Conditions: Low Risk Acute Graft-versus-host Disease Graft-versus-host-disease GVHD
Keywords: Graft-versus-host disease Itacitinib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
Graft-versus-host disease (GVHD) is treated with high doses of systemic steroids which can lead to serious complications. A new blood test can identify patients whose GVHD is most likely to respond to well to treatment (low risk GVHD). This study will test whether patients with low risk GVHD can be successfully treated without steroids. Patients who participate with this study will be treated with itacitinib instead of steroids. Itacitinib is an experimental drug with an excellent safety record and appears to have activity as a GVHD treatment.

Detailed description:
Patients with newly diagnosed low risk acute GVHD defined as Minnesota standard risk based on symptoms and Ann Arbor 1 GVHD based on biomarkers were eligible if they met all other eligible criteria (see eligibility criteria below). Enrolled patients were required to start treatment within 4 days of confirmation of Ann Arbor 1 status. Treatment consisted of itacitinib 200 mg daily for 28 days. Patients with a clinical response on day 28 were eligible for a second 28 day cycle of itacitinib 200 mg daily. Missed doses could be made up by extending the treatment duration for up to 2 additional weeks. Medications given for GVHD prophylaxis and topical treatments for GVHD were allowed. Supportive care was provided according to institutional standards. Itacitinib was permanently discontinued after any of the following:

administration of 56 doses of itacitinib or initiation of systemic corticosteroids or any other systemic treatment for GVHD or patient withdrawal from the study or general or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator OR ten weeks elapsed since the first dose of itacitinib.

Arms:
arm 1: Itacitinib 200 mg administered orally daily

Interventions: intervention 1: Itacitinib
Intervention descriptions: intervention 1: for up to 56 days

Protocol document:
Prot_SAP_000.pdf: 
Itacitinib Monotherapy for Low Risk Graft-Vs-Host Disease
Dr. John E. Levine, MD, MS
NCT03846479
Document Date: May 13, 2020


Initial version: 
February 12, 2018  v2.0 
 
 
 
ITACITINIB MONOTHERAPY FOR LOW RISK GRAFT-VS-HOST DISEASE 
 
 
Principal Investigator: 
 
John E. Levine, MD, MS 
Bone Marrow Transplantation Program 
The Tisch Cancer Institute 
Division of Hematology/Medical Oncology 
Icahn School of Medicine at Mount Sinai 
1 Gustave L. Levy Pl, Box 1410,  
New York, New York 10029 
Phone: 212-241-3429 
Fax: 212-241-8618 
john.levine@mssm.edu 
 
Co-Investigators: 
 
James Ferrara, MD, DSc 
Mount Sinai  
New York, NY 
james.ferrara@mssm.edu 
 
Aaron Etra, MD 
Mount Sinai 
New York, NY 
aaron.etra@mountsinai.org 
 
Umut Özbek, Ph.D. (Biostatistician) 
Mount Sinai 
New York, NY 
umut.ozbek@mountsinai.org 
 
William Hogan, M.B. B.Ch. 
Mayo Clinic 
Rochester, MN 
hogan.william@mayo.edu 
 
Ryotara Nakamura, MD 
City of Hope 
Duarte, CA 
rnakamura@coh.org 
 
Madan Jagasia, MBBS 
Vanderbilt University 
Nashville, TN 
madan.jagasia@vanderbilt.edu  
 
Carrie Kitko, MD 
Vanderbilt University 
Nashville, TN 
carrie.l.kitko@vanderbilt.edu 
 
Yi-Bin Chen, MD 
Massachusetts General 
Boston, MA 
ychen6@partners.org 
 
Hannah Choe, MD 
Ohio State University 
Columbus, OH 
hannah.choe@osumc.edu 
 
David Porter, MD 
University of Pennsylvania 
Philadelphia, PA 
david.porter@uphs.upenn.edu 
 
Stephan Grupp, MD 
Children’s Hospital of Philadelphia 
Philadelphia, PA 
grupp@email.chop.edu  
 
Michael Pulsipher, MD 
Children’s Hospital of Los Angeles 
Los Angeles, CA 
mpulsipher@chla.usc.edu 
 
Edmund Waller, MD 
Emory University 
Atlanta, GA 
zalkadh@emory.edu 
 
Muna Qayed, MD 
Emory/Children’s Hospital of Atlanta 
Atlanta, GA 
muna.qayed@choa.org 
 
Sunil Abhyankar, MD 
University of Kansas 
Kansas City, KS 
sabhyankar@kumc.edu 
Amin Alousi, MD 
 
 
          Marco Mielcarek, MD 
MD Anderson Cancer Center  
          Fred Hutchinson  
Houston, TX 
 
 
          Seattle, WA 
aalousi@mdanderson.org      
          mmielcar@fredhutch.org        
 
 
 
 
 
Study Drug: 
 
 
Itacitinib 
US IND No.: 
 
 
140280 
 
 
Protocol Version Date: 
 
5/13/2020 
 
Protocol Number:  
 
V3.4 
 
BDW Approval Date: 
 
02/19/2018 
 
 
 
 
 
 
 
 


 
Page ii of iv 
 
 
TABLE OF CONTENTS 
ABBREVIATIONS ........................................................................................................................... 5 
1.0 
BACKGROUND AND RATIONALE .................................................................................... 9 
1.1 
Acute GVHD .................................................................................................................... 9 
1.2 
Steroid Treatment ............................................................................................................ 9 
1.3 
GVHD Biomarker Algorithms Risk Categorize Patients ................................................ 10 
1.4 
JAK-inhibition as a target for GVHD .............................................................................. 10 
1.5 
Mount Sinai Acute GVHD International Consortium (MAGIC) ...................................... 12 
1.6 
Correlative Studies ........................................................................................................ 12 
1.7 
Summary of Study Rationale ......................................................................................... 12 
2.0 
STUDY OBJECTIVES ....................................................................................................... 13 
2.1 
Primary Objectives ......................................................................................................... 13 
2.2 
Secondary Objectives .................................................................................................... 13 
2.3 
Primary Endpoint ........................................................................................................... 13 
3.0 
PATIENT ELIGIBILITY ...................................................................................................... 14 
3.1 
Inclusion Criteria ............................................................................................................ 14 
3.2 
Exclusion Criteria ........................................................................................................... 14 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES .................................... 15 
5.0 
TREATMENT PLAN .......................................................................................................... 16 
5.1 
Treatment Dosage and Administration .......................................................................... 16 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 18 
5.3 
Concomitant Medications/Treatments ........................................................................... 18 
5.4 
Other Modalities or Procedures ..................................................................................... 18 
5.5 
Duration of Therapy ....................................................................................................... 18 
5.6 
Off Treatment Criteria .................................................................................................... 19 
5.7 
Duration of Follow-Up .................................................................................................... 19 


 
Page iii of iv 
 
 
5.8 
Off Study Criteria ........................................................................................................... 19 
5.9 
Patient Replacement ..................................................................................................... 19 
6.0 
STUDY PROCEDURES ..................................................................................................... 20 
6.1 
Screening/Baseline Procedures .................................................................................... 20 
6.2 
Follow-Up Procedures ................................................................................................... 20 
7.0 
GVHD CLINICAL STAGING .............................................................................................. 22 
7.1 
ENDPOINT AND RESPONSE CRITERIA..................................................................... 22 
7.2 
SAFETY/TOXICITY DEFINITIONS ............................................................................... 23 
7.3 
Safety/Tolerability .......................................................................................................... 25 
8.0 
ADVERSE EVENTS .......................................................................................................... 25 
8.1 
Itacitinib .......................................................................................................................... 25 
8.2 
Adverse Event Reporting Requirements ....................................................................... 25 
8.3 
Definitions ...................................................................................................................... 26 
8.4 
Adverse Event Characteristics ...................................................................................... 28 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 28 
8.6 
Reporting of Unanticipated Problems ............................................................................ 30 
8.7 
Stopping Rules .............................................................................................................. 30 
9.0 
DRUG INFORMATION ...................................................................................................... 32 
9.1 
Itacitinib Adipate ............................................................................................................ 32 
10.0 
CORRELATIVES/SPECIAL STUDIES .......................................................................... 38 
10.1 
Sample Collection Guidelines ........................................................................................ 38 
10.2 
Assay Methodology ....................................................................................................... 38 
10.3 
Specimen Banking ......................................................................................................... 38 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................. 38 
11.1 
Study Design/Study Endpoints ...................................................................................... 38 
11.2 
Sample Size and Accrual .............................................................................................. 39 


 
Page iv of iv 
 
 
11.3 
Data Analyses Plans...................................................................................................... 40 
12.0 
DATA AND SAFETY MONITORING ............................................................................. 40 
12.1 
Multisite Clinical Monitoring Procedures........................................................................ 41 
13.0 
QUALITY ASSURANCE AND AUDITS ........................................................................ 42 
14.0 
REFERENCES ............................................................................................................... 43 


5 
 
ABBREVIATIONS 
 
Examples Include: 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BMT 
Bone Marrow Transplant 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CD 
Crohn’s Disease 
CMP 
Comprehensive Metabolic Panel 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
Co-I 
Co-Investigator 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DCC 
Data Coordinating Center 
DDI 
Drug-Drug Interaction 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMR 
Data and Safety Monitoring Report 
EBV 
Epstein-Barr Virus 
ELISA 
Enzyme-Linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
GI 
Gastrointestinal 
GVHD 
Graft-Versus-Host Disease 
HCT 
Hematopoietic Stem Cell Transplantation 
HHV6 
Human Herpes Virus 6 
HSV 
Herpes Simplex Virus 
IND 
Investigational New Drug 
IL2Rα 
Interleukin-2 receptor-alpha 
IRB 
Institutional Review Board 
IV (or iv) 
Intravenously 
JC 
John Cunningham (virus) 
MAGIC 
Mount Sinai Acute GVHD International Consortium  
MS 
Multiple Sclerosis 
NCI 
National Cancer Institute 
NOS 
Not Otherwise Specified 


6 
 
NR 
No Response 
NRM 
Non-Relapse Mortality 
OS 
Overall Survival 
PE 
Physical Exam 
PI 
Principal Investigator 
PJP 
Pneumocystis Jiroveci Pneumonia 
PML 
Progressive Multifocal Leukoencephalopathy 
PR 
Partial Response 
PTLD 
Post-Transplant Lymphoproliferative Disorder 
REG3α 
Regenerating islet-derived 3 alpha 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
ST2 
Suppressor of tumorigenicity-2 
TCI 
The Tisch Cancer Institute at Mount Sinai 
TNFR1 
Tumor necrosis factor receptor-1 
UGI 
Upper Gastrointestinal 
VZV 
Varicella-Zoster Virus 
 
 
 


7 
 
STUDY SYNOPSIS 
Title 
Itacitinib Monotherapy For Low Risk Graft-Vs-Host Disease 
Phase 
II 
Methodology 
Open label, single arm, non-inferiority study 
Study Duration 
2 years 
Study Center(s) 
Mount Sinai (lead), City of Hope, Emory University, Massachusetts 
General, Mayo Clinic, Ohio State University, University of Kansas, 
University of Pennsylvania, Vanderbilt University, Children’s Hospital of 
Los Angeles, Children’s Hospital of Philadelphia, MD Anderson Cancer 
Center, Fred Hutchinson Cancer Research Center 
Objectives 
Primary Objective: To determine the effectiveness of itacitinib 
monotherapy as primary treatment of newly diagnosed, low-risk acute 
graft-versus-host disease (GVHD) defined by standard risk clinical criteria 
(Minnesota) and low risk biomarkers (Ann Arbor 1). 
 
Secondary Objectives: 
1. To assess the safety of itacitinib monotherapy as the primary 
treatment of newly diagnosed, low-risk acute GVHD defined by 
standard risk clinical criteria (Minnesota) and biomarkers (Ann 
Arbor 1 GVHD) 
2. To determine the incidence of serious infectious complications in 
patients with GVHD treated with itacitinib 
3. To determine the GVHD response rate to systemic steroid 
treatment in patients whose GVHD is not responsive to itacitinib 
Number of Subjects 
70 
Inclusion Criteria 
1. Newly diagnosed GVHD that meets criteria for Minnesota 
standard risk  
2. Ann Arbor 1 GVHD by biomarkers 
3. GVHD not previously treated systemically (topical therapies and 
non-absorbed steroids are allowed) 
4. Any donor type, HLA-match, conditioning regimen is acceptable 
5. Age 12 years and up (children <18 years must also weigh 50 kg 
or more) 
6. Patients must be engrafted post-transplant (ANC ≥500/μL and 
platelet count ≥20,000). Use of growth factor supplementation to 
maintain neutrophil count is allowed.  
7. Direct bilirubin must be <2 mg/dL unless the elevation is known to 
be due to Gilbert syndrome within 3 days prior to enrollment. 
8. ALT/SGPT and AST/SGOT must be <5x the upper limit of the 
normal range within 3 days prior to enrollment.  
9. Signed and dated written informed consent obtained from patient 
or legal representative.  


