Clinical trial NCT04071366
Conditions: Cytokine Release Syndrome
Keywords: Cytokine release syndrome immune effector cell-associated neurotoxicity syndrome Janus kinase inhibitor immune effector cell therapy
Sponsor: Incyte Corporation
Start date: 2020-02-07; Completion date: 2023-08-22
Enrollment: 112 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
"The purpose of this study is to assess the safety and efficacy of oral administration of itacitinib for the prevention of cytokine release syndrome (CRS) in male or female participants aged 12 years or older and who are planning to receive an approved immune effector cell (IEC) therapy for hematologic malignancies.

Detailed description:

Arms: arm 1: During Part 1, all participants receive itacitinib 200mg once daily (open label) for 30 days. The study population will include participants receiving any approved IEC for an approved indication. arm 2: During Part 2, participants will be randomized to receive itacitinib 200mg or placebo twice daily for 30 days. The study population also includes participants who are receiving Yescarta for relapsed or refractory large B-cell lymphoma or follicular lymphoma.
Interventions: intervention 1: Itacitinib intervention 2: Immune effector cell therapy intervention 3: Placebo intervention 4: Yescarta
Intervention descriptions: intervention 1: Part 1: Itacitinib 200 mg once daily for 30 days. Part 2: Itacitinib 200 mg twice daily for 30 days. intervention 2: Participants will receive IEC therapy that is approved by the health authority in the country where the study is being conducted for any approved hematologic indication. intervention 3: Participants will receive placebo twice daily. intervention 4: Eligible participants are receiving Yescarta (An infusion of chimeric antigen receptor (CAR)-transduced autologous T cells) for relapsed or refractory larbe B-cell lymphoma or follicular lymphoma intravenously.

Protocol documents:
Prot_000.pdf: 
NCT Number:   NCT04071366   
Document Date: Clinical Study Protocol Version 5: 08 Dec 2022
Official Title: A Phase 2 Study of Itacitinib, for the Prevention of Cytokine Release Syndrome 
Induced by Immune Effector Cell Therapy


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Incyte Corporation 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 39110-211 Protocol Amendment 4 (dated 08 DEC 2022) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
(Printed Name of Investigator) 
(Signature of Investigator) 
(Date) 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR'S AGREEMENT ................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................10 
1.
PROTOCOL SUMMARY ..........................................................................................13 
2.
INTRODUCTION ......................................................................................................19 
2.1. 
Background .................................................................................................................19 
2.2. 
Product Information and Overview of Itacitinib ........................................................20 
2.2.1. 
Nonclinical Drug Metabolism and Pharmacokinetics ................................................20 
2.2.2. 
Clinical Drug Metabolism and Pharmacokinetics ......................................................21 
2.2.3. 
Itacitinib Clinical Safety Summary ............................................................................23 
2.3. 
Study Rationale ...........................................................................................................23 
2.3.1. 
Scientific Rationale for Study Design ........................................................................24 
2.3.2. 
Justification for Dose, Part 1 ......................................................................................25 
2.3.3. 
Preliminary Results from Part 1 .................................................................................25 
2.3.4. 
Rationale for Part 2 .....................................................................................................26 
2.4. 
Benefit/Risk Assessment ............................................................................................27 
2.5. 
Preclinical Summary ...................................................................................................27 
2.5.1. 
Preclinical Summary Conclusions ..............................................................................30 
3.
OBJECTIVES AND ENDPOINTS ............................................................................31 
4.
STUDY DESIGN .......................................................................................................32 
4.1. 
Overall Design ............................................................................................................32 
4.2. 
Overall Study Duration ...............................................................................................33 
4.3. 
Study Termination ......................................................................................................33 
5.
STUDY POPULATION .............................................................................................34 
5.1. 
Inclusion Criteria ........................................................................................................34 
5.2. 
Exclusion Criteria .......................................................................................................35 
5.3. 
Lifestyle Considerations .............................................................................................36 
5.4. 
Screen Failures ............................................................................................................37 
5.5. 
Replacement of Participants .......................................................................................37 
6.
STUDY TREATMENT ..............................................................................................37 


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6.1. 
Study Treatment Administered ...................................................................................37 
6.1.1. 
Study Treatment Preparation, Handling, and Accountability .....................................38 
6.1.2. 
Study Treatment Compliance .....................................................................................38 
6.1.3. 
Dose Modifications for Itacitinib ................................................................................39 
6.1.4. 
Criteria for Permanent Discontinuation of Study Treatment ......................................39 
6.2. 
Immune Effector Cell Therapy ...................................................................................39 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................40 
6.4. 
Concomitant Medications and Procedures .................................................................40 
6.4.1. 
Permitted Medications and Procedures ......................................................................40 
6.4.2. 
Restricted Medications and Procedures ......................................................................40 
6.4.3. 
Prohibited Medications and Procedures .....................................................................41 
6.5. 
Treatment After the End of the Study .........................................................................41 
7.
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ..................................................................41 
7.1. 
Discontinuation of Study Treatment ...........................................................................41 
7.1.1. 
Reasons for Discontinuation .......................................................................................41 
7.1.2. 
Discontinuation Procedures ........................................................................................42 
7.2. 
Participant Withdrawal From the Study .....................................................................42 
7.3. 
Lost to Follow-Up.......................................................................................................42 
7.4. 
Study Treatment Completion ......................................................................................43 
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................................44 
8.1. 
Administrative and General Procedures .....................................................................44 
8.1.1. 
Informed Consent Process ..........................................................................................44 
8.1.2. 
Screening Procedures ..................................................................................................45 
8.1.3. 
Interactive Response Technology Procedure ..............................................................45 
8.1.4. 
Distribution of Reminder Cards ..................................................................................45 
8.1.5. 
Demography and Medical History ..............................................................................45 
8.1.5.1. 
Demographics and General Medical History .............................................................45 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................46 
8.2. 
Efficacy and Endpoint Assessments ...........................................................................46 
8.2.1. 
CRS Status ..................................................................................................................46 
8.2.2. 
ICANS Status..............................................................................................................46 
8.2.3. 
Lee's CRS Revised Grading System ...........................................................................48 


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8.3. 
Safety Assessments .....................................................................................................49 
8.3.1. 
Adverse Events ...........................................................................................................49 
8.3.2. 
Physical Examinations ................................................................................................50 
8.3.3. 
Vital Signs and Temperature Monitoring ...................................................................50 
8.3.4. 
Eastern Cooperative Oncology Group Performance Status ........................................50 
8.3.5. 
Local Laboratory Assessments ...................................................................................51 
8.3.5.1. 
Pregnancy Testing ......................................................................................................52 
8.3.5.2. 
Serology ......................................................................................................................53 
8.4. 
Hematologic Disease Status .......................................................................................53 
 
53 
 
54 
8.7. 
Unscheduled Visits .....................................................................................................55 
8.8. 
End of Treatment ........................................................................................................55 
8.9. 
Follow-Up ...................................................................................................................55 
8.9.1. 
Safety Follow-Up ........................................................................................................55 
8.9.2. 
Hematologic Disease Follow-Up ................................................................................56 
8.9.3. 
Electrocardiograms and Echocardiograms .................................................................56 
8.9.4. 
Survival Follow-Up ....................................................................................................56 
8.10. 
End of Study ...............................................................................................................56 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................57 
9.1. 
Definition of Adverse Event .......................................................................................57 
9.2. 
Definition of Serious Adverse Event ..........................................................................58 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........59 
9.4. 
Reporting of Serious Adverse Events .........................................................................61 
9.5. 
Adverse Events of Special Interest .............................................................................62 
9.6. 
Emergency Unblinding of Treatment Assignment .....................................................62 
9.7. 
Pregnancy ...................................................................................................................63 
9.8. 
Warnings and Precautions ..........................................................................................63 
9.9. 
Product Complaints ....................................................................................................63 
9.10. 
Treatment of Overdose ...............................................................................................64 
10. 
STATISTICS ..............................................................................................................65 
10.1. 
Sample Size Determination ........................................................................................65 


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10.2. 
Populations for Analysis .............................................................................................66 
10.3. 
Level of Significance ..................................................................................................67 
10.4. 
Statistical Analyses .....................................................................................................67 
10.4.1. 
Primary Analysis ........................................................................................................67 
10.4.1.1. 
CRS Rate by Day 14 ...................................................................................................67 
10.4.1.2. 
Cytokine Release Syndrome Rate by Day 14 – Part 2 ...............................................67 
10.4.2. 
Secondary Analysis ....................................................................................................67 
10.4.2.1. 
Part 2 Analysis ............................................................................................................67 
10.4.2.2. 
ICANS Incidence ........................................................................................................68 
10.4.2.3. 
Onset and Duration of ICANS ....................................................................................68 
10.4.2.4. 
Onset and Duration of CRS ........................................................................................68 
10.4.2.5. 
Occurrence of CRS Within 48 Hours .........................................................................68 
10.4.2.6. 
CRS Rate Within 28 Days ..........................................................................................68 
10.4.2.7. 
Hospitalization on Study .............................................................................................68 
10.4.3. 
Safety Analyses ..........................................................................................................69 
10.4.3.1. 
Adverse Events ...........................................................................................................69 
10.4.3.2. 
Clinical Laboratory Tests ...........................................................................................69 
10.4.3.3. 
Vital Signs ..................................................................................................................69 
10.4.3.4. 
Dose Intensity .............................................................................................................70 
 
70 
 
70 
 
70 
 
70 
10.5. 
Interim Analysis ..........................................................................................................70 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................72 
11.1. 
Investigator Responsibilities .......................................................................................72 
11.2. 
Data Management .......................................................................................................73 
11.3. 
Data Quality Assurance ..............................................................................................75 
11.4. 
Data Privacy and Confidentiality of Study Records ...................................................75 
11.5. 
Financial Disclosure ...................................................................................................76 
11.6. 
Publication Policy .......................................................................................................76 
11.7. 
Study and Site Closure................................................................................................77 


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12. 
REFERENCES ...........................................................................................................78 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................80 
APPENDIX B. CYTOCHROME P450 AND P-GLYCOPROTEIN INHIBITORS 
AND CYTOCHROME P450 INDUCERS ................................................................81 
APPENDIX C. INSTRUCTION TO PARTICIPANTS FOR HANDLING STUDY 
TREATMENT ............................................................................................................82 
APPENDIX D. MANAGEMENT OF POTENTIAL HY'S LAW CASES ................................83 
APPENDIX E. RESPONSE CRITERIA FOR LYMPHOMA – THE LUGANO 
CLASSIFICATION ....................................................................................................87 
APPENDIX F. RESPONSE CRITERIA FOR ACUTE LYMPHOBLASTIC 
LEUKEMIA ...............................................................................................................89 
APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES ...........................91 
 


