further itacitinib dose reductions, below 100 mg, will not be considered. Note: The tacrolimus dose and sirolimus dose 
will remain fixed for all defined dose levels and will not be reduced at any point. 
Evaluation Criteria and Endpoints 
Primary Endpoint(s):  
 GRFS at 1 year 
 The primary endpoint for the patient saftey lead-in segment of the study is toxicity. Toxicity will be scored on both the 
Bearman Scale and NCI CTCAE v5.0 Scale.  Dose limiting toxicity (DLT) in a given patient will be defined as any of the 
following that are assigned an attribution level of at least possibly related to itacitinib:  
o 
For non-hematologic toxicities, any regimen-related grade III/IV toxicity per Bearman criteria  
o 
For hematologic toxicities, per NCI CTCAE v5.0 toxicity criteria, any grade 4 neutropenia associated with 
fever or infection and lasting for more than 21 days, or grade 4 neutropenia lasting for more than 28 
days (engraftment failure) 
o 
Any other regimen-related cause of death.  
o 
Discontinuation or dose reduction of itacitinib due to any toxicity (regardless of grade) 
In addition, septic DLT is defined as: any grade 5 sepsis-related toxicity that is assigned an attribution level of at least 
possibly related to the itacitinib. 
Secondary Endpoints:  
 Cumulative incidence of acute and NRM at 100-days post HCT 
 Feasibility, Patients who have received at least 80% of planned doses of itacitinib are deemed to meet feasibility 
criteria. 
 Cumulative incidence of chronic GvHD at 1 and 2 years post-HCT 
 overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant 

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 infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-
transplant 
 Quality of life at 100 days and 1 year post-HCT 
Statistical Considerations 
Patient demographic and baseline characteristics, including age, gender, medical history, and prior therapy, will be 
summarized using descriptive statistics. For continuous variables, descriptive statistics [number (n), mean, standard 
deviation, standard error, median (range)] will be provided. For categorical variables, patient counts and percentages will 
be provided. 
Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of 
onset, duration, probable association with the study treatment and reversibility or outcome. Baseline disease (e.g. )  
demographic information and donor characteristics will be presented as well to describe the patients treated in this 
study. 
Kaplan-Meier curve will be generated for GRFS, OS, and PFS. The cumulative incidence of acute and chronic GVHD will be 
calculated using the Gray method with  death or relapse considered competing events. The cumulative incidence of 
relapse/progression and non-relapse mortality will be calculated as competing risks using the Gray method. Descriptive 
statistics will also be used to assess the possible relationship between pre-HCT disease status and outcomes. As the 
results of these evaluations are considered hypothesis-generating in nature, the statistics used will not include any 
formal statistical tests/comparisons. 
Also, as described in section 9, statistical analysis will be conducted for correlative assays. Generally, for all 
cytokines/biomarkers that are measured repeatedly over time, a nonparametric smoothing plot will be produced in the 
first step to view changes in the trend. Expression level changes on the onset of aGVHD from baseline measures will be 
correlated with aGVHD grade (0-1 vs. 2-4 or 0-2 vs. 3-4). Furthermore, GVHD biomarkers, Reg-3α, TNF R1, and a 
composite biomarker panel of 4 proteins (IL-2Rα, TNFR1, IL-8, and hepatocyte growth factor) will be correlated with 
survival outcomes in a continuous manner or dichotomized manner (the rpart package in R will be used to find the 
optimal cut-off value as needed or cut-off established in the literature will be adopted.) 
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
 Age 18 to 75 years if meets criteria for HCT per SOP 
 Performance status: Karnofsky ≥ 70%. 
 Patients with neoplastic hematologic disorders with indication of allogeneic transplant according to the standard 
guidelines as follows: 
o 
Acute leukemia (AL) in CR1 or subsequent CR or active disease with BM blast of <5% 
o 
Myelodysplastic syndrome (MDS) with intermediate-2 or high risk per IPSS or 
o 
Myelofibrosis; primary or secondary if intermediate-2 or high risk per DIPPS 
o 
Myelodysplastic syndrome / myeloproliferative neoplasm (MDS/MPN) and Chronic myelomonocytic 
leukemia (CMML) if high risk per IPSS-R or lower risk IPSS_R with poor-risk genetic features, profound 
cytopenia, and high transfusion burden  
o 
First Chronic phase CML 
 
 All candidates for this study must have a matched related donor (MRD) who is willing to donate BM/peripheral blood 
stem cells or an 8/8 allele matched unrelated donor (MUD) 
Main Exclusion Criteria 
 Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to Day 1 of protocol 
therapy. Note: Patients on maintenance chemotherapy with agents listed in Section 5.5.2 are not excluded. 
 Females only: Pregnant or breastfeeding 
 History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent 

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 Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of 
the attending physician) 
 Clinically significant uncontrolled illness, active infection, known history of HIV or Hepatitis B or C infection 
 Other active malignancies 
Investigational Product Dosage and Administration 
 Itacitinib will be administered PO at 200 mg QD from day -3 pre-alloHCT until day +100 post-alloHCT.  
Clinical Observations and Tests to be Performed 
 Medical history and physical exam per city of hope standard of care procedures (COH SOPs)  
 Safety assessments (CBCs with differential, comprehensive chemistry panel including calcium and phosphorous  
panel, thyroid function and coagulation)-per COH SOPs  
 Response assessments.  
 Correlative, blood samples. 
 
 

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TABLE OF CONTENTS 
SECTION ....................................................................................................................................................................... PAGE 
Protocol Team ..................................................................................................................................................................... 2 
Study Schema ...................................................................................................................................................................... 3 
Protocol Synopsis ................................................................................................................................................................ 4 
Table of Contents ................................................................................................................................................................ 8 
Abbreviations .................................................................................................................................................................... 11 
1.0 
Objectives ............................................................................................................................................................ 12 
1.1 
Primary Objectives 
12 
1.2 
Secondary Objectives 
12 
1.3 
Exploratory Objectives 
12 
2.0 
Background .......................................................................................................................................................... 12 
2.1 
Allogeneic Hematopoietic Cell Transplantation and Graft-versus-Host Disease 
12 
2.2 
Role of Janus Kinase Signaling in GVHD 
13 
2.3 
Itacitinib 
15 
2.4 
Preclinical Studies Using Itacitinib in Prevention and Treatment of aGVHD 
15 
2.5 
Clinical Studies of Itacitinib in aGVHD 
16 
2.6 
Overview and Rationale of Study Design 
17 
3.0 
Eligibility Criteria .................................................................................................................................................. 19 
3.1 
Inclusion Criteria 
19 
3.2 
Exclusion Criteria 
20 
4.0 
Participant Enrollment ......................................................................................................................................... 22 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
22 
4.2 
Participant Enrollment 
22 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
23 
5.0 
Treatment Program ............................................................................................................................................. 23 
5.1 
Treatment Program Overview 
23 
5.2 
Cycle Definition 
23 
5.3 
Treatment Plan 
23 
5.4 
Agent Administration 
24 
5.5 
Assessments and Special Monitoring 
24 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy 
24 
5.7 
Follow-Up 
25 
5.8 
Quality of life Assessment 
25 
5.9 
Duration of Study Participation 
25 
5.10 
Supportive care 
26 
6.0 
Anticipated Adverse Event List ............................................................................................................................. 26 
6.1 
Itacitinib 
26 
7.0 
Dose Delay / Modification Guidelines and DLT Definition .................................................................................... 29 
7.1 
Dose Modifications 
29 
7.2 
DLT Definition 
30 
8.0 
Agent Information ............................................................................................................................................... 30 
8.1 
Itacitinib 
30 
9.0 
Correlative/ Special Studies ................................................................................................................................. 31 
9.1 
Research Sample Collection and Dispensation 
31 
9.2 
Laboratory Studies Performed 
31 
10.0 
Study Calendar ..................................................................................................................................................... 33 
11.0 
Endpoint Definitions/Measurement of Effect ...................................................................................................... 35 
11.1 
Primary Endpoints 
35 
11.2 
Secondary Endpoints 
35 
11.3 
Exploratory Endpoints 
36 

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11.4 
Response Criteria 
37 
12.0 
Statistical Considerations ..................................................................................................................................... 39 
12.1 
Study Design 
39 
12.2 
Safety Lead-in Segment 
39 
12.3 
Sample Size 
40 
12.4 
Accrual Rate 
41 
12.5 
Interim Analysis/Stopping Rules for Severe acute GvHD and Feasibility 
41 
12.6 
Adverse Event Stopping Rule 
41 
12.7 
Stopping Rules for Excessive Toxicities during phase IIa 
42 
12.8 
Statistical Analysis Plan 
43 
13.0 
Data Handling, Data Management, Record Keeping ............................................................................................ 44 
13.1 
Source Documents 
44 
13.2 
Data Capture Methods and Management 
44 
13.3 
Case Report Forms/Data Submission Schedule 
44 
13.4 
Regulatory Records 
44 
14.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest .............................................. 45 
14.1 
Adverse Event Definitions 
45 
14.2 
Assessment of Adverse Events 
45 
14.3 
Unanticipated Problems 
46 
14.4 
Reporting Adverse Events 
46 
14.5 
Pregnancies 
47 
14.6 
Reporting to the FDA 
48 
14.7 
Expedited Reporting 
49 
15.0 
Adherence to the Protocol & Reporting of Protocol Deviations ........................................................................... 49 
15.1 
Definitions 
49 
15.2 
Reporting of Deviations 
50 
16.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .................................................................... 50 
16.1 
Study PI Responsibilities 
50 
16.2 
All Investigator Responsibilities 
50 
16.3 
Protocol Management Team (PMT) 
51 
16.4 
Monitoring/ Auditing 
51 
16.5 
Quality Assurance 
51 
16.6 
City of Hope Data and Safety Monitoring Committee (DSMC) 
52 
17.0 
Ethical and Regulatory Considerations ................................................................................................................. 52 
17.1 
Ethical Standard 
52 
17.2 
Regulatory Compliance 
52 
17.3 
Institutional Review Board 
53 
17.4 
Informed Consent 
53 
17.5 
Participant Withdrawal 
53 
17.6 
Special and Vulnerable Populations 
54 
17.7 
Participant Confidentiality 
54 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial 
55 
17.9 
Conflict of Interest 
55 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants 
55 
17.11 
Publication/ Data Sharing 
56 
18.0 
References ........................................................................................................................................................... 57 
Appendix A: Performance Status Scales............................................................................................................................. 60 
Appendix B: Response Criteria/Grading/staging Criteria ................................................................................................... 62 
Appendix C. Coversheets ................................................................................................................................................... 64 
18.1 
Registration Coversheet 
64 
Appendix D. Response assessment .................................................................................................................................... 65 
18.2 
NCCN guidelines version 1.2020, Acute Lymphoblastic Leukemia 
65 
18.3 
NCCN guidelines for Acute Myeloid Leukemia Version 3.2020 
66 

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ABBREVIATIONS  
 
Abbreviation 
Meaning 
AE 
AlloHCT 
CFR 
COH 
CR 
CRA 
CRF 
CTCAE 
DLT 
DSMC 
EOT 
FDA 
GCP 
GRFS 
GVHD 
HIV 
IB 
IDS 
IND 
IRB 
NCI 
NRM 
OIDRA 
OS 
PD 
PFS 
PI 
PMT 
PR 
SAE 
SD 
QOL 
Adverse Event 
Allogeneic Hematopoietic Cell Transplantation 
Code of Federal Regulations 
City of Hope 
Complete Response 
Clinical Research Coordinator 
Case Report Form 
Common Terminology Criteria for Adverse Events 
Dose Limiting Toxicity 
Data & Safety Monitoring Committee 
End of Treatment 
Food and Drug Administration 
Good Clinical Practice 
Graft-versus-host disease-free Relapse-Free Survival 
Graft-Versus-Host Disease 
Human Immunodeficiency Virus 
Investigator’s Brochure 
Investigational Drug Services 
Investigational New Drug 
Institutional Review Board 
National Cancer Institute 
Non-relapse Mortality 
Office of IND Development and Regulatory Affairs 
Overall Survival 
Progressive Disease 
Progression-Free Survival 
Principal Investigator 
Protocol Management Team 
Partial Response 
Serious Adverse Event 
Stable Disease 
Quality of Life 

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1.0 OBJECTIVES 
1.1 Primary Objectives  
o Following a patient safety lead-in, estimate graft-versus-host disease free relapse free (GRFS) survival at 
1- year post allogeneic stem cell transplantation (alloHCT). 
1.2 Secondary Objectives 
o Estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality 
(NRM) at 100-days post-transplant, 
o Assess feasibility, defined as ability of patients to receive at least 80% of planned doses of itacitinib from 
Day -3 to 100, 
o Estimate the cumulative incidence of chronic GVHD at 1- and 2-years post-transplant, 
o Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post-
transplant,  
o Estimate rate of infection and development of second malignancies including lymphoproliferative 
disorders at 1- and 2-years post-transplant, and 
o Assess patients’ quality of life (QOL) at day 100 and 1 year post alloHCT. (optional questionairs) 
1.3 Exploratory Objectives 
o Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by 
cell count and flow cytometry of lymphocyte subsets, 
o Characterize changes in aGVHD biomarkers (Reg-3α, TNF-RI, and ST2) and a composite biomarker panel 
(IL2Rα, TNF-R1, IL-8, and hepatocyte growth factor), JAK-regulated pro-inflammatory cytokines (i.e., IL-6, 
TNFα, CRP, β2 Microglubuolin, and IFNγ) and STAT3 phosphorylation (downstream of JAK signaling) over 
time and by aGVHD status/grade. 
2.0 BACKGROUND 
2.1 Allogeneic Hematopoietic Cell Transplantation and Graft-versus-Host Disease  
Allogeneic hematopoietic cell transplantation (alloHCT) is an established treatment for a large number of inherited 
metabolic and immune deficiencies and for benign and malignant blood and marrow conditions. However, Graft-
versus-Host-Disease (GvHD) continues to be a major problem with substantial morbidity and mortality limiting the 
general value on the procedure. GvHD results from a complex interaction between recipient tissues and 
genetically disparate donor immune system.1  
In the initial phase, damage to the host tissues results in a self-limited burst of inflammatory cytokines. Later, 
donor T cells recognize alloantigens presented by host antigen presenting cells (APC) leading to amplification of 
the systemic inflammatory response, now with contribution of donor cells. In the last phase, host tissues are 
subjected to damage and apoptosis driven inflammatory cytokines and cellular effectors, thus establishing a 
positive inflammatory feedback loop. Even in the setting of HLA-matched donors, patient and donor can differ in 
self-peptides derived from minor histocompatibility antigens (mHA). Those polymorphic peptides are presented 
by HLA class I antigens (rarely HLA class II) and can trigger the activation of donor-derived T cells. A number of 
these mHAs have been identified.2 In fact, mismatches of known mHA among HLA identical donor-recipient pairs 
have been associated with the development of GvHD after HCT.3  
The currently used GvHD prophylactic regimens are based on the routine use of different combinations of 
methotrexate, calcineurin or mTOR inhibitors, mycophenolate mofetil and antithymocyte globulins (ATG).4 Yet, 
even in the setting of HLA-matched donors, clinically significant (grade II-IV) and severe (grade III-IV) acute GvHD 