8 
 
Exclusion Criteria 
1. Patients currently being treated with any JAK inhibitor including 
ruxolitinib 
2. Relapsed, progressing, or persistent malignancy requiring 
withdrawal of systemic immune suppression 
3. Patients with uncontrolled infection (i.e., progressive symptoms 
related to infection despite treatment or persistently positive 
microbiological cultures despite treatment or any other evidence 
of severe sepsis) 
4. Severe organ dysfunction including requirement for dialysis, 
mechanical ventilation or oxygen supplementation exceeding 
40% FiO2 within 7 days of enrollment. 
5. Creatinine clearance or estimated glomerular filtration rate <30 
ml/min as calculated by institutional practice (e.g., Cockcroft-
Gault equation, CKD-EPI equation, etc) 
6. A clinical presentation resembling de novo chronic GVHD or 
overlap syndrome developing before or present at the time of 
enrollment 
7. Patients receiving corticosteroids >10 mg/day prednisone (or 
other steroid equivalent) for any indication within 7 days before 
the onset of acute GVHD except for adrenal insufficiency or 
premedication for transfusions/IV meds 
8. Patients who are pregnant 
9. Patients receiving investigational agents within 30 days of 
enrollment. However, the Principal Investigator (PI) may approve 
prior use of an investigational agent if the agent is not expected 
to interfere with the safety or the efficacy of itactinib 
10. History of allergic reaction to itacitinib or any JAK inhibitor 
Study Product(s), Dose, 
Route, Regimen 
Itacitinib 200 mg orally daily for 28 day induction cycle followed by 28 
day maintenance cycle  
Duration of 
Administration 
56 days 
Statistical Methodology 
The primary study measure is the proportion of patients who achieve CR 
or PR by day 28 of treatment with itacitinib without the addition of any other 
systemic GVHD treatment including steroids. The expected proportion of 
low-risk acute GVHD patients who achieve CR or PR by day 28 of standard 
steroid treatment is 67%. Extensive preliminary discussion indicate that 
physicians would accept a 15% decrease in the overall response rate to 
primary GVHD treatment (from 67% to 52%) if steroid treatment could be 
avoided in the responders without an increase in the incidence of steroid 
refractory GVHD. A sample size of 70 achieves 81% power to detect a non-
inferiority proportion of 52% using a one-sided exact test with a significance 
level of 0.04 calculated using binomial enumeration of all possible 
outcomes. This study will terminate early if the incidence of steroid 
refractory GVHD exceeds the historical rate of 38% or if the incidence of 
non-relapse mortality (as a measure of all potential toxicities) exceeds the 
historical rate of 9% (section 8.7). 
 
 
 


9 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Acute GVHD 
 
Hematopoietic cellular transplantation (HCT) is an important treatment for high-risk hematologic 
malignancies whose curative potential depends on the graft-versus-leukemia (GVL) effect which is 
mediated by alloreactive T cells in the donor graft.  GVL effects are closely associated with graft-
versus-host disease (GVHD), which is mediated by those same T cells1. Graft-versus-host disease 
(GVHD) targets the skin, liver and GI tract. GVHD is the major cause of non-relapse mortality (NRM) 
after HCT1-3. Maximal GVHD grade, which only reflects response to treatment, correlates with 
NRM4. GVHD symptom severity at presentation modestly correlates with outcomes but not 
sufficiently to guide treatment5,6. For example, the Minnesota classification system uses GVHD 
symptom severity at diagnosis to stratify patients into standard and high risk groups with 
significantly different risk for NRM (22% vs 43%, p<0.001)6. The risk for NRM even in the favorable 
group remains too high to de-escalate treatment, high dose systemic glucocorticoids (steroids). As 
a result, primary treatment for GVHD has not changed over the past 40 years7.  
1.2 
Steroid Treatment 
 
Systemic steroid treatment is well known to increase the risk of serious infections such as bacterial 
sepsis and bacteremia8-11, viral disease such as CMV11-14 and EBV11,15, and invasive fungal 
infections10,11. These complications have remained morbidities in the HCT literature despite modern 
infection prophylaxis8,10,11,16-19.  
 
HCT patients are highly immunocompromised, both as a result of the pre-transplant conditioning 
regimen and GVHD prophylaxis. GVHD itself is immunosuppressive16,17. To better understand the 
contribution of steroid treatment to the infectious complication rate in current patients, we analyzed 
the six-month incidence of serious infections in 79 patients from two centers (Icahn School of 
Medicine at Mount Sinai and Ohio State University) transplanted between 2014-2017 [Fig 1]. 
Patients were categorized into two groups – those who were diagnosed with GVHD that was treated 
with systemic steroid therapy (n=43) and those who did not develop GVHD and did not receive 
systemic steroid therapy 
(n=36). We analyzed rates 
of blood culture proven 
bacterial infections, viral 
reactivations 
requiring 
treatment (CMV and EBV), 
and proven invasive fungal 
infections. Patients who 
developed more than one 
infection in a category (e.g., 
multiple 
episodes 
of 
bacterial 
sepsis) 
were 
counted only once. As 
expected, systemic steroid-
treated 
GVHD 
patients 
developed 
significantly 
more bacterial (37% vs 
12%, p=0.009) and viral 
infections (CMV 54% vs 
28%, p=0.02; EBV 12% vs 0%, p=0.04). Interestingly, the incidence of invasive fungal infections 
was lower than published reports and not statistically different between the two groups, perhaps a 
result of the widespread adoption of highly effective broad spectrum anti-fungal prophylaxis10,11,18,19. 
The proportion of patients developing at least one of these life threatening bacterial, viral, or fungal 
infections was significantly higher in the steroid exposed group (59% vs 33%, p=0.03).  


10 
 
 
It is important to note that children are susceptible to the same steroid related toxicities as adults 
as well as additional toxicities. Corticosteroids are potent inhibitors of linear growth, especially 
during the adolescent growth spurt20. Likewise, the incidence of corticosteroid-related 
osteonecrosis, a debilitating skeletal complication, is highest in adolescents, presumably reflective 
of the vulnerability of rapidly growing bone21. Steroid-sparing GVHD treatments are thus even more 
urgently needed in the high risk adolescent population. 
 
1.3 
GVHD Biomarker Algorithms Risk Categorize Patients 
 
The past several years have shown remarkable advances in the prediction of long term outcomes 
by biomarkers22-26. The best algorithm requires only measurements of ST2 and REG3α at GVHD 
diagnosis to accurately stratify patients into three distinct “Ann Arbor” risk groups (Fig 2)27. ST2 and 
REG3α are closely associated with GI GVHD22,28 and increased concentrations at GVHD diagnosis, 
(i.e. Ann Arbor 3) predict for the development of steroid-refractory GI GVHD while low 
concentrations (i.e., Ann Arbor 1) predict for steroid responsiveness and low rates of NRM.  
 
As noted above, clinical symptom severity at GVHD onset as determined by Minnesota risk, 
correlates with outcomes6. Patients with Minnesota standard risk GVHD, the more favorable group, 
primarily present with skin GVHD or mild GI GVHD. We hypothesized that the biomarker algorithm 
would identify a low risk subset within this population (Fig 3). We studied 183 patients with newly 
diagnosed GVHD from the Mount Sinai Acute GVHD International Consortium (MAGIC). Patients 
with both favorable clinical and biomarker features (i.e, Minnesota standard risk and Ann Arbor 1) 
had significantly lower rates of six-month NRM compared to patients with Minnesota standard risk 
but Ann Arbor 2/3 GVHD (9% vs 25%, p=0.002). This novel low risk population comprised 51% 
(94/183) of the standard risk patients, had high response rates to systemic steroid therapy (67% 
CR/PR), and represents the ideal population in which to test steroid-free approaches to GVHD 
treatment. 
 
1.4 
JAK-inhibition as a target for GVHD 
The JAK-STAT pathway provides promising targets for GVHD treatment with less potential toxicity 
than systemic corticosteroids.  
 
GVHD pathogenesis is a three step process consisting of damage to a transplant recipient’s tissue 
during conditioning which primes antigen presenting cells such as dendritic cells, consequent donor 
T-cell activation, and subsequent T-cell mediated tissue damage to the host1. The JAK-STAT 
pathway, whose purpose is to regulate gene expression via cytokine binding to homodimers or 
heterodimers of JAK1, JAK2, JAK3 and/or TYK229, has been implicated in all three phases of 


11 
 
GVHD development30. Preclinical and clinical data from studies with ruxolitinib, a JAK1/2 inhibitor, 
provide a strong rationale to further investigate JAK inhibitors in patients with GVHD. In vivo 
JAK/STAT-signaling inhibition improved survival of mice with GVHD, and decreased dendritic cell 
maturation, T cell activation, and chemokine-induced T cell migration to the target tissues, liver and 
small intestine31. Biochemical studies of these mice showed decreased TNFα and IL12p70 
supporting the role of JAK1/JAK2 signaling in T cell activation and trafficking. Additionally, 
ruxolitinib treatment of murine GVHD increased FoxP3+ regulatory T cells, which are important 
regulators of GVHD31,32. 
 
Ruxolitinib is associated with clinical benefit in human disease30. Zeisser et al reported that the 
overall response rate (ORR) for patients with steroid-refractory GVHD treated with ruxolitinib was 
81.5% (44/54)33. A similar high ORR (85.4%, 35/41) was observed in patients with steroid refractory 
chronic GVHD33. In a small pediatric study of 11 children ages 1 to 16 years with GVHD refractory 
to multiple lines of treatment, including steroids, the ORR was 45% (5/11)34.The primary 
complication of ruxolitinib treatment was grade 3-4 cytopenias which developed in 18% of patients. 
High rates of ruxolitinib-related grade 3-4 cytopenias have also been identified in patients treated 
with myelofibrosis, a JAK/STAT dependent myeloproliferative disorder35-37. These effects are likely 
mediated by JAK2 inhibition, as homodimers of JAK2 are associated with G-CSF, GM-CSF, EPO, 
and TPO signaling29. These undesirable hematologic side effects of ruxolitinib led to the 
development of a more selective JAK1 inhibitor.  
 
Itacitinib, a selective JAK1 inhibitor 
Itacitinib (INCB39110) is an oral selective JAK1 inhibitor that potently inhibits JAK1 (half maximal 
inhibitory concentration, 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 
potently inhibits the phosphorylation of STAT proteins and the production of proinflammatory 
factors induced by other cytokines, such as IL-23 and IL-6 with IC50 values of approximately 30 nM 
to 100 nM.  In contrast, itacitinib shows less inhibition in cell-based assays dependent on JAK2 with 
IC50 values of approximately 1 μM or greater, suggesting that itacitinib is JAK2 sparing in cells.  In 
in vivo models of JAK dependent malignancy, itacitinib impedes subcutaneous tumor growth of 
INA-6 cells expressing WT JAKs when administered by continuous infusion, achieving plasma 
concentrations well below those necessary to inhibit JAK2.   
 
In ongoing and completed clinical pharmacology studies, itacitinib was generally safe and well-
tolerated in 284 healthy subjects, with few discontinuations. The majority of treatment-emergent 
adverse events (TEAEs) were mild in severity. There have been no clinically significant, 
unanticipated safety findings or trends observed. The main drug effect identified was a rapidly 
reversible dose-related decrease in neutrophil counts presumably caused by neutrophil 
margination; neutrophil decreases generally resolved within 24 to 48 hours of dose discontinuation. 
Other reversible hematologic abnormalities, including decreased reticulocyte count, were observed 
after multiple-dose administration of higher dose levels at which JAK2 inhibition was noted (Itacinib 
investigator brochure v9, Feb 9 2017). In contrast to ruxolitinib, withdrawal syndrome has not been 
observed with itacitinib.   
 
Itacitinib has demonstrated an encouraging safety profile in clinical trials for myelofibrosis and 
psoriasis. Mascarenhas et al. reported that itacitinib, administered at 100 mg BID, 200 mg BID, or 
600 mg daily decreased the symptom burden of myelofibrosis patients38. At the highest dose levels, 
only one patient (3.1%) experienced grade 4 thrombocytopenia, no patient experienced grade 3-4 
neutropenia, and 25% patients developed grade 3 anemia. The rate of grade 3-4 neutropenia, 
anemia, and thrombocytopenia decreased with increased itacitinib dose, suggesting that 
cytopenias were a consequence of the myelofibrosis rather than the drug. Likewise, no significant 
hematologic toxicity was noted in a phase II trial of itacitinib for psoriasis39. Non-hematologic 
toxicities were generally grade 1-2.  
 


12 
 
In total, 777 subjects have been exposed to itacitinib across all clinical trials. Serious adverse 
effects have been infrequent. Expected serious adverse events include anemia (2.4%), fever (1%), 
and urinary tract infection (1%). When all clinical experiences are taken together itacitinib has a 
favorable safety profile. 
 
Itacitinib for the treatment of acute GVHD 
Thirty-one subjects have received itacitinib in combination with high dose steroids for the treatment 
of moderate to severe acute GVHD in a randomized, phase I trial. Patients had either newly 
diagnosed (n=17) or steroid-refractory (n=14) GVHD when randomized to either 200 mg daily or 
300 mg daily of itacitinib. The overall response rate as a first line therapy for GVHD was 83.3% and 
64.7% in the steroid refractory cohort40. The most common adverse events were thrombocytopenia 
(26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%) and hyperglycemia (16.7%), 
all of which are more likely related to the underlying GVHD and/or concurrent use of high dose 
steroids than to itacitinib because these events were not observed in other itacitinib trials. The 
incidence of infections was not higher than expected. There were three CMV infections and three 
cases of sepsis out of 31 patients. GI bleeding, a symptom of severe GI tract GVHD, was observed 
in three patients. These preliminary data demonstrate both a promising efficacy signal and a good 
safety profile for itacitinib for the treatment of acute GVHD.   
 