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LIST OF TABLES 
Table 1: 
Primary and Major Secondary Objectives and Endpoints ..........................................13 
Table 2: 
Key Study Design Elements .......................................................................................14 
Table 3: 
Schedule of Activities .................................................................................................16 
Table 4: 
Summary of Itacitinib Steady-State (Day 7) Pharmacokinetic Parameters by 
Actual Dose Regimen .................................................................................................22 
Table 5: 
Summary of Itacitinib Steady-State (Day 7) Pharmacokinetic Parameters by 
Actual Dose Regimens and Concomitant CYP3A4 Inhibitors ...................................23 
Table 6: 
Enzyme Inhibitory Activity of Itacitinib Against Different Members of the 
Human JAK Family ....................................................................................................28 
Table 7: 
Objectives and Endpoints ...........................................................................................31 
Table 8: 
Exclusionary Laboratory Values ................................................................................36 
Table 9: 
Study Treatment Information .....................................................................................37 
Table 10: ASBMT CRS Consensus Grading ..............................................................................46 
Table 11: Encephalopathy Assessment Tool for Grading of Immune Effector Cell–
Associated Neurotoxicity Syndrome ..........................................................................47 
Table 12: ASBMT Immune Effector Cell–Associated Neurotoxicity Syndrome 
Consensus Grading .....................................................................................................48 
Table 13: Lee CRS Revised Grading System .............................................................................49 
Table 14: Eastern Cooperative Oncology Group Performance Status Scoring ..........................51 
Table 15: Required Laboratory Analytes ....................................................................................52 
 
54 
 
55 
Table 18: CRS Rates and 95% Confidence Intervals .................................................................65 
Table 19: Bayesian Posterior Probability of Demonstrating a Treatment Difference ................66 
Table 20: Populations for Analysis .............................................................................................66 
 


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LIST OF FIGURES 
Figure 1: 
Study Design Schema Part 1 .......................................................................................15 
Figure 2: 
Study Design Schema Part 2 .......................................................................................15 
Figure 3: 
Simulated Free Itacitinib Concentration-Time Profiles ..............................................26 
Figure 4: 
Effect of Increasing Itacitinib Concentrations on CAR-T Cell Proliferation 
and Effector Function .................................................................................................28 
Figure 5: 
Itacitinib Effect on CD19-CAR-T Cells In Vivo Antitumor Activity ........................29 
Figure 6: 
Itacitinib Effect on CAR-T Cells Production of Inflammatory Cytokines .................30 


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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AAGP 
α-1-acid glycoprotein 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplant and Cellular Therapy 
BCRP 
breast cancer resistance protein 
BID 
twice daily 
CAR 
chimeric antigen receptor 
CAR-T 
chimeric antigen receptor therapy 
CFR 
Code of Federal Regulations  
Cmax 
maximum serum concentration of drug after administration 
CNS 
central nervous system 
CR 
complete response 
CRES 
chimeric antigen receptor T-cell–related encephalopathy syndrome 
CRi 
complete response with incomplete blood count recovery 
CRP 
C-reactive protein 
CRS 
cytokine release syndrome 
CSF 
cerebral spinal fluid 
CSR 
Clinical Study Report 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events version 5.0 
DDI 
drug-drug interaction 
DNA 
deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board  
EAS 
evaluable analysis set 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment   


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Abbreviations and 
Special Terms 
Definition 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GVHD 
graft-versus-host disease 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HSA 
human serum albumin 
IB 
Investigator's Brochure 
ICANS 
immune effector cell–associated neurotoxicity syndrome 
ICE 
immune effector cell–associated encephalopathy 
ICF 
informed consent form  
ICH 
International Council on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
immune effector cell 
IFN-γ 
interferon-gamma 
IL-1 
interleukin-1 
IL-6 
interleukin-6 
IL-6R 
interleukin-6 receptor 
IRB 
institutional review board (or ethics committee) 
IRT 
interactive response technology 
JAK 
Janus kinase 
LVEF 
left ventricular ejection fraction 
 
 
 
  
OVA 
ovalbumin 
 
 
PD 
progressive disease  
PK 
pharmacokinetic 
PR 
partial response 
QD 
once daily 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SoA 
schedule of activities 


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Abbreviations and 
Special Terms 
Definition 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription pathway 
TEAE 
treatment-emergent adverse event 
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
WBC 
white blood cell 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Phase 2 Study of Itacitinib for the Prevention of Cytokine Release Syndrome 
Induced by Immune Effector Cell Therapy 
Protocol Number:  INCB 39110-211 
Objectives and Endpoints: 
Table 1 presents the primary and major secondary objectives and endpoints. 
Table 1: 
Primary and Major Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of itacitinib as a 
preventative treatment for CRS associated with 
IEC therapy. 
Efficacy, as determined by the proportion of 
participants who develop ≥ Grade 2 CRS by Day 14 
using ASBMT CRS Consensus Grading. 
Secondary 
To evaluate the proportion of participants with 
ICANS regardless of CRS, after IEC therapy. 
Incidence and severity of ICANS, as determined by 
the proportion of participants with ICANS by 
Day 28, after IEC therapy using the ICANS 
Consensus Grading. 
To evaluate the onset and episode of ICANS 
using the ICANS Consensus Grading, regardless 
of CRS, by Day 28. 
Time to onset and duration of ICANS using the 
ICANS Consensus Grading, regardless of CRS, by 
Day 28. 
To evaluate the duration of all grades of CRS, 
by Day 28. 
Time to onset and duration of all grades of CRS by 
Day 28 using ASBMT CRS Consensus Grading. 
To evaluate the proportion of participants who 
develop any grade of CRS within 48 hours after 
IEC therapy. 
Proportion of participants with any grade CRS at 
48 hours, after IEC therapy using ASBMT CRS 
Consensus Grading. 
To evaluate the proportion of participants who 
develop ≥ Grade 2 CRS by Day 28 of 
administration after first IEC therapy. 
Proportion of participants with ≥ Grade 2 CRS by 
Day 28, after first IEC therapy. 
To characterize the safety of itacitinib, before 
and after IEC therapy, excluding CRS and 
ICANS. 
Safety of itacitinib assessed by the incidence of all 
AEs except CRS and ICANS, by collecting 
laboratory data, performing physical examinations, 
and collecting vital signs beginning at Day –3 and 
through the duration of safety follow-up. 
≥ Grade 3 Cytopenias ongoing by Day 30. 
To assess intervention for CRS and ICANS. 
Proportion of participants who were treated with 
tocilizumab for CRS. 
Proportion of participants requiring more than 
1 dose of dexamethasone (or equivalent) for 
ICANS. 


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Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 
Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
Prevention of CRS after IEC therapy 
Population 
Male or female participants aged 12 years or older eligible to receive an 
approved immune effector cell (IEC) therapy for hematologic 
malignancies.   
Number of Participants 
Part 1:  Approximately 62 participants  
Part 2:  Approximately 46 evaluable participants (23 participants per 
arm) 
Study Design 
This is a 2-part study designed to assess the safety and efficacy of oral 
administration of itacitinib to participants planning to receive IEC 
therapy.  In Part 1, participants will be administered open label itacitinib 
200 mg QD.  In Part 2, participants will be randomized to receive either 
itacitinib 200 mg BID or placebo. 
Study treatment will begin on Day –3 (pre-IEC) and continue through 
Day 26 (study treatment period).  IEC therapy will be administered on 
Day 0 (IEC infusion day).  Protocol-defined assessments will be 
conducted on Days –3, –1, 0, 1, 3, 5, 7, 14, 21, and 28 (see Table 3).  
Restaging of disease will be conducted as applicable per institutional 
guidelines.  A completer is defined as a participant who completes 30 
days (Day –3 to Day 26) of study treatment administration.  Safety will 
be monitored beginning at screening and continue until 30 days after the 
last dose of study treatment. 
Additional post-therapy follow-up visits will be conducted at Day 90 
and Day 180 (90 and 180 days after IEC).  End of study is met at Day 
180 (6 months after IEC).  All participants should complete a Day 28 
assessment, unless the participant withdraws consent, even if treatment 
ends early. 
Estimated Duration of 
Study Participation 
This study includes a 14-day screening period.  Enrollment and study 
treatment administration begin on Day –3 (Day 0 = IEC infusion day).  
Study treatment continues through Day 26.  The participant will 
continue to be assessed for survival follow-up for 6 months, with a final 
EOS assessment at Day 180.  Hematologic disease assessments that are 
conducted during this time should be captured in the eCRF. 
DSMB 
Internal 
Coordinating Principal 
Investigator 
 MD 
 
 
Treatment Groups and Duration: 
This Protocol includes a 14-day screening period after apheresis. 


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This Protocol includes treatment with IEC therapy administered per the prescribing label on 
Day 0. 
In Part 1, study treatment is defined as itacitinib beginning at Day –3 (pre-IEC) using itacitinib 
200 mg QD through Day 26 (30 days of treatment). 
In Part 2, study treatment is defined as itacitinib 200 mg BID or placebo beginning at Day –3 
(pre-IEC) through Day 26 (post-IEC), counting for a total of 30 days of treatment. 
See Figure 1 for the study design and Table 3 for the SoA.  Adherence to the study design 
requirements, including those specified in the SoA, is essential and required for study conduct. 
Figure 1: 
Study Design Schema Part 1 
 
Figure 2: 
Study Design Schema Part 2 
 
 


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Table 3: 
Schedule of Activities 
 
Screeninga 
Study Treatment 
Post-Treatment Follow-Upa 
Protocol 
Section 
D –17 to D –4 D –3 D –1 
IEC 
D0 
D1 
D3 
D5 
D7 
D14 
(± 2 d) 
D21 
(± 2 d) 
EOTb 
D28 
(± 2 d) 
D56 
30 d After 
Last Dose 
(± 3 d) 
D90 
(± 1 wk) 
EOS 
D180 
(± 2 wk) 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.1 
Contact IRT 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
8.1.3 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
5.1, 5.2 
Demography/medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.5 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
6.3 
Administer study treatment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
6.1 
Administer IEC therapy 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
6.2 
Document compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
6.1.2 
Dispense reminder cards 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8.1.4 
Drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
6.1.1 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
8.9.4 
Safety assessments 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
8.3.1 
ECOG 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
8.3.4 
Physical examination 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
8.3.2 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
8.3.3 
ECHO 
X 
Only if clinically relevant 
 
 
8.9.3 
12-lead ECG 
X 
Only if clinically relevant 
 
 
8.9.3 
Disease assessments 
FDG-PET CT/MRIc 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
8.4 
Bone marrow evaluation 
X 
 
 
 
 
 
 
 
 
 
Only if clinically relevant 
8.4 
Endpoint assessments 
Temperature monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
8.3.3 
CRS assessment (ASBMT CRS 
consensus grading)d 
 
 
Continuous monitoring based on fever 
X 
 
 
8.2.1 
ICANS assessment (ASBMT ICE 
consensus grading)e 
 
 
Continuous monitoring based on signs and symptoms 
X 
 
 
8.2.2 
Lee's CRS revised grading system 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
8.2.3 


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Table 3: 
Schedule of Activities (Continued) 
 