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(aGvHD) still occur in about 35-50% and 15% of cases, respectively. The latter is always associated with decreased 
survival.5 Chronic GvHD (cGvHD) occurs in up to 70% of patients either after aGvHD or de novo and is associated 
with substantial morbidity and mortality.5 Risk of GvHD is further increased in those undergoing mismatched 
donor transplants leading to absolute decrease in survival approaching up to 10% in different studies.5-11  
Furthermore, it has been suggested that some drugs used in the prevention of GvHD might indeed have 
deleterious effects. For instance, methotrexate can independently cause tissue injury; paradoxically exacerbating 
the cytokine cascade associated with GvHD.12 In addition, calcineurin inhibitors, by suppressing IL-2 T-cell 
responses can be damaging to regulatory (CD4+ CD25+ FoxP3+) T cell population. 13 The decrease in number and 
function of regulatory T cell is associated with worsening of cGvHD. 14,15 
Approximately 40% and up to 70% of patients with acute and chronic GvHD will have durable responses to 
corticosteroid therapy, respectively. Over the past 20 years, there has been little change in this response rate, 
despite addition or substitution of other immunosuppressive drugs to GvHD treatment regimens.16  The prognosis 
of patients with steroid refractory GvHD is poor.17  A strategy that minimizes the incidence and severity of GvHD, 
without other adverse effects, would be an effective approach to improve survival after allogeneic HCT. 
2.2 Role of Janus Kinase Signaling in 
GVHD 
Janus Kinases (JAK) are intracellular 
signaling molecules well-positioned to 
regulate GvHD. A variety of cytokines that 
signal through the JAK signaling pathway 
play a role in regulating the development, 
proliferation, and activation of several 
immune cell types important for GvHD 
pathogenesis, including dendritic cells, 
macrophages, T cells, B cells, and 
neutrophils. Figure 2.1 depicts JAK 
activity in all 3 phases of aGVHD:  
2.2.1 
The conditioning regimen 
The conditioning regimen may cause the 
release of inflammatory cytokines, which 
signal through JAK to activate APC, 
activated macrophages migrate toward 
CXCL9 secreted from lymph nodes in a 
JAK1/JAK2-dependent process. 
2.2.2 
Allogeneic donor T cell activation 
after transplantation  
After HCT, JAK regulate allogeneic donor 
T cell-activation through secondary signal 
in APCs, such as CD80/86, IDO, and IFN 
signaling, and in T cells downstream of 
the γ-chain cytokine receptor. JAK activity 
in CD4+ and CD8+ T cells also promotes 
proliferation, whereas JAK signaling 
inhibits proliferation of Tregs. 
Figure 2.1 JAK activity in aGVHD. 
DAMP: damage associated molecular pattern, IDO: indoleamine 2,3 dioxygenase, 
PAMP: pathogen-associated molecular pattern, PD-1: programmed cell death 
protein, PD-L1: programmed cell death protein ligand-1. 
Figure adopted from: Schroeder et al, BBMT 2018 

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2.2.3 
Immune cell migration and tissue damage 
After T cell activation, migration out of the secondary lymphoid tissue is regulated by chemokine receptors, which 
are in turn regulated by JAK signaling. T cell cytotoxic activity, including granzymes B production is promoted by 
JAK activity. Neutrophils, which may participate in GVHD, use JAK signaling pathways to regulate their 
development and activity. 
Various JAK inhibitors are approved or under investigation for treating various malignancies, autoimmune 
disorders and inflammatory disease. Preliminary studies support the efficacy of JAK1/JAK2 inhibitors for the 
treatment of patients with aGVHD. Table 2.1 (Adopted from Schroeder et al, BBMT 2018) summarizes clinical 
reports of JAK Inhibitor treatment for GVHD. 
Table 2.1. Clinical Reports of JAK Inhibitor Treatment for GVHD 
Reference 
JAK 
Inhibitor 
Study Type 
GVHD Severity 
Patients 
Prior 
Treatments, 
Median (Range) 
Follow-Up 
Duration, 
Median 
(Range) 
Response* 
OS (95% CI) 
aGVHD 
Zeiser et al.18 ;  
Zeiser et al. 19  
Ruxolitinib 
Retrospective 
Grade 3/4 
54 
3 (1-7) 
26.5 (3-106) wk ORR, 
82% 
(CR, 46%) 
6 mo, 
79% 
(67%-91%) 
 
 
 
 
 
19 (NA) mo 
Ongoing, 
41% 
12 mo, 
62% 
(49%-75%) 
Khandelwal et 
al. 20  
Ruxolitinib 
Retrospective 
(pediatric) 
Grades 2-4 
13 
4 (1-6) 
2-306 d† 
ORR, 
45% 
(CR, 9%) 
13 mo,‡54% 
Spoerl et al. 21  Ruxolitinib 
Pilot 
Grade 3/4 
4 
4.5 (4-7) 
18.5 (15-21) wk ORR, 100% 
(CR, 25%) 
NA 
Mori et al. 22  
Ruxolitinib 
Retrospective 
Grade 3/4 
1 
2 
NA 
ORR, 100% 
(CR, 100%) 
NA 
Maffini et al. 23  Ruxolitinib 
Case report 
Grade 2 
1 
3 
22.3 wk 
ORR, 100% 
(CR, 100%) 
NA 
Schroeder 
et 
al. 24  
Itacitinib 
Phase 
1 
prospective 
Grades IIB–IVD 
30 
NA 
56.5-60.8 d§ 
NA 
NA 
cGVHD 
Khoury et al. 25  Ruxolitinib 
Retrospective 
Severe¶ 
19 
NA 
18 (6-27) mo† 
ORR, 89% 
NA 
Zeiser etal. 18; 
Zeiser et al. 19  
Ruxolitinib 
Retrospective 
Moderate 
or 
severe 
41 
3 (1-10) 
22.4 (3-135) wk ORR, 
85% 
(CR, 7%) 
6 mo, 
97% 
(92%-100%) 
 
 
 
 
 
24 (NA) mo 
Ongoing, 
24% 
12 mo, 
93% 
(85%-100%) 
Spoerl et al. 21  Ruxolitinib 
Pilot 
Grade 3 
2 
4 (3-5) 
23.5 (10-37) wk Response, 
100% 
NA 
Mori et al. 22  
Ruxolitinib 
Retrospective 
Severe 
3 
2 (1-2) 
NA 
ORR, 100% 
(CR, 57%)# 
NA 

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2.3 Itacitinib 
Itacitinib adipate (Figure 2.2) is a novel, potent, and 
selective inhibitor of JAK family of protein TYKs with 
selectivity for JAK1. Itacitinib is an investigational product 
that is proposed for development for treatment of MPNs, 
including MF; inflammatory disease, including rheumatoid 
arthritis and psoriasis; GVHD; solid tumors; and B cell 
malignancies. Janus kinases play an important role in 
signal transduction following cytokine and growth factor 
binding to their receptors. Aberrant production of chronic 
inflammatory conditions, and JAK1 has been shown to 
cooperate with other JAKs to mediate the signaling of a number of inflammatory cytokines.  
2.3.1 
Pharmacology 
Itacitinib potently inhibits JAK1 (IC50= 3.6 nM at 1 mM adenosine triphosphate concentration), with 22- to >500-
fold selectivity over the other JAK family members, JAK2, JAK3 and TYK2.  It does not significantly inhibit (<30% 
inhibition) a broad panel of approximately 60 other kinases. Itacitinib is also potent (IC50 values of approximately 
10 nM to 350 nM) in cytokine driven cell-based assays.  This effect of not due to the general toxicity. Itacitinib also 
inhibits the growth of the cytokine-dependent cell line INA-6. Itacitinib potently inhibits the phosphorylation of 
STAT proteins and production of proinflammatory factors induced by other cytokines, such as IL-23 and IL-6 with 
IC50 values of approximately 30 nM to 100 nM. In contrast, itacitinib shows less inhibition in cell-based assays 
dependent on JAK2 with IC50 values of approximately 1 μM or greater, suggesting that itacitinib is JAK2 sparing in 
cells. In in vivo models of JAK-dependent malignancies, itacitinib impedes subcutaneous tumor growth of INA-6 
cells expressing wildtype JAKs when administered by continues infusion, achieving plasma concentrations well 
below those necessary to inhibit JAK2. Oral itacitinib also reduced splenomegaly in a model of JAK2  V617F-driven 
neoplasia relevant MF. 
2.4 Preclinical Studies Using Itacitinib in Prevention and Treatment of aGVHD 
A series of studies were undertaken to 
evaluate the effects of prophylactic dosing 
regimens of the itacitinib on engraftment 
and disease severity of a MHC-mismatched 
allogeneic transplantation model of aGVHD. 
26  
GVHD was induced in BLAB/c mice using a 
single acute dose of 8 Gy on day -1. On day 
0, the BALB/c recipients were given an 
intravenous injection of a combination of 
splenocytes and T cell depleted bone 
marrow cells; all groups received an 
allogeneic or syngeneic cell transfer from 
donor C57BL/6 mice or BALB/c mice. Animals 
were dosed with vehicle or itacitinib by oral 
gavage twice daily, every day from day-3 
until day 35. Immediately following TBI of 
mice on day -1, the numbers of host 
leukocytes (CD45+, H-2Kd) dramatically 
dropped, plateauing by day 14.  By contrast, 
donor leukocytes (CD45+, H-2Kb) steadily 
Figure 2.2 Itacitinib chemical structure 
Effects of Itacitinib on Allogeneic Donor Engraftment 
1 x 106 
1 x 10-1 
1 x 100 
1 x 101 
1 x 102 
1 x 103 
1 x 104 
Total CD45+ Count 
0 
7 
14 
21 
28 
35 
Days 
Vehicle
Itacitinib 60 mg/kg 
Figure 2.3 Effects of oral prophylactic itacitinib administration 
(60 and 120 mg/kg) on allogeneic donor cell engraftment in an 
MHC mismatched mouse model of aGVHD. Animals in all groups 
were bled (~ 100 μl retro orbital) twice per week. The blood was 
processed for FAS analysis to assess surface expression of CD45 and 
donor H-2Kb and host H-2Kd MHC molecules. Data are presented as 
mean ± SEM, with n=5 per group per time-point. 
Itacitinib 120 mg/kg 

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increased in number between days 0 (day of transfer) and plateauing by day 7 (Figure 2.3). There were no 
significant differences between any of the treatment groups, indicating that neither dose of itacitinib adversely 
affected allogeneic engraftment of donor cells into recipient mice. 
As shown in Figure 2.4a, GVHD score in all treatment groups initially increased between Days 0 to 7, followed by 
partial recovery until day 13, presumably due to TBI and donor cells engraftment. As expected, the allogeneic 
vehicle control group demonstrated highest GVHD scores over the course of the study, while syngeneic vehicle 
control mice had lowest GVHD scores (figure 2.4a). I contrast to allogenic controls with severe aGVHD, both 
itacitinib treatment groups had comparable and significantly reduced GVHD scores, suggesting amelioration of 
disease severity in this model.   
Initial body weight loss (reaching a nadir on days 7-8) followed by partial recovery was observed for all 
nonsyngeneic treatment groups by approximately day 13. Animals in the allogeneic vehicle control group had the 
most profound overall weight loss, approximately 22% at nadir, while syngeneic control mice gained 
approximately 15% body weight over the course of these studies (Figure 2.4b). In contract to allogeneic control 
mice, both itacitinib treatment groups had comparable and significantly lower body weight loss by comparison, 
suggesting a treatment benefit of prophylactic itacitinib administration on the severity of GVHD in this model.  
2.5 Clinical Studies of Itacitinib in aGVHD  
In phase I study that assessed the safety and tolerability of itacitinib in combination with corticosteroids, 30 
aGVHD subjects were randomized to 1 of 2 treatment cohorts (200 mg cohort, n=14; 300 mg cohort, n=16).24 One 
subject was randomized to the 200 mg cohort but withdrew from the study before starting treatment. One DLT 
of Grade 3 thrombocytopenia was reported in 1 subject with pre-existing thrombocytopenia who was randomized 
to the 300 mg cohort. Adverse events reported in greater than 20% of all subjects included diarrhea, 
hypomagnesemia, and sepsis. Thrombocytopenia and platelet count decreases were observed in 24.2% and 20.7% 
4 
Figure 2.4 (a) Effects of oral prophylactic itacitinib administration (60 and 120 mg/kg) on GVHD scores in an MHC 
mismatched mouse model of GVHD. GVHD scores were obtained daily for the entire study duration as assessed 
by a standard scoring system based on a completion of 5 criteria evaluated in MHC mismatched allogeneic 
transplantation mouse model: percentage of body weight change, animal posture (hunching), animal activity, 
fur texture, and skin integrity (maximum severity index =10) the overall score was reported, as well as the score 
for each individual parameter. (b) Effects of oral prophylactic itacitinib administration (60 and 120 mg/kg) on 
percent body weight change in MHC mismatched mouse model of aGVHD. Animals were weighed daily, and 
their percent body weight relative to day -4 calculated. 
21 
35 
0 
7 
14 
28 
Days 
Vehicle (syngeneic) 
Vehicle 
Itacitinib 60 mg/kg 
Itacitinib 120 mg/kg 
0 
-30 
20 
10 
-10 
-20 
Percent Weight Change 
0 
2 
GvHD Score 
6 
21 
35 
0 
7 
14 
28 
Days 
Vehicle (syngeneic) 
Vehicle 
Itacitinib 60 mg/kg 
Itacitinib 120 mg/kg 
b) 
Effects of Itacitinib on Percent Body Weight 
a) 
Effects of Itacitinib on aGVHD Score 

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of subjects, respectively, with a higher proportion of these events occurring in the 300 mg cohort, although a 
higher incidence of pre-existing thrombocytopenia was also observed in this group. The day 28 ORR in first-line 
aGVHD subjects in both treatment cohorts was 83.3%; for subjects with SR-aGVHD, the overall day 28 ORR was 
64.7% (200 mg cohort, 62.5%; 300 mg cohort, 66.7%). Most responses occurred within the first 14 days of 
treatment, and responses were durable, with a median duration of response of 130 days and 136 days in the 200 
mg cohort and 300 mg cohort, respectively. Pharmacokinetics of itacitinib were evaluated using plasma samples 
collected pre-dose and at 1 hour, 2, 4 and 8 hours post dose on days 1 and 7. Although intersubject variability was 
found to be high, PK exposure (Cmax and AUC) was consistent with historical data, and a large overlap in steady-
state exposure was observed between the 200 mg and 300 mg cohorts. The higher incidence of thrombocytopenia 
and DLT of thrombocytopenia in the 300 mg cohort, as well as similarities in PK and efficacy between dose groups, 
led to the identification of the 200 mg dose of itacitinib as recommended dose for future GVHD studies. 
2.6 Overview and Rationale of Study Design 
2.6.1 
Overview 
Allogeneic hematopoietic stem cell transplantation (HCT) is a curative treatment option for various hematologic 
malignant conditions. However, allogeneic HCT can be associated with significant morbidity and mortality due to 
relapse and acute and chronic graft-versus-host disease (GVHD). Current GvHD preventive strategies include 
combinations of calcineurin inhibitors, mTOR inhibitors, anti-thymocyte globulins and chemotherapeutic agent. 
Despite these preventive measures the incidence of acute GVHD remains high, 30-50% in patients with related 
donors and 50-70% in those with unrelated donor.  
Itacitinib adipate is a novel, potent, and selective inhibitor of JAK family of protein TYKs with selectivity for JAK1. 
Itacitinib is an investigational product that is proposed for development for treatment of MPNs, including MF; 
inflammatory disease, including rheumatoid arthritis and psoriasis; GVHD; solid tumors; and B cell malignancies. 
Janus kinases play an important role in signal transduction following cytokine and growth factor binding to their 
receptors. Aberrant production of chronic inflammatory conditions, and JAK1 has been shown to cooperate with 
other JAKs to mediate the signaling of a number of inflammatory cytokines. 
In addition, due to the high morbidity and mortality related to GVHD, as explained above, there is a great interest 
in reducing GVHD to improve overall outcome and survival in alloHCT patients.  Therefore, JAK inhibitors represent 
potential therapeutic agents for these disease states. 
2.6.2 
Rationale 
This multi-center phase IIa study proposes to enroll eligible adult patients with acute leukemias, MDS, and MPN 
who are undergoing reduced intensity conditioning allogeneic HCT with fludarabine and melphalan as the 
conditioning regimen, for estimating GRFS at 1-year post transplantation examining with administering itacitinib 
during the peri-transplant period. Oral administration of itacitinib will take place from day -3 pre-HCT to day +100 
post-HCT.  The proposed study explores the efficacy and pharmacologic inhibition of JAK1/2 by administering 
itacitinib during reduced intensity conditioning allogeneic HCT. Reduced intensity conditioning transplant was 
chosen as it is commonly used for patients for diseases included in this trial, patients tolerate it well, and we have 
pioneered its use at City of Hope with excellent outcomes.  
In this study patients undergoing allogeneic HCT (related, unrelated) from 8/8 HLA matched donors will use the 
standard conditioning regimen for reduced intensity (RIC) allogeneic HCT: fludarabine (25 mg/m2) and melphalan 
(140 mg/m2) with GVHD prophylaxis: tacrolimus and sirolimus (see schema). Itacitinib, at 200 mg PO QD, will be 
started on day -3 pre-HCT and continued until day +100 post-transplant. The proposed dose is chosen since 200 
mg PO QD dose has already been studied in transplant patients for treatment of GVHD without affecting 
engraftment.24 The proposed duration of itacitinib administration is based on immune tolerance, in order to 
prevent development of acute and chronic GvHD. 