Itacitinib dosing 
In the phase I aGVHD trial, the pharmacokinetics of itacitinib were evaluated using plasma samples 
collected pre-dose and on days 1 and 7 at 1 hour, 2 hours, and 4 to 8 hours post-dose.  Although 
inter-subject 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.  Given the similarities in PK and efficacy between dose groups, and the 
increased likelihood of unwanted JAK2 inhibition at higher doses, itacitinib at 200 mg daily has 
been identified as the recommended dose for future GVHD studies.  
1.5 
Mount Sinai Acute GVHD International Consortium (MAGIC) 
MAGIC, a collaboration of 23 international HCT centers in the United States, Canada, Germany, 
Italy, and Thailand, was formed in 2013 for the purposes of conducting innovative translational 
clinical trials in GVHD. Because GVHD grading can be inconsistent among centers41, MAGIC 
centers follow standardized GVHD staging and grading guidance42 whose use is reinforced by 
monthly webinars and remote data audits conducted by the MAGIC Data Coordinating Center 
(DCC) in New York. All MAGIC centers participate in an observational trial of prospective data and 
research sample collection and as a result collection of research samples at GVHD diagnosis is 
very high (85%). MAGIC centers in the US are already highly experienced in enrolling patients on 
GVHD biomarker guided treatment trials. For example, US centers have submitted screening 
samples from more than 300 patients to the CLIA-certified Mount Sinai GVHD laboratory for real 
time Ann Arbor scoring since 2016. Conduct of this low risk GVHD trial through MAGIC will leverage 
an existing infrastructure with substantial experience in successful conduct of similar trials. 
1.6 
Correlative Studies 
Serial serum biomarkers. GVHD biomarkers are prognostic early after HCT, at diagnosis, and 
during treatment23,26,27, but the relationship between changes in GVHD biomarker concentrations 
measured serially over time and outcomes is not yet well understood. We will collect four weekly 
samples from patients on this study and correlate changes in biomarkers with long term outcomes. 
We expect that GVHD biomarkers will remain low in study patients who respond to itacitinib 
treatment, but will rise in non-responders. 
1.7 
Summary of Study Rationale 
 
Standard treatment for GVHD involves high doses of steroids which are highly toxic. The MAGIC 
algorithm identifies the low risk patients most likely to benefit from a steroid-free GVHD treatment 
approach. Itacitinib at a 200 mg/day dose has been shown to be safe with few side effects and 


13 
 
phase I data in patients with GVHD showed encouraging efficacy. In this study, patients with low 
risk GVHD will receive itacitinib monotherapy as first line treatment. Patients will be carefully 
monitored for efficacy and toxicity and the salvage rate with steroids for patients who do not respond 
to primary therapy with itacitinib will also be closely monitored. The use of objective laboratory 
measures in addition to clinical symptoms has the potential to transform GVHD therapy and 
represents a key step towards a precision medicine approach for GVHD. This phase II study will 
develop the data required for a definitive randomized phase III trial comparing itacitinib to steroid 
treatment for low risk GVHD. 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To determine the effectiveness of itacitinib monotherapy as primary treatment of 
newly diagnosed, low-risk acute GVHD defined by standard risk clinical criteria 
(Minnesota) and low risk biomarkers (Ann Arbor 1). 
2.2 
Secondary Objectives  
2.2.1 
To assess the safety of itacitinib monotherapy in these patients. 
2.2.2 
To determine the incidence of serious infectious complications in patients with 
GVHD treated with itacitinib  
2.2.3 
To determine the incidence of steroid refractory GVHD in patients whose GVHD 
is not responsive to itacitinib 
2.3 
Primary Endpoint 
 
Proportion of patients who achieve CR or PR by day 28 of treatment with itacitinib 
without the addition of any other systemic GVHD treatment including steroids. 
 
CR is defined as absence of GVHD symptoms. PR is defined as improvement in one 
or more organs involved with GVHD symptoms without progression in other organs. 
For a response to be scored as CR or PR on day 28, the patient must be in CR or PR 
on day 28 and have had no intervening systemic therapy for acute GVHD other than 
itacitinib. 
 
Secondary endpoints: 
 
1. Cumulative incidence of steroid-refractory GVHD (defined as GVHD that worsens 
(increase by one or more grade) after 3 days, or fails to respond to treatment within 
7 days (for GVHD grade III) or 14 days (for GVHD grade II) or 2nd line therapy 
beyond systemic steroid treatment is begun within 28 days of starting steroids. 
2. Distribution of maximal GVHD grade (I-IV) by day 28 after starting treatment with 
itacitinib 
3. Cumulative incidence of serious infections (defined as bacteremia, CMV infection 
needing treatment, EBV infection needing treatment, or invasive fungal infection) 
4. Overall survival at 6 and 12 months 
5. Cumulative incidence of NRM at 6 and 12 months 
6. Relapse rate at 6 and 12 months 
7. Cumulative incidence of chronic GVHD requiring systemic steroid treatment by one 
year from enrollment 


14 
 
8. Cumulative steroid dose (over 4 weeks) in patients who receive steroids as second 
line therapy  
 
Safety endpoints  
 
1. Number and proportion of patients developing reportable AEs and SAEs according to 
relatedness to study drug and stratified by severity 
 
Exploratory endpoints 
 
1. GVHD biomarker concentrations (ST2 and REG3) and their associations with clinical 
endpoints at day 28 after starting treatment with itacitinib 
 
The two hypotheses are: 1) that GVHD biomarkers will remain low in study patients 
who respond to itacitinib treatment, but will rise in non-responders and (2) biomarker 
concentrations will be equivalent to those in historical control patients who respond to 
steroid treatment for low risk GVHD. 
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and none of the exclusion criteria to be eligible to participate 
in the study. Study treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
 
3.1.1 
Newly diagnosed GVHD that meets criteria for Minnesota standard risk (see 
section 7.0) 
 
3.1.2 
Ann Arbor 1 GVHD by biomarkers 
 
3.1.3 
GVHD not previously treated systemically (topical therapies and non-absorbed 
steroids are allowed) 
 
3.1.4 
Any donor type, HLA-match, conditioning regimen is acceptable 
 
3.1.5 
Age 12 years and up (children <18 years must weight 50 kg or more) 
 
3.1.6 
Patients must be engrafted post-transplant (ANC ≥500/μL and platelet count 
≥20,000). Use of growth factor supplementation to maintain neutrophil count is 
allowed.  
 
3.1.7 
Direct bilirubin must be <2 mg/dL unless the elevation is known to be due to Gilbert 
syndrome within 3 days prior to enrollment. 
 
3.1.8 
ALT/SGPT and AST/SGOT must be <5x the upper limit of the normal range within 
3 days prior to enrollment.  
  
3.1.9 
Signed and dated written informed consent obtained from patient or legal 
representative.  
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patients currently being treated with any JAK inhibitor including ruxolitinib 


15 
 
 
3.2.2 
Relapsed, progressing, or persistent malignancy requiring withdrawal of systemic 
immune suppression 
 
3.2.3 
Patients with uncontrolled infection (i.e., progressive symptoms related to infection 
despite treatment or persistently positive microbiological cultures despite 
treatment or any other evidence of severe sepsis) 
 
3.2.4 
Severe organ dysfunction including requirement for dialysis, mechanical 
ventilation, or oxygen supplementation exceeding 40% FiO2 within 7 days of 
enrollment. 
 
3.2.5 
Creatinine clearance or estimated glomerular filtration rate <30 ml/min as 
calculated by institutional practice (e.g., Cockcroft-Gault equation, CKD-EPI 
equation, etc) 
 
3.2.6 
A clinical presentation resembling de novo chronic GVHD or overlap syndrome 
developing before or present at the time of enrollment 
 
3.2.7 
Patients receiving corticosteroids >10 mg/day prednisone (or other steroid 
equivalent) for any indication within 7 days before the onset of acute GVHD 
except for adrenal insufficiency or premedication for transfusions/IV meds 
 
3.2.8 
Patients who are pregnant 
 
3.2.9 
Patients receiving investigational agents within 30 days of enrollment. However, 
the Principal Investigator (PI) may approve prior use of an investigational agent if 
the agent is not expected to interfere with the safety or the efficacy of itactinib 
 
3.2.10 History of allergic reaction to itacitinib or any JAK inhibitor 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
 
Study Schema 
 
To be eligible for this study, patients must have newly diagnosed low risk acute GVHD defined as 
Minnesota standard risk based on symptoms and Ann Arbor 1 GVHD based on biomarkers (see 
Appendix A). Patients will be recruited from centers participating in the Mount Sinai Acute GVHD 
International Consortium (MAGIC) where the procedures for obtaining screening samples for 
biomarker scoring are already established.  
 
The pre-screening process is outlined in Figure 4 above. Consented patients will be registered into 
the remote data entry system using a unique study number assigned by the MAGIC DCC. Five mL 
of serum will be collected from patients after GVHD has been diagnosed and before any systemic 


16 
 
treatment has begun and shipped priority overnight to the Mount Sinai GVHD laboratory for early 
AM arrival (see MAGIC Sample Collection and Storage manual for shipping procedures). 
Samples can be received Tuesday through Saturday. Once received in the laboratory, the GVHD 
biomarkers used to assign the Ann Arbor GVHD risk score will be measured by ELISA using 
standard technical procedures. Processing, measuring, and confirming the ELISA assay results 
take 4.5 hours (range 4-6 hours). Once the Ann Arbor GVHD risk score is confirmed by Dr. Ferrara 
(or Dr. Levine in Dr. Ferrara’s absence), the investigator at the participating center will be notified 
of the score by telephone and written confirmation by email. 
 
Patients who meet eligibility criteria will begin treatment with the study drug, itacitinib. Patients who 
do not meet eligibility criteria will be considered screen failures and treated according to local 
institutional practice. 
 
Patient registration for this trial will be centrally managed by the MAGIC Data Coordinating Center 
of the Icahn School of Medicine at Mount Sinai as described below: 
 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the MAGIC Data Coordinating Center (DCC).  
 
It is the responsibility of the local site investigator to confirm patient eligibility for the clinical trial. 
Confirmation of a high MAGIC GVHD risk score will be provided directly to the identified Primary 
Site contact from the participating site by Dr. Ferrara, Dr. Levine or designee. All other eligibility 
criteria will be provided by the participating site. After patient eligibility has been determined, a copy 
of the completed Eligibility form will be submitted by the requesting site to the MAGIC Data 
Coordinating Center by email to magic@mssm.edu with local site investigator signature and 
supporting source documentation. 
 
The MAGIC Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration. An email will be sent by the registrar to the requesting site registrar to 
confirm patient registration. Patients found to be ineligible for participation after being consented 
will be considered screen failures, and documented as such in the Screening and Enrollment Log. 
These patients will not receive study treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
5.1.1 
Protocol treatment must start within 4 days of confirmation of Ann Arbor 1 GVHD 
risk score. For example, a patient who is diagnosed with GVHD skin stage 3 
(Minnesota standard risk GVHD) on day 21 post-HCT, is consented on a Monday 
and has a research sample shipped to the Ferrara Lab that day, will have their 
GVHD risk score assigned on Tuesday (day 22). Such a patient must begin study 
treatment no later than Friday (day 25).  
5.1.2 
Itacitinib will be supplied by Incyte. Each participating site will have a sufficient 
supply of itacitinib on hand to begin treatment. Additional doses will be shipped to 
the participating site to complete treatment.  See section 9.1 for preparation, 
dispensing, and administration information. 
 


17 
 
5.1.3 
Study treatment will consist of itacitinib 200 mg administered orally daily for a 28 
day induction cycle followed by a 28 day maintenance cycle. 
5.1.4 
Missed doses will be made by extending the schedule until all 28 doses (or 56 
doses in responding patients) have been administered or ten weeks from first 
dose, whichever comes first. 
5.1.5 
Subjects who miss more than five consecutive doses of the first 28 doses due to 
noncompliance will be analyzed for safety but considered inevaluable for efficacy 
assessment and replaced. 
5.1.6 
GVHD Prophylaxis Medications 
Medications given for GVHD prophylaxis such as cyclosporine, tacrolimus, 
sirolimus, methotrexate, mycophenolate should be continued at therapeutic doses 
(according to institutional standards) and adjusted as necessary for renal, central 
nervous system (CNS) or other toxicity using institutional guidelines.  This study 
allows for changes in GVHD prophylaxis medication (e.g., replacement of 
cyclosporine 
with 
sirolimus 
for 
management 
of 
posterior 
reversible 
encephalopathy syndrome [PRES]) as per institutional standards. GVHD 
prophylaxis medications will be tapered according to local institutional tapering 
practices. 
5.1.7 
GVHD treatment 
The preliminary data for this study were generated from patients transplanted at 
multiple centers with heterogeneous GVHD treatment practices. In order to 
develop “real world” experience in this study, institutional GVHD treatment 
practices are permitted unless their use is explicitly prohibited.  
 
Systemic steroid treatment should be started if any of the following criteria are met: 
GVHD worsens (increase by one or more grade) after 3 days, or failure to respond 
to treatment within 7 days (for GVHD grade III) or 14 days (for GVHD grade II). 
The decision to remove a patient from study treatment should be discussed with 
the site PI. Itacitinib must be stopped when systemic steroid treatment is begun. 
When systemic steroid treatment is initiated, the minimum starting dose is 
prednisone (or other steroid form equivalent) 1 mg/kg/day for GVHD that involves 
only the skin and/or upper GI tract and 2 mg/kg/d for GVHD that involves the lower 
GI tract and/or liver. Institutional practices can be followed for steroid tapering 
schedules. 
 