Screeninga 
Study Treatment 
Post-Treatment Follow-Upa 
Protocol 
Section 
D –17 to D –4 D –3 D –1 
IEC 
D0 
D1 
D3 
D5 
D7 
D14 
(± 2 d) 
D21 
(± 2 d) 
EOTb 
D28 
(± 2 d) 
D56 
30 d After 
Last Dose 
(± 3 d) 
D90 
(± 1 wk) 
EOS 
D180 
(± 2 wk) 
Local laboratory assessmentsf 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8.3.5 
Serum chemistries (including LDH) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
8.3.5 
Coagulation panel 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
8.3.5 
Lipid panel 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
8.3.5 
Hepatitis screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.5.2 
Pregnancy testing 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
8.3.5.1 
Lumbar puncture with paired blood 
samplesg 
Only if performed based on SOC 
 
 
 
— 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
8.3.5 
CRP 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
8.3.5 
Ferritin levels 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
8.3.5 
ASBMT = Association for Blood and Bone Marrow Transplantation; CRP = C-reactive protein; CRS = cytokine release syndrome; CT = computed tomography; 
ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = end of study; EOT = end of treatment; 
FDG-PET = fluorodeoxyglucose positron emission tomography; ICANS = immune effector cell–associated neurotoxicity syndrome; ICE = immune effector cell–associated 
encephalopathy; IEC = immune effector cell; LDH = lactase dehydrogenase; MRI = magnetic resonance imaging; PBMC = peripheral blood mononuclear cell; 
PK = pharmacokinetics; SOC = standard of care. 
a Decentralized assessments are acceptable during screening and post-treatment (see Section 11.1). 
b EOT:  Treatment will end on Day 26; however, the participant will be assessed at Day 28 ± 2 days.  If a participant ends treatment early, an EOT visit should be conducted at the 
time that the participant discontinues treatment. 
c If hematologic disease assessments are performed at different timepoints, based on institutional guidelines, then this is acceptable.  All disease assessments should be captured in 
the eCRF. 
d CRS will be evaluated at each visit during the study. In addition, participants should monitored be during the study and evaluated for CRS if fever is present. 
e ICANS will be evaluated at each visit during the study. In addition, participants should be monitored during the study and evaluated for ICANS if there are signs and symptoms 
relating to neurotoxicity. 


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f Screening for central laboratory assessments must be performed within 7 days of Day –3.  If screening laboratory assessments are performed within 3 days before Day –3, then 
the tests do not need to be repeated on Day −3.  Any laboratory samples collected on Day –3 must be collected before study treatment administration. 
g Lumbar puncture is not required; however, if one is performed per SOC, then it should be captured in the eCRF. 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Cytokine-related diseases or disorders are characterized by excessive immune activation and 
include CRS, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and 
ICANS. 
Cytokine release syndrome is a result of overproduction of inflammatory cytokines caused by 
robust and rapid immune activation and is manifested as a clinical constellation of symptoms 
including fever, nausea, fatigue, myalgia, malaise, hypotension, hypoxia, and capillary leak, 
resulting in potential multiorgan toxicity.  
CRS has been observed as a consequence of various immune-based therapies such as 
monoclonal antibodies and, more recently, adoptive T-cell therapies for cancer (Lee et al 2014).  
Examples of FDA-approved CAR T-cell therapies include axicabtagene ciloleucel and 
tisagenlecleucel, both being engineered T-cell products used in refractory CD19+ B-cell 
malignancies such as non-Hodgkin's lymphoma and pediatric relapsed/refractory ALL.  
Brexucabtagene autoleucel was recently FDA approved as well.  This product is a CD19-directed 
genetically modified autologous T cell immunotherapy indicated for the treatment of adult 
patients with relapsed or refractory mantle cell lymphoma (Tecartus 2020). 
The cytokine profiles involved in CRS encompass 2 main cellular sources:   
T lymphocyte–derived cytokines including IFN-γ, IL-2, IL-6, and granulocyte macrophage 
colony-stimulating factor, and cytokines mainly secreted by monocytes and/or macrophages such 
as IL-1β, IL-6, IL-12, IL-18, and TNF-α (Brentjens et al 2010, Xu and Tang 2014, Zhang 
et al 2016). 
Modulation of the exaggerated cytokine response resulting in CRS has the potential to provide 
significant clinical benefit.  For example, tocilizumab, a humanized monoclonal antibody against 
the IL-6R, decreases the rates of severe CRS and is FDA-approved for use in CRS (Le et al 2018).  
However, tocilizumab's mechanism of action is restricted to anti–IL-6 only. 
The CRES is the second most common AE, after CRS, associated with CAR-T-cell 
therapy.  CRES (or ICANS) is characterized by a toxic encephalopathy state with symptoms of 
confusion, delirium, occasional seizures and cerebral edema.  The manifestation of CRES can be 
biphasic with symptoms occurring within the first 5 days and/or 3 to 4 weeks after cellular 
immunotherapy.  The pathophysiological mechanism is believed to involve passive diffusion of 
cytokines into the CNS of patients treated with CAR-T-cell therapy.  The reduction or 
elimination of this mechanism can be beneficial to such patients (Neelapu et al 2018).  While 
targeting IL-6 with tocilizumab has been effective in the management of CRS, it does not 
attenuate symptoms of neurotoxicity and is currently not FDA approved for the treatment of 
CRES (Kotch et al 2019, Teachey et al 2016). 


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2.2. 
Product Information and Overview of Itacitinib 
Itacitinib represents a novel, potent, and selective inhibitor of the JAKs with selectivity for 
JAK1.  There are 4 known JAK family members, JAK1, JAK2, JAK3, and TYK2. 
The pharmacology and additional details on toxicology of itacitinib are described in the itacitinib 
IB.  In brief, itacitinib potently inhibits JAK1 (IC50 = 3.6 nM) with 22- to > 500-fold selectivity 
compared with JAK2, JAK3, and TYK2, and it does not significantly inhibit a broad panel of 
approximately 60 other kinases.  Itacitinib is potent (IC50 values 10-100 nM) in cytokine-driven 
cell-based assays, such as IL-2–stimulated phosphorylation of JAKs and STATs and IL-2induced 
proliferation of primary human T cells.  Itacitinib inhibits the growth of the cytokine-dependent 
cell line INA-6, this effect is not due to general cytotoxicity.  Itacitinib potently inhibits the 
phosphorylation of STAT proteins and the production of proinflammatory factors (eg, IL-17, 
MCP-1) induced by cytokines such as IL-23 and IL-6 (IC50 ~30-100 nM).  In contrast, itacitinib 
shows less inhibition in cell-based assays dependent on JAK2 (eg, thrombopoietin or prolactin-
stimulated STAT phosphorylation) with IC50 approximately 1 μM or greater, suggesting that 
itacitinib is JAK2-sparing in cells.  In in vivo models of JAK-dependent malignancy, itacitinib 
impedes subcutaneous tumor growth of INA-6 cells expressing wild-type JAKs plasma 
concentrations well below those necessary to inhibit JAK2.  Moreover, oral itacitinib improved 
splenomegaly in a JAK2 V617F–driven neoplasia model of MF. 
Administration of itacitinib did not result in QT prolongation or cardiovascular effects.  Adverse 
findings were noted only at high dose (1000 mg/kg) suggesting the primary toxicities are 
expected to be on-target, and these observations are considered to be well beyond the needed 
safety margin compared to the therapeutic dose. 
In summary, pharmacological data obtained in both in vitro and in vivo model systems support 
the potential utility of orally administered itacitinib in the treatment of MF. 
2.2.1. 
Nonclinical Drug Metabolism and Pharmacokinetics 
In single-dose PK studies in rats, dogs, and monkeys, orally administered itacitinib was rapidly 
absorbed (tmax ≤ 2.0 hours).  The protein binding of itacitinib in plasma and serum from rats, 
dogs, and humans was moderate (unbound fraction of 29%-43%) and not dependent on itacitinib 
concentration. 
In a separate in vitro experiment.  The protein binding of itacitinib was determined using HSA 
and AAGP at concentrations ranging from 0.3 to 1.0 μM.  The unbound fractions of itacitinib 
0.3 and 1.0 μM in 40 mg/mL HSA were 31.2% and 32.7%, respectively (aligned with previous 
results); in 25 mg/mL HSA were 41.5% and 42.6%, respectively; and in 10 mg/mL HSA were 
60.9% and 61.7%, respectively.  The unbound fractions in AAGP were 85.5% and 89.5% at 
0.3 μM and 1.0 μM, respectively.  The free fraction in HSA was independent of compound 
concentration.  The free fraction in HSA decreased with increasing protein concentration.  The 
free fraction in AAGP was independent of compound concentration.  In male rats administered a 
4-hour IV infusion of itacitinib, the average brain homogenate concentration of itacitinib at 
4 hours was 6.18% of the corresponding total plasma concentration, while the average CSF 
concentration was 2.93% of the corresponding free plasma concentration, suggesting minimal 
penetration across the blood-brain barrier in rats. 


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Transport studies using Caco-2 monolayers show that itacitinib is likely a substrate for P-gp, and 
the efflux transport is likely saturated when the itacitinib concentration is greater than 300 μM.  
In addition, the bidirectional transport ratio of digoxin (a P-gp substrate) decreased in the 
presence of itacitinib in a concentration-dependent manner, with an IC50 of 41.4 μM, indicating 
that itacitinib is a weak P-gp inhibitor.  The interaction of itacitinib with human BCRP was also 
determined in MDCKII-BCRP cells.  The net efflux ratio of itacitinib was 3.3 at 10 µM, 
suggesting that itacitinib is a substrate of BCRP.  Itacitinib is not an inhibitor of BCRP.  Given 
the moderate solubility and permeability of itacitinib, and marginal efflux in the gut at the 
proposed clinical doses, a DDI study with a P-gp/BCRP inhibitor may not be clinically relevant.  
In addition, based on physiologically based pharmacokinetic modeling, a clinical DDI study with a 
P-gp substrate such as digoxin may not need to be considered (EMA 2012, FDA 2017). 
CYP3A4 is the major isozyme responsible for the metabolism of itacitinib.  Itacitinib did not 
inhibit or induce CYP activity, suggesting a low potential for DDIs. 
In vitro studies also demonstrated that itacitinib is not a substrate of hepatic transporters 
OATP1B1/1B3 or renal transporter OCT2.  Although itacitinib inhibited the hepatic transporters 
OATP1B1/1B3 and renal transporters OAT1/3, OCT2, and MATE1/2K, the potential to cause a 
clinical DDI is low.  Overall, DDI mediated by the major drug transporters for itacitinib is 
unlikely at the proposed clinical doses. 
2.2.2. 
Clinical Drug Metabolism and Pharmacokinetics 
Coadministration with a high-fat meal increased Cmax by 22% and AUC0-∞ by 30% following a 
single dose of itacitinib 200 mg compared with administration in the fasted state.  This increase 
is not clinically significant, and itacitinib may be administered without regard to food.  Itacitinib 
displays supraproportional PK, that is, exposure increases greater than proportionally with 
increasing dose. 
A single dose of three 100 mg SR3 tablets of itacitinib followed by an oral solution of 
[14C]itacitinib adipate approximately 500 μCi free base equivalent was administered to 7 healthy 
participants in Study INCB 39110-109.  A mean of 71.7% of the dose was recovered in feces, 
and 24.5% was recovered in urine through the last collection interval.  The overall mean 
recovery of radioactivity in urine and fecal samples was 96.2% by the end of the 240-hour study 
period.  No major metabolites (≥ 10% of total drug-related material) were detected in plasma, 
and itacitinib was the major circulating species in plasma.  Itacitinib was the major species in 
urine and feces.  All metabolites identified in urine and feces accounted for < 10% of the 
excreted dose each. 
Based on data from the renal impairment Study INCB 39110-122, total (AUC0-∞) and maximal 
exposure (Cmax) increased by 2.23-fold (90% CI:  1.56, 3.18) and 1.65-fold (90% CI:  1.13, 
2.39), respectively, in participants with severe renal impairment compared with participants with 
normal renal function.  However, there was no notable change in total or maximal exposure in 
participants with end-stage renal disease receiving dialysis predose or 4 hours postdose. 
In participants with moderate hepatic impairment, total (AUC0-∞) and maximal exposure (Cmax) 
increased by 2.51-fold (90% CI:  1.54, 4.08) and 1.95-fold (90% CI:  1.14, 3.35), respectively, 
compared with normal participants (Study INCB 39110-113).  In participants with severe hepatic 