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GRFS as primary endpoint: Graft-versus-host disease free, relapse-free survival (GRFS), a composite endpoint, is 
proposed as an ideal measure to reflect HCT success more comprehensively compared to other individual 
measures, including GvHD, relapse, or death.27 Based on our previous analysis the estimate 1-year GRFS for 
patients with myelofibrosis (figure 2.5.a), patients over 70 years of age with AML, MDS, ALL, MPN, Lymphoma, 
APL, and BPDCN (figure 2.5.b), and patients with AML, ALL, MDS, or lymphoma (figure 2.5.c) who underwent 
allogeneic HCT at City of Hope were from 37% to 42%. Table 2.3 summarizes some of the transplant characteristics 
for these patients.   The rational for the 2-year follow-up for chronic GvHD is based on 2-year survival follow-up. 
Table 2.3. Historical estimates of GRFS at City of Hope 
 
Disease 
N 
Conditionin
g 
GvHD prophylaxis 
Donor 
1-year GRFS 
(95% CI) 
A 
MF 
110 
Flu/Mel 
Tacro/Siro, Cyclosporine 
/Cellcept based 
10/10 MUD (40%) 
<10/10 mMUD (14%) 
41%  
(32%-50%) 
B* 
AML, 
MDS, 
ALL, 
MPN, 
Lymphoma, APL, BPDCN 
53 
Flu/Mel. 
Clo/Mel 
Tacro/Siro ± MTX, ATG 
8/8 MUD (72%) 
42%  
(28%-54%) 
C 
AML, ALL, MDS, Lymphoma 
94 
Flu/Mel 
Tacro/Siro 
MUD 
37% 
(27%-46%) 
* Patients in cohort B were 70 years and older. 
Figure 
2.5. 
Kaplan-Meier 
curves 
demonstrating overall survival, progression-
free survival, and GvHD-free Relapse-free 
survival in A) patients with myelofibrosis, B) 
patients 70 years and older with AML, MDS, 
ALL, MPN, Lymphoma, APL, and BPDCN, and C) 
Patients with AML, ALL, MDS, or Lymphoma 
who underwent allogeneic HCT at City of Hope. 

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3.0 ELIGIBILITY CRITERIA 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Participants must meet all of the following criteria on screening examination to be eligible to participate in the 
study:  
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent of the participant and/or legally authorized representative. 
 
Assent, when appropriate, will be obtained per institutional guidelines 
Age Criteria, Performance status 
__2. Age: 18 to 75 years if meets transplant criteria per institutional guidelines per SOP. 
__3. Performance status: Karnofsky ≥70% 
Nature of Illness and Illness Related Criteria 
__4. Patients with neoplastic hematologic disorders with indication of allogeneic transplant according to the 
standard guidelines as follows: 
• 
Acute leukemia (AL) in CR1 or subsequent CR or active disease with BM blast of <5% 
• 
Myelodysplastic syndrome (MDS) with intermediate-2 or high risk per IPSS or 
• 
Myelofibrosis; primary or secondary if intermediate-2 or high risk per DIPPS 
• 
Myelodysplastic syndrome / myeloproliferative neoplasm (MDS/MPN) and Chronic myelomonocytic 
leukemia (CMML) if high risk per IPSS-R or lower risk IPSS_R with poor-risk genetic features, profound 
cytopenia, and high transfusion burden  
• 
Chronic phase CML 
__5. All candidates for this study must have a matched related donor (MRD) who is willing to donate BM or 
peripheral blood stem cells or an 8/8 allele matched unrelated donor (MUD) 
Note: Donor Selection process will be in accordance with COH-SOPs (B.001.09 Allogeneic Cellular Therapy 
Product Donor Evaluation, Selection & Consent), which follows FDA guidelines for donation of hematopoietic 
stem/progenitor cells (HPCs) obtained from peripheral blood or bone marrow. 
Clinical Laboratory and Organ Function Criteria (To be performed within 28 days prior to Day 1 of protocol therapy unless 
otherwise stated. In case of active disease, evaluation should be done within 15 days) 
 
__6. Total bilirubin ≤ 1.5 X ULN (unless has Gilbert’s disease) 
ULN: 
Bil: 
Date: 
__7. AST ≤ 2.5 x ULN 
ULN: 
AST: 
Date: 
__8. ALT ≤ 2.5 x ULN 
ULN: 
ALT: 
Date: 

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__9. Creatinine clearance of ≥ 60 mL/min per 24 hour urine test or the 
Cockcroft-Gault formula or  
 
Serum Cr: 
 
Cr Clearance: 
Date: 
__10. Left ventricular ejection fraction (LVEF) ≥ 50%  
Note: To be performed within 28 days prior to Day 1 of protocol 
therapy. 
LVEF: 
Date: 
__11. If able to perform pulmonary function tests: FEV1, FVC and 
DLCO (diffusion capacity) ≥ 50% of predicted (corrected for 
hemoglobin). 
If unable to perform pulmonary function tests: O2 saturation > 
92% on room air. 
Note To be performed within 28 days prior to Day 1 of protocol 
therapy. 
FEV1: 
FVC: 
DLCO: 
O2 sat:  
Date: 
__12. Seronegative for HIV Ag/Ab combo, HCV*, active HBV (Surface 
Antigen Negative), and syphilis (RPR) 
*If positive, Hepatitis C RNA quantitation must be performed. 
__13. Meets other institutional and federal requirements for 
infectious disease titer requirements 
Note Infectious disease testing to be performed within 28 days 
prior to Day 1 of protocol therapy. 
HIV: 
HCV: 
HBV: 
Syphilis: 
 
Date: 
__14. Women of childbearing potential (WOCBP): negative urine or 
serum pregnancy test  
If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required 
Urine: 
Serum: 
Date: 
 
 
 
 
 
 
 
Contraception 
__15. Agreement by females and males of childbearing potential* to use an effective method of birth control or 
abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of 
protocol therapy.  
* Childbearing potential defined as not being surgically sterilized (men and women) or have not 
been free from menses for > 1 year (women only).  
3.2 Exclusion Criteria 
Prior and concomitant therapies 
__1.  Prior allogeneic transplantation. 
__2.  Chemotherapy, radiation therapy, biological therapy, and/or immunotherapy within 21 days prior to Day 1 
of protocol therapy  
Note: Conditioning regimen within 21 days prior to Day 1 of protocol therapy is not considered as an 
exclusion criterion. 
Note: Patients on maintenance chemotherapy with agents listed in Section 5.5.2 are not excluded. 

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Other illnesses or conditions 
__3.  History of allergic reactions attributed to compounds of similar chemical or biologic composition to study 
agent 
__4.  Psychological issues, no appropriate caregivers identified, or non-compliant to medication 
__5.  Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies 
(Discretion of the attending physician) 
__6.  Active diarrhea due to inflammatory bowel disease or malabsorption syndrome.  
__7.  Clinically significant uncontrolled illness  
__8.  Active, uncontrolled systemic infection (bacterial, viral, or fungal) requiring antibiotics  
__9.  Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection 
__10.  Other active malignancy 
__11.  Females only: Pregnant or breastfeeding 
__12.  Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation 
in the clinical study due to safety concerns with clinical study procedures. 
Noncompliance 
__13.  Prospective participants who, in the opinion of the investigator, may not be able to comply with all study 
procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
 
 

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4.0 PARTICIPANT ENROLLMENT  
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after obtaining 
written informed consent. Studies or procedures that are performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values and/or to determine pre-eligibility, even if the studies 
were done before informed consent was obtained.  
The informed consent process is to be fully documented (see Section 17.4), and the prospective participant must 
receive a copy of the signed informed consent document. Screening procedures are listed in Section 10.0 (Study 
Calendar). 
4.2 Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Refer to Section 5.1. 
Eligible participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City of Hope. 
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except holidays).  
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
A designated study team member should email the DCC to verify current slot availability, and to reserve a slot for 
a specific prospective subject (provide DCC with subject initials), including a tentative treatment date. Slots can 
only be held for a limited time, at the discretion of the study PI. 
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible.   
4.2.3 
Registration Process  
Allow up to 24 hours for the DCC to review. To register a participant the following procedure must be followed: 
1. The study team should contact the DCC via email to provide notification regarding the pending registration 
and communicate desired timeline of the registration, especially if it must be completed promptly to meet 
the registration window.  
2. The study team will email a Complete Registration Packet to the DCC, which consists of a copy of the 
following documents: 
o Completed eligibility checklist (printed from Section 3.0 of the protocol) with the required 
signature(s) 
o Signed Informed Consent  
o Signed subject’s bill of Rights  
o Signed HIPAA authorization form (if separate from informed consent) 
3. In some cases, the DCC may request additional documentation prior to registration. Please refer to the 
Work Instruction – Reviewing Registration Packets and Registering Subjects for more information. A copy 
of this work instruction can be provided by the DCC, upon request.  
 
4. When all documents are received, the DCC will review and work with the study team to resolve any 
missing elements. A participant failing to meet all requirements will not be registered and the study team 
will be immediately notified. 
5. The DCC will send a Confirmation of Registration Form, including the Subject Study Number and Cohort 
assignment to: 

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o The COH Study PI and COH study team designees (including but not limited to study monitor(s) 
and statistician(s)). 
6. Upon receipt of the Confirmation of Registration email from the DCC, COH study team will register the 
patient in OnCore.  
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC if the participant screen fails after registration or if the participant does not start treatment. Issues 
that would cause treatment delays should be discussed with the Study Principal Investigator. 
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This study will be done as single center phase IIa trial to estimate GRFS at 1-year after administration of itacitinib 
at 200 mg (PO QD) pre- and post-alloHCT, in patients receiving alloHCT with reduced intensity conditioning for 
treatment of acute leukemias, MDS/MPN, chronic phase of CMML, 1st chronic phase of CML and MF.  All subjects 
will be followed-up for 24 months. Treatment on study will be in both outpatient and inpatient setting and will 
consist of daily treatment with itacitinib (200 mg, once per day) from day -3 (pre-transplant) until day +100 post-
alloHCT.   
5.2 Cycle Definition 
There will be on one treatment cycle for this trial. Itacitinib treatment cycle starts on day -3 (prior to alloHCT) and 
will continue until day +100 post stem cell administration. 
5.3 Treatment Plan 
5.3.1 
Pre-transplant evaluation and tests 
Pre-transplant evaluations and tests are listed in details in Section 10 (Study Calendar). Note: Patients with 
myelofibrosis who have been stable on Jak inhibitors (i.e., ruxolitinib, fedaritinib) can continue the medication 
until the day before starting the conditioning. 
5.3.2 
Preparative regimen dose and schedule  
Therapy begins on day -9 as outpatient. Fludarabine will be administered as a daily infusion from day -9 to day -5. 
On day -4, patients will be admitted prior to melphalan administration and will remain inpatient until engraftment 
(typically ~day 28) according to transplant SOPs. Melphalan is administered at a single dose of 140 mg/m2 given 
in one dose on day -4 and is calculated using actual body weight. Note: For patients older than 70 years of age, 
melphalan will be administered at 100 mg/m2, or per treating physician desertion.  
Itacitinib administration will begin on day -3 at 200 mg dose once daily and will continue until day +100. On day 
0, peripheral blood stem cell or bone marrow will be collected and infused according to standard guidelines.  
5.3.3 
GVHD prophylactic regimen schedule 
Immunosuppression with Tacrolimus/Sirolimus: Tacrolimus will initially be administered at 0.02 mg/kg/d 
continuous IV, beginning on day –3 and converting to oral dosing when the patient is able to tolerate and absorb 
oral medications. Sirolimus will be administered at a 12 mg oral loading dose on day –3, followed by 4 mg orally 
as a single morning daily dose. Target serum levels for both tacrolimus and sirolimus are 5-10 ng/ml for each by 
HPLC and will be adjusted by physicians to maintain this range. In the absence of GvHD, the immunosuppressive 
taper will be as per institutional guidelines. Note: For patients older than 70 years of age, tacrolimus will be 
administered at flat dose of 1 mg per day and sirolimus loading dose will be 8 mg, or per treating physician 
desertion.  

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5.4 Agent Administration 
Itacitinib will be administered orally once a day at 200 mg dose. 
5.5 Assessments and Special Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 10.0.  
5.5.1 
Treatment compliance 
Treatment compliance with all study related medication should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study. Itacitinib compliance 
will be calculated by the sponsor based on the drug accountability documented by the site staff and monitored 
by the sponsor/designee (tablet counts). Subjects will be instructed to bring all used and unused bottles of study 
medication with them to each study visit in order for site personnel to conduct tablet counts to assess study drug 
accountability. The drug accountability documentation will be used by the sponsor to calculate treatment 
compliance.  
5.5.2 
Targeted agents allowed pre-conditioning 
A 3-week washout period is required before initiation of the protocol therapy. The following targeted agents for 
underlying myeloid malignancies may be continued up to one day before conditioning: 
• 
Venetoclax 
• 
Jakafi 
• 
Inrebic 
• 
Dasatinib 
• 
Imatinib 
• 
Ponatinib 
• 
Nilotinib 
• 
Bosutinib 
• 
Gilteritinib 
• 
Midostaurin 
• 
Idhifa 
• 
Tibsovo 
• 
Hydrea 
5.6 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Therapy begins on day -9 as outpatient. On day -4, patients will be admitted prior to melphalan administration 
and will remain inpatient until engraftment (typically ~day 28) according to transplant SOP. Study therapy with 
itacitinib will continue until day +100. Thus, the total study duration will be 110 days.  
Participants will receive protocol therapy until one of the below criteria are met: 
o Confirmed disease progression or relapse 
o Completed protocol therapy  
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose modification/ 
delay  