 
5.1.8 
Ancillary therapies 
Ancillary/supportive care measures for acute GVHD such as the use of anti-motility 
agents for diarrhea, including octreotide, is allowed at the discretion of the treating 
physician.  Use of ursodiol to prevent/reduce gall bladder sludging or prevent 
hepatic transplant-related complications is allowed according to institutional 
guidelines 
5.1.9 
Supportive Care Guidelines 
All patients should receive the following: 
 
 
Transfusion support per institutional practice 
 
Anti-infective prophylaxis against herpes virus is required but otherwise 
institutional practice can be followed. 
 
Anti-infective prophylaxis against Pneumocystis jiroveci, bacterial and 


18 
 
fungal infections according to standard institutional guidelines. 
 
Pre-emptive monitoring and treatment for CMV and EBV infections is 
required but otherwise institutional practice can be followed. 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.  
 
The dose of itacitinib will not be modified. In the event of a SAE causally related to study 
drug, itacitinib should be discontinued and the patient will be included in all analyses of 
safety and efficacy. Up to five doses of itacitinib may be held at investigator discretion for 
nausea, difficulty swallowing, or other complications unrelated to itacitinib and then 
restarted.  
5.3 
Concomitant Medications/Treatments 
Concomitant use of other investigational agents is not permitted during the treatment phase 
of the study without PI approval.   
 
Coadministration of a strong CYP3A4 inhibitor (itraconazole) increased itacitinib exposure 
inhealthy subjects by approximately 5-fold. Concomitant use of strong CYP3A inhibitors 
should be avoided if clinically feasible. If coadministration of itacitinib with a strong CYP3A 
inhibitor cannot be avoided, use of an agent with less CYP3A4 inhibition in a class, for 
example, posaconazole for fungal infection, or prophylaxis is recommended over other 
choices like voriconazole or itraconazole. Careful monitoring of hematology parameters 
and clinical signs and symptoms of itacitinib-related adverse reactions is recommended 
upon initiation of a strong CYP3A4 inhibitor. 
 
Subjects receiving itacitinib should avoid pomegranates or pomegranate juice, grapefruit 
and grapefruit juice, all of which are known to inhibit cytochrome CYP3A enzymes and may 
increase the exposure to itacitinib. 
 
Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure 
of itacitinib in healthy subjects by approximately 80%. Concomitant use of strong CYP3A 
inducers (such as, but not limited to, phenytoin, rifampin, carbamazepine, and St John's 
Wort (Hypericum perforatum) should be avoided. 
5.4 
Other Modalities or Procedures 
Patients who have undergone allogeneic HCT are often simultaneously being treated for 
other conditions and transplant-related complications. Such treatments will be considered 
distinct from the study drug treatment. 
5.5 
Duration of Therapy 
The duration of protocol therapy on this study is eight weeks (56 doses). Protocol therapy 
will end after the 56th dose of itactinib has been administered or if any of the following 
criteria apply: 
 
 
Systemic steroid treatment (or any other systemic treatment) for GVHD is 
initiated OR 
 
Patient voluntarily withdraws from treatment OR 
 
General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator OR 
 
Ten weeks has elapsed since the first dose of itacitinib 


19 
 
5.6 
Off Treatment Criteria  
Patients will be removed from receiving the investigational drug when any of the criteria 
listed in Section 5.5 apply. The reason for ending investigational drug therapy and the date 
the patient was removed from treatment will be documented in the study record. All patients 
who discontinue treatment should comply with protocol specific follow-up procedures as 
outlined in Section 5.7. The only exception to this requirement is when a subject withdraws 
consent for all study procedures or dies. 
5.7 
Duration of Follow-Up 
Patients will be followed until 1 year post-enrollment, withdrawal of consent or until death, 
whichever occurs first. HCT patients are followed closely and frequent clinical evaluations 
are the norm. While the following outlines the minimum frequency of follow-up evaluations, 
it is anticipated that the majority of patients will be evaluated more frequently.  
 
During the first 4 weeks of participation (i.e., through the last dose of the first cycle of 
itactinib), patients will be seen at least weekly for assessment of their GVHD. During the 
second four weeks (i.e., the maintenance cycle of itacitinib), patients should be seen at 
least every other week, although it is anticipated that most patients will be seen more 
frequently, i.e., weekly. Patients will be evaluated at least at three, six and twelve months 
from treatment initiation.  
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral, or 
administrative reasons. The reason(s) for discontinuation from study will be 
documented and may include: 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment;  
5.8.3 
Patient is unable to comply with protocol requirements; 
5.8.4 
The subject has any disorder or condition that in the investigator's judgment may 
impede the participant's participation in the study, pose increased risk to the 
participant, or confound the results of the study 
5.8.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.8.6 
Termination of the study; 
5.8.7 
Patient completes protocol treatment and follow-up criteria. 
 
 
Discontinuation of study treatment (such as subsequent to starting systemic steroids) does 
not remove the patient from other aspects of study participation including providing follow-
up data. Participants will be encouraged to provide this information whether or not they 
complete the anticipated course of study treatment. 
5.9 
Patient Replacement 
Patients who enroll in the study but do not receive any study treatment will be replaced. 
Patients who initiate study treatment but miss more than five consecutive doses of the first 


20 
 
28 doses for reasons other than toxicity will also be replaced. The number of patients and 
reason(s) for replacement will be recorded and will be used to assess the feasibility of the 
study design. This study will allow up to 20% of patients who start treatment (n=14) to be 
replaced. 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. Frequent monitoring of clinical 
chemistry and hematology is routine in HCT patients. This study does not require specific 
laboratory monitoring other than specified below. 
6.1.1 Informed Consent  
6.1.2 Demographics 
6.1.3 Review subject eligibility criteria 
6.1.4 Review concomitant medications (immunosuppressants and GVHD prophylaxis 
medications only) 
6.1.5 Adverse event assessment 
Baseline adverse events will be assessed and preexisting conditions will be 
recorded. See Section 8.0 for Adverse Event monitoring and reporting. 
6.1.6 Serum chemistries (within 3 days prior to enrollment) 
ALT/SGPT, AST/SGOT, and total bilirubin are required for assessment of exclusion 
criteria within 3 days prior to enrollment. 
6.2 
Follow-Up Procedures 
The following outlines the minimum frequency of follow-up evaluations, it is anticipated that 
the majority of patients will be evaluated more frequently.  
 
During the first 4 weeks of participation (i.e., through the primary endpoint), patients will be 
seen at least weekly for assessment of their GVHD. During the second four weeks patients 
should be seen at least every other week, although it is anticipated that most patients will 
be seen more frequently, i.e., weekly. Patients will also be evaluated at study day 86 (30 
days from completion of treatment). In addition, relapse, survival, and chronic GVHD will 
be reported at six and twelve months from treatment initiation. 
 
Infections, as defined in sections 7.2.3 to 7.2.5 will be closely monitored on this study. In 
our preliminary data (section 1.2), 100% of CMV infections requiring treatment developed 
within 90 days from starting systemic GVHD treatment, 100% of EBV infections requiring 
treatment, 85% of bacteremia, and 75% of invasive fungal infections. All patients who 
developed at least one serious infection did so within 90 days. Given these data, we will 
monitor for serious infections from start of itacitinib treatment through study day 90. 
 
 
 


21 
 
Follow-up studies are detailed in the Time and Events Table below. 
 
 
CALENDAR BASED ASSESSMENTS 
 
Screening 
 
Study day 0 
Study 
day 7 
Study 
day 14 
Study 
day 21 
Study 
day 281 
Study 
day 42 
Study 
day 56  
Study 
day 90 
Study day 
180 
Study 
day 365 
GVHD 
Flare7 
Windows 
Newly 
diagnosed 
acute GVHD 
in need of 
systemic 
treatment 
+/- 1 day 
Within 4 
days of Ann 
Arbor Score 
Notification 
+/- 2 
days 
+/- 2 
days 
+/- 2 
days 
+/- 1 
day 
+/- 3 
days 
+/- 3 
days 
+/- 5 
days 
+/- 14 
days 
+/- 14 
days 
+/- 3 
days 
Eligibility Review 
X 
  
  
  
  
  
  
  
  
  
  
 
Concomitant 
Medication 
Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Event 
Evaluations3 
X 
Adverse events will be reported from study day 0 through 30 days after the last dose of study drug.  
Report serious adverse events as they occur. 
 
Infections 
 
Infections as defined in sections 7.2.3-7.2.5 will be reported from study day 0 through study day 90  
 
Serum Chemistry 
X 
  
  
  
  
  
  
  
  
  
  
 
GVHD Staging4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Itacitinib 
  
200 mg daily induction cycle 
200 mg daily 
maintenance cycle 
(responders only)5 
 
 
  
  
 
Survival, Relapse 
& Chronic GVHD 
Status 
  
  
  
  
  
  
  
  
 
X 
X 
 
 
CORRELATIVE STUDIES 
 
5 ml serum6 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
1 The primary endpoint is assessed on day 28 ±1 day 
2 Concomitant medication review will record only immunosuppressants and other drugs administered during 
the reporting period for GVHD prevention and treatment. 
3 Serious adverse events are reported as they occur. Other adverse events can be batch reported after the 
patient has been followed for 30 days from the last dose of study drug. 
4 GVHD staging will follow the detailed guidelines provided in the MAGIC Acute GVHD Staging Guidance. 
During the maintenance cycle GVHD staging is required every other week. GVHD staging and treatment 
should be reported weekly through day 100 post-HCT for patients co-enrolled on the MAGIC observational 
study as per the observational study calendar of events. 
5 Itacitinib maintenance dosing is only given to patients who respond to the induction cycle 
6 Serum samples will be banked for correlative studies. To avoid unnecessary sample collection, when 
GVHD driven samples are collected within 3 days of a scheduled calendar based sample, the calendar 
based sample should not be collected. 
7  Collect GVHD staging data and a serum sample if GVHD flares during the study. 
 
 


22 
 
7.0 
GVHD CLINICAL STAGING 
GVHD clinical staging will be according to the established criteria used for MAGIC clinical trials. 
 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No rash 
Rash < 25% BSA 
25-50% 
> 50% Generalized 
erythroderma 
Plus bullae and 
desquamation 
>5% BSA 
Liver 
Bilirubin ≤  2 mg/dl 
2.1-3 mg/dl 
3.1-6mg/dl 
6.1-15mg/dl 
>15mg/dl 
GI tract 
Adult: < 500 
ml/day 
Children <10 
mg/kg/d 
Adult: 500–1000 
ml/day  
Children 10-19.9 
mg/kg/d 
Adult: 1001-1500 
ml/day  
Children 20- 30 
mg/kg/d 
Adult: >1500 
ml/day  
Children > 30 
mg/kg/d 
Severe abdominal 
pain +/- ileus, frank 
blood or melena 
(regardless of stool 
volume) 
UGI 
 
Severe 
nausea/vomiting 
 
 
 
 
For GI GVHD, children is defined as <18 years of age and <50 kg weight 
 
For stage 4 GI GVHD, severe abdominal pain is defined as (1) pain that requires opioid use and (2) pain that 
significantly impacts on performance status as determined by the treating physician 
 
Comprehensive GVHD staging guidance is provided in the MAGIC GVHD Staging Guidance. 
 
Overall Clinical Grade: 
Grade 0 
No stage 1-4 of any organ 
Grade I  
Stage 1-2 skin and no liver or GI involvement 
Grade II 
Stage 3 skin and/or Stage 1 liver and/or Stage 1 GI 
Grade III 
Stage 0-3 skin with Stage 2-3 liver and/or Stage 2-3 GI 
Grade IV 
Stage 4 in any target organ (skin, liver, GI) 
 
Minnesota Risk Scoring6: 
Standard Risk:  
Stage 1-3 skin (single organ system) 
Stage 1-2 GI (single organ system) 
Stage 1-3 skin + Stage 1 GI (two organ system involvement) 
Stage 1-3 skin + Stage 1-4 liver (two organ system involvement) 
High Risk: Any other combination of single or dual organ aGVHD stages  
 
Minnesota risk scoring calculator: http://z.umn.edu/MNAcuteGVHDRiskScore 
7.1 
ENDPOINT AND RESPONSE CRITERIA 
7.1.1 
Definitions 
Evaluable for response: Safety, tolerability, and efficacy of itacitinib will be 
assessed from the initiation of the first itacitinib treatment 
 
Complete Response (CR): All evaluable organs (skin, liver, GI tract) stage 0. For 
a response to be scored as CR on day 28, the patient must be in CR on that day 
and have had no intervening additional GVHD therapy. 
 
Partial Response (PR): An improvement in one or more organ involved with GVHD 
symptoms without worsening in others. For a response to be scored as PR on day 


23 
 
28, the patient must be in PR on that day and have had no intervening additional 
GVHD therapy. 
 