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impairment, total (AUC0-∞) and maximal exposure (Cmax) increased by 4.08-fold (90% CI:  2.41, 
6.89) and 3.48-fold (90% CI:  1.94, 6.23), respectively, compared with normal participants. 
Study INCB 39110-115 demonstrated that, while itacitinib may increase serum creatinine in 
some participants, there was no effect on GFR as measured by iohexol clearance. 
A post-hoc ECG exposure-response analysis was conducted to assess the cardiac safety of 
itacitinib using data from the first-in-human study, INCB 39110-101.  Itacitinib at the studied 
doses did not have a relevant effect on cardiac conduction.  A QTc effect exceeding the threshold 
of concern (10 ms) can be excluded within the observed range of itacitinib plasma concentrations 
(ie, up to ~13,000 nM, which is expected to be well-above the maximum concentration expected 
in various subpopulations [eg, renal impairment] receiving therapeutic itacitinib). 
In a pilot study in acute GVHD participants (Study INCB 39110-108), characterization of the PK 
of itacitinib after single and multiple doses of itacitinib was performed.  In this study, doses of 
200 mg or 300 mg QD were administered and appear to display similar PK in this participant 
population, noting the small sample size (see Table 4).  Additionally, participants who were 
concomitantly on a strong CYP3A4 inhibitor, mainly posaconazole, appeared to have exposures 
(AUC0-τ) approximately 2 × higher than those who were not concomitantly on a strong CYP3A 
inhibitor (see Table 5).  Based on preliminary data, exposures following 200 mg QD were 
similar in a Phase 3 study in acute GVHD participants as compared to the pilot study.  
Additionally, based on preliminary data from this Phase 3 study, exposures in participants 
concomitantly receiving posaconazole were similar to those concomitantly receiving 
voriconazole, supporting similar dosing recommendations for itacitinib when coadministered 
with any strong CYP3A inhibitor regardless of the specific inhibitor. 
Table 4: 
Summary of Itacitinib Steady-State (Day 7) Pharmacokinetic Parameters by 
Actual Dose Regimen 
Actual 
Regimen 
No. of Participants 
Cmax (nM) 
tmax(h) 
Ctau (nM) 
AUCtau (nM•h)a 
200 mg QD 
11 
624 ± 340 
(534) 
4.0 
(1.3, 7.0) 
64.0 ± 79.3 
(NC) 
5560 ± 3430 
(4700) 
300 mg QD 
13 
781 ± 668 
(484) 
2.0 
(0.0, 5.6) 
53.1 ± 64.0 
(NC) 
5880 ± 5170 
(4110) 
NC = not calculable. 
Note:  Values are mean ± SD (geometric mean), except tmax, which is median (min, max). 
a AUCtau is calculated from time 0-24 hours postdose, where the 24-hour concentration is imputed from predose trough. 


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Table 5: 
Summary of Itacitinib Steady-State (Day 7) Pharmacokinetic Parameters by 
Actual Dose Regimens and Concomitant CYP3A4 Inhibitors 
Actual 
Regimen 
CYP3A4 
Inhibitora 
No. of 
Participants 
Cmax (nM) 
Tmax (h) 
Ctau (nM) 
AUCtau (nM•h) 
200 mg 
QD 
1 
6 
580 ± 341 
(492) 
4.2 
(2.1, 7.0) 
27.0 ± 33.2 
(NC) 
4240 ± 2630 
(3720) 
3 
5 
678 ± 371 
(589) 
2.1 
(1.3, 4.2) 
108 ± 99.2 
(NC) 
7140 ± 3870 
(6250) 
300 mg 
QD 
1 
6 
307 ± 282 
(204) 
1.5 
(0.0, 5.6) 
66.5 ± 85.7 
(36.6) 
2920 ± 1800 
(2320) 
3 
7 
1190 ± 639 
(1010) 
2.1 
(1.0, 4.8) 
41.6 ± 41.5 
(NC) 
8410 ± 5880 
(6720) 
NC = not calculable. 
Note:  Values are mean ± SD (geometric mean), except tmax, which is median (min, max). 
a 1 indicates no concomitant CYP inhibitor or mild CYP inhibitor; 3 indicates potent CYP inhibitor. 
2.2.3. 
Itacitinib Clinical Safety Summary 
As of the data cutoff date (30 APR 2021), 1699 unique participants have been exposed to 
itacitinib; which includes 543 healthy adult participants.  Thirty four clinical studies with 
itacitinib have been completed or are ongoing.  The studies include those with itacitinib as 
monotherapy and/or in one of the following combinations: 
• Itacitinib in combination with chemotherapeutic agents for the treatment of solid 
tumors. 
• Itacitinib in combination with a novel PI3Kδ inhibitor for the treatment of lymphoid 
malignancies (INCB040093 or INCB050465). 
• Itacitinib in combination with INCB050465 for the treatment of solid tumors. 
• Itacitinib in combination with pembrolizumab for the treatment of solid tumors. 
• Itacitinib in combination with epacadostat for the treatment of solid tumors. 
• Itacitinib in combination with corticosteroids for the treatment of acute GVHD. 
• Itacitinib in combination with osimertinib. 
• Itacitinib in combination with ibrutinib. 
• Itacitinib with low-dose ruxolitinib. 
Additional details regarding the study designs and primary endpoints of these studies are 
summarized in the itacitinib IB. 
2.3. 
Study Rationale 
In AUG 2017, tocilizumab was approved by the FDA for the treatment of severe or 
life-threatening CAR T cell-induced CRS.  The approval was based on a retrospective analysis of 
data from patients who developed CRS after treatment with CTL019 tisagenlecleucel 
(Kymriah® 2018) and axicabtagene ciloleucel KTE-C19 (Yescarta® 2021).  The efficacy 
population for the CTL019 cohort included 24 male and 21 female patients.  The median time 


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from the start of CRS to the first dose of tocilizumab was 4 days (range, 0-18 days).  Patients 
were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if 
not more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and 
corticosteroids were used for treatment.  Thirty-one patients (69%; 95% CI: 53%, 28%) achieved 
a response as described, while an additional cohort of 15 patients treated with KTE-C19–induced 
CRS demonstrated a 53% response rate.  The activity of tocilizumab was supported by a 
literature review.  The available data is wholly insufficient to extend the indication to CRS 
induced by other immunotherapeutics (Lee et al 2018). 
Neurologic symptoms may result from CRS.  Lee et al (2014) hypothesizes these neurotoxicities 
may be related to IL-6 and has been implicated in other neurological diseases such as 
Alzheimer's, Parkinson's, multiple sclerosis, schizophrenia, and depression.  Elevated levels of 
IL-6 within the CNS are likely due to diffusion of peripheral IL-6 into the CNS or direct 
production within the CNS by CNS residing CAR T cells.  IL-6 levels have been found in the 
cerebrospinal fluid associated with ICANS.  IL-6 levels rise transiently following administration 
of tocilizumab due to the blockage of the receptor which inhibits receptor-mediated clearance.  
As tocilizumab is not expected to cross the blood brain barrier, elevated levels within the CNS 
are not likely to be ameliorated and may even be transiently aggravated by tocilizumab therapy 
(Brudno and Kochenderfer 2016, Lee et al 2014).  The seriousness of CRS followed by ICANS 
in the setting of a potentially curative therapy for cancer warrants as aggressive supportive care 
as possible.  Accordingly, there is a need to develop a new therapy for the treatment of CRS 
(Hay et al 2019, Neelapu 2019, Park et al 2018). 
2.3.1. 
Scientific Rationale for Study Design  
Itacitinib is a small molecule inhibitor of the JAK family of protein TYKs, with selectivity for 
JAK1.  Members of the JAK family play an important role in signal transduction after cytokine 
and growth factor binding to their receptors.  Activated JAKs phosphorylate tyrosine residues on 
cytokine receptors and are the principal kinases associated with phosphorylation and activation 
of the STAT pathway (Murray 2007).  JAK1 plays a central role in a number of cytokine and 
growth factor–signaling pathways that, when dysregulated, can result in or contribute to disease 
and/or associated symptoms, such as CRS.  Excessive production of cytokines is associated with 
IEC therapy leading to CRS.  The therapeutic profile of itacitinib encompasses multiple 
pathogenic cytokines and not restricted to IL-6/IL-6R axis only (unlike, eg, tocilizumab).  
Efficacy is achieved by inhibiting cytokines derived from T-cells and monocyte/macrophages 
with high clinical relevance to CRS pathogenesis.  Furthermore, the prevention benefit is 
achieved without broad cytokine immunosuppression (eg, as demonstrated by unchanged IL-5 
levels; Guschin et al 1995). 
In preclinical mouse models, itacitinib was able to significantly reduce serum levels of many of 
the cytokines implicated in CRS (ie, IL-6, IL-12, and IFN-γ) in a dose-dependent manner.  As 
expected, itacitinib did not have a significant effect on cytokines independent of JAK-1 pathway 
(ie, IL-5).  As confirmatory experiments, itacitinib was also able to significantly and 
dose-dependently reduce serum levels of inflammatory cytokines in a therapeutic Con-A-induced 
CRS as well as in prophylactic and therapeutic CD3-induced CRS mouse models.  Importantly, 
in preclinical models where human CD19-CAR-T cells were adoptively transferred into 
CD19+ tumor-bearing immunodeficient animals, itacitinib does not affect the antitumor activity 
of CAR-T cells.  See Section 2.5 for preclinical summary. 