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o General or specific changes in the patient's condition which render the patient unacceptable for further 
treatment in the judgment of the investigator 
o Withdrawal of consent for further protocol therapy (Refer to Withdrawal Section from Ethical 
Considerations) 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed to End of 
Treatment assessments, and then to follow-up (Section 5.7). 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF.  
5.7 Follow-Up 
Patients will be actively followed for 2 years post-transplantation. After 2 years, we will access each center’s 
CIBMTR data repository to retrieve data regarding post-HCT long-term outcomes through study termination. 
All participants will enter follow-up after completing End of Treatment assessments. This is comprised of: 
o Safety Follow-up- 30 days post-last dose of protocol therapy. 
 Note the period for safety follow-up will be extended until stabilization or resolution for all 
reportable AEs (per the agreement of the Study PI) and accompanying follow-up safety report. 
o Response Follow-up- for those who have yet to have disease progression. 
o Survival Follow-up- for all participants who have progressed OR completed Active Response Follow-Up.  
Assessment time points and windows are detailed in Section 10.0. 
5.8 Quality of life Assessment 
QOL assessments include self-reported patient questionnaires: SF-12, FACT-BMT, and MDASI for English and 
Spanish speaking patients > 18 years. Patients will be asked to fill out QOL assessment forms at 100 days, 6 
months, and 1 and 2 years post-HCT. Patients can choose not to participate in Quality of Life Assessments.  
5.9 Duration of Study Participation 
Study participation may conclude when any of the following occur:  
o Completion of study activities (treatment and 2 years of follow-up after allogeneic transplantation) 
o Withdrawal of consent (Refer to Withdrawal Section from Ethical Considerations) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative reasons 
o Initiation of systemic treatment for cGVHD or grade II-IV acute GVHD. 
Documentation of the reason for discontinuing study participation and the date effective should be made in the 
Electronic 
Health 
Record/medical 
record 
and 
appropriate 
eCRF. 
Prohibited 
and 
Concomitant 
Therapies/Medications  
5.9.1 
Allowed concomitant medications 
If concomitant therapy must be added or changed, including over-the-counter medications or alternative 
therapies, the reason and name of the agent/therapy should documented in the Electronic Health Record/medical 
record.  
5.9.2 
Restricted medications 
The following medications have restrictions on use during the treatment period of the study: 

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• 
Aspirin in doses exceeding 125 mg per day is not permitted. Low-dose aspirin (≤125 mg per day) is 
permitted unless clinically contraindicated. 
• 
Co-administration with potent CYP3A inhibitors; consider alternative agents with less CYP3A inhibition. 
Differences in individual sensitivity and variation CYP enzyme inhibition may result in the need for dose 
reduction of itacitinib and/or concomitant CYP3A4 inhibitor as appropriate. The sponsor medical monitor 
may be consulted for advice when using these agents. 
• 
Co-administration with CYP3A4 inducers. 
• 
If concomitant administration of an anticoagulant/antiplatelet medication is indicated, then caution and 
enhanced monitoring is required. History of thrombocytopenia should be a factor in the choice of 
anticoagulant and dose. 
5.9.3 
Prohibited medications 
The following medications are prohibited during the treatment period of the study: 
• 
GVHD prophylactic regimens other than Tacrolimus/Sirolimus is not allowed. Initiation of systemic 
treatment for cGVHD or grade II-IV acute GVHD with other agents including corticosteroids is not allowed 
as concomitant medication (See Section 5.9) 
• 
Any concurrent anti-cancer therapy (e.g., chemotherapy, radiation therapy, surgery, immunotherapy, 
biologic therapy, hormonal therapy, or tumor immobilization). 
• 
Concomitant use of another JAK inhibitor. 
• 
Initiating therapy with an investigational medication unless otherwise approved by the medical monitor. 
5.10 Supportive care 
With the exception of prohibited therapies (refer to Prohibited therapies sub-section above), participants should 
receive prophylactic or supportive as clinically indicated per institutional policies. 
Patients who undergo allogeneic HCT 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 immunization in addition to prophylactic therapies. Additional 
supportive care measures are permitted at the investigator’s discretion. 
6.0 ANTICIPATED ADVERSE EVENT LIST 
6.1 Itacitinib 
6.1.1 
Toxicology 
For toxicology details please refer to the Investigation Brochure.  
6.1.2 
Adverse Events 
6.1.2.1 Side effects associated with use of itacitinib 
The following adverse events were reported as very common (occurring in greater than or equal to 10% of 
subjects) or common (occurring in 1-10% of subjects) in 209 subjects treated with itacitinib.   
Very Common (greater than or equal to 10%) 
• 
Anemia (low red blood cells) 
• 
Fatigue 
• 
Thrombocytopenia (low levels of a type of clotting cell) 

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• 
Upper respiratory tract infection 
• 
Nausea 
• 
Diarrhea 
 
Common (1% but less than 10%) 
• 
Headache 
• 
Pyrexia (fever) 
• 
Vomiting 
• 
Dizziness 
• 
Urinary tract infection (infection of the bladder) 
• 
Sinusitis (sinus infection) 
• 
Neutropenia (low white blood cell count) 
• 
AST increase (increased liver enzymes) 
• 
ALT increase (increased liver enzymes) 
• 
Asthenia (weakness) 
• 
Herpes zoster 
Oral candidiasis (an infection in your mouth) 
6.1.2.2 Side Effects Associated with the Use of Itacitinib in Combination with Corticosteroids 
The following adverse events were reported as very common (occurring in greater than or equal to 20% of 
subjects) in 29 acute GVHD patients who were treated with itacitinib and corticosteroids: 
Very Common (greater than or equal to 20%) 
• 
Thrombocytopenia (low levels of a type of clotting cell) 
• 
Diarrhea 
• 
Abdominal pain 
• 
Edema peripheral (swelling of the limbs) 
• 
Fatigue 
• 
Hypokalemia (low potassium) 
• 
Hyperglycemia (high blood sugar) 
• 
Decreased appetite 
• 
Headache 
• 
Hypophosphatemia (low phosphate) 
• 
Nausea 
• 
Tachycardia (fast heart rate) 
• 
Dry mouth 
• 
Hypoalbuminemia (a low blood protein) 
• 
Sepsis (a life threatening complication of an infection) 
• 
Vomiting 
6.1.3 
Side Effects Associated with the Use of Corticosteroids 
6.1.3.1  Prednisone 
Prednisone is a corticosteroid. It prevents the release of substances in the body that cause inflammation.  It also 
suppresses the immune system.  Therefore, it is used as an anti-inflammatory or an immunosuppressant 
medication.  Prednisone treats many different conditions where there is increased inflammation, such as allergic 
disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, or breathing disorders. 

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The most common side effects of Prednisone are hostile or violent behavior, feeling nervous, feeling on edge, 
blurred vision, decrease in the amount of urine, dizziness, heartbeats that feel fast, slow, pounding, or irregular, 
headache, being easily annoyed or angry, feeling depressed, mood changes, nervousness, can’t fall asleep, rattling 
breathing, numbness or tingling in the arms or legs, pounding in the ears, shortness of breath, swelling of the 
fingers, hands, feet, or lower legs, trouble thinking, speaking, or walking, troubled breathing at rest, increases in 
blood glucose levels, feel hungry, weight gain, muscle weakness, bone weakness, stretch marks, bruising, and 
reduced immune defense leading to possible increase in the number and seriousness of infections. 
6.1.3.2 Methylprednisolone 
Methylprednisolone is a steroid that prevents the release of substances in the body that cause inflammation.  
Methylprednisolone is used to treat many different inflammatory conditions such as arthritis, lupus, psoriasis, 
ulcerative colitis, allergic disorders, gland (endocrine) disorders, and conditions that affect the skin, eyes, lungs, 
stomach, nervous system, or blood cells. 
Common side effects of Methylprednisolone are the same as prednisone: hostile or violent behavior, feeling 
nervous, feeling on edge, blurred vision, decrease in the amount of urine, dizziness, fast, slow, pounding, or 
irregular heartbeat or pulse, headache, being easily annoyed or angry, feeling depression, mood changes, 
nervousness, can’t fall asleep, rattling breathing, numbness or tingling in the arms or legs, pounding in the ears, 
shortness of breath, swelling of the fingers, hands, feet, or lower legs, trouble thinking, speaking, or walking, 
troubled breathing at rest, increases in blood glucose levels, feel hungry, weight gain, muscle weakness, bone 
weakness, stretch marks, bruising, and reduced immune defense leading to possible increase in the number and 
seriousness of infections. 
 

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7.0 DOSE DELAY / MODIFICATION GUIDELINES AND DLT DEFINITION 
The treatment involves a single cycle of the planned regimen; there are no planned dose delays. One dose 
reductions, to 100 mg will be considered if unacceptable toxicity is experienced at the 200 mg dose level.  
7.1 Dose Modifications 
Dose reductions are provided as guidelines (see Table 7.1 and Table 7.2); individual decisions regarding dose 
reduction should be made using clinical judgment and should be based on an individual benefit/risk assessment, 
taking into account relatedness of the AE to the study treatment and the subject's underlying condition.  Adverse 
events that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory values without 
associated clinically significant signs or symptoms may be exempt from dose-reduction rules.  The sponsor's 
medical monitor may be consulted for advice. 
Treatment with itacitinib may be delayed up to 14 days to allow for resolution of toxicity.  After interruption, 
subjects should be evaluated on a weekly basis until resolution/improvement of the AE.  Subjects receiving 
itacitinib at a dose of 200 mg QD may have their dose reduced to 100 mg QD.  Subjects who are unable to tolerate 
itacitinib/ at a dose of 100 mg QD should be withdrawn from study treatment. 
Table 7.1: 
Guidelines for Interruption and Restarting of Itacitinib 
ADVERSE EVENT 
ACTION TAKEN 
Chemistry 
• AST and/or ALT > 3.0 × ULN in subjects 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 considered related to itacitinib, restart at next 
lower dose and monitor as clinically indicated. 
Hematology 
• ANC < 0.5 × 109/L 
Days 1-28:  Monitor; no modification required. 
Day 29-EOT:  
• Reduce dose by 1 dose level. 
• Monitor ANC count as clinically indicated. 
• Resume previous dose if ANC count is ≥ 0.5 × 109/L for more than 7 days. 
• Platelet count is < 10 × 109/L or platelet count 
has decreased by ≥ 50% from time of 
engraftment 
Days 1-28:  Monitor; no modification required. 
Day 29-EOT:  
• Reduce dose by 1 dose level. 
• Monitor platelet count as clinically indicated. 
• Resume previous dose if platelet count is ≥ 20 × 109/L for more than 7 days. 
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 considered related to itacitinib, restart at next lower 
dose, and monitor as clinically indicated. 
• Any recurrent Grade 3 toxicity at 100 mg QD 
dose 
• Discontinue study treatment; follow-up per Protocol.  Exceptions require 
sponsor approval. 
• Any Grade 4 toxicity 
• Discontinue study treatment; follow-up per Protocol. 
Table 7.2: 
Dose Reduction Levels for Itacitinib 
Current Dose 
First Dose Reduction 
Second Dose Reduction 
200 mg QD 
100 mg QD 
Discontinue 
 

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7.2 DLT Definition  
For the safety lead-in portion of the study, DLT monitoring period will be until Day +30 post-HCT. The worst grade 
for all toxicities will be collected from day -3 to +30 (itacitinib treatment period).  DLT in a given patient will be 
defined as any of the following that are assigned an attribution level of at least possibly related to the addition 
of itacitinib to the GvHD prophylaxis regimen.  
• 
For non-hematologic toxicities, any regimen-related grade III/IV toxicity per Bearman criteria, from Day -
3 to +30 or 
• 
For hematologic toxicities, per NCI CTCAE v5.0 toxicity criteria, any grade 4 neutropenia associated with 
fever or infection and lasting for more than 21 days, or grade 4 neutropenia lasting for more than 28 days 
(engraftment failure) 
• 
Any other regimen-related cause of death.  
• 
Permanent discontinuation or dose reduction of itacitinib due to any drug-related toxicity (regardless of 
grade). 
In addition, septic DLT is defined as: any grade 5 sepsis-related toxicity that is assigned an attribution level of at 
least possibly related to the addition of itacitinib to the conditioning regimen. 
8.0 AGENT INFORMATION 
8.1 Itacitinib 
8.1.1 
Drug description 
Itacitinib adipate is a novel, potent, and selective inhibitor of the JAK family of protein TYKs with selectivity for 
JAK1. Itacitinib is an investigational product that is proposed for development for treatment of MPNs, including 
MF; inflammatory diseases, including RA and psoriasis; GVHD; solid tumors; and B-cell malignancies. Janus kinases 
play an important role in signal transduction following cytokine and growth factor binding to their receptors. 
Aberrant production of cytokines and growth factors has been associated with MPNs and a number of chronic 
inflammatory conditions, and JAK1 has been shown to cooperate with other JAKs to mediate the signaling of a 
number of inflammatory cytokines. Therefore, JAK inhibitors represent potential therapeutic agents for these 
disease states (refer to the IB). 
8.1.1.1 Administration 
Itacitinib 100 mg (free base equivalent) sustained-release tablets contain the active ingredient, hypromellose, 
microcrystalline cellulose, lactose monohydrate, and magnesium stearate. 
Itacitinib will be administered PO at a starting dose of 200 mg QD (2 × 100 mg tablets). Itacitinib may be taken 
without regard to food. 
Subjects may have dose reductions or modifications of itacitinib or placebo during the course of treatment based 
on AEs, clinical evaluation, and laboratory assessments. 
8.1.1.2 Supply, Packaging and Labeling 
Itacitinib tablets will be provided in high-density polyethylene bottles as applicable by Incyte. No preparation is 
required. 
8.1.1.3 Storage 
Itacitinib or placebo should be stored at ambient conditions (15° C to 30° C, or 59° F to 86° F) as per the IB. 

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9.0 CORRELATIVE/ SPECIAL STUDIES 
9.1 Research Sample Collection and Dispensation 
Peripheral blood samples will be collected from the patient at the designated time points defined in this section 
and section 10 (Study Calendar). Samples will be delivered, processed, stored, and evaluated in accordance with 
established laboratory practices at COH. The following correlative studies will be performed: 
9.2 Laboratory Studies Performed 
9.2.1 
Pharmacokinetics 
All patients will be asked to undergo serial blood sampling to evaluate the steady-state pharmacokinetics of 
itacitinib when administered with tacrolimus/sirolimus.  
9.2.1.1 Specimen Collection 
Prior to the morning itacitinib doses on day -3 through day +5, 4 mL of venous blood will be collected into purple-
top (K2-EDTA) tubes. Additional post-dose samples will be obtained following the morning dose on day +5 at 0.25, 
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours. Blood samples will be kept on ice until plasma is separated from whole blood 
by centrifugation at 1500 x g (within 1 hour). Plasma will then be transferred to appropriately labeled 
polypropylene tubes and stored at < -70°C until analysis. Each sample will be labeled with the patient’s name, 
medical record number, date of collection, and actual sample collection time.   
9.2.1.2 Analytical Method 
Itacitinib concentrations in plasma will be measured using an LC-MS/MS assay in the Analytical Pharmacology 
Core Facility (APCF) at the City of Hope. The analytical method will be based on a previously reported assay 
(Veeraraghavan S et al. J Pharm Biomed Anal. 2014) that has been validated over a concentration range of 0.2-
250 ng/mL from a starting plasma volume of 50 µl28.  
9.2.1.3 Pharmacokinetic Data Analysis 
itacitinib concentration-versus-time data will be analyzed using standard non-compartmental analysis methods 
according to the Rule of Linear Trapezoids. Non-compartmental pharmacokinetic parameters will be derived for 
each patient and will include trough concentrations (Ctrough), maximum plasma concentration (Cmax), time to 
maximum plasma concentration (Tmax), terminal-phase elimination half-life (t1/2), area under the plasma 
concentration–time curve from 0 to t (AUC0–t), and oral clearance (CL/F).  The individual parameters will be 
summarized as the means or medians, along with standard deviations or ranges. 
9.2.2 
Proinflammatory Cytokines 
5 ml of blood will be collected in a red top tube (serum) on days shown in the table below for ELISA analyses of 
pro-inflammatory cytokines and GVHD biomarkers (5ml total for both). The research samples will be sent to Fox 
South Building, 1st floor (Experimental Therapeutic) and processed by Dr. Nakamura’s research associate. Pro-
inflammatory cytokines including but not limited to CRP, β-2 microglobulin, IL-6, TNF-α, and IFNγ will be measured 
by standard ELISA assay on the following days:  Day -9 (prior to starting conditioning), Day -3 (prior to starting 
itacitinib), Days 0, +14, +28, +42, and +100 (post-transplantation). 
These cytokines have been shown to rise rapidly in the early post-transplant setting and play roles in the 
pathogenesis of acute GVHD.12,29 We would like to observe the inhibition of these cytokines by itacitinib post-
transplant and explore whether their levels are associated with the development of acute GVHD. 