No response (NR): All responses that are not CR or PR. Patients who receive any 
systemic GVHD therapy other than the continuation or modification of GVHD 
prophylaxis, systemic steroids, and topical/non-absorbable oral steroid therapy, 
will be scored as NR on day 28 regardless of organ staging.  
7.1.2 
Proportion of CR and CR+PR 
CR and PR on day 28 are scored in comparison to the patient’s acute GVHD 
staging on the day itacitinib treatment began. 
7.1.3 
Steroid refractory GVHD 
The first salvage therapy for patients who are not responding to itacitinib is 
systemic steroid treatment.  Patients treated with systemic steroids whose GVHD 
worsens (increase by one or more grade) after 3 days, or fails to respond to 
treatment within 7 days (for GVHD grade III) or 14 days (for GVHD grade II) or 
who start additional lines of therapy beyond systemic steroid treatment within 28 
days of starting steroids will be considered steroid refractory. Escalation of steroid 
doses during treatment for GVHD are not considered in the definition of steroid 
refractory GVHD. 
7.1.4 
Steroid discontinuation 
For patients who initiate systemic steroid treatment for GVHD, the date of 
discontinuation of steroid therapy will be recorded. 
7.1.5 
Lines of GVHD therapy 
The initiation of systemic steroids for treatment of GVHD will be considered second 
line therapy. Any additional systemic immunosuppression treatment to steroid 
therapy for acute GVHD will be considered 3rd line therapy and considered a failure 
to respond to steroid treatment. Resumption or changes in GVHD prophylaxis 
(e.g., substitution of mycophenolate for tacrolimus due to PRES) are not 
considered new lines of therapy. Topical steroids and non-absorbable oral steroids 
are not considered new lines of therapy. 
7.1.6 
Non-Relapse Mortality (NRM) 
Any death that occurs after HCT not attributable to relapse of the underlying 
disease will be considered a non-relapse death. 
7.1.7 
Chronic GVHD 
The occurrence of chronic GVHD as defined by NIH consensus criteria requiring 
systemic treatment, including date of diagnosis, will be recorded.  
7.1.8 
Relapse 
Relapse, including date of relapse, of the underlying malignancy will be recorded. 
7.2 
SAFETY/TOXICITY DEFINITIONS 
7.2.1 
Itacitinib monotherapy was generally safe and well tolerated in clinical studies of 
777 adults including healthy subjects and patients with psoriasis or myelofibrosis 
(Itacitinib investigator brochure v9, Feb 9 2017). There were no non-hematologic 
adverse events that occurred in >1% of subjects. Hematologic adverse events 
grade 3 or 4 included decreased hemoglobin (12.4%), decreased platelet count 
(9.1%) and decreased neutrophil count (1.4%) of patients. These hematologic 


24 
 
adverse events were most common in patients with myelofibrosis and improved 
with higher doses of itacitinib38 suggesting they were more likely due to the 
underlying disease than itacitinib. There were no toxicities observed in a study of 
itacitinib plus steroids in patients with acute GVHD that were felt to be related to 
itacitinib administration. Known or plausible toxicities that may be related to 
itacitinib will be reported.  
7.2.2 
Hematologic Toxicities 
Hematologic toxicities will be graded according to CTCAE v4 criteria. 
7.2.3 
Infectious Toxicities 
Infections, including serious and/or life-threatening infections, are common in 
patients who undergo HCT. MAGIC clinical trial practice requires the reporting of 
any life-threatening infection as defined by the Blood and Marrow Transplant 
Clinical Trials Network grade 3 (see Appendix B for further details).  
 
Grade 3 Bacterial Infections: 
a. 
Bacteremia with deep organ involvement 
b. 
Severe sepsis with bacteremia 
c. 
Fasciitis requiring debridement 
d. 
Pneumonia requiring intubation 
e. 
Brain abscess or meningitis without bacteremia 
f. 
Clostridium difficile toxin positive stool with toxic dilatation or renal 
insufficiency with/without diarrhea. 
 
Grade 3 Fungal Infections: 
a. 
Fungemia, including candidemia 
b. 
Proven or probable invasive fungal infections (e.g. Aspergillus, Mucor, 
Fusarium, Scedosporium) 
c. 
Disseminated fungal infections (e.g. multifocal pneumonia, presence of 
urinary/blood antigen, CNS involvement) with Histoplasmosis, 
Blastomycosis, Coccidiomycosis or Cryptomycosis 
d. 
Pneumocystis jiroveci pneumonia  
 
Grade 3 Viral Infections: 
a. 
Severe VZV infection with either associated coagulopathy or organ 
involvement 
b. 
CMV end organ involvement (e.g. pneumonitis, enteritis, retinitis) 
c. 
EBV Post-transplant lymphoproliferative disorder (PTLD) 
d. 
Adenovirus with end organ involvement (except adenoviral conjunctivitis 
or upper respiratory tract disease) 
e. 
All lower respiratory tract viruses 
f.  
Viral encephalitis or meningitis 
 
Grade 3 parasitic infections: 
a. 
Toxoplasmosis involving the CNS 
b. 
Strongyloides hyperinfection 
 
Non-microbiologically documented infections: 
a. 
Any acute pneumonia requiring mechanical ventilation 
b. 
Severe sepsis without an identified organism 
 
In addition, the following non-BMT CTN infections will be reported: bacteremia 
requiring systemic antibiotics and CMV and EBV reactivation requiring treatment. 


25 
 
7.2.4 
Bacteremia 
The date, identification, and treatment of bacteremia requiring systemic antibiotic 
therapy will be reported. 
7.2.5 
Viral Reactivations 
Because viral reactivations often require treatment in the HCT population, even in 
the absence of end organ disease, the following viral infections/reactivations and 
their treatment, if any, will be reported: 
 
The date, anatomical site or body fluid (e.g., blood, nasopharyngeal swab, stool, 
etc.), and method of detection for CMV, EBV, HHV6, VZV, HSV and adenovirus 
will be reported. 
7.3 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE version 4.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
7.4 
Children as a Special Population 
 
 
 
This study will enroll minor subjects age 12-17 years. It is important to include children in 
this clinical trial for GVHD because children are not only susceptible to the same risks from 
standard care with systemic steroids as adults but are particularly at risk for permanent 
skeletal damage20,21. Although itacitinib has not been studied in children, the JAK inhibitor 
ruxolitinib has been used therapeutically in children as a treatment for GVHD34 and as 
monotherapy in a phase I trial of 49 children with refractory cancer43. The side effect profile 
was the same as in adults with no unexpected toxicities. Ruxolitinib is considered safe for 
use in children based on the phase I trial and experience with this agent in children 
continues to grow44,45. Itacitinib has not yet been tested in children but we do not expect 
children to experience different toxicities than adults. In the interest of subject safety we 
will closely monitor the efficacy and toxicity of itacitinib in patients under the age of 18 years 
and, in the event of any unexpected toxicities or lack of efficacy, accrual to children will be 
halted (see section 12.0). 
8.0 
ADVERSE EVENTS 
8.1 
Itacitinib 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 
8.1.1 
Contraindications 
 
 
Patients who have had an allergic reaction to itacitinib or any other JAK inhibitor. 
8.1.2 
Special Warnings and Precautions for Use: none 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll 
in future studies using similar agents. Data on adverse events will be collected from the 
time of the initial study treatment (day 0) through 30 days after the last dose of itacitinib. 
Any serious adverse event that occurs more than 30 days after the last dose of itacitinib 
that is considered related to the study treatment must also be reported. Serious Adverse 
Events (SAEs) will continue to be followed until: 


26 
 
 
Resolution or the symptoms or signs that constitute the serious adverse event 
return to baseline; 
 
There is satisfactory explanation other than the study treatment for the changes 
observed; or  
 
Death. 
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical history. 
All events meeting the criteria and definition of an AE (CTCAE grade 3 or higher) or SAE, 
as defined in Section 8.3, occurring from the initial study treatment administration through 
30 days following the last dose of the study treatment or study intervention must be 
recorded as an adverse event in the patient’s source documents and on the CRF.  
8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  
 
 
Diagnostic and therapeutic non-invasive and invasive (i.e., surgical) 
procedures will not be reported as adverse events. However, the medical 
condition for which the procedure was performed must be reported if it meets 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 
 
 
Event reporting for GVHD treatment protocols can be complicated and 
confusing for investigators, data managers, and regulatory oversight bodies 
because patients typically develop numerous complications as part of the 
typical treatment course not related to study therapy. Furthermore, transplant-
related complications often occur both simultaneously and in series, as one 
complication leads to a series of downstream events. Therefore, a well-
conceived event reporting plan separates background transplant and GVHD 
noise as might be seen with any transplant where GVHD develops from study 
related events that are relevant to patient safety. On this study, we will not 
report any CTCAE grade 1 and 2 adverse events (which make up the majority 
of events) unless the investigator determines the event should be reported to 
protect subject safety. 
 
 
It is common for HCT recipients to experience multiple complications as part 
of the transplant itself that are unrelated to exposure to investigational agents. 
Symptoms of the original or targeted disease are not to be considered adverse 
events for this study except for hematological toxicities as defined below. From 
start of study treatment through 30 days from last dose of itacitinib, symptoms 
related to the conditioning regimen or GVHD will not be reported unless the 
event is both serious (see section 8.3.2) and considered by the investigator to 


27 
 
also be possibly, probably, or definitely related to itacitinib. After 30 days from 
the last dose of itacitinib, adverse events should only be reported if they are 
both serious and probably or definitely related to itacitinib. Events that are 
unlikely or unrelated to itacitinib are not required to be reported. Reporting of 
such events should include the investigator’s assessment as to whether the 
event should be attributed to any of the HCT procedure itself, GVHD, exposure 
to immunosuppressive agents other than itacitinib, and itacitinib. An event may 
be attributable to all, some, or one of these categories.  
 
 
Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms or require therapy and otherwise meet 
the criteria for a reportable adverse event as defined above. They are to be 
captured under the signs, symptoms or diagnoses associated with them. 
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, it results 
in any of the following outcomes: 
  
o 
Death 
If death results from (progression of) the disease, the disease should be 
reported as event (SAE) itself. 
 
o 
A life-threatening adverse event 
An adverse event is considered ‘life-threatening’ if, in the view of either the 
investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.  
 
o 
Inpatient hospitalization or prolongation of existing hospitalization for ≥24 
hours. 
 
o 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
o 
A congenital anomaly/birth defect 
 
o 
Important medical event 
Any event that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition of “Serious Adverse Event”. 
Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home; convulsions that do not 
result in inpatient hospitalization or the development of drug dependency or drug 
abuse. 
 
As additional guidance, previously planned (prior to signing the informed consent 
form) surgeries should not be reported as SAEs unless the underlying medical 
condition has worsened during the course of the study and the definitions in section 
8.3.1 are met. Preplanned hospitalizations or procedures for preexisting conditions 
that are already recorded in the patient’s medical history at the time of study 
enrollment should also not be considered SAEs. Hospitalization or prolongation of 
hospitalization without a precipitating clinical AE (for example, for the 
administration of study therapy or other protocol-required procedure) should not 
be considered SAEs. However, if the preexisting condition worsened during the 


28 
 
course of the study, and the reporting requirements in section 8.3.1 are also met, 
it should be reported as an SAE. 
 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 
 
For approved and marketed drugs or devices, those adverse events are 
described in the approved Package Insert (Label).  
 
For investigational new drugs or devices, those adverse events are 
described in the FDA Investigator’s Brochure.  
 
In clinical research studies, information on expected adverse events is 
also summarized in the protocol and in the consent document.  See 
section 9.1 for the list of expected adverse events related to the drug under 
study. 
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
 
The Sponsor Investigator will report SAEs to regulatory bodies and to the participating 
sites in the following manner: 
 
 
 


29 
 
Sponsor SAE Reporting  
Event occurring 
from Consent to 
30 Days post last 
itacitinib dose 
Report to: 
Event occurring 
after 30 Days 
post last 
itacitinib dose 
Report to: 
FDA / 
IRB/Incyte 
Consortium 
FDA / IRB/ 
Incyte 
Consortium 
All SAEs;  
 Expected or 
Unexpected 
 Possible, 
Probable, or 
Definite  
24 hours 
from 
knowledge 
Monthly 
SAEs –  
 Expected  
 Probable or 
Definite 
 
OR 
 
 Unexpected 
 
 Possible, 
Probable or 
Definite 
24 hours 
from 
knowledge 
Monthly 
8.5.2 
The Principal Investigator must be notified within 3 business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse 
event, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the itacitinib.  Incyte should be notified by the PI within 24 
hours to enable reporting to regulatory authorities as required. 
8.5.3 
The investigator must report all events meeting the criteria and definition of a 
serious adverse event that are unexpected and possibly related (definite, probable 
or possible to study treatment administration) to the local IRB as per local IRB 
policy.  
8.5.4 
All Serious Adverse Events will be reported using the Serious Adverse Event form 
within 3 days of first awareness of the event to the MAGIC Data Coordinating 
Center. A copy of the form should be sent to the MAGIC Coordinator via email to 
magic@mssm.edu. 
 
The MAGIC Data Coordinating Center will disseminate information regarding 
serious adverse events to the participating sites within 3 days of review of the 
information by Dr. Levine if the event(s) is believed to be related (i.e. probably or 
definitely) to the study medication. All other Serious Adverse Events will be 
discussed on monthly webinars held with all participating centers (see section 12). 
 
The Principal Investigator will be responsible for reporting of events to the FDA 
and supporters, as appropriate and defined in the regulations under 21 CFR 
312.32. 
8.5.5 
SAE/Pregnancy Reporting to Incyte: 
 
Initial Serious Adverse Events (SAEs) and/or subsequent follow-up reports will be 
reported to Incyte via email to: SafetyReporting@Incyte.com, fax (+) 1-866-981-
2057.  SAE reports should be for a single subject with any additional documents 
(i.e. discharge summary, relevant test results) included for the same subject as 
individual attachments to the email. One email can have multiple attachments as 


30 
 
long as each attachment contains relevant information for the same subject. 
Please email your SAE form with a cover sheet and any additional 
attachments to the IST email address: SafetyReporting@Incyte.com, fax (+) 
1-866-981-2057 
 
Reporting 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 hrs of discovery 
of a pregnancy of a subject who has taken itacitinib or the pregnancy of a partner 
for a subject who has taken itacitinib.  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 
8.6 
Reporting of Unanticipated Problems 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem involving risks to subjects or others, 
the investigator should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience or outcomes are considered unanticipated 
if it meets all of the following criteria: 
1. Unexpected (not previously documented in terms of nature, severity, or frequency); 
2. Causally related or possibly related to participation in the study; and 
3. Suggests that the research places subjects or others at a greater risk of harm than 
was previously known or recognized. 
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the MAGIC Data Coordinating 
Center within 3 days of first awareness of the events, and to the local IRB as per local IRB 
policy. 
8.7 
Stopping Rules 
We will monitor the study subjects for both efficacy and toxicity. We will allow continuous 
accrual on to the study unless a stopping rule is met or the target accrual is reached. The 
study may also be stopped based on the recommendation of the investigators, the TCI 
DSMC, or at Incyte’s discretion for any reason. 
 