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Therefore, it is hypothesized that itacitinib may provide selective coverage to prevent CRS and 
the downstream effects of neurotoxicities unlike tocilizumab with broad IL-6 implications.  
2.3.2. 
Justification for Dose, Part 1 
Itacitinib 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 is also potent (IC50 values of 
approximately 10 nM to 350 nM) in cytokine-driven cell-based assays.  This effect is not due to 
general cytotoxicity.  Itacitinib also inhibits the growth of the cytokine-dependent cell line 
INA-6.  Itacitinib potently inhibits the phosphorylation of STAT proteins and the production of 
proinflammatory factors induced by other cytokines, such as IL-23 and IL-6 with IC50 values of 
approximately 30 nM to 100 nM. 
In a pilot study with itacitinib for acute GVHD, 200 mg QD and 300 mg QD doses were 
similarly efficacious; therefore, preclinical studies were performed using a 60 and 120 mg/kg 
BID dosing paradigm, which provides whole blood JAK1 IC50 (141 nM) coverage for 4 and 
12 hours respectively.  This coverage would be similar to human 200 mg QD dosing JAK1 IC50 
(6.5 to 10 hours).  The studies showed that with a dose equivalent to 200 mg QD in humans, 
itacitinib significantly reduced CRS inflammation without negatively impacting CAR-T function 
(see Section 2.5, Preclinical Summary). 
In conclusion, itacitinib is a highly selective and potent inhibitor of the JAK STAT pathway.  
CAR-T cell expansion demonstrated a relationship to a Grade 3 CRS and ICANS, but also to 
response (Neelapu et al 2017).  It is our hypothesis that by administering a dose of itacitinib 
200 mg QD for 3 days prior to IEC, there will be adequate dampening of the cytokines to prevent 
≥ Grade 2 CRS and ICANS without affecting the response rate of IEC therapy.  It is also 
hypothesized that by continuing treatment for 26 days after IEC therapy, the continued exposure 
to itacitinib will prevent ≥ Grade 2 CRS and ICANS.  Therefore, itacitinib 200 mg QD will be 
administered at Day –3 through Day 26. 
2.3.3. 
Preliminary Results from Part 1 
As of the preplanned interim analysis data cutoff (08 JAN 2021), 26 participants were enrolled, 
25 participants had completed Day 28 (EOT visit), and 26 participants had completed Day 14.  
The primary intent of this analysis was to minimize unnecessary exposure to itacitinib in the 
event of futility of preventing CRS.  Of the 26 participants, 3 (11.5%) participants experienced 
CRS Grade 2, and there was no participant with ≥ Grade 3 CRS.  Two participants received 
tocilizumab for CRS Grade 1.  Five (19.2%) participants had ≥ Grade 2 ICANS.  Results from 
this interim analysis have shown itacitinib to be well-tolerated, with preliminary evidence of 
clinical activity for the prevention of CRS and ICANS. 
A PK analysis was also performed, based on the interim data cutoff described above.  Exposures 
were generally similar in this patient population to those observed in other patient populations 
receiving the same dose at steady state, 200 mg QD.  The exposure range for itacitinib when 
dosed with axicabtagen ciloleucel or tisagenlecleucel are highly overlapping, although limited 
patients had received tisagenlecleucel.  At the time of this interim analysis there was no apparent 


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exposure/response relationship between measures of exposure (ie, AUC, Cmax, and Cmin) and 
CRS or ICANS grade. 
2.3.4. 
Rationale for Part 2 
An additional dosing regimen of itacitinib will be explored in an expanded, Part 2, of the study 
based on the following rationale: 
• Although preliminary data from Part 1 are promising, target coverage following 
200 mg QD is < 10 hours, suggesting BID dosing may offer greater target coverage 
over 24 hours. 
• The dose of itacitinib 200 mg BID was selected for the Part 2 expansion, based on 
nonclinical experiments and using a population PK model.  Nonclinical experiments 
utilizing a dose which achieved a similar level of target coverage as itacitinib 200 mg 
QD in humans, demonstrated that itacitinib does not impact CAR-T function.  
However, in vitro experiments showed that T-cell proliferation may be impacted at 
high concentrations with continuous exposure (ie, > 500 nM; see Figure 4) which 
exceed those following 200 mg QD after protein binding adjustment.  Using a 
population PK model (DMB-20.40), the concentration-time profiles following 
200 mg BID were simulated.  Free concentrations are predicted to remain below 
500 nM in at least 95% of participants, while the target coverage is maintained for a 
vast majority of the BID dosing interval as compared to less than half of the QD 
dosing interval (see Figure 3). 
Figure 3: 
Simulated Free Itacitinib Concentration-Time Profiles 
 
Blue = 400 mg, Green = 200 mg, Black = 100 mg.  Solid = QD, Dashed = BID.  Dotted red = 500 nM, Dotted purple = 49 nM.  
Free concentrations are used to account for in vivo protein binding which was not present in the in vitro T-cell proliferation 
experiments.  The IC50 is also protein binding adjusted as it was calculated using total plasma concentrations (141nM for total 
concentrations). 
Part 2 is a randomized, placebo-controlled portion of the study to determine the efficacy and 
safety of itacitinib 200 mg BID.  Investigators and participants will be blinded.  Approximately 
46 participants treated with Yescarta for relapsed or refractory large B-cell lymphoma or 
follicular lymphoma will be enrolled in Part 2 of the study.  Participants will be randomized in a 
1:1 ratio to receive either itacitinib or placebo.  The comparison to placebo is relevant to provide 
a well-controlled assessment of efficacy, and it is justified considering that there is no available 
drug therapy to be used as a comparator. 


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2.4. 
Benefit/Risk Assessment 
Adverse events that have been most frequently reported in at least 10% of participants receiving 
itacitinib monotherapy include anemia, thrombocytopenia, diarrhea, nausea, fatigue, and upper 
respiratory tract infection. 
As a result of itacitinib-mediated immunomodulation, an increased incidence of infections could 
possibly occur with itacitinib therapy.  Strict clinical monitoring is indicated to identify and treat 
infections in study participants should they occur. 
Because of the potential for myelosuppression, participants will have hematologic parameters 
closely monitored during clinical studies.  At the investigator's discretion, if there are clinically 
relevant declines in hematology parameters, therapy may be interrupted until resolution or 
discontinuation.  As itacitinib also has the potential to cause WBC margination (ie, a transient 
decrease in ANC), assessment of hematology parameters should be performed before study 
treatment administration at all applicable study visits. 
As described previously, murine models of JAK/STAT inhibition using itacitinib have 
demonstrated that efficacy is achieved by inhibiting cytokines derived from T-cells and 
monocyte/macrophages with high clinical relevance to CRS pathogenesis.  Further, the 
prevention benefit is achieved without broad cytokine immunosuppression.  To the extent that 
the thrombocytopenia and anemia observed with other JAK inhibitors reflect the inhibition of 
JAK2-mediated erythropoiesis and thrombopoiesis, a selective JAK1 inhibitor would likely be 
associated with a lower incidence of thrombocytopenia and anemia, while still resulting in a 
significant reduction in the production and the signaling of inflammatory and immune cytokines. 
The use of a JAK 1 inhibitor to prevent CRS in the presence of IEC therapy administration is 
being tested for the first time in this clinical study and, therefore, any potential benefit is 
hypothesized based on preclinical studies.  As described in Section 2.5, preclinical data suggest 
that JAK STAT pathway may contribute to driving an increase in cytokine and growth factor 
signaling pathways; thereby, inhibiting this pathway may prevent CRS with a downstream effect 
on neurotoxicities. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of itacitinib may be found in the IB, Section 6 Reference Safety Information (IB).  
Refer to the prescribing information for reference therapies of Kymriah (2018), Yescarta (2021), 
and Tecartus (2020). 
2.5. 
Preclinical Summary 
The biochemical potency of itacitinib for the inhibition of human JAK1, JAK2, JAK3, and 
TYK2 was determined in enzymatic assays using a recombinant truncated form of each family 
member that contained the catalytic domain.  The ability of itacitinib to block enzyme activity is 
reported as the concentration required for IC50.  The average IC50 values from multiple lots of 
itacitinib are indicated in Table 6.  Based on these data, itacitinib is a potent inhibitor of JAK1 
(IC50 value = 3.2 ± 2.2 nM), with 22- to > 600-fold selectivity for the other JAK family 
members. 


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Table 6: 
Enzyme Inhibitory Activity of Itacitinib Against Different Members of the 
Human JAK Family 
Enzyme 
IC50 
Mean ± SD (nM)a 
Number of Experiments 
Fold Selectivity for JAK1 
JAK1 
3.2 ± 2.2 
70 
– 
JAK2 
71.6 ± 32.0 
68 
22 
JAK3 
> 2000 
13 
> 600 
TYK2 
818 ± 272 
13 
256 
a Assays were performed at 1 mM ATP concentration. 
Using similar assay conditions as the JAK biochemical assays (ie, 1 mM ATP), itacitinib was 
selective against a broad panel of additional kinases when tested at a concentration of 20 μM. 
To study the effect of itacitinib on CAR-T-cells expansion and cytolytic activity, Ganglioside 
GD2 specific CAR-T-cells were expanded in vitro with anti-CD3/anti-CD28 coated beads in the 
presence of increasing itacitinib concentrations, ranging from 100 to 500 nM.  As shown in 
Figure 4 when compared with the DMSO control, itacitinib at 100 to 250 nM did not have a 
significant effect on CD3/CD28-induced expansion of human T-cells, while 500 nM was enough 
to block CAR-T cell proliferation.  Importantly, GD2-CAR-T-cells expanded in the presence of 
low (100 and 250 nM) itacitinib concentrations were able to efficiently lyse GD2-expressing 
tumor cells.  As shown in Figure 4 itacitinib  250 nM did not significantly impair CAR-T 
expansion, while  500 nM reduced the proliferative response.  Importantly, GD2-CAR-T cells 
expanded in the presence of itacitinib concentrations  250 nM were able to efficiently lyse 
GD2 expressing tumor cells. 
Figure 4: 
Effect of Increasing Itacitinib Concentrations on CAR-T Cell Proliferation 
and Effector Function 
 
Flow cytometry quantification of GD2-CAR-T expansion expanded with increasing concentrations of itacitinib.  T cells CAR-T 
cells were expanded using anti-CD3/anti-CD28 coated beads and proliferation measured every other day by flow cytometry (left 
panel).  GD2-CAR-T cells were expanded in the presence of different itacitinib concentrations and then co-cultured with 
luciferase expressing SY5Y neuroblastoma cells (GD-2+).  Lytic activity of GD2-CAR-T cells was determined by measuring 
luciferase activity.  As internal control, lytic activity of nontransduced T cells was also measured (background dotted line; right 
panel). 
To further elucidate the potential impact of itacitinib on CAR-T cell function we adoptively 
transferred human CD19-CAR-T cells into immunodeficient recipient mice that were harboring 