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9.2.3 
GVHD biomarkers 
On the days indicated below, 5 ml of whole blood will be collected in lavender top tubes (K2 EDTA) and samples 
will be transported to the Clinical Immunobiology Correlative Studies Laboratory (CICSL) for processing within 4 
hours of drawing.  
GVHD biomarkers (i.e., Reg-3α, TNF R1, and ST2) and a composite biomarker panel of 4 proteins (IL-2Rα, TNFR1, 
IL-8, and hepatocyte growth factor), will be measured on the following days: day -3 pre-HCT, day 0, and post-
transplantation on days +14, + 28, and +42. 
Concentrations of Reg-3α have been shown to be 3-fold higher in patients at GI GVHD onset than in other 
transplant patients30,31.  In addition, such high Reg-3α concentrations correlated closely with lower GI GVHD. We 
will assess possible association of Reg-3α concentrations with GVHD diagnosis, and survival outcomes.   
Increases in TNF R1 levels at day 7 post-transplant of ≥2.5-fold over baseline have been associated with grade II-
IV GVHD32. We will assess possible association of TNF R1 increased levels at day 7, with GVHD diagnosis, and 
survival outcomes.   
A composite biomarker panel of 4 proteins (IL-2Rα, TNFR1, IL-8, and hepatocyte growth factor) has been 
developed by Paczesny et al. to discriminate patients with and without GVHD, using a logistic regression33. We will 
investigate the correlation between these 4 biomarkers and acute GVHD grade.  
9.2.4 
STAT3 Phosphorylation Assay 
30 ml of blood in 3 green top tubes will be collected on days -9, +21, +35, and +100 for flow-cytometry analyses 
(STAT3 phosphorylation and Treg: 30 ml total for both). The research samples will be sent to Fox South Building, 
1st floor (Experimental Therapeutic) and processed by Dr. Nakamura’s research associate, Weimin Tsai. 
Whole blood samples will be obtained on day -9 (baseline pre-dose), day +21 (trough pre-dose and 2 hours ± 15 
min post-dose), day +35 and day 100, pSTAT3 levels will be measured accordingly.  
Pidala et al. reported that pSTAT3 levels increased significantly in CD4+ cells before the onset of acute GVHD34. 
Administration of itacitinib will inhibit the expression of pSTAT3 through Janus kinases (JAK) inhibition. Changes 
in pSTAT3 expression levels during transplant will be studied to measure targeted effect of itacitinib. 
9.2.5 
Regulatory T cell (Treg) measurements 
Approximately 4 ml of fresh whole blood samples (from the 30 ml collected for section 9.2.4) will be obtained on 
day -9, +21, day +35, and +100 to measure frequency of Treg by flow cytometry (CD4+CD25+FOXP3+). We will 
study the impact of itacitinib on Tregs post-transplant and correlate Tregs with maximum aGVHD grade.    
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as authorized.  
 
10.0 STUDY CALENDAR 
All assessments may increase in frequency as clinically indicated.  
Required studies 
Pre Admit 
Day -9 
Day-8 
Day -7 
Day -6 
Day-5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
Day +1 
Day +2 
Day +3 
Day +4 
Day +5 
Day +6 
Day +7 
Day +14 
Day +21 
±3 days 
Day +28 
±3 days 
Day +30 
±3 days 
Day +35 
±3 days 
Day +42 
 ±3 days  
Day +60  
±3 days 
Day +100 
±7 days 
Day +180 
±7 days  
1 & 2 years  
±14 days 
CBC, Diff, Plt1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
After discharge, outpatient CBC labs will be done once a 
week until day +100 
 
X 
BMP1 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMP2 
X 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mg1 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uric Acid, LDH, Phos1 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis b,c 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT,PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24hr Cr Cl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV, HSV Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV PCR3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
starting on Day +7 until discharge. After discharge, CMV PCR will be 
done once a week until day +100.  
 
 
IgG level4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Chest 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BM BX, Cytogenetics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
RESEARCH PROCEDURES 
 
Pharmacokinetics 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
 
 
 
 
 
 
 
 
 
 
 
 
Pro-infl. Cytokines 5 
 
X9 
 
 
 
 
 
X10 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
GVHD biomarkers 5 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
P-STAT-3 & -55 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X12 
 
 
X 
 
 
X 
 
X 
T-reg assay 5 
 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
TREATMENT 
 
 
Fludarabine 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Melphalan 6 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sirolimus 7 
 
 
 
 
 
 
 
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
Tacrolimus 7 
 
 
 
 
 
 
 
X----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
Itacitinib 8 
 
 
 
 
 
 
 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
PBSC /BMT 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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QOL Assessment13 
 
 
 
 
 
 
 
 
X 
X 
X 
Toxicity Assessment 
 
 
 
 
 
 
 
X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
 
HD Therapy/Transplant therapy (ALL testing (except BM bx, 30 days & CBC, Diff, Plats, CMP, 5 days) to be completed ≤ 28 days prior to starting treatment. 
1. Daily during hospitalization, diff in not done after admission until WBC> 1,000 then Monday, Wednesday, and Friday. After discharge, CBC will be done once a week until day +100.  
2. To be done Monday, Wednesday, and Friday 
3. Testing to be done twice a week on Mondays and Thursdays, starting on Day +7 until discharge. After discharge, CMV PCR will be done once a week until day +100.  
4. To be drawn weekly on Monday 
5. Correlative studies blood samples to be drawn on the days indicated AND on the date of clinical diagnosis of aGVHD (±2 days) 
6. For patients older than 70 years of age, melphalan will be administered at 100 mg/m2 dose. 
7. Tacrolimus and sirolimus will be tapered as per COH SOP based on donor match and presence of GVHD. For patients older than 70 years old, tacrolimus dose will be at the flat dose of 1 mg/day and sirolimus loading dose will be 
8 mg. 
8. Itacitinib given daily starting on day -3 pre-transplant to day 100 post-transplant.  
9. Take blood sample before first dose of fludarabine 
10. Take blood sample before first dose of itacitinib 
11. Prior to the morning itacitinib doses on day -3 through day +5, 4 mL of venous blood will be collected into purple-top (K2-EDTA) tubes. Day 5 pharmacokinetics will not only include trough sampling pre-dose, but also at the 
post-dose time-points: 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-itacitinib dose.  
12. Take blood both pre-dose and post dose (2 hours ±15 minutes) 
13. QOL assessments are optional. 
 
 

This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except 
as authorized.  
 
11.0 ENDPOINT DEFINITIONS/MEASUREMENT OF EFFECT 
11.1 Primary Endpoints 
11.1.1 Safety lead-in segment 
The primary endpoint for the patient safety lead-in segment of this study is toxicity.  Dose limiting toxicity 
(DLT) is defined in section 7.2 of the protocol. DLT monitoring period will be until Day +30 post-HCT.  
Toxicities will be recorded using two distinct grading systems; the modified Bearman Scale35 (Appendix A) 
and the NCI CTCAE v5.0 scale36. Generally, the modified Bearman Scale will be used to define non-
hematologic DLT events through day +30 post-HCT and the CTCAE v5.0 scale will be used for reporting 
adverse events, hematologic DLTs through day +30. Out of abundance of caution, we will continue 
collecting toxicities from day +31 to day +130 using CTCAE V.5.0.  The worst grade for all toxicities will be 
collected from day -3 to 100 (itacitinib treatment period) and again from day 100 to day 130 (post-
itacitinib treatment/taper period). From day 100-130 only ≥grade 3 toxicities that are considered at least 
possibly related to the itacitinib treatment will be collected. In addition, start and stop dates will be 
collected for adverse events where duration is required for DLT assessment. From day 130 to 1 year post-
transplant only toxicities that are considered serious adverse events (SAEs) will be collected. Note: The 
modified Bearman scale will only be used through day +30 post-transplant.  
To be evaluable for toxicity during safety-lead-in segment, patients should start itacitinib treatment and 
be followed for DLTs from day -3 to day 30 or have experienced DLTs.  Patients who do not experience 
DLTs and have not been followed until the end of DLT observation period will be not evaluable for DLTs 
and be replaced.  
11.1.2 GRFS 
The primary endpoint is GRFS at 1-year post-transplantation. GRFS is defined as time from the date of 
transplantation to the first time of observing following events: grade 3-4 acute GVHD, chronic GVHD 
requiring systemic treatment, relapse, or death, whichever occurs first. 27 If a patient has not experienced 
any of these events, GRFS is censored at time of last follow-up.  Acute GVHD will be graded per MAGIC 
criteria.37 Grading and staging tables are included in Appendix B. The first day of acute GVHD onset at a 
certain grade will be used to calculate the cumulative incidence (grades II-IV). Chronic graft versus host 
disease will be evaluated and scored according to NIH Consensus Staging,38,39 as shown in Appendix B. 
The first day of chronic GVHD onset will be used to calculate the cumulative incidence. 
Note: Only patients who took at least one dose of itacitinib will be evaluable for efficacy. 
11.2 Secondary Endpoints 
11.2.1 Cumulative incidence of acute GVHD and NRM at 100-days post-transplant 
Acute GVHD will be graded and staged according to MAGIC criteria. 37Grading and staging tables are 
included in Appendix B. The first day of acute GVHD onset at a certain grade will be used to calculate the 
cumulative incidence (grades II-IV). The endpoint will be evaluated from day 0 (date of stem cell infusion) 
through 100 days post-transplant.  
Non-relapse mortality (NRM) is defined as death occurring in a patient from causes other than relapse or 
progression. NRM is measured from date of stem cell infusion until non-disease related death, or last 
follow-up, whichever comes first. Deaths from relapse/progression are considered a competing risk. 

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11.2.2 Feasibility 
Patients who have received at least 80% of planned doses of itacitinib are deemed to meet 
feasibility criteria. 
Note:  Patients who took at least one dose of itacitinib will be evaluable for efficacy (see Primary 
endpoint definition Section 11.1.2) 
11.2.3 Cumulative incidence of chronic GVHD at 1- and 2-years post-transplant 
Chronic graft versus host disease will be evaluated and scored according to NIH Consensus Staging,38,39 as 
shown in Appendix B. The first day of chronic GVHD onset will be used to calculate the cumulative 
incidence. The endpoint will be evaluated from day 80 through 2 years post-transplant. 
11.2.4 Overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant 
OS: Patients are considered a failure for this endpoint if they die, regardless of cause. The time to this 
event is the time from the day of stem cell infusion until death, or last follow-up, whichever comes first. 
PFS: Patients are considered a failure for this endpoint if they die (regardless of cause) or experience 
disease progression or relapse. Time to this event is measured from the date of stem cell infusion to the 
date of death, disease relapse/progression, or last follow-up, whichever occurs first.  
11.2.5 Infection and development of second malignancies including lymphoproliferative disorders at 1- 
and 2-years post-transplant. 
Infection: Microbiologically documented infections will be reported by site of disease, date of onset, 
severity and resolution, if any. This data will be captured via case report form and will be collected from 
day -9 to day 100 post-transplant and will follow the same data collection intervals as the toxicity and 
adverse event data. 
Relapse/progression: The time to this event is measured from day of stem cell infusion (day 0). Deaths 
without relapse/progression are considered a competing risk. Surviving patients with no history of 
relapse/progression are censored at time of last follow-up. 
11.2.6 Quality of life (QOL)  
Assessments include self-reported patient questionnaires: SF-12, FACT-BMT, and MDASI for English and 
Spanish speaking patients > 18 years. Patients can choose not to participate in the Quality of Life 
Assessment. 
11.3 Exploratory Endpoints 
11.3.1 Hematologic recovery, donor cell engraftment and immune reconstitution  
• 
ANC (neutrophils) ≥0.5 x 103/μL achieved and sustained for 3 consecutive lab values on different 
days with no subsequent decline  
• 
Platelets ≥ 20 K/μL independent of platelet transfusion support (date should reflect no 
transfusions in previous 7 days, and the first of 3 consecutive lab values on different days) 
• 
Immune reconstitution studies will be done by flow cytometry as described in Section 9 
(Correlative Studies). 

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11.3.2  Acute GVHD biomarkers, JAK-regulated pro-inflammatory cytokines, and STAT3 
phosphorylation  
Detailed description is provided in Section 9 (Correlative Studies). 
11.4 Response Criteria 
Response criteria will be specific to each disease with only the following categories being relevant post-
transplant: 
a. Complete remission 
b. Relapse 
c. Disease persistence/progression  
For detailed description of the corresponding categories within the response criteria for each disease 
please check the following references: 
11.4.1 ALL: NCCN guidelines for ALL Version 1.2020 
See Appendix D for NCCN guidelines. 
11.4.2 AML: NCCN guidelines for AML Version 3.2020 
See Appendix D for NCCN guidelines. 
11.4.3 MDS and CMML: CIBMTR MDS/MPN response Criteria Manuals (Last modified: 2018/10/18)  
a. Complete Remission: Requires all of the following maintained for a minimum of four weeks: 
o Bone marrow evaluation:  
 
< 5% myeloblasts with normal maturation of all cell lines 
o Peripheral blood evaluation: 
 
Hemoglobin ≥ 11 g/dL untransfused without erythropoietic support 
 
ANC ≥ 1000/mm3 without myeloid growth factor support 
 
Platelets ≥ 100,000/mm3 without thrombopoietic support 
 
0% blasts in blood 
In some cases, there may not be a four-week interval between completion of therapy and the pre-
transplant disease assessment. In this case, CR should still be reported as the status at transplant since it 
represents the “best assessment” prior to HCT. This is an exception to the criteria that CR be durable 
beyond four weeks; the pre-transplant disease status should not be changed based on early relapse or 
disease assessment post-transplant. 
 Hematologic Improvement: Requires one measurement of the following maintained for at least 
eight weeks without ongoing cytotoxic therapy: 
 Hematologic improvement – erythropoietic (HI-E): 
• 
Hemoglobin increase of ≥ 1.5 g/dL untransfused, OR 
• 
For RBC transfusions performed for hemoglobin ≤ 9.0: reduction in RBC units transfused 
in 8 weeks by ≥ 4 units compared to the number of units transfused in the 8 weeks prior 
to treatment 

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 Hematologic improvement – platelets (HI-P): 
• 
For pre-treatment platelet count of ≥ 20 ×109, platelet absolute increase of ≥ 30 ×109 
• 
For pre-treatment platelet count of < 20 ×109, platelet absolute increase of ≥ 20 ×109 and 
≥ 100% increase from pre-treatment level 
 Hematologic improvement – neutrophils (HI-N): 
• 
Neutrophil count increase of ≥ 100% from pre-treatment level and an absolute 
increase of ≥ 500/mm3 
b. No Response (NR)/Stable Disease (SD) 
Does not meet the criteria for at least HI, but no evidence of disease progression to AML 
 
c. Relapse: Requires at least one of the following: 
 Return to pre-treatment bone marrow blast percentage 
 Decrease of ≥ 50% from maximum response levels in granulocytes or platelets 
 Transfusion dependence or hemoglobin level ≥ 1.5 g/dL lower than prior to therapy 
Note: declining donor chimerism does not meet the criteria for relapse. 
 