Steroid-refractory GVHD: 
We expect itacitinib monotherapy to be safe because of its extensive use in >700 patients 
prior to this trial. However, in order to protect study subjects we have designed three 
stopping rules that will terminate the trial early if itacitinib monotherapy as a treatment for 
GVHD is either too toxic or ineffective. First, our preliminary data show that the incidence 
of steroid-refractory GVHD using the definition in section 2.3 in the low risk population 
eligible for this trial is 38%. For an itacitinib monotherapy trial to be successful, the 
proportion of patients who develop steroid-refractory GVHD should not exceed 38%. We 
expect that patients who do not respond to itacitinib will be responsive to steroid treatment 
and we will continuously monitor the incidence of steroid-refractory GVHD in all study 
subjects.  Patients will be considered to have steroid refractory GVHD if their GVHD is 
treated with systemic steroids and they either do not respond by day 28 of steroid treatment 
or they receive additional systemic GVHD treatment prior to 28 days of steroid treatment. 
The trial will be halted if the incidence of steroid-refractory GVHD is greater than the 


31 
 
associated boundary value bk listed in the table below, among the k patients enrolled in the 
trial, then accrual will be halted. 
 
Maximum # of Patients, k 
5 
6-8 
9-10 11-13 14-16 17-19 20-22 23-25 26-28 29-31 32-35 
Boundary, bk 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Maximum # of Patients, k 
36-38 39-41 42-44 45-48 49-51 52-54 55-58 59-61 62-65 66-68 69-70 
Boundary, bk 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
 
 
Specifically, if more than 3 out of the first 5 patients, 4 out of the first 8 patients, 5 out of 
the first 10 patients, 6 out of the first 13 patients, or 24 out of the first 70 patients, experience 
steroid-refractory GVHD, the trial will be halted for safety considerations. 
 
The operating characteristics of this stopping rule are as follows: 
  
 
True Steroid Refractory Rate 
24% 
30% 
33% 
0.38 
40% 
42% 
Probability of Early Stopping 
0.10 
0.36 
0.54 
0.83 
0.88 
0.94 
  
Using these boundaries, if the true steroid refractory rate is 24%, 30%, 33%, 38%, 40% or 
42%, the probability of stopping the trial early is 0.10, 0.36, 0.54, 0.83, 0.88, and 0.94 
respectively.  
   
   
Serious infections: 
Itacitinib monotherapy has been shown to be safe in over 700 patients. However, its use 
as a therapy for acute GVHD is investigational. The primary toxicity of treatment for GVHD 
is infection. Our preliminary data show that the incidence of serious infections in the first 
90 days of systemic steroid treatment for GVHD is 59%. Therefore, if the proportion of 
study patients who experience serious infections exceeds 59%, we would not further study 
itacitinib monotherapy for GVHD treatment. If the incidence of serious infections is greater 
than the associated boundary value bk listed in the table below among the k patients 
enrolled in the trial, then accrual will be ended. 
 
 
  
Specifically, if more than 4 out of the first 6 patients, 5 out of the first 9 patients, 10 out of 
the first 20 patients, 14 out of the first 31 patients, or 29 out of the first 70 patients, 
experience serious infections within 3 months, the trial will be halted for safety 
considerations. 
  
The operating characteristics of this stopping rule are as follows: 
  
 
 
True Serious Infections Rate 
35% 
41% 
45% 
50% 
55% 
60% 
Probability of Early Stopping 
0.10 
0.31 
0.55 
0.79 
0.96 
0.99 
 
  
Maximum # of Patients, k 
6 
7 
8-9 
10-11 
12-14 
15-16 
17-18 
19-20 
21-22 
23-24 
Boundary, bk 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Maximum # of Patients, k 
25-27 
28-29 
30-31 
32-34 
35-36 
37-38 
39-41 
42-43 
44-45 
46-48 
Boundary, bk 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
Maximum # of Patients, k 
49-50 
51-52 
53-55 
56-57 
58-60 
61-62 
63-65 
66-67 
68-70 
 
Boundary, bk 
24 
25 
26 
27 
28 
29 
30 
31 
32 
 


32 
 
Using these boundaries, if the true serious infections rate is 30%, 33%, 40%, 45%, 50% or 
60%, the probability of stopping the trial early is 0.10, 0.18, 0.57, 0.83, 0.96, and 1 
respectively. 
 
Non-relapse mortality: 
In this low risk patient population the the six-month non-relapse mortality rate is 9%. If, in 
the unlikely event that itacitinib-related toxicities increased the risk for non-relapse mortality 
we would want to terminate the trial early. We will continuously monitor the rate of non-
relapse mortality. The trial will be halted if there is sufficient evidence that the six month 
NRM rate is higher than 9%. Specifically, if the incidence of non-relapse deaths within 6 
months of study administration is greater than the associated boundary value bk listed in 
the table below, among the k patients enrolled in the trial, then accrual will be halted for 
safety considerations. 
 
Maximum # of Patients, k 
11 
12-26 
27-45 
46-65 
66-70 
Boundary, bk 
1 
2 
3 
4 
5 
 
Specifically, if more than 1 out of the first 11 patients, 2 out of the first 26 patients, 3 out of 
the first 45 patients, 4 out of the first 65 patients, or 5 out of the first 70 patients, experience 
NRM within 6 months of study administration, the trial will be halted for safety 
considerations. 
  
The operating characteristics of this stopping rule are as follows: 
  
 
True NRM Rate 
3% 
6% 
8% 
9% 
11% 
Probability of Early Stopping 
0.10 
0.45 
0.68 
0.77 
0.89 
  
Using these boundaries, if the true NRM rate is 3%, 6%, 8%, 9%, or 11%, the probability 
of stopping the trial early is 0.10, 0.45, 0.68, 0.77, and 0.89 respectively.  
 
All the stopping rules were computed using the toxbdry function in R and calculations of 
this function are based on methods described in Chapter 12 of Jennison and Turnbull and 
in the illustrative paper by Ivanova, Qaquish and Schell46,47. 
 
An enrollment rule to prevent an excessive number of toxicities as described in Song and 
Ivanova will be used to inform us of the number of additional patients we can recruit when 
the current patient has not yet completed follow-up48  Formally, the trial can enroll m new 
patients such that r + x + m ≤bn+m + M, r + x + m– 1 < bn+m−1 + M, and n + m ≤ K where r is 
defined as the number of patients that have not completed follow-up and are still being 
followed for toxicity; x is the number of patients that have experienced toxicity, n is the total 
number of patients enrolled to date and M is the fixed design parameter. To be able to 
complete this low-risk study in a timely manner, we allow M to be 30. 
All the stopping rules were computed using the toxbdry function in R and calculations of 
this function are based on methods described in Chapter 12 of Jennison and Turnbull and 
in the illustrative paper by Ivanova, Qaquish and Schell46,47. 
9.0 
DRUG INFORMATION 
9.1 
Itacitinib Adipate 
 
 
Commercial names for the drug: Itacitinib (INCB389110) 
 
 
Classification-type of agent: selective JAK1 inhibitor 
 


33 
 
 
Description: Itacitinib may be formulated as 25 mg, 100 mg, 200 mg, or 300 mg (free base 
equivalent) SR tablets. These tablets contain the active ingredient, hypromellose, microcrystalline 
cellulose, lactose monohydrate, and magnesium stearate, and may be coated with a nonfunctional 
coating. Itacitinib also may be formulated as an IR tablet but this preparation will not be used in this 
trial.  
 
 
Mode of action:  
Pharmacologic inhibition of JAK/STAT signaling has shown potential in the treatment of GVHD 
while maintaining the anti-leukemia effect of allogenic transplant49,50. In vivo JAK/STAT-signaling 
inhibition with ruxolitinib improved survival of mice developing aGVHD and reduced 
histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of 
alloreactive luc-transgenic T cells31. Additionally, ruxolitinib impaired differentiation of CD4+ T cells 
into IFN-γ and IL-17A–producing cells, both T-cell phenotypes linked to GVHD. Ruxolitinib also 
increased FoxP3+ regulatory T cells, which are linked to immunologic tolerance.  
 
JAK1/2 inhibition with ruxolitinib has also shown clinical benefit in patients with acute GVHD and 
chronic graft-versus-host disease (cGVHD). In patients with steroid-refractory GVHD treated with 
ruxolitinib, the ORR was 84.3% (27/32; 10 CRs and 17 PRs) in acute GVHD and 80% (16/20) in 
cGVHD33. The median time to response was less than 2 weeks. After additional follow-up (medians 
of 19 and 24 months for acute GVHD and cGVHD, respectively), 1-year overall survival rates of 
62.4% (confidence interval [CI]: 49.4%-75.4%) and 92.7% (CI: 84.7%-100%) were reported for 
steroid-refractory acute GVHD and cGVHD, respectively. The median duration of ruxolitinib 
treatment was 5 months for patients with steroid-refractory aGVHD and 10 months for patients with 
steroid-refractory cGVHD, reflecting the different biology of the diseases (Zeiser et al 2016).   
 
Itacitinib, an inhibitor of JAK/STAT signaling with selectivity for JAK1, showed similar 
pharmacologic inhibition of interferon signaling, resulting in the decreased expression of CXCR3, 
reduced GVHD, and improved survival when administered for 30 days after allo-HSCT in mice 
(Investigator brochure). Preliminary data in subjects with acute GVHD who received itacitinib in 
combination with corticosteroids (prednisone or methylprednisolone; Study INCB 39110-108) 
indicate ORRs of 83.3% at Day 28 for subjects with first-line aGVHD and up to 66.7% for subjects 
with steroid-refractory aGVHD.  
 
 
Pharmacokinetics:  
Eight formulations of itacitinib (IR or SR) have been studied in multiple healthy volunteer studies. 
Sustained release is likely needed to maintain JAK inhibition over the dose administration interval 
given the relatively short half-life of IR formulation and to reduce the peak/trough ratio. Of the 
formulations studied, the SR3 formulation was selected for future study as other formulations had 
a larger food effect, lower relative bioavailability compared with the reference IR formulation 
(relative bioavailability = 48% for SR3), or more variable PK. Following a single dose of 300 mg 
itacitinib SR3 (3 × 100 mg tablets), there was a 46% increase in Cmax but only a 17% increase in 
total exposure (AUC0-∞) when administered with a medium-fat meal. The non-clinically significant 
impact on total exposure when administered with a medium-fat meal supported the administration 
of itacitinib SR3 without regard to food. Currently, the SR3 100 mg formulation is the only 
formulation being used in any study of subjects with underlying conditions. A preliminary analysis 
comparing single doses of 100 mg (1 × 100 mg SR3 tablet), 200 mg (2 × 100 mg SR3 tablet), and 
300 mg (3 × 100 mg SR3 tablet; fasted) demonstrated that exposures increase in a greater-than-
proportional manner.  
 
Following multiple-dose administration of itacitinib SR3 400 BID or 800 QD with a medium fat meal, 
steady state was generally reached after 48 hours. Compared with Day 1, there was approximately 
60% and 15% accumulation in AUC0-τ for the 400 mg BID and 800 mg QD doses, respectively, 
following a medium-fat meal. The highest total daily exposure after multiple-dose administration 
was achieved after administration of 600 mg BID (29.0 μM·h [calculated as 2 × AUC0-12]). Mean 
half-life of itacitinib is generally reported in the range of 3 to 9 hours with an overall mean of 


34 
 
approximately 5 hours. After itacitinib 400 mg BID and 800 mg QD administration with a medium-
fat meal, the intersubject CV% ranged from 25% to 34% for Cmax and 23% to 40% for AUC0-τ.  
Pharmacokinetics of Itacitinib SR3 100 mg Tablet in Healthy Subjects After Single Dose Administration 
Dose (mg) 
Study INCB39110- 
N 
Cmax (M) 
Tmax (h) 
AUCb (M.h) 
Cmin (M) 
200mg  
(fasting) 
105 a 
36 
0.343 ± 0.176  
2.0 (0.5-4.0)  
1.48 ± 0.572  
NA 
300mg 
(fasting) 
105 a 
23 
0.668 ± 0.335  
1.5 (0.5-4.0)  
2.85 ± 1.45  
NA 
300mg 
(fasting) 
102 
23 
0.587 ± 0.334  
1.5 (0.5-4)  
2.49 ± 0.928  
NA 
300mg 
(medium fat 
meal) 
102 
12 
0.875 ± 0.468  
2.5 (1.5-6.0)  
3.02 ± 1.35  
NA 
300mg (high 
fat meal) 
102 
12 
1.05 ± 0.465  
4.0 (1.5-8.0)  
3.59 ± 1.13  
NA 
NA = not applicable.  
PK parameters reported as mean ± SD except tmax, which is presented as median (range).  
a Data (Study INCB 39110-105) are preliminary.  
b AUC is AUC0–∞ for single-dose administration or AUC0-τ for multiple-dose administration.  
 