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CD19 expressing NAMALWA human lymphoma cells.  As shown in Figure 5, animals that 
received non-tumor targeting T cells (control) reached humane endpoint by Day 21.  In contrast, 
vehicle-treated mice receiving an adoptive transfer of CAR-T cells demonstrated a significant 
delay in mortality (p = 0.0014).  Daily itacitinib dosing (120 mg/kg) achieved a significant 
survival improvement (p = 0.0003) compared with control T cells and was similar to vehicle 
dosed CAR-T-cell animals (p = 01860), thus indicating that itacitinib treatment did not 
negatively impact the antitumor activity of CAR-T cells (see Figure 5). 
Figure 5: 
Itacitinib Effect on CD19-CAR-T Cells In Vivo Antitumor Activity 
 
Immunodeficient mice were inoculated with CD19+ human lymphoma NAMALWA-luciferase cell line and treatment initiated 
5 days later.  Animal received BID doses of itacitinib or vehicle for 10 days.  At Day 8, post-tumor injection, animals received an 
adoptive transfer of either control T cells or CD19-CAR-T cells.  N = 12 animals per group.  Left panel represents a 
Kaplan-Meier curve for the overall survival of the mice.  In vivo bioluminescence imaging of representative animals challenged 
with luciferase-expressing NAMALWA lymphoma cells and different treatments over time (right panel).  Data representative of 
2 independent experiments. 
Finally, the potential of itacitinib to reduce CRS-related cytokines produced by human 
CD19-CAR-T cells was explored.  As a positive control tocilizumab was utilized.  In vitro, 
CD19-CAR-T cells were expanded in the presence of increasing concentrations of itacitinib 
(100 or 300 nM) or tocilizumab (20, 100, or 200 μg/mL).  After a 3-day expansion in the 
presence of drug, CAR-T cells were co-cultured with CD19 expressing NAMALWA tumor 
target cells and 6 hours later supernatants collected.  As shown in Figure 6, itacitinib, but not 
tocilizumab, significantly reduced the levels of multiple inflammatory cytokines (ie, IL-2, IFN-γ, 
IL-6, or IL-8).  As background control, nontransduced T cells unable to target NAMALWA 
tumor target cells demonstrated no meaningful cytokines response. 


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Figure 6: 
Itacitinib Effect on CAR-T Cells Production of Inflammatory Cytokines 
 
ELISA = enzyme-linked immunosorbent assay. 
CD19-CAR-T cells were expanded with either itacitinib or tocilizumab (anti–IL-6 receptor).  Three days later, they were co-
cultured with CD-19+ lymphoma cells (E:T ratio = 2.5:1) for 6 hours and cytokines measured in the supernatant by ELISA.  Data 
represent mean ± SEM, and p-values were calculated by 2-way ANOVA. 
** p<0.01, *** p<0.001 versus vehicle control.  Data representative of 2 independent experiments.  
2.5.1. 
Preclinical Summary Conclusions 
Itacitinib potently inhibits JAK1 (IC50 = 3.2 nM), with 22- to > 600-fold selectivity for the other 
JAK family members, JAK2, JAK3, and TYK2. 
Itacitinib concentrations relevant to the in vitro IC50 did not adversely affect the proliferation or 
antitumor killing capacity of human CAR-T cells.  In an in vivo model of adoptively transferred 
human CD19-CAR-T cells into CD19+ NAMALWA bearing mice, itacitinib did not reduce the 
antitumor activity.  Furthermore, itacitinib did not reduce in vitro antigen driven proliferation of 
OVA-specific mouse T cells.  Consistent with this observation, itacitinib in vivo did not affect 
antitumor T cell activity against an OVA-expressing tumor cell line within an immune 
competent recipient mouse. 
In 2 in vivo mouse models (concanavalin A and anti-CD3) of T-cell hyperactivation resulting in 
cytokine storm, itacitinib reduced serum levels of CRS-related cytokines in a dose-dependent 
manner.  
Finally, in an in vitro model, itacitinib, but not tocilizumab, significantly reduced CRS-related 
cytokines produced by CD19-CAR-T cells (PRECLIN-19.16.1). 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 7 presents the objectives and endpoints for Part 1 and Part 2, supporting selection of 
optimal dosing/schedule of itacitinib for subsequent trials. 
Table 7: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of itacitinib as a 
preventative treatment for CRS associated with 
IEC therapy. 
Efficacy, as determined by the proportion of 
participants who develop ≥ Grade 2 CRS by 
Day 14, using ASBMT CRS Consensus Grading. 
Secondary 
To evaluate the proportion of participants with 
ICANS regardless of CRS, after IEC therapy. 
Incidence and severity of ICANS, as determined 
by the proportion of participants with ICANS by 
Day 28, after IEC therapy using the ICANS 
Consensus Grading. 
To evaluate the onset and episode of ICANS 
using the ICANS Consensus Grading, regardless 
of CRS, by Day 28. 
Time to onset and duration of ICANS using the 
ICANS Consensus Grading, regardless of CRS, 
by Day 28. 
To evaluate the duration of all grades of CRS, by 
Day 28. 
Time to onset and duration of all grades of CRS 
by Day 28 using ASBMT CRS Consensus 
Grading. 
To evaluate the proportion of participants who 
develop any grade of CRS within 48 hours after 
IEC therapy. 
Proportion of participants with any grade of CRS 
at 48 hours, after IEC therapy using ASBMT CRS 
Consensus Grading. 
To evaluate the proportion of participants who 
develop ≥ Grade 2 CRS by Day 28 of 
administration after first IEC therapy. 
Proportion of participants with ≥ Grade 2 CRS by 
Day 28, after first IEC therapy. 
To characterize the safety of itacitinib, before and 
after IEC therapy, excluding CRS and ICANS. 
Safety of itacitinib assessed by the incidence of all 
AEs except CRS and ICANS, by collecting 
laboratory data, performing physical 
examinations, and collecting vital signs beginning 
at Day –3 and through the duration of safety 
follow-up. 
≥ Grade 3 Cytopenias ongoing by Day 30. 
To evaluate the number of and length of hospital 
admissions for CRS and ICANS. 
Number of hospital admissions and duration of 
stay for participants with CRS and/or ICANS by 
EOS. 
To assess intervention for CRS and ICANS. 
Proportion of participants who were treated with 
tocilizumab for CRS. 
Proportion of participants requiring more than 1 
dose of dexamethasone (or equivalent) for 
ICANS. 


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Table 7: 
Objectives and Endpoints (Continued) 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a 2-part study designed to assess the safety and efficacy of oral administration of 
itacitinib for the prevention of CRS in male or female participants aged 12 years or older and 
who are planning to receive IEC therapy for any approved hematologic indication. 
Part 1:  Approximately 62 participants will be administered itacitinib 200mg QD (open label).  
The study population will include participants receiving any approved IEC for an approved 
indication. 
Part 2:  Approximately 46 participants will be randomized to 1 of 2 cohorts (~23 evaluable 
participants in each cohort).  Participants will be randomized 1:1 to receive either itacitinib 
200 mg BID or placebo.  The study population will include participants who are receiving 
Yescarta for relapsed or refractory large B-cell lymphoma or follicular lymphoma.  Investigators 
and participants will be blinded.  The sponsor will be unblinded in order to ensure ongoing safety 
monitoring for the itacitinib 200 mg BID cohort. 
This study includes a 14-day screening period after apheresis.  Apheresis will be per institutional 
standard of care.  Conditioning chemotherapy will be administered at the discretion of the 
investigator. 
Participants will be administered study treatment beginning at Day –3 to Day –1 before IEC 
infusion.  IEC therapy will be administered on Day 0 along with study treatment.  Participants 
will continue to receive study treatment through Day 26 to complete a 30-day study treatment 
period. 
During the treatment period, Protocol-defined assessments will be conducted on Day –3, Day –1, 
Day 0 (IEC infusion day), Day 1, Day 3, Day 5, Day 7, Day 14, Day 21, and Day 28.  Restaging 


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of hematologic disease will be conducted per institutional guidelines.  Completers are defined as 
participants who complete 30 days of study treatment administration (Day –3 to Day 26).  An 
EOT assessment will be conducted at Day 28 ± 2 days.  Additional post-therapy follow-up visits 
will be conducted 30 days after the last dose of study treatment and 90 and 180 days after IEC 
infusion. 
Safety will be monitored beginning at screening and will continue through to a 30-day 
post-treatment safety follow-up visit.  Collection of 6-month survival follow-up will be required 
and recorded in the electronic database.  End of study is met at the 6-month survival follow-up. 
Hematologic disease assessments should be conducted as indicated in the SoA.  The date of the 
assessment as well as the results should be recorded in the eCRF.  
An interim analysis for CRS futility will be conducted when 24 participants are treated with IEC 
therapy, in Part 1, and complete the Day 28 (EOT) visit.  The study may be stopped for futility at 
the interim analysis if the conditional power based on interim results is lower than 20%, which is 
equivalent to more than 17 out of 24 participants experiencing ≥ Grade 2 CRS by Day 14. 
See Section 6.1 for full itacitinib administration information and to Table 3, Schedule of 
Assessments in Section 1, Protocol Summary.  Decentralized assessments are acceptable; 
however, principal investigator oversight is required. 
4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF.  The end of the study is expected to 
occur when the last participant reaches their 6-month follow-up visit. 
Completers (of treatment) are defined as participants who complete 30 days of study treatment 
administration (Day –3 to Day 26).  A participant is considered to have completed the study if 
he/she has completed all periods of the study including the 6-month follow-up for which a 
disease assessment is required. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision or upon 
advice of the internal DSMB.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs, and regulatory bodies of the decision and reason for termination of the 
study.  The DSMB will recommend termination of the study if warranted, as described in 
Section 11.7. 


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5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Part 1:  Male or female, 12 years of age or older.  The participant (or legally acceptable 
representative for participants < 18 years of age) has the ability to comprehend and 
provides written informed consent for the study. 
Note:  The participants who are < 18 years of age will have a parent or legal guardian 
able to give written informed consent and assent (as appropriate) according to 
institutional standards and to comply with all study visits and procedures. 
Part 2:  Male or female, 18 years of age or older.  
2. Eligible to receive an IEC therapy that is approved by the health authority in the country 
where the study is being conducted, for hematologic indications.  
Part 1:  Eligible to receive any IEC therapy for any approved indication. 
Part 2:  Eligible to receive Yescarta for relapsed or refractory large B-cell lymphoma 
or follicular lymphoma. 
3. ECOG performance status 0 to 1. 
4. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Men must agree to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through safety follow-up and must refrain from 
donating sperm during this period.  Permitted methods that are at least 99% effective 
in preventing pregnancy (see Appendix A) should be communicated to the 
participants and their understanding confirmed.  
b. Women of childbearing potential must have a negative serum pregnancy test at 
screening and before the first dose on Day 1 and must agree to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
safety follow-up.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the participants and their 
understanding confirmed. 
c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea) are eligible. 