d. Progression from Hematologic improvement: Requires at least one of the following in the absence 
of another explanation (e.g., infection, bleeding, ongoing chemotherapy, etc.): 
 ≥ 50% reduction from maximum response levels in granulocytes or platelets 
 Reduction in hemoglobin by ≥ 1.5 g/dL 
 Transfusion dependence 
Note:  declining donor chimerism does not meet the criteria for progression. If the above criteria 
for progression have been met, but a hematologic improvement was not previously achieved, 
report “No Response (NR) / Stable Disease (SD)”. 
 
e. Progression to AML: ≥ 20% blasts in the blood or bone marrow 
 
11.4.4 Myelofibrosis: Tefferi, Cervantes et al. 201340 and Zang and Deeg 200941 
a. Complete Remission: 
 Bone marrow: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF and, 
 Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and 
<UNL; 
 Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and 
 Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of 
EMH 
b. Relapse: 
 No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 

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 Loss of anemia response persisting for at least 1 month or 
 Loss of spleen response persisting for at least 1 month 
 Recommendations for assessing treatment-induced cytogenetic and molecular changes 
c. Disease persistence/progression: 
 Appearance of a new splenomegaly that is palpable at least 5 cm below the LCM or 
 A ≥100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 
cm or 
 A 50% increase in palpable distance, below LCM, for baseline splenomegaly of >10 cm or 
 Leukemic transformation confirmed by a bone marrow blast count of ≥20% or 
 A peripheral blood blast content of ≥20% associated with an absolute blast count of ≥1 × 
10(9)/L that lasts for at least 2 weeks 
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This is a single center single arm phase IIa trial to estimate GRFS after adding itacitinib at a single dose of 
200 mg QD from day -3 pre-HCT to day +100 post-HCT in addition to the tacrolimus/sirolimus regimen for 
GVHD prophylaxis for patients with hematologic malignancy who undergo fludarabine melphalan non-
myeloablative conditioning followed by matched (8/8) related or unrelated donor hematopoietic cell 
transplantation (HCT). A patient safety lead-in will be conducted to ensure there are no unexpected 
toxicities. Ultimately a total of 59 patients will be treated at the itacitinib dose level considered safe as 
determined during the patient safety lead-in segment of this study. The primary endpoint is 1-year GVHD 
free, relapse/progression-free survival (GRFS). 
12.2 Safety Lead-in Segment 
Up to two dose levels may be studied: Dose level -1 will be tested if dose level 1 is not well tolerated.  We 
will use the modified rolling 6 phase I design of Skolnik,42 in the safety lead-in segment. At any time of 
safety-lead-in segment, at most 3 patients will be under observation for DLT on the current dose level. 
The number of new patients who can be enrolled depends on the number of patients who experience 
DLTs, who are evaluable for DLTs, and who are at risk or evaluable. Dose evaluation rules are outlined in 
Table 12.2. Once a dose level is determined to be safe (at most 1 patient has experienced DLT out of 6 
evaluable patients, we will continue to accrual patients during phase IIa segment. 
 
Table 12.1. Dose level assignment 
Dose Level 1 
Dose level -1 
Reduction 
Dose Level -2 
200 mg QD 
100 mg QD 
Discontinue 
 
Table 12.2: Dose evaluation rules during safety lead-in segment 
# Patients on Current Level 
Action 
DLT 
EVAL 
EVAL+At Risk 
0 
0 
1-2 
Accrue next patient at this level* 
0 
0 
3 
Hold accrual 

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12.3 Sample Size 
Safety Lead-in, Expected: 6, Maximum: 12 
Phase II: Expected 59 (including the 6 patients brought forward from the safety lead-in) 
We expect to treat a total of 59 patients in this single arm phase II study, assuming the itacitinib dose of 
200 mg is well tolerated. With one dose reduction permissible, the overall maximum study sample size 
could reach 65 patients.  
In 907 consecutive patients who underwent allogeneic HCT at University of Minnesota from 2000 to 2012, 
1-year GRFS was 31%.27 Results from the phase II BMT CTN 1203 study 1203, comparing three RIC 
regimens with 1) Tacrolimus, mycophenolate and PTCy, 2) Tacrolimus, methotrexate and bortezomib, and 
3) Tacrolimus, methotrexate and maraviroc to prevent GvHD  and comparing each group with the a non-
randomized control group of patients treated with tacrolimus and methotrexate showed 1-year GRFS rate 
of 43% in the tacrolimus, mycophenolate and PTCy group versus 34%. At our center, as demonstrated in 
Figure 2.5, 1-year GRFS was between 37% and 42% in different cohorts. The GRFS rates may vary by 
disease diagnosis, disease risk, recipient age and/or conditioning intensity.27 Based on these historical 
data, we consider 1-year GRFS rate of 45% to be clinically meaningful.  With 59 patients enrolled in this 
study, 1-year GRFS can be estimated with precision of 0.13 (half width of distance of 2-sided 95% 
confidence limits). 
0 
1 
1-3 
Accrue next patient at this level 
0 
1 
4 
Hold accrual 
0 
2 
2-4 
Accrue next patient at this level 
0 
2 
5 
Hold accrual 
0 
3-5 
3-5 
Accrue next patient at this level 
0 
3-5 
6 
Hold accrual 
0 
6 
6 
Safety-lead segment is complete, continue to accrual patients at this 
level during phase IIa segment 
1 
1 
1-3 
Accrue next patient at this level 
1 
1 
4 
Hold Accrual 
1 
2 
2-4 
Accrue next patient at this level 
1 
2 
5 
Hold accrual 
1 
3-5 
3-5 
Accrue next patient at this level 
1 
3-5 
6 
Hold accrual 
1 
6 
6 
Safety-lead segment is complete, continue to accrual patients at this 
level during phase IIa segment 
≥2 
Any 
Any 
Stop accrual at this level and accrue next patient at dose level -1 to a 
maximum of 6 
*During dose level 1 is already closed, dose level -1 will accrue to a total of 6 patients, with 2 or higher 
DLTs requiring stopping accrual and reviewing toxicity profile. 
DLT: a patient with a documented DLT; PASS: a patient without a DLT fully evaluable for toxicity for the
purpose of dose escalations (see section 11.1 for detail); EVAL: a patient who is either DLT or PASS;
Inevaluable:  a patient who is off treatment without being DLT or PASS (see section 11.1 for detail); At 
Risk: a patient who is on study and not yet DLT, PASS, or Inevaluable 

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12.4 Accrual Rate  
The first six patients enrolled/treated on this study will be part of a patient safety lead-in. The safety lead-
in segment will follow rolling 6 dose expansion/de-escalation rules based on observed toxicity.  
If as expected, ≤ 1/6 patients treated at the 200 mg dose experiences a DLT, the trial will enroll up to an 
additional 53 patients. Ultimately a total of 59 rule patients will be treated at the itacitinib dose level 
considered safe as determined during the patient safety lead-in segment of this study. With one dose 
reductions permissible, the overall maximum study sample size could reach 65. 
We assume 2-year accrual and additional 1 year follow-up after the last accrual. About 94 patients with 
hematological malignancy underwent fludarabine/melphalan reduced intensity allogeneic HCT with 
Tacrolimus/Sirolimus GvHD prophylaxis in the past 2 years at City of Hope alone.  Therefore, we 
contemplate a 2-year accrual period would be reasonable.   
12.5 Interim Analysis/Stopping Rules for Severe acute GvHD and Feasibility 
No interim analyses will be performed for the primary endpoint, 1-year GRFS because at least 1-year 
follow-up is needed if events of interest have not been observed within 1-year post-HCT. We expect 
adding itacitinib with tacrolimus/sirolimus regimen for GvHD prophylaxis to decrease incidence of severe 
acute GVHD. We will perform an interim analysis to check whether the incidence of grade III-IV aGVHD is 
reduced or not.  After 30 patients are enrolled and followed at 100 days post-HCT, the cumulative 
incidence of grade III-IV aGVHD will be estimated. If 6 or more patients have grade III-IV aGVHD, we would 
stop accrual and a full review of the data by Data Safety Monitoring Committee (DSMC) will be mandated. 
Patient accrual will not be resumed until DSMC approval. Using this rule, the probability of stopping 
accrual at the interim analysis for aGVHD will be 0.07, 0.29, and 0.92 if the grade III-IV aGVHD rate is 10%, 
15%, and 30%, respectively. 
We will also check the feasibility of itacitinib administration in these patients. The study will be feasible if 
at least 80% of patients are able to receive at least 80% of planned doses of itacitinib (about 83 days or 
longer from day -3 to 100). 
We will perform one interim analysis for feasibility when the first 30 patients are enrolled and completed 
or stop treatment with itacitinib early. If ≥9 out of 30 patients have received <80% of planned doses of 
itacitinib, we will suspend the accrual and review the study for feasibility. Otherwise, if ≥20 out of 30 
patients have received at least 80% of planned doses of itacitinib, we will continue patient accrual. We 
won’t stop accrual when any of the first 30 patients are still receiving treatment and stopping boundary 
for feasibility is not crossed. Using this rule, the probability of stopping accrual at the interim analysis for 
feasibility will be 0.81, 0.27 and 0.03 if feasibility rate is 57%, 70%, and 80%, respectively.  
 
12.6 Adverse Event Stopping Rule 
12.6.1  Persistent Thrombocytopenia 
Based on previous experience with itacitinib in transplant setting, we expect the cumulative incidence of 
grade 4 Persistent thrombocytopenia (per CTCAE v 5.0, at day 45 post-HCT) to be ≤30% at day 45 post-
HCT (28.6% at 200 mg dose and 66.7% at 300 mg dose). We will assess incidence of Persistent grade 4 
thrombocytopenia when every 10 patients have been followed through day 45 post HCT. Study accrual 
will be temporarily suspended to allow for full review of data, if at any time, the percentage of patients 
with Persistent grade 4 thrombocytopenia at day 45 exceeds 30% (>30% see following table for stopping 
boundary). After consideration by the study team (study PI, statistician, etc.) and the City of Hope DSMC, 

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a decision will be made as to whether accrual/treatment can be resumed safely or whether protocol 
modifications are necessary. 
N of patients evaluated for thrombocytopenia at day 45 
10 
20 
30 
40 
50 
N of patients developed Grade 4 thrombocytopenia by day 45 
≥4 
≥7 
≥10 
≥13 
≥16 
Using the abovementioned rule, the chance of stopping accrual early for excessive thrombocytopenia will 
be 6%, 64%, and 85% when the true probability of developing Persistent grade 4 thrombocytopenia is 
0.15, 0.3, and 0.35, respectively. 
12.6.2 Non-Relapse Mortality at Day 100 (Day +100 NRM) 
Day +100 NRM will be monitored as every 20th patient reaches the day +100 evaluation point; i.e., day 
+100 of follow-up or death. All patients who start itacitinib will be counted regardless of the segment they 
were enrolled. Operationally, the CRC will notify the monitoring statistician as cohorts of 20 patients near 
the day 100 mark. Stopping rules are specified in the following Table, which gives the maximum tolerated 
day 100 NRM at each monitoring point. If NRM frequencies exceed these bounds, which are based on 
historical rates, the study will be suspended for safety review by the study team. These numbers were 
selected to limit the false-alarm probability for this event to below 0.05 when there is no additional risk 
due to itacitinib, and the expected NRM rate in this population may be up to 10%.  
Total patients followed at day +100 
20 
40 
Suspend accrual if patients with NRM at day 100  (10% is expected) 
≥5 
≥7 
Using this rule, the probability of early stopping for excessive day 100 NRM is 0.046, 0.57, and 0.95 when 
the true day 100 NRM is at 10%, 20%, and 30%, respectively. 
12.7 Stopping Rules for Excessive Toxicities during phase IIa 
12.7.1 DLT from Day -3 to Day +30 during Phase IIa 
We will continue to monitor for DLTs during phase IIa segment using the modified Pocock-type boundary 
(Ivanova et al 2005). The following table will be consulted as relevant toxicities are encountered following 
the patient safety lead-in. The early stopping rule for safety/toxicity will be assessed for each patient at 
day +30 post-transplant/stem cell infusion. The expected rate of unacceptable toxicity should not be 
≥20%. See the table below for detailed early stopping rules. Patients with ongoing toxicity (beyond day 
+30) will be followed until resolution or stability. If more than the specified number of patients has 
significant treatment related toxicities, patient accrual will be halted and a full review of the data by the 
Data Safety Monitoring Committee will be mandated. Patient accrual will not resume until approved by 
the Data Safety Monitoring Committee to do so. 
# of patients experiencing 
DLTs at phase IIa 1 
# of patients treated to halt 
enrollment 
Cumulative probability of early 
stopping given a toxicity rate of: 
10% 
20% 
30% 
3 
≤12 
0.108 
0.444 
0.751 
4 
≤17 
0.129 
0.531 
0.843 
5 
≤22 
0.140 
0.582 
0.891 
6 
≤27 
0.146 
0.618 
0.921 

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7 
≤32 
0.150 
0.647 
0.944 
8 
≤37 
0.153 
0.674 
0.957 
9 
≤42 
0.154 
0.692 
0.968 
10 
≤47 
0.156 
0.706 
0.981 
11 
≤52 
0.157 
0.720 
0.981 
≥12 
Any 
0.157 
0.720 
0.981 
1: For each unacceptable toxicity, halt enrollment and evaluate if the cumulative # of patients 
reaches or exceeds the specified limits. 
12.7.2 Excessive Toxicity from Day 31 to Day 130 post HCT 
We will also assess the toxicities from Day +31 to Day +130 post-HCT. The following adverse events per 
NCI CTCAE v5.0 that are probably or definitely related to itacitinib will be assessed: 
• 
Grade 3 or 4 non-hematologic toxicity lasting for more than 14 days, 
• 
Grade 4 hematologic toxicity lasting for more than 21 days 
• 
Any other regimen-related cause of death.  
Patients who do not have DLTs during Day -3 and Day +30 and continue to receive itacitinib on Day +31 
or later regardless of the segment (safety-lead-in or phase IIa) will be counted in terms of monitoring 
excessive toxicity during this period. We will perform 2 interim checks for excessive toxicity when 20 and 
40 patients have been followed for excessive toxicity from Day +31 to Day +130 post HCT, respectively. In 
this supportive care setting, we would like to avoid treating patients with itacitinib if the rate of excessive 
toxicity is too high (≥20%). If the following boundary is crossed, we will suspend the accrual temporarily. 
After consideration by the study team (study PI, statistician, etc.) and the City of Hope DSMC, a decision 
will be made as to whether accrual/treatment can be resumed safely or whether protocol modifications 
are necessary. 
N of patients evaluated for excessive toxicity from Day 31 to 130 
20 40 
N of patients experienced excessive toxicity from Day 31 to 130  
≥4 
≥8 
Using this rule, the probability of stopping early for excessive toxicity is 0.067, 0.61, and 0.84 if the rate of 
excessive toxicity during Day +31 to Day +130 is at 10%, 20%, and 25%, respectively. 
12.8 Statistical Analysis Plan  
Patient demographic and baseline transplant characteristics, including age, gender, primary diagnosis, 
disease status, and donor type etc., will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], median)43 will be provided. For categorical variables, patient 
counts and percentages will be provided. Survival outcomes will be estimated using the product-limit 
method of Kaplan and Meier. The cumulative incidence of acute GVHD, chronic GVHD, 
relapse/progression, and NRM will be estimated using the method described by Gooley et al (1999). 
 