 
 
Adverse reactions:  
The underlying GVHD condition is a major contributor to morbidity in the post-transplant setting 
and should not be confused with adverse reactions attributable to investigational agents. 
Treatment-emergent adverse events (TEAE) are reported regardless of attribution to GVHD, 
steroids, other transplant related events, or study drug and full safety assessments must take 
attribution into account. As of the data cutoff, 29 subjects in Study INCB 39110-108 had 
received itacitinib in combination with corticosteroids, a pharmacologic class with its own 
significant toxicity (section 1.2). All 29 subjects had at least 1 TEAE, 28 of those (96.6%) were 
grade 3 or higher. The most frequently reported TEAEs were consistent with expectations for 
GVHD patients and included thrombocytopenia (41.4%), diarrhea (37.9%), abdominal pain 
(34.5%), and peripheral edema, fatigue, and hypokalemia (31.0% each). One subject with pre-
existing thrombocytopenia had a Grade 3 dose-limiting event of thrombocytopenia that was 
attributed to GVHD progression. Other frequently reported TEAEs (≥20%) included 
hyperglycemia (27.6%), decreased appetite, headache, hypophosphatemia, nausea, and 
tachycardia (24.1% each), and dry mouth, hypoalbuminemia, sepsis, and vomiting (20.7%), all 
common events in patients with GVHD treated with steroids.  The most frequently reported 
TEAE leading to permanent discontinuation of itacitinib was GI hemorrhage (3 subjects; 
10.3%), a known complication of GI GVHD. The only other TEAE leading to permanent 
discontinuation of itacitinib in more than 1 subject was thrombocytopenia (2 subjects; 6.9%). 
Eight subjects (27.6%) in the study had a fatal TEAE, six of which occurred after discontinuing 
study treatment.  Three subjects experienced multi-organ failure (10.3%); two sepsis (6.9%); 
and one patient each developed GI hemorrhage, hematochezia, electrolyte imbalance, or acute 
respiratory distress syndrome (3.4% each). Of note, two of these patients discontinued the 
study drug due to a TEAE (electrolyte imbalance and multiorgan failure).  None of these deaths 
were attributed to itacitinib. 
 
Serious adverse events were reported in 22 subjects (75.9%) of which 7 (24.1%) were 
treatment related. The most frequently reported SAE was sepsis (6 subjects; 20.7%). Other 
SAEs reported in more than 1 subject included GI hemorrhage (4 subjects; 13.8%), multiorgan 
failure (3 subjects; 10.3%), diarrhea (3 subjects; 10.3%), and acute kidney injury (2 subjects; 
6.9%). Treatment-related SAEs included sepsis (3 subjects; 10.3%) and klebsiella sepsis, 
pancytopenia, diarrhea, pneumatosis intestinalis, pneumoperitoneum, and CMV viremia (1 
subject each; 3.4%). As of the data cutoff, 25 subjects (83.3%) had discontinued treatment: 11 
subjects (36.7%) because of a TEAE, 4 subjects (13.3%) because of progressive disease, 4 
subjects (13.3%) because of physician decision, 2 subjects (6.7%) because of death, and 4 
subjects (13.3%) for reasons classified as 'Other.' The most frequently reported TEAE leading 
to permanent discontinuation of itacitinib was GI hemorrhage (3 subjects; 10.3%). The only 
other TEAE leading to permanent discontinuation of itacitinib in more than 1 subject was 


35 
 
thrombocytopenia (2 subjects; 6.9%). A preliminary, unaudited summary of the TEAEs in ≥ 3 
subjects from Study INCB 39110-108 is presented in the following table: 
 
MedDRA Preferred Term  
200 mg QD (n = 14)  
300 mg QD (n = 15)  
Total (N = 29)  
Thrombocytopenia  
2 (14.3)  
10 (66.7)  
12 (41.4)  
Diarrhea  
7 (50.0)  
4 (26.7)  
11 (37.9)  
Abdominal pain  
6 (42.9)  
4 (26.7)  
10 (34.5)  
Edema peripheral  
4 (28.6)  
5 (33.3)  
9 (31.0)  
Fatigue  
5 (35.7)  
4 (26.7)  
9 (31.0)  
Hypokalemia  
5 (35.7)  
4 (26.7)  
9 (31.0)  
Hyperglycemia  
5 (35.7)  
3 (20.0)  
8 (27.6)  
Decreased appetite  
3 (21.4)  
4 (26.7)  
7 (24.1)  
Headache  
5 (35.7)  
2 (13.3)  
7 (24.1)  
Hypophosphatemia  
4 (28.6)  
3 (20.0)  
7 (24.1)  
Nausea  
5 (35.7)  
2 (13.3)  
7 (24.1)  
Tachycardia  
5 (35.7)  
2 (13.3)  
7 (24.1)  
Dry mouth  
4 (28.6)  
2 (13.3)  
6 (20.7)  
Hypoalbuminemia  
4 (28.6)  
2 (13.3)  
6 (20.7)  
Sepsis  
3 (21.4)  
3 (20.0)  
6 (20.7)  
Vomiting  
5 (35.7)  
1 (6.7)  
6 (20.7)  
Acute kidney injury  
4 (28.6)  
1 (6.7)  
5 (17.2)  
Anemia  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Edema  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Fall  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Gastrointestinal hemorrhage  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Hematochezia  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Hypertension  
1 (7.1)  
4 (26.7)  
5 (17.2)  
Hypocalcemia  
5 (35.7)  
0  
5 (17.2)  
Hypogammaglobulinemia  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Hypomagnesemia  
3 (21.4)  
2 (13.3)  
5 (17.2)  
Alanine 
aminotransferase 
increased  
2 (14.3)  
2 (13.3)  
4 (13.8)  
Asthenia  
4 (28.6)  
0  
4 (13.8)  
Blood creatinine increased  
3 (21.4)  
1 (6.7)  
4 (13.8)  
Cough  
3 (21.4)  
1 (6.7)  
4 (13.8)  
Cytomegalovirus infection  
4 (28.6)  
0  
4 (13.8)  
Neutrophil count decreased  
2 (14.3)  
2 (13.3)  
4 (13.8)  
Weight decreased  
4 (28.6)  
0  
4 (13.8)  
Abdominal distension  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Arthralgia  
0  
3 (20.0)  
3 (10.3)  
BK virus infection  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Blood bilirubin increased  
3 (21.4)  
0  
3 (10.3)  
Blood fibrinogen decreased  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Confusional state  
0  
3 (20.0)  
3 (10.3)  
Constipation  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Cytomegalovirus viremia  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Dizziness  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Dyspnea  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Ecchymosis  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Hematuria  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Hyperbilirubinemia  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Hyponatremia  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Hypotension  
3 (21.4)  
0  
3 (10.3)  
Hypoxia  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Malnutrition  
3 (21.4)  
0  
3 (10.3)  
Mental status changes  
3 (21.4)  
0  
3 (10.3)  
Multiorgan failure  
1 (7.1)  
2 (13.3)  
3 (10.3)  
Pancytopenia  
3 (21.4)  
0  
3 (10.3)  
Pneumatosis intestinalis  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Pyrexia  
3 (21.4)  
0  
3 (10.3)  
Syncope  
2 (14.3)  
1 (6.7)  
3 (10.3)  
Weight increased  
3 (21.4)  
0  
3 (10.3)  
White 
blood 
cell 
count 
decreased  
0  
3 (20.0)  
3 (10.3)  
 


36 
 
 
Experience with itacitinib monotherapy in non-GVHD disease states suggests a favorable 
safety profile. The following TEAE data are based on all Incyte-sponsored clinical studies from 
the start of the itacitinib clinical development program through December 13, 2016. As of the 
data cutoff date, 777 subjects have been exposed to itacitinib as monotherapy (493 subjects; 
including 284 healthy volunteers and 209 subjects with underlying disease such as RA, chronic 
plaque psoriasis, or MF). 
 
The following table presents expected TEAEs attributable to itacitinib monotherapy: 
System 
Organ 
Class 
MedDRA Preferred Term  
Overall Frequency  
(All Grades)  
N (%)  
Grade 3 or Grade 4  
N (%)  
Frequency 
of 
Serious 
Eventsa  
N (%)  
Blood and lymphatic system disorders  
Anemiab  
36 (17.2)  
26 (12.4)  
5 (2.4)  
Neutropeniac  
8 (3.8)  
3 (1.4)  
-  
Thrombocytopeniad  
31 (14.8)  
19 (9.1)  
-  
Gastrointestinal disorders  
Diarrhea  
21 (10.0)  
-  
-  
Nausea  
26 (12.4)  
1 (0.5)  
-  
Vomiting  
15 (7.2)  
1 (0.5)  
-  
General disorders and administration site conditions  
Asthenia  
6 (2.9)  
2 (1.0)  
-  
Fatigue  
35 (16.7)  
-  
-  
Pyrexia  
17 (8.1)  
2 (1.0)  
2 (1.0)  
Infections and infestations  
Herpes zoster  
6 (2.9)  
-  
-  
Nasopharyngitis  
12 (5.7)  
-  
-  
Oral candidiasis  
2 (1.0)  
-  
-  
Sinusitis  
9 (4.3)  
-  
-  
Upper 
respiratory 
tract 
infection  
30 (14.4)  
-  
-  
Urinary tract infection  
10 (4.8)  
2 (1.0)  
2 (1.0)  
Investigations  
Alanine 
aminotransferase 
increased  
6 (2.9)  
-  
-  
Aspartate aminotransferase 
increased  
7 (3.3)  
-  
-  
Nervous system disorders  
Dizziness  
15 (7.2)  
-  
-  
Headache  
18 (8.6)  
2 (1.0)  
-  
aFor the purpose of expediting safety reporting in clinical trials, only serious adverse reactions that occurred for more 
than 1 subject will be considered expected.  
 
SUMMARY OF SERIOUS NON-HEMATOLOGIC AND HEMATOLOGIC ADVERSE EFFECTS WITH 
ITACITINIB MONTHERAPY 
DISEASE 
PHASE 
INTERVENTION 
SERIOUS NON-
HEME AE (>1%) 
GRADE 3-4 HEME AE 
Psoriasis 
II 
(n=50) 
ITA dose escalation 
vs placebo 
None 
None reported 
 
Myelofibrosis 
II 
(n=87) 
3 ITA dose cohorts 
(100mg BID, 200mg 
BID, 600mg QD) 
None 
AE’s decreased with higher doses 
suggesting heme effects were from 
myelofibrosis 
Hb: 0 grade 4, 25-33% grade 3 
PLT: 3-6% grade 4, 12.5-44% grade 3 
ANC: 0-2.4% grade 4, 0-2.4% grade 3 
All ITA 
monotherapy 
studies 
Pooled 
data 
(n=777) 
n/a 
None  
Hb:  12.4% 
PLT: 9.1% 
ANC: 1.4% 
 
 
Drug interactions: 


37 
 
Cytochrome P450 3A4 is the major isozyme responsible for the metabolism of itacitinib in 
human liver microsomes. In a cultured human hepatocyte assay, itacitinib did not induce 
CYP1A2, CYP2B6, or CYP3A4/5 activity or mRNA levels, suggesting that the potential to 
induce P450 in clinical studies is low. In vitro assays indicated that itacitinib is a substrate of 
P glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In addition, the potential for 
itacitinib to cause clinical drug-drug interactions (DDIs) through CYP inhibition is low based on 
IC50 values and clinical doses based on the current Committee for Medicinal Products for Human 
Use guideline and draft FDA guidance51,52. For efflux transporters, in vitro studies demonstrated 
that itacitinib is a substrate of P-gp and BCRP. In addition, itacitinib is not an inhibitor of BCRP but 
is a weak inhibitor of P-gp with an IC50 of 41.4 μM. For uptake transporters, in vitro studies 
demonstrated that itacitinib is not a substrate of hepatic transporters OATP1B1/1B3, and inhibitory 
potentials toward hepatic transporters OATP1B1/1B3 and renal transporters OAT1/3 and OCT2 
are low. 
 
Because the primary metabolic pathway is metabolism by CYP3A4, a 1-way drug-drug interaction 
study (INCB 39110-110) was conducted to evaluate the impact of co-administration of itraconazole 
(a potent CYP3A4 inhibitor) or rifampin (a potent CYP3A4 inducer) on itacitinib exposure in healthy 
subjects. This was an open-label study to assess the effect of multiple doses of itraconazole or 
rifampin on the single-dose PK of itacitinib. Thirty-six healthy subjects were divided into 2 cohorts 
of 18 subjects. 
In Cohort 1, subjects received each of the following treatments in succession, as shown below: 
Day 1: Itacitinib 200 mg SR (100 mg SR × 2) single dose administered orally in the 
fasted state. 
Days 2 through 5: Itraconazole 200 mg QD in the fed state (4 doses). 
Day 6: Itacitinib 200 mg SR (100 mg SR × 2) single dose and itraconazole 200 mg 
single dose in the fasted state. 
Day 7: Itraconazole 200 mg single dose in the fed state. 
 
In Cohort 2, subjects received each of the following treatments in succession, as shown below: 
Day 1: Itacitinib 200 mg SR (100 mg SR × 2) single dose administered orally in the fasted state. 
Days 2 through 8: Rifampin 600 mg QD in the fasted state (7 doses). 
Day 9: Itacitinib 200 mg SR (100 mg SR × 2) single dose and rifampin 600 mg single dose in the 
fasted state. 
 