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5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Evidence of active uncontrolled/untreated infection (viral, bacterial, fungal, 
opportunistic) of any origin. 
2. Evidence of active HBV or HCV infection as defined in Section 8.3.5.2. 
3. Known human immunodeficiency virus. 
4. Active acute or chronic GVHD requiring systemic therapy. 
5. Concurrent use of chronic systemic steroids or immunosuppressant medications.   
6. Known hypersensitivity or severe reaction to itacitinib, similar compounds, or excipients 
of itacitinib. 
7. Any unresolved toxicity ≥ Grade 2 (except stable Grade 2 peripheral neuropathy or 
alopecia) from previous anticancer therapy. 
8. Participants with a known history or prior diagnosis of immunologic or 
inflammatory/autoimmune disease affecting the CNS, and unrelated to their disease 
under study or previous treatment. 
9. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day –3 of itacitinib administration, New 
York Heart Association Class III or IV congestive heart failure, and circulatory collapse 
requiring vasopressor or inotropic support.  Participants with arrhythmias that are not 
stable on a medical management program within 2 weeks of induction Day –3 are also 
excluded. 
10. Central nervous system status: 
a. Acute lymphoblastic leukemia participants with the following CNS status are eligible 
only in the absence of neurologic symptoms suggestive of CNS leukemia, such as 
cranial nerve palsy: 
− CNS1, defined as absence of blasts in CSF on cytospin preparation, regardless of 
the number of WBCs. 
− CNS2, defined as presence of < 0.5 × 109/L WBCs in CSF and cytospin positive 
for blasts, or > 5/μL WBCs, but negative by Steinherz/Bleyer algorithm: 
▪ CNS2a:  < 1.0 × 109/L RBCs; < 0.5 × 109/L WBCs and cytospin positive for 
blasts. 
▪ CNS2b:  ≥ 1.0 × 109/L RBCs; < 0.5 × 109/L WBCs and cytospin positive for 
blasts. 
▪ CNS2c:  ≥ 1.0 × 109/L RBCs; ≥ 0.5 × 109/L WBCs and cytospin positive for 
blast, but negative by Steinherz/Bleyer algorithm. 


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b. Diffuse large B-cell lymphoma participants:  Participants must have no signs or 
symptoms of CNS disease or detectable evidence of CNS disease; participants who 
have been previously treated for CNS disease but have no evidence of disease at 
screening are eligible. 
11. Participants who are currently breastfeeding. 
12. Receipt of a prior investigational study agent within 4 weeks before screening visit. 
Note:  Participants who have received anti-CD19 IEC therapy on a study where cell 
infusion occurred greater than 4 weeks before the screening visit are NOT excluded.  
13. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of itacitinib and attending required study visits (if 
outpatient); pose a significant risk to the participant; or interfere with interpretation of 
study data. 
14. Inability of the participant to swallow and retain oral medication. 
15. Participants with laboratory values at screening defined in Table 8. 
Table 8: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a 
Platelets 
≤ 10 × 109/L 
b 
Hemoglobin 
≤ 8 g/dL 
Hepatic 
e 
ALT 
≥ 2.5 × ULN for age, > 5 × ULN in the presence of liver metastases 
f 
AST 
≥ 2.5 × ULN for age, > 5 × ULN in the presence of liver metastases 
g 
Total bilirubin 
> 1.5 × ULN or > 3 × ULN in the presence of documented Gilbert's 
syndrome (unconjugated hyperbilirubinemia) 
Renal 
h 
Creatinine clearance 
Participants ≥ 18 years of age:  ≤ 50 mL/minute based on Cockcroft-
Gault formula. 
Participants < 18 years of age:  GFR < 15 based on revised Schwartz 
formula 2009. 
The cutoffs for mild, moderate, and severe renal insufficiency based on 
Cockcroft-Gault are 60-90 mL/min, 30-59 mL/min, and 0-29 mL/min, 
respectively. 
Note:  Creatinine clearance necessitates a 24-hour urine sample 
before the blood draw to calculate.  An estimated value is acceptable. 
Cardiopulmonary 
i 
Cardiac LVEF 
≤ 40% confirmed by ECHO/multigated analysis 
j 
Adequate pulmonary function 
≥ Grade 2 dyspnea and ≥ Grade 2 hypoxia 
5.3. 
Lifestyle Considerations 
Participants should be instructed to refrain from the consumption of pomegranates or 
pomegranate juice and grapefruit and grapefruit juice, as these are known to inhibit CYP3A 
enzymes and may increase the exposure to itacitinib. 


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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study within the 14-day screening period.  At a minimum, the 
following information must be collected and entered into the eCRF:  demography, screen failure 
details, and eligibility criteria. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened 1 time if the investigator believes that there has been a change in eligibility status. 
Participants who rescreen must be assigned a new participant number, must be re-consented to 
participate in the study, and must repeat all screening procedures (laboratory assessments do not 
need to be repeated if done within 3 days of rescreening). 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error. 
5.5. 
Replacement of Participants 
Participants who do not meet the eligibility requirements of the study may be replaced. 
6. 
STUDY TREATMENT 
6.1. 
Study Treatment Administered 
Table 9 presents the study treatment information. 
Table 9: 
Study Treatment Information 
 
Study Treatment 
Study treatment name: 
Part 1:  Itacitinib (all participants) 
Part 2:  Itacitinib or placebo 
Dosage formulation: 
Sustained release 
Unit dose strength(s)/dosage 
level(s): 
100 mg tablets 
Part 1:  200 mg QD 
Part 2:  200 mg BID or placebo 
Route of administration:  
Oral 
Administration instructions: 
Study treatment should be taken with water and regardless of food.  
 
 
Packaging and labeling: 
Study treatment will be provided to sites in high-density polyethylene 
bottles as applicable by Incyte.  No preparation is required. 
Each bottle will be labeled as per country requirement. 
Storage: 
Study treatment should be stored at ambient conditions 
(15°C-30°C or 59°F-86°F) as per the IB.  


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6.1.1. 
Study Treatment Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment.  All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff. 
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study treatment to the study site. 
• Inventory of study treatment at the site. 
• Participant use of the study treatment including pill counts from each supply 
dispensed. 
• Return of study treatment to the investigator or designee by participants. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified itacitinib.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of itacitinib until 
verified by the study monitor (unless otherwise agreed to by the sponsor).  At the conclusion of 
the study, the investigator or designee will oversee shipment of any remaining itacitinib back to 
the sponsor or its designee for destruction according to institutional SOPs.  If local procedures 
mandate on-site destruction of investigational supply, the site should (where local procedures 
allow) maintain the investigational supply until the study monitor inspects the accountability 
records in order to evaluate compliance and accuracy of accountability by the investigative site.  
At sites where the itacitinib is destroyed before monitor inspection, the monitors rely on 
documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual. 
See Appendix C for instructions for participants for handling itacitinib. 
6.1.2. 
Study Treatment Compliance 
Compliance with study treatment should be emphasized to the participant by the site personnel, 
and appropriate steps should be taken to optimize compliance during the study.  Compliance 
with study treatment will be calculated by the sponsor based on the drug accountability or dose 


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administration record documented by the site staff and monitored by the sponsor/designee.  
Participants will be instructed to bring all tablets with them to the study visits in order for site 
personnel to conduct tablet counts to assess itacitinib accountability.  The drug accountability 
documentation or dose administration record will be used by the sponsor to calculate treatment 
compliance. 
6.1.3. 
Dose Modifications for Itacitinib 
Part 1 
This Protocol includes a treatment regimen which is defined as follows:  itacitinib beginning on 
Day –3 of itacitinib 200 mg QD through Day 26. 
If a dose reduction of itacitinib from 200 mg QD to 100 mg QD, outside of the treatment 
regimen, is warranted in the judgment of the principal investigator, and in consultation with the 
medical monitor (whenever possible), while taking into account either the relatedness of an AE 
to the study treatment and/or the participant's underlying condition, then the dose reduction may 
be allowed.  There will be no further dose reductions below 100 mg QD. 
If a dose interruption is needed, the sponsor/medical monitor should be contacted. 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study treatment. 
Part 2 
The treatment regimen in Part 2 is defined as 200 mg BID or placebo. 
If a dose reduction is required, from 200 mg BID to 100 mg BID, the participant may take 
1 tablet of study treatment instead of 2 tablets. 
6.1.4. 
Criteria for Permanent Discontinuation of Study Treatment 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
study treatment be permanently discontinued.  See Section 7.1.2 for discontinuation procedures. 
Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to study treatment that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest. 
6.2. 
Immune Effector Cell Therapy 
In Part 1 participants will receive IEC therapy that is approved by the health authority in the 
country where the study is being conducted for any approved hematologic indication. 
In Part 2 participants will receive Yescarta. 
IEC therapy will be supplied by the site and administered per standard of care.  If conditioning 
chemotherapy is required, this will also be administered per standard of care at the discretion of 
the investigator. 


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6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
In Part 2, participants will be randomized to receive either itacitinib 200 mg BID or placebo.  
Investigators and participants will be blinded. 
6.4. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 30 days before the first dose of study treatment and 30 days after 
the last dose of study treatment will be recorded in the eCRF.  Any addition, deletion, or change 
in the dose of these medications will also be recorded.  Concomitant medications administered 
up to 30 days after the last dose of study treatment for an SAE should be recorded for SAEs as 
defined in Section 9. 
6.4.1. 
Permitted Medications and Procedures 
Concomitant treatments and/or procedures that are required to manage a participant's medical 
condition during the study will also be recorded in the eCRF. 
6.4.2. 
Restricted Medications and Procedures 
The following medications have restrictions on use during the treatment period of the study: 
• Aspirin in doses exceeding 125 mg per day is not permitted.  Low-dose aspirin 
(≤ 125 mg per day) is permitted unless clinically contraindicated. 
• Coadministration with strong CYP3A inhibitors. 
− If the participant's medical condition requires treatment with posaconazole, 
itraconazole, voriconazole, mibefradil, or clarithromycin, a dose reduction of 
itacitinib is recommended (see below), as strong CYP3A inhibitors have been 
shown to increase exposure to itacitinib (see Appendix B). 
Part 1 dose reduction:  Itacitinib 200 mg QD may be reduced to 100 mg QD. 
Part 2 dose reduction:  Itacitinib 200 mg BID (or Placebo) may be reduced to 
100 mg BID or placebo.  
− The sponsor medical monitor may be consulted for advice when CYP3A 
inhibitors are considered. 
• If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
then caution and enhanced monitoring is required.  History of thrombocytopenia 
should be a factor in the choice of anticoagulant and dose. 
• Tocilizumab and/or corticosteroids for CRS Grade 1 is not allowed.  However, 
tocilizumab may be given as rescue medication for CRS Grade 1 if no improvement 
is observed within 72 hours from onset, and the participant's medical condition 
requires intervention per investigator judgment. 