 

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13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. 
The investigator or their designee will prepare and maintain adequate and accurate source documents. 
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system that is compliant with 21 
CFR Part 11.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
13.3 Case Report Forms/Data Submission Schedule 
The Investigator is responsible for all information collected on subjects enrolled in this study. All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the Investigator. All case report forms must be completed by designated study personnel. The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 10 calendar days of treatment administration 
Adverse Event Report Forms 
Within 10 calendar days of AE assessment/notification 
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of end of treatment/study 
Follow up/Survival Forms 
Within 14 calendar days of the follow up activity 
13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
 

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14.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST 
14.1 Adverse Event Definitions 
Adverse Event (AE) - [Modified from 21 CFR 312.32 (a)] An adverse event is any untoward medical 
experience or change of an existing condition that occurs during or after treatment, whether or not it is 
considered to be related to the protocol intervention.  
Serious Adverse Event (SAE) - [Modified from 21 CFR 312.32] A serious adverse event is any expected or 
unexpected adverse event that results in any of the following outcomes: 
o Death 
o Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
o Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
o A persistent or significant disability/incapacity 
o A congenital anomaly/birth defect 
o Secondary malignancy 
o Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse). 
14.2 Assessment of Adverse Events 
The study PI will be responsible for determining the event name, assessing the severity (i.e. grade), 
expectedness, and attribution of all adverse events. 
14.2.1 Assessment of Adverse Event Name and Grade 
Adverse events will be characterized using the descriptions and grading scales found in CTCAE version 5.0.  
A copy of the scale can be found at [ctep.cancer.org]. The determination of severity for all other events 
not listed in the CTCAE V.5.0 should be made by the investigator based on medical judgment and the 
severity categories of Grade 1 to 5 as defined below: 
• 
Grade 1 (mild) – An event that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily living. 
• 
Grade 2 (moderate) – An event that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
• 
Grade 3 (severe) – An event that requires intensive therapeutic intervention. The event interrupts 
usual activities of daily living, or significantly affects the clinical status of the subject. 
• 
Grade 4 (life threatening) – An event, and/or its immediate sequelae, that is associated with an 
imminent risk of death or with physical or mental disabilities that affect or limit the ability of the subject 
to perform activities of daily living (eating, ambulation, toileting, etc). 
• 
Grade 5 (fatal) – Death (loss of life) as a result of an event. 

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14.2.2 Assessment of Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
o Definite - The AE is clearly related to the investigational agent or study procedure and unrelated 
to any other cause. 
o Probable - The AE is likely related to the investigational agent or study procedure and unlikely 
related to other cause(s). 
o Possible - The AE may be related to the investigational agent or study procedure and may be 
related to another cause(s). 
o Unlikely - The AE is doubtfully related to the investigational agent or study procedure and likely 
related to another cause(s). 
o Unrelated - The AE is clearly not related to the investigational agent or study procedure and is 
attributable to another cause(s 
14.2.3 Assessment of Expectedness 
The following definitions will be used to determine the expectedness of the event: 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not listed in the 
investigator’s brochure and/or package insert; is not listed at the specificity or severity that has been 
observed; is not consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event, OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
14.3 Unanticipated Problems 
Unanticipated Problem (UP) - An unanticipated problem is any incident, experience, or outcome that 
meets all three of the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
14.4 Reporting Adverse Events 
14.4.1 Routine Reporting of Non-serious Adverse Events by Site Investigators 
Routine AE recording will occur via data entry into the study eCRF. Recording of adverse events will begin 
once the patient is consented and will continue until 30 days post last dose of itacitinib. Adverse events 
will be monitored by the Protocol Management Team (PMT). Adverse events that do not meet the criteria 

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of serious OR are not unanticipated problems do not require expedited reporting.  AEs reported through 
expedited processes (i.e. reported to the IRB, DSMC, FDA, etc.) must also be reported in routine study 
data submissions. 
14.4.2 Additional Reporting Requirements of the Study Principal Investigator 
14.4.2.1 
Reporting to COH IRB and DSMC 
The study PI (or designee) will report to COH IRB and DSMC via iRIS all reportable serious adverse events 
that occur at COH and non-COH sites and meet COH IRB and DSMC expedited reporting criteria 
according to City of Hope’s Institutional policy.  The study PI will also submit a Protocol Management 
Team (PMT) report to the COH DSMC at the frequency outlined in Section 3.6. This report will include a 
review of aggregate adverse event data.   
14.4.2.2 
Reporting to Incyte 
Incyte needs to be notified within 24 hours of learning of an event. Incyte also needs to be provided a 
completed SAE form via email. SAE reporting for each subject begins the day the informed consent is 
signed by the patient and within 30 days after subject has completed or discontinued from the study or 
has taken last dose of the study drug, or as described in the IIR protocol. 
SAEs, occurring using Incyte Study drug, are reported in accordance with the effective protocol.  SAEs 
occurring with any another commercial drug are reported to manufacturer of that drug in accordance 
with regulations and protocol.  
Initial Serious Adverse events (SAEs) and/or subsequent follow-up reports should be reported via email 
to: SafetyReporting@Incyte.com, fax (+) 1-866-981-2057.  SAE reports should be for a single subject. 
Please email your SAE form with a cover sheet and any additional attachments to the IIR email address: 
SafetyReporting@Incyte.com  , fax (+) 1-866-981-2057. 
14.5 Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or disease 
state) of a female participant occurring while the participant receives the first dose of protocol therapy 
up to 30 days post-last dose of itacitinib are considered immediately reportable events.  Protocol therapy 
is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to the Study PI immediately within 24 hours of awareness. The female subject may be 
referred to an obstetrician-gynecologist (preferably one with reproductive toxicity experience) or another 
appropriate healthcare professional for further evaluation. 
The Investigator should make every effort to follow the female participant until completion of the 
pregnancy per institutional policies, and should notify the Study PI.  
Abnormal pregnancy outcomes and neonatal deaths that occur within 30 days of birth should be reported 
as an SAE per expedited reporting guidelines. 
Any infant death after 30 days that the Investigator suspects is related to the in utero exposure to protocol 
therapy should also be reported as an SAE per expedited reporting guidelines. The Study PI or designee 
will subsequently inform Incyte. 

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14.5.1 Male participants 
If a female partner of a male participant becomes pregnant, the male participant should notify the 
Investigator, and the pregnant female partner should be advised to call their healthcare provider 
immediately.  
The Investigator should make every effort to follow the outcome of the pregnancy per institutional 
policies, and should notify the Study PI. 
14.5.2 Reporting of Pregnancies to Incyte 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com, fax (+) 1-866-981-2057 within 24 hours of discovery of a pregnancy of a 
subject who has taken the Incyte product or the pregnancy of a partner for a subject who has taken the 
Incyte product.  The “Follow-up Pregnancy Report Form” or equivalent must be completed and emailed 
to SafetyReporting@Incyte.com, fax (+) 1-866-981-2057 within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the pregnancy.  If the pregnancy results in any events 
which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be 
followed and the timelines associated with an SAE should be followed. 
The Incyte Pregnancy reporting form and cover sheet could be find in the protocol Appendix file. 
Table 14.6 Timeframes for Reporting to Incyte 
Type of Report 
Reporting Timeframes to Incyte 
Pregnancy 
Within 24 hours of being aware of the event using the Incyte Pregnancy Report Form 
(Appendix D)  
All expedited SAE 
reports (includes AESIs) 
Within 24 hours of being aware of the event via a MedWatch 3500A form. 
 
Aggregate safety reports  Forward to Incyte at time of COH DSMC report 
14.6 Reporting to the FDA 
The study PI (or designee) will be responsible for contacting the Office of IND Development and Regulatory 
Affairs (OIDRA) at COH to ensure prompt reporting of safety reports to the FDA. OIDRA will assist the PI 
with the preparation of the report and submit the report to the FDA in accordance with the approved City 
of Hope’s Institutional policy. 
Serious Adverse Events meeting the requirements for expedited reporting to the Food and Drug 
Administration (FDA), as defined in 21 CFR 312.32, will be reported as an IND safety report using the 
MedWatch Form FDA 3500A for Mandatory Reporting. 
The criteria that require reporting using the MedWatch 3500A are: 
o Any unexpected fatal or life threatening adverse experience associated with use of the drug must 
be reported to the FDA no later than 7 calendar days after initial receipt of the information [21 
CFR 312.32(c)(2)] 
o Any adverse experience associated with use of the drug that is both serious and unexpected must 
be submitted no later than 15 calendar days after initial receipt of the information [21 CFR 
312.32(c)(1)] 
o Any follow-up information to a study report shall be reported as soon as the relevant information 
becomes available. [21 CFR 312.32(d)(3)] 

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In addition, on behalf of the study PI, OIDRA will submit annually within 60 days (via COH OIDRA) of the 
anniversary of the date the IND went into effect, an annual report to the FDA which is to include a 
narrative summary and analysis of the information of all FDA reports within the reporting interval, a 
summary report adverse drug experiences, and history of actions taken since the last report because of 
adverse drug experiences. 
14.7 Expedited Reporting  
14.7.1 Expedited Reporting of Graft Failure to the FDA 
Incidence of graft failure is expected to be low. FDA will be notified within 72 hours of learning of graft 
failure.  
The table below indicates what events to report to expeditiously (Table 14.3). 
Table 14.3 Expedited Reporting Guidelines 
Time point 
What to report  
From signing of the consent to study completion 
 All UPs 
For the time period beginning at treatment 
through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, 
whichever is earlier 
All reportable events will require follow up until 
stabilization or resolution per the agreement of 
the Study PI.  
 All SAEs regardless of relationship to protocol therapy 
unless they meet exceptions to expedited reporting 
 All AEs that meet the definition of a UP 
 All AESIs- irAEs, overdose of either agent,  
 pregnancies and lactation 
From Day 1 of protocol therapy up to 120 days 
post-last itacitinib dose 
 Pregnancies and lactation  
Post Safety follow-up to removal from study  
 All SAEs that are considered possibly, probably or 
definitely related to itacitinib.  
15.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
A deviation is a divergence from a specific element of a protocol. It is understood that deviations from the 
protocol should be avoided, except when necessary to eliminate an immediate hazard to a research 
participant. Protocol deviations may be on the part of the subject, the investigator, or study staff.  
15.1 Definitions 
15.1.1 Unplanned Deviations: 
▪ 
Emergency modifications - Investigators may implement a deviation from the protocol to 
eliminate an immediate hazard for the protection, safety, and well-being of the study patient to 
trial participants without prior COH IRB or Sponsor approval. 
▪ 
Deviations Discovered After They Have Occurred. 
Unplanned deviations from the protocol must be documented in study subject source documents.   

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15.1.2 Planned Non-Emergency Deviations (Single Subject Exception) 
A planned deviation involves circumstances in which the specific procedures called for in a protocol are 
not in the best interests of a specific patient. It is a deviation that is anticipated and receives prior approval 
by the Study PI and the COH IRB. 
15.2 Reporting of Deviations 
15.2.1 Reporting Unplanned Deviations 
For any such deviation, the Study PI will notify the COH DSMC and IRB within 5 calendar days of its 
occurrence via iRIS in accordance with the Clinical Research Protocol Deviation policy. 
A list of these deviations will be submitted along with the Protocol Management Team (PMT) reports to 
the COH DSMC. 
15.2.2 Reporting Planned Non-Emergency Deviations/ Single Subject Exceptions 
Any planned deviation must be submitted as a “planned protocol deviation” via iRIS in accordance with 
IRB guidelines and the Clinical Research Protocol Deviation policy. An IRB approved planned deviation 
does not need to be submitted as a deviation to the DSMC. 
16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, & DATA AND SAFETY MONITORING 
16.1 Study PI Responsibilities 
The Study PI is responsible for the conduct of the clinical trial, including overseeing that sponsor 
responsibilities are fulfilled as defined in § 21 CFR 312. 
16.2 All Investigator Responsibilities 
All investigators agree to: 
o Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of subjects.  
o Personally conduct or supervise the study (or investigation).  
o Ensure that the requirements relating to obtaining informed consent and IRB review and approval 
meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
o Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
o Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
o Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
o Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for 
initial and continuing review and approval of the clinical study.  
o Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
o Seek IRB and Sponsor approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects.  

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o Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312. 
16.3 Protocol Management Team (PMT) 
The PMT, minimally consisting of the Study Principal Investigator, collaborating investigators, the research 
nurse, the clinical research associate/coordinator, and the study biostatistician, is responsible for ongoing 
monitoring of the data and safety of this study, including implementation of stopping rules for 
safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) monthly to review study status. This 
review will include, but not be limited to, reportable AEs and UPs, and an update of the ongoing study 
summary that describes study progress in terms of the study schema. The meeting will be a forum to 
discuss study related issues including accrual, SAE/AEs experienced, study response, deviations/violations 
and study management issues. The appropriateness of further subject enrollment and the specific 
intervention for subsequent subject enrollment are addressed, including the implementation of stopping 
rules. It is recommended that minutes of these discussions be taken to document the date of these 
meetings, attendees and the issues that were discussed. 
The Study PI is required to submit periodic status reports (the PMT report) according to the guidelines 
outlined in the City of Hope Institutional Data and Safety Monitoring Plan. The PMT report will be 
submitted to the COH DSMC quarterly from the date of activation. 
16.4  Monitoring/ Auditing 
Clinical site monitoring/auditing is conducted to ensure that the rights of human subjects are protected, 
that the study is implemented in accordance with the protocol and regulatory requirements, and that the 
quality and integrity of study data and data collection methods are maintained. Monitoring/auditing for 
this study will be performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM). 
The Investigator will permit the study monitors and appropriate regulatory authorities direct access to the 
study data and to the corresponding source data and documents to verify the accuracy of this data. The 
Investigator will allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all the above noted 
study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has 
adequate space to conduct the monitoring visit. 
Details of clinical site monitoring are documented in the OCTAM SOP. This document specifies the 
frequency of monitoring, monitoring procedures, the level of clinical site monitoring activities (e.g., the 
percentage of subject data to be reviewed), and the distribution of monitoring reports.  Staff from OCTAM 
will conduct monitoring activities and provide reports of the findings and associated action items in 
accordance with the details described in the SOP.  Documentation of monitoring activities and findings 
will be provided to the study team, and the COH DSMC.  
Documentation of monitoring/auditing activities and findings by OCTAM will be provided to the study 
team, Study PI, and the COH DSMC. 
16.5 Quality Assurance 
The City of Hope Clinical Research Information Support will provide quality assurance.  

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16.6 City of Hope Data and Safety Monitoring Committee (DSMC) 
This is a risk level 4 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan. This 
determination was made because the trial involves COH IND. 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. The committee reviews the 
progress and safety of all active research protocols that are not monitored by another safety and data 
monitoring committee or board.  
The Study Principal Investigator is required to submit periodic status reports (the PMT report) according 
to the guidelines outlined in the City of Hope Institutional Data and Safety Monitoring Plan.  The PMT 
report will be submitted to the COH DSMC semi-annually from the date of activation.   
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this trial. The DSMC will review up-to-date participant accrual; summary of all adverse events 
captured via routine and expedited reporting; a summary of deviations; any response information; 
monitoring reports, and summary comments provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. For Phase I studies, a Phase I Tracking Log will be utilized 
and reviewed by the DSMC to monitor data and safety for dose escalation.  A review of outcome results 
(response, toxicity and adverse events) and factors external to the study (such as scientific or therapeutic 
developments) is discussed, and the Committee votes on the status of each study. Information that raises 
any questions about participant safety will be addressed with the Principal Investigator, statistician and 
study team. The PMT report and DSMC recommendations will be circulated to all participating sites for 
submission to their IRBs, in accordance with NIH guidance. 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application 
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  

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 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable, NIH policies and procedures 
o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 
56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study.  Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
17.4 Informed Consent 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Prospective participants will be informed that they may withdraw 
from the study at any time and for any reason without prejudice, including as applicable, their current or 
future care or employment at City of Hope or any relationship they have with City of Hope.  Prospective 
participants will be afforded sufficient time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   

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Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures and 
chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review and 
survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form. Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations 
17.6.1 Women and Minorities 
The study is open to anyone regardless of gender, race or ethnicity.  Efforts will be made to extend the 
accrual to a representative population.  If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
Pregnant women are excluded because the study drugs have been determined to be embryolethal and 
teratogenic in animal testing.  
17.6.2 Vulnerable Populations 
Per 45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, and economically or educationally disadvantaged persons as vulnerable 
populations.  
Economically/educationally disadvantaged persons are not actively targeted for participation, nor are 
they excluded from participation. This study does not pose additional risks for economically/educationally 
disadvantaged persons than for the general population. 
17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, and the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects 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 subject is alive) at the end 
of their scheduled study period. 