There was a notable change in exposure when itacitinib was coadministered with either a potent 
CYP3A4 inhibitor (~5-fold increase in exposure) or a potent CYP3A4 inducers (~80% decrease in 
exposure). 
 
 
Storage and stability: 
All itacitinib drug product should be stored at ambient conditions (15°C to 30°C, or 59°F to 86°F). 
 
 
Administration: 
Itacitinib tablets are to be administered orally. 
 
 
Availability: 
Provided by Incyte 
 
 
Any remaining/expired/used is to be destroyed on site according to the institution standard 
operating procedure for drug destruction and documented on the drug accountability logs. 
 
 
Drug Accountability: 
 
The principal investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the investigational drug, itacitinib. The drug 
accountability records will capture drug receipt, drug dispensing, drug return and final disposition.   
 


38 
 
10.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to improve our understanding of the 
biological processes that drive GVHD and its clinical outcomes. 
10.1 
Sample Collection Guidelines 
The correlative sample collection schedule is detailed in section 6.3 above. Serum will be 
collected in no additive, silicone coated glass or plastic tubes containing no anticoagulant 
(red or gold top tube). Samples will be processed at the participating center and batch 
shipped to Ferrara Laboratory quarterly for storage. Sample processing details are found 
in the appendices. Instructions for quarterly batch shipping are found in the MAGIC Sample 
Collection and Storage Manual. 
10.2 
Assay Methodology 
See Appendix A. 
10.3 
Specimen Banking 
Patient samples collected for this study will be stored indefinitely or until they are used up. 
If future use is denied or withdrawn by the patient, best efforts will be made to stop any 
additional studies and to destroy the specimens. In addition to the biomarker studies 
planned as part of this study, additional studies may be performed on the banked research 
samples as part of collaborations with other institutions and entities.   
 
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that 
there is the potential for financial gain by the Icahn School of Medicine at Mount Sinai, the 
investigator or a collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:  
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a non-inferiority, phase II, single arm, open-label, multicenter clinical trial to 
determine the effectiveness of itacitinib monotherapy as primary treatment of newly 
diagnosed, low-risk acute GVHD defined by standard risk clinical criteria (Minnesota) and 
low risk biomarkers (Ann Arbor 1). The primary study measure is the proportion of patients 
who achieve CR or PR by day 28 of treatment with itacitinib without the addition of any 
other systemic GVHD treatment including steroids. CR is defined as absence of GVHD 
symptoms. PR is defined as improvement in one or more organs involved with GVHD 
symptoms without progression in other organs. For a response to be scored as CR or PR 
on day 28, the patient must be in CR or PR on day 28 and have had no intervening systemic 
therapy for acute GVHD other than itacitinib. 
 
To further investigate the treatment regimen, we will assess the safety of itacitinib 
monotherapy in these patients, determine the incidence of serious complications within 
three months in patients with GVHD treated with itacitinib and determine the incidence of 
steroid refractory GVHD in patients whose GVHD is not responsive to itacitinib (as defined 
in section 2.3) as secondary objectives. Secondary endpoints will include cumulative 
incidence of steroid-refractory GVHD, proportion of patients with maximal grade I, II, III, 


39 
 
and IV GVHD by day 28 after starting treatment with itacitinib, cumulative incidence of 
serious infections (defined as bacteremia needing treatment, CMV infection needing 
treatment, EBV infection needing treatment, or invasive fungal infection), overall survival 
at 6 and 12 months, cumulative incidence of NRM at 6 and 12 months, relapse rate, and 
cumulative incidence of chronic GVHD requiring systemic steroid treatment by one year. 
 
As a safety endpoint, we will calculate number and proportion of patients developing 
reportable AEs and SAEs according to relatedness to study drug and stratified by severity.  
 
Our exploratory hypotheses are as follows: 1) GVHD biomarkers (such as ST2 and 
REG3α) will remain low in study patients who respond to itacitinib treatment, but will rise 
in non-responders. 2) biomarker concentrations will be equivalent to those in historical 
control patients who respond to steroid treatment for low risk GVHD. The historical control 
population for this study will be derived from MAGIC patients worldwide who enroll from 
2014-2019. We expect at least 500 patients with Minnesota standard risk/Ann Arbor 1 
GVHD will be available as control patients.   
 
11.2 
Sample Size and Accrual 
In this phase II clinical trial, our aim is to determine if itacitinib monotherapy as primary 
treatment of newly diagnosed, low-risk acute GVHD defined by standard risk clinical criteria 
(Minnesota) and low risk biomarkers (Ann Arbor 1) is non-inferior to standard steroid 
therapy. The expected proportion of low-risk acute GVHD patients who achieve CR or PR 
by day 28 of standard steroid treatment is 67%. Avoidance of the toxicity of steroid 
treatment is a priority for the HCT community in general and MAGIC centers specifically. 
Extensive preliminary discussion indicate that physicians would accept a 15% decrease in 
the overall response rate to primary GVHD treatment (from 67% to 52%) if steroid treatment 
could be avoided in the responders without an increase in the incidence of steroid 
refractory GVHD. This study will terminate early if the incidence of steroid refractory GVHD 
exceeds the historical rate of 33%, if the incidence of serious infections exceeds the 
historical rate of 59% or if the incidence of non-relapse mortality (as a measure of all 
potential toxicities) exceeds the historical rate of 9% (section 8.7).  
A one-sided group sequential design that uses O’Brien-Fleming method testing an upper 
(futility) stopping boundary is used to stop the trial early for futility. Two equally spaced 
formal interim analyses will be performed during the monitoring of the study. Under such a 
monitoring schedule and assuming a baseline 28-day response rate of 0.67 in standard 
steroid treatment, a sample size of 70 patients will provide 80% power to detect a non-
inferiority margin of 0.15 in response rate by day 28. Under the planned schedule of two 
equally spaced analysis and assuming a baseline response rate of 0.67, the table below 
presents the stopping boundaries at each analysis for the specified stopping rule 
expressed as the number of responses by day 28. 
 
Stage 
Sample Size 
Futility stopping boundary 
Z statistic 
Number of CR and PR 
by day 28 
1 
35 
0.558 
19 
2 
70 
1.734 
44 
 
 
According to the above table, if at first analysis the response rate by day 28 is less than or 
equal to 19, the stopping rule suggests that the study be terminated early with a decision 
that it was futile to continue the trial because there is not sufficient evidence that any 
beneficial effect of the experimental treatment is clinically important. 
 
The combination of the primary efficacy endpoint (overall response rate) and the secondary 
endpoints (steroid-refractory GVHD, NRM, and serious infections) will be used to 


40 
 
determine if itacitinib monotherapy should be compared to systemic steroid treatment in a 
phase III trial for patients with low risk GVHD. We will continuously monitor these outcomes 
and if at any point during this trial sufficient evidence emerges that itacitinib monotherapy 
is not likely to result in improvement in any of these parameters, the protocol committee 
will terminate the trial for futility.  
 
Sample size calculations were performed using seqdesign statement in PASS 14 Power 
Analysis and Sample Size Software (2015) NCSS, LLC. Kaysville, Utah, USA, 
ncss.com/software/passSAS software version 9.4 (SAS Institute Inc., Raleigh, NC). 
 
 
The centers participating in this clinical trial collectively perform >700 allogeneic HCT per 
year. Based on data from these MAGIC centers from 2013-2017, we expect 300 patients 
will develop GVHD per year, including 255 with Minnesota Standard Risk GVHD. Although 
it is likely we will accrue faster, a conservative estimate is that we will consent and screen 
50% of these cases which should result in 48 patients enrolled per year or approximately 
4 per month. We do not expect all centers to open to enrollment simultaneously and 
therefore we realistically expect to meet our accrual goals within two years. 
11.3 
Data Analysis Plans 
The primary endpoint is the proportion of patients who achieve CR or PR by day 28 of 
treatment with itacitinib without the addition of any other systemic GVHD treatment 
including steroids. Death, lack of GVHD response to itacitinib by day 28 of treatment, or 
initiation of steroid or other systemic immunosuppressive therapy for GVHD will be 
considered failures for this endpoint. The proportion of patients who achieve CR or PR by 
day 28 in the study patients will be compared to the historical control rate of 67%. 
 
Secondary outcomes such as cumulative incidence of steroid-refractory GVHD, proportion 
of patients with maximal grade I, II, III, and IV GVHD by day 28 after starting treatment with 
itacitinib, cumulative incidence of serious infections, cumulative incidence of hematologic 
toxicities, cumulative steroid dose over four weeks in patients who fail itacitinib 
monotherapy, overall survival at 6 and 12 months, cumulative incidence of NRM at 6 and 
12 months, relapse rate at 6 and 12 months, and cumulative incidence of chronic GVHD 
requiring systemic steroid treatment by one year will be estimated and compared to 
historical controls. 
 
Continuous variables will be summarized using standard summary statistics such as 
number of observations (n), mean, standard deviation (SD), minimum and maximum 
values, median, and 1st and 3rd quartiles. Categorical variables will be summarized in 
frequency tables as counts and percentages. 
 
Cumulative incidence of non-relapse mortality will be estimated by Gray’s method53  and 
relapse will be considered as a competing risk. Disease free and overall survival, defined 
as the time from the transplantation to death or to last follow-up if alive, will be estimated 
by the method of Kaplan-Meier and the probability curves and 95% confidence intervals 
will be provided based on the method of Brookmeyer and Crowley54. 
12.0 
DATA AND SAFETY MONITORING 
The safety of subjects is paramount and supersedes all other concerns. This study employs several 
layers of oversight to ensure that patient safety is protected.  
 
1. The local Data and Safety Monitoring Committee (DSMC) at each site which will be responsible 
for reviews of patient data at each site 
2. The Protocol Data and Safety Monitoring Committee (DSMC), composed of the individual site 
PI’s which will review all facets of study conduct at all sites on monthly webinars 


41 
 
3. The Tisch Cancer Institute Data and Safety Monitoring Committee (TCI DSMC) of the Mount 
Sinai Health System is the DSMB of record for this study. The DSMB will be compliant with the 
NIH approved DSMP Charter. This committee will be responsible for monitoring the safety and 
data integrity of the trial. It is a DSMB entirely composed of members with no connection to this 
clinical trial. 
4. Annual reviews and safety reporting will be provided to the IRBs at each participating site,  the 
Mount Sinai Health System, and the FDA as required by IND regulations (21 CFR 312.3). 
 
This study will enroll adolescent patients who we expect will provide up to 20% of the study 
subjects. These patients will be enrolled from pediatric HCT centers and will receive their care from 
trained pediatric HCT physicians. We will closely monitor toxicity and efficacy in patients <18 years 
of age. The oversight boards (Protocol DSMB and TCI DSMC) can halt pediatric accrual to the 
study if an unexpected safety concern develops in children, while continuing adult accrual. 
 
Protocol DSMB: The centers participating in this study are collaborating centers in MAGIC (Mount 
Sinai Acute GVHD International Consortium). The local site principal investigator, data manager, 
and study coordinator participates in monthly webinars where all facets of study conduct are 
discussed, thereby providing an additional layer of safety oversight. 
 
The MAGIC Data Coordinating Center is responsible for collating all data and safety reports from 
all the participating sites, and providing the information to the TCI Data Safety Monitoring 
Committee. 
 
TCI DSMC: The TCI DSMC serves as the data and safety monitoring board (DSMB) for investigator 
initiated studies conducted under the auspices of the Tisch Cancer Institute (TCI) at the Mount 
Sinai Health System. It is compliant with the National Institutes of Health and National Cancer 
Institute charter for DSMBs. This board will be responsible for monitoring the safety and data 
integrity of the trial. It is a DSMB entirely composed of members with no connection to this clinical 
trial. 
 
12.1 
Multisite Clinical Monitoring Procedures 
This clinical study will be coordinated by the MAGIC Data Coordinating Center (DCC) of 
the Icahn School of Medicine at Mount Sinai. As such it will be conducted in accordance 
with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. 
 
Prior to subject recruitment, a participating site will undergo a site initiation meeting to be 
conducted by the DCC. This will be done as an actual site visit, teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and 
his/her study staff should make every effort in attending the site initiation meeting. Study-
related questions or issues identified during the site initiation meeting will be followed-up 
by the appropriate DCC personnel until they have been answered and resolved. 
 
This study will be monitored by a representative of the MAGIC Data Coordinating Center. 
Monitoring visits, whether remote or in person, will be made during the conduct of the study 
and at study close-out. The following issues will be monitored. 
 
 
Signed and dated ICF 
 
Adherence to the protocol 
 
Completeness and accuracy of study data and laboratory samples collection 
 
Proper storage, dispensing and inventory control of investigational drug 
 
Compliance with state and local regulations 
 


42 
 
Any issues identified during these visits will be communicated to the site and are expected 
to be corrected by the site in a timely manner.  For review of study-related documents at 
the DCC, the site will be required to ship, fax, or email documents to be reviewed, ensuring 
compliance with HIPAA and other privacy regulations.  
 
Participating sites will also undergo a site close-out upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the site Investigator is aware of his/her ongoing responsibilities. At the time 
of the close-out any investigational agents not dispensed need to be returned as defined 
for the study or destroyed and accounted for properly. 
 
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data Safety Monitoring Board can request a ‘for cause’ audit of the trial if the board identifies 
a need for a more rigorous evaluation of study-related issues. A “for cause” audit would be 
conducted by the Project Manager of the MAGIC Data Coordinating Center. 
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the MAGIC Data Coordinating Center that 
such a request has been made. 
 


43 
 
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