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Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 
Participant specimens with a limited data set will be provided to research laboratories. The specimens will 
be labeled with the study number, subject (accession) ID, date and time point of collection. The key to the 
code will be maintained in the COH clinical trials management system which is a secure environment.  
17.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will either be: (a) placed in a COH IRB approved CTCL biorepository (COH#15185) with some clinical 
information and potentially PHI attached or (b) discarded. 
17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.10 Financial Obligations, Compensation, and Reimbursement of Participants 
Itacitinib will be provided free of charge to participants.  
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier.  The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope to the injured participant. There are no plans for City of Hope 
to provide financial compensation in the event of physical injury to a participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 

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17.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI.  Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope and Incyte. 
The publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov. Results will be 
reported on ClinicalTrials.gov generally within 12 months after the completion date unless criteria to delay 
submission are met per the final rule. 
 
 

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18.0 REFERENCES 
1. 
Ferrara JL. Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother 
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2. 
den Haan JM, Sherman NE, Blokland E, et al. Identification of a graft versus host disease-associated human 
minor histocompatibility antigen. Science. 1995;268(5216):1476-1480. 
3. 
Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical 
donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl 
J Med. 1996;334(5):281-285. 
4. 
Simpson D. New developments in the prophylaxis and treatment of graft versus host disease. Expert Opin 
Pharmacother. 2001;2(7):1109-1117. 
5. 
Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cells compared with bone marrow as a source of 
hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working 
Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood. 2000;95(12):3702-3709. 
6. 
Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA-specific alloantibodies in 
recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010;115(13):2704-
2708. 
7. 
Lee SJ, Klein J, Haagenson M, et al. High-resolution donor-recipient HLA matching contributes to the success 
of unrelated donor marrow transplantation. Blood. 2007;110(13):4576-4583. 
8. 
Eapen M, Logan BR, Confer DL, et al. Peripheral blood grafts from unrelated donors are associated with 
increased acute and chronic graft-versus-host disease without improved survival. Biol Blood Marrow Transplant. 
2007;13(12):1461-1468. 
9. 
Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatch is associated with worse outcome in 
unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(6):885-892. 
10. 
Ringden O, Pavletic SZ, Anasetti C, et al. The graft-versus-leukemia effect using matched unrelated donors 
is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood. 2009;113(13):3110-3118. 
11. 
Shaw BE, Gooley TA, Malkki M, et al. The importance of HLA-DPB1 in unrelated donor hematopoietic cell 
transplantation. Blood. 2007;110(13):4560-4566. 
12. 
Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood. 1992;80(12):2964-
2968. 
13. 
Baan CC, van der Mast BJ, Klepper M, et al. Differential effect of calcineurin inhibitors, anti-CD25 antibodies 
and rapamycin on the induction of FOXP3 in human T cells. Transplantation. 2005;80(1):110-117. 
14. 
Zorn E. CD4+CD25+ regulatory T cells in human hematopoietic cell transplantation. Semin Cancer Biol. 
2006;16(2):150-159. 
15. 
Rieger K, Loddenkemper C, Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in 
acute and chronic GvHD. Blood. 2006;107(4):1717-1723. 
16. 
Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after 
allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome. Blood. 1990;75(4):1024-
1030. 
17. 
Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-versus-host disease: 
secondary treatment. Blood. 1991;77(8):1821-1828. 
18. 
Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after 
allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062-2068. 
19. 
Zeiser R, Burchert A, Lengerke C, et al. Long-Term Follow-up of Patients with Corticosteroid-Refractory 
Graft-Versus-Host Disease Treated with Ruxolitinib. Blood. 2016;128(22):4561-4561. 
20. 
Khandelwal P, Teusink-Cross A, Davies SM, et al. Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute 
Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients. Biol Blood Marrow Transplant. 
2017;23(7):1122-1127. 

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21. 
Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host 
disease. Blood. 2014;123(24):3832-3842. 
22. 
Mori Y, Ikeda K, Inomata T, et al. Ruxolitinib treatment for GvHD in patients with myelofibrosis. Bone 
Marrow Transplant. 2016;51(12):1584-1587. 
23. 
Maffini E, Giaccone L, Festuccia M, et al. Ruxolitinib in steroid refractory graft-vs.-host disease: a case 
report. J Hematol Oncol. 2016;9(1):67. 
24. 
Schroeder MA, Khoury HJ, Jagasia M, et al. A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 
in Acute Graft-Versus-Host Disease (aGVHD). Blood. 2016;128(22):390-390. 
25. 
Khoury HJ, Kota V, Arellano M, et al. Ruxolitinib As Sparing Agent for Steroid-Dependent Chronic Graft-
Versus-Host Disease (cGVHD). Blood. 2015;126(23):1938-1938. 
26. 
Juvekar A, Ruggeri B, Condon S, Borkowski A, Huber R, Smith P. Itacitinib, a JAK1 Selective Inhibitor 
Preserves Graft-Versus-Leukemia (GVL), Enhances Survival and Is Highly Efficacious in a MHC-Mismatched Mouse 
Model of Acute GvHD. Blood. 2018;132(Suppl 1):4522-4522. 
27. 
Holtan SG, DeFor TE, Lazaryan A, et al. Composite end point of graft-versus-host disease-free, relapse-free 
survival after allogeneic hematopoietic cell transplantation. Blood. 2015;125(8):1333-1338. 
28. 
Veeraraghavan S, Thappali S, Viswanadha S, et al. Simultaneous quantification of ruxolitinib and nilotinib in 
rat plasma by LC-MS/MS: application to a pharmacokinetic study. J Pharm Biomed Anal. 2014;94:125-131. 
29. 
Schots R, Kaufman L, Van Riet I, et al. Proinflammatory cytokines and their role in the development of major 
transplant-related complications in the early phase after allogeneic bone marrow transplantation. Leukemia. 
2003;17(6):1150-1156. 
30. 
Harris AC, Ferrara JL, Braun TM, et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. 
Blood. 2012;119(12):2960-2963. 
31. 
Ferrara JL, Harris AC, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal 
graft-versus-host disease. Blood. 2011;118(25):6702-6708. 
32. 
Choi SW, Kitko CL, Braun T, et al. Change in plasma tumor necrosis factor receptor 1 levels in the first week 
after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival. Blood. 
2008;112(4):1539-1542. 
33. 
Paczesny S, Krijanovski OI, Braun TM, et al. A biomarker panel for acute graft-versus-host disease. Blood. 
2009;113(2):273-278. 
34. 
Betts BC, Sagatys EM, Veerapathran A, et al. CD4+ T cell STAT3 phosphorylation precedes acute GVHD, and 
subsequent Th17 tissue invasion correlates with GVHD severity and therapeutic response. J Leukoc Biol. 
2015;97(4):807-819. 
35. 
Bearman SI, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients undergoing bone 
marrow transplantation. J Clin Oncol. 1988;6(10):1562-1568. 
36. 
Cancer Therapy Evaluation Program, National Cancer Institute, National Institues of Health. Common 
Terminology 
Criteria 
for 
Adverse 
Events 
(CTCAE) 
Version 
4.03; 
2010:http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
37. 
Harris AC, Young R, Devine S, et al. International, Multicenter Standardization of Acute Graft-versus-Host 
Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium. Biol Blood 
Marrow Transplant. 2016;22(1):4-10. 
38. 
Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on 
criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood 
Marrow Transplant. 2005;11(12):945-956. 
39. 
Jagasia MH, Greinix HT, Arora M, 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):389-401 e381. 

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40. 
Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working 
Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) 
consensus report. Blood. 2013;122(8):1395-1398. 
41. 
Zang DY, Deeg HJ. Allogeneic hematopoietic cell transplantation for patients with myelofibrosis. Curr Opin 
Hematol. 2009;16(2):140-146. 
42. 
Skolnik JM, Barrett JS, Jayaraman B, Patel D, Adamson PC. Shortening the timeline of pediatric phase I trials: 
the rolling six design. J Clin Oncol. 2008;26(2):190-195. 
43. 
Srinivasan M, Flynn R, Price A, et al. Donor B-cell alloantibody deposition and germinal center formation 
are required for the development of murine chronic GVHD and bronchiolitis obliterans. Blood. 2012;119(6):1570-
1580. 
 
 

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APPENDIX A: PERFORMANCE STATUS SCALES 
 
 
Karnofsky 
Scale % 
Karnofsky 
Description 
ECOG* 
Scale 
ECOG 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Fully active, able to carry on all 
pre-disease activities without 
restriction. 
90 
Able to carry on normal activity, 
minor symptoms or signs of 
disease. 
80 
Normal activity with effort, some 
signs or symptoms of disease. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary nature e.g. light house 
work office work.  
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of own 
needs. 
2 
Ambulatory and capable of all self-
care but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours  
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
Capable of only limited self-care, 
confined to bed or chair more than 
50% of waking hours  
30 
Severely disabled, hospitalization is 
indicated although death is not 
imminent. 
20 
Hospitalization necessary, very sick, 
active supportive treatment 
necessary. 
4 
Completely disabled. Cannot carry 
on any self-care. Totally confined 
to bed or chair  
10 
Moribund, fatal processes 
Dead 
 
5 
Dead 
*also known as Zubrod, SWOG or WHO scale 
 
 

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Modified Bearman Scale 35 
HCT Regimen-related toxicity by organ system 
Organ 
Grade I 
Grade II 
Grade III 
Cardiac 
toxicity 
Mild 
EKG 
abnormality, 
not 
requiring medical intervention; 
or noted heart enlargement on 
chest x-ray with no clinical 
symptoms 
Moderate 
EKG 
abnormalities 
requiring and responding to medical 
intervention; or requiring continuous 
monitoring without treatment; or 
congestiveheart failure responsive to 
digitalis or diuretics  
Severe EKG abnormalities with 
no or only partial response to 
medical intervention; or heart 
failure with no or only minor 
response 
to 
medical 
intervention; or decrease in 
voltage by more than 50%  
Bladder 
toxicity 
Macroscopic hematuria after 2 
days from last chemotherapy 
dose 
with 
no 
subjective 
symptoms of cystitis and not 
caused by infection  
Macroscopic hematuria after 7 days 
from last chemotherapy dose not 
caused by infection; or hematuria 
after 
2 
days 
with 
subjective 
symptoms of cystitis not caused by 
infection  
Hemorrhagic cystitis with frank 
blood, necessitating invasive 
local 
intervention 
with 
installation 
of 
sclerosing 
agents, nephrostomy or other 
surgical procedure  
Renal 
toxicity 
Increase in creatinine up to twice 
the baseline value (usually the 
last recorded before start of 
conditioning)  
Increase in creatinine above twice 
baseline but not requiring dialysis  
Requirement of dialysis  
Pulmonary 
toxicity 
Dyspnea without chest x-ray 
changes not caused by infection 
or congestive heart failure; or 
chest x-ray showing isolated 
infiltrate or mild interstitial 
changes without symptoms not 
caused by infection or congestive 
heart failure  
Chest x-ray with extensive localized 
infiltrate or moderate interstitial 
changes combined with dyspnea and 
not caused by infection or CHF; or 
decrease of PO2 (> 10% from 
baseline) 
but 
not 
requiring 
mechanical ventilation or > 50% O2 
on mask and not caused by infection 
or CHF 
Interstitial changes requiring 
mechanical ventilatory support 
or > 50% oxygen on mask and 
not caused by infection or CHF  
Hepatic 
toxicity 
Mild hepatic dysfunction with 
bilirubin ≥ 2.0 mg/dL and ≤ 6.0 
mg/dL or weight gain > 2.5% and 
< 5% from baseline, of non-
cardiac origin; or SGOT increase 
more than 2-fold but less than 5-
fold from lowest preconditioning  
Moderate hepatic dysfunction with 
bilirubin > 6.0 mg/dL and < 20 mg/dL; 
or SGOT increase > 5-fold from 
preconditioning; or clinical ascitis or 
image documented ascitis > 100 mL; 
or weight gain > 5% from baseline of 
non-cardiac origin  
Severe 
hepatic 
dysfunction 
with bilirubin > 20 mg/dL; or 
hepatic encephalopathy; or 
ascitis 
compromising 
respiratory function  
CNS 
toxicity 
Somnolence but the patient is 
easily arousable and oriented 
after arousal  
Somnolence with confusion after 
arousal; or other new objective CNS 
symptoms 
with 
no 
loss 
of 
consciousness 
not 
more 
easily 
explained 
by 
other 
medication, 
bleeding or CNS infection  
Seizures or coma not explained 
(documented) 
by 
other 
medication, CNS infection, or 
bleeding  
Stomatitis 
Pain 
and/or 
ulceration 
not 
requiring 
a 
continuous 
IV 
narcotic drug  
Pain and/or ulceration requiring a 
continuous 
IV 
narcotic 
drug 
(morphine drip)  
Severe 
ulceration 
and/or 
mucositis requiring preventive 
intubation; or resulting in 
documented 
aspiration 
pneumonia with or without 
intubation  
GI toxicity 
Watery stools > 500 mL but < 
2,000 mL every day not related 
to infection  
Watery stools > 2,000 mL every day 
not 
related 
to 
infection; 
or 
macroscopic hemorrhagic stools with 
no effect on cardiovascular status not 
caused by infection; or subileus not 
related to infection 
Ileus 
requiring 
nasogastric 
suction and/or surgery and not 
related 
to 
infection; 
or 
hemorrhagic 
enterocolitis 
affecting cardiovascular status 
and requiring transfusion  
Note: Grade IV regimen-related toxicity is defined as fatal toxicity 
 
 

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APPENDIX B: RESPONSE CRITERIA/GRADING/STAGING CRITERIA 
Acute GvHD organ staging per MAGIC criteria37 
 
 

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Chronic GVHD Grading 
 
 

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APPENDIX C. COVERSHEETS 
18.1 Registration Coversheet 
COH IRB#:  
 
Data Coordinating Center:   
City of Hope 
1500 Duarte Road 
Duarte, CA 91010  
Tel:  626-256-4673 x 83968  
Email:  DCC@coh.org (use #secure# in subject line) 
Site Principal Investigator  
Name: 
Address: 
 
 
Phone:  
Fax:  
e-mail: 
CRA/Study Coordinator:     
Contact Number:   
Patient’s Initials: (F M L): 
Institution: 
Medical Record No: 
Investigator/Treating Physician: 
Patient’s DOB: 
IRB approval valid until (date): 
Sex: 
______Male 
______Female 
Date Informed Consent Signed: 
Projected start date of treatment: 
Race 
Ethnicity 
Method of 
Payment:_______________________ 
 
Black 
 Hispanic 
Codes: 
 
Caucasian 
 Non-Hispanic 
01 Private 
06 Military or Veterans 
Adm. sponsored 
 
Asian 
 Other_________________ 
02 Medicare 
07 Self-pay (no 
insurance) 
 
American Indian 
 
03 Medicare & 
private ins. 
08 No means of 
payment  (no insurance) 
 
Native Hawaiian/Pacific 
Islander 
04 Medicaid 
09 Unknown 
 
Other_______________
____________________ 
05 Medicaid & Medicare 
Reason for Screen Failure:  
 
Reason for Failing to Initiate Protocol Therapy: 
 
 
 
 

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APPENDIX D. RESPONSE ASSESSMENT 
18.2 NCCN guidelines version 1.2020, Acute Lymphoblastic Leukemia 
 
 

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18.3 NCCN guidelines for Acute Myeloid Leukemia Version 3.2020