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6.4.3. 
Prohibited Medications and Procedures 
The following medications are prohibited during the treatment period of the study: 
• Concomitant use of another JAK inhibitor. 
• Initiating therapy with an investigational medication unless otherwise approved by 
the medical monitor, such as anakinra in the treatment of CRS. 
• Coadministration with strong CYP3A inducers.  The FDA DDI website provides the 
most current list of strong CYP3A inducers.  
6.5. 
Treatment After the End of the Study 
There will be no further treatment of itacitinib after Day 26. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be withdrawn from study treatment for the following reasons: 
• The participant becomes pregnant. 
• Consent is withdrawn.   
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or itacitinib/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 


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7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment before 
Day 28, the EOT visit should be conducted.  Reasonable efforts should be made to have the 
participant return for a 30-day safety follow-up visit.  These visits are described in Table 3.  The 
last date of the last dose of itacitinib and the reason for discontinuation of study treatment will be 
recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IRT. 
• Participants must be followed for safety until the time of the 30-day follow-up visit or 
until itacitinib–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or survival follow-up), then no additional data collection should 
occur; however, participants will have the option of withdrawing consent for study treatment but 
continuing in the follow-up period of the study.   
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 3 for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 


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assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
7.4. 
Study Treatment Completion 
A completer is defined as a participant who completed itacitinib administration for the 30-day 
treatment period (Day –3 to Day 26). 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or their representative will explain the nature of the study to the 
participant or their legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant. An ICF template 
will be provided by the sponsor or its designee. The sponsor or its designee must 
review and acknowledge the site-specific changes to the ICF template. The ICF 
must include a statement that the sponsor or its designee and regulatory 
authorities have direct access to participant records. 
− The ICF must contain all required elements including optional 
samples/procedures (eg, optional biopsy) and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the applicable requirements and regulations within the USA as 
well as the IRB or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 


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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is enrolled in the 
study, which is Day –3, pre-IEC.  Assessments that are required to demonstrate eligibility may 
be performed over the course of 1 or more days during the screening process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 14 days of Day –3) unless otherwise 
specified.  For participants who are enrolled in the study, information associated with eligibility 
requirements must be entered into the appropriate eCRF pages, as an example, information about 
apheresis and conditioning chemotherapy, if applicable. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
enrollment or the administration of itacitinib.  Individuals who do not meet the criteria for 
participation in this study (screen failure) may be rescreened 1 time if the investigator believes 
that there has been a change in eligibility status.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
dosing itacitinib will be used to determine eligibility. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site staff should contact the IRT to obtain the 
participant ID number during screening.  Upon determining that the participant is eligible for 
enrollment, the IRT will be contacted in order to register the participant for enrollment.  The IRT 
will contacted again at EOT.  Additional details are provided in the IRT manual. 
8.1.4. 
Distribution of Reminder Cards  
Participants will be provided with a reminder card at each visit.  The reminder card will indicate 
the date/time of the next visit and will also remind the participant that they should not take their 
morning dose of itacitinib/treatment 
 
 
 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 2 years that are considered to be clinically significant by the investigator. 


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8.1.5.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening.  Details 
regarding the participant's hematologic disease under study, including date of diagnosis, initial 
and current cancer stage, tumor histology, and relevant disease characteristics, and prior 
treatments, including systemic treatments, radiation, and surgical procedures, will be recorded. 
8.2. 
Efficacy and Endpoint Assessments 
8.2.1. 
CRS Status 
The ASBMT/ASTCT CRS Consensus Grading Criteria will be used to assess CRS (see 
Table 10).  CRS status will be captured on a CRS form within the eCRF.  Fever should be 
monitored, once IEC is administered through EOT.  If a participant has a fever, CRS should be 
graded and recorded in the eCRF. 
Table 10: 
ASBMT CRS Consensus Grading 
CRS Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
Temperature ≥ 38°C 
With Either: 
Hypotension 
None 
Not requiring 
vasopressors 
Requiring one 
vasopressor with or 
without vasopressin 
Requiring multiple 
vasopressors 
(excluding 
vasopressin) 
And/Orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow 
nasal cannulac, 
facemask, non-
rebreather mask, or 
Venturi mask 
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation, 
mechanical 
ventilation) 
BiPAP = bi-level positive airway pressure; CPAP = continuous positive airway pressure. 
Note:  Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading. 
a Fever is defined as temperature ≥ 38°C not attributable to any other cause.  In participants who have CRS and then receive 
antipyretics or anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS 
severity.  In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event:  hypotension or hypoxia not attributable to any other cause.  For example, a 
participant with temperature of 39.5°C, hypotension requiring one vasopressor and hypoxia requiring low flow nasal cannula is 
classified as having Grade 3 CRS. 
c Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 liters/minute.  Low-flow also includes blow-by oxygen delivery, 
sometimes used in pediatrics.  High-flow nasal cannula is defined as oxygen delivered at > 6 liters/minute. 
Source:  Lee et al 2018 and Neelapu 2019. 
8.2.2. 
ICANS Status 
The ASBMT/ASTCT ICANS Consensus Grading Criteria will be used to assess neurotoxicity 
(see Table 11).  ICANS status will be captured on an ICANS form within the eCRF.  The 
participant should be monitored for signs and symptoms of ICANS, if symptoms develop at any 
point after IEC, the participant should be evaluated in order to determine an ICANS grade and 
the details recorded in the eCRF. 


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Table 11: 
Encephalopathy Assessment Tool for Grading of Immune Effector 
Cell–Associated Neurotoxicity Syndrome 
Neurotoxicity Domain 
Command 
Total Points 
Orientation 
Orient to year, month, city and hospital 
4 points (1 point each) 
Naming 
Name 3 objects (point to 3 objects, such as a 
clock, pen, and button) 
3 points (1 point each) 
Following Commands 
Follow commands such as:  show me 2 fingers or 
close your eyes and stick out your tongue 
1 point in total 
Writing 
Ability to write a standard sentence such as:  Our 
national bird is the bald eagle. 
1 point in total 
Attention 
Count backwards from 100 by ten; eg, 100, 90, 80 
1 point in total 
Score 10:  No Impairment 
Score 7-9:  Grade 1 ICANS 
Score 3-6:  Grade 2 ICANS 
Score 0-2:  Grade 3 ICANS 
Score 0 due to participant unarousable and unable to perform ICE assessment:  Grade 4 ICANS 
Grading of IEC therapy related encephalopathy syndrome (ICANS) will be assessed using the 
ASBMT Consensus Grading for Neurological Toxicity Associated With Immune Effector Cells 
(see Table 12). 


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Table 12: 
ASBMT Immune Effector Cell–Associated Neurotoxicity Syndrome 
Consensus Grading 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7-9 
3-6 
0-2 
0 (participant is 
unarousable and unable 
to perform ICE). 
Depressed level of 
consciousnessb 
Awakens 
spontaneously. 
Awakens to 
voice. 
Awakens only to tactile 
stimulus. 
Participant is 
unarousable or requires 
vigorous or repetitive 
tactile stimuli to around.  
Stupor or coma. 
Seizure 
N/A 
N/A 
Any clinical seizure focal or 
generalized that resolves 
rapidly; or nonconvulsive 
seizures on EEG that 
resolve with intervention. 
Life-threatening 
prolonged seizure 
(> 5 min); or repetitive 
clinical or electrical 
seizures without return 
to baseline in between. 
Motor findingsc 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis. 
Raised 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimagingd. 
Diffuse cerebral edema 
on neuroimaging; 
decerebrate or 
decorticate posturing; or 
cranial nerve VI palsy; 
or papilledema; or 
Cushing's triad. 
ICE = immune effector cell–associated encephalopathy; ICP = intracranial pressure; EEG = electroencephalogram. 
Note:  ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, and 
raised ICP/cerebral edema) not attributable to any other cause.  For example, a participant with an ICE score of 3 who has a 
generalized seizure is classified as having Grade 3 ICANS. 
a A participant with an ICE score of 0 may be classified as having Grade 3 ICANS if the participant is awake with global 
aphasia.  But a participant with an ICE score of 0 may be classified as having Grade 4 ICANS if the participant is unarousable. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
c Tremors and myoclonus associated with IEC therapies may be graded according to CTCAE v5.0 but they do not influence 
ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from 
ICANS grading.  It may be graded according to CTCAE v5.0. 
If the participant has no impairment (ICE score of 10), then Grade 0 may be entered in the EDC 
for ICANS Grade. 
8.2.3. 
Lee's CRS Revised Grading System 
The following grading information will be collected in the eCRF for purposes of historical 
comparison of previous captured published grading scales. 


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Table 13: 
Lee CRS Revised Grading System 
Grade 
Toxicity 
Grade 1 
Symptoms are not life-threatening and require symptomatic treatment only, eg, fever, 
nausea, fatigue, headache, myalgias, malaise. 
Grade 2 
Symptoms require and respond to moderate intervention: 
Oxygen requirement < 40%; or hypotension responsive to fluids or low dose of 
1 vasopressor or Grade 2 organ toxicity. 
Grade 3 
Symptoms require and respond to aggressive intervention: 
Oxygen requirement ≥ 40% or hypotension requiring high dose or multiple vasopressors or 
Grade 3 organ toxicity or Grade 4 transaminitis. 
Grade 4 
Life-threatening symptoms such as requirement for ventilator support or Grade 4 organ 
toxicity (excluding transaminitis). 
Grade 5 
Death. 
Source:  Lee et al 2014. 
8.3. 
Safety Assessments 
The following safety assessments will be collected according to the SoA (see Table 3) unless 
directed otherwise. 
8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
30 days after the last dose of study treatment.  Adverse events that begin or worsen after 
informed consent should be recorded on the Adverse Events Form in the eCRF regardless of the 
assumption of a causal relationship with the itacitinib.  Conditions that were already present at 
the time of informed consent should be recorded on the Medical History Form in the eCRF.  
Adverse events (including laboratory abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible rather than by individual underlying signs and symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following up on AEs that are serious, 
that are considered related to the study treatment/procedures, or that caused the participant to 
discontinue the itacitinib.  Care will be taken not to introduce bias when detecting AEs and/or 
SAEs.  Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits, or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 


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After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual, such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Height will be assessed at screening only.  Weight should be assessed at each 
timepoint.  Abnormalities identified after the first dose of itacitinib constitute an AE if they are 
considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
therapy, or require changes in study itacitinib.  Investigators should pay special attention to 
clinical signs related to previous serious illnesses. 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional standard of care.  These assessments should be an evaluation as 
indicated by participant symptoms, AEs, or other findings and documented on the AE eCRF. 
8.3.3. 
Vital Signs and Temperature Monitoring  
Vitals will include blood pressure, pulse, respiratory rate, and body temperature.  Blood pressure 
and pulse will be taken with the participant in the recumbent, semirecumbent, or sitting position 
after 5 minutes of rest.  Abnormal vital sign results identified after the first dose of study 
treatment constitute an AE if they are considered clinically meaningful, induce clinical signs or 
symptoms, require concomitant therapy, or require changes in itacitinib. 
Temperature should be monitored starting on Day −3 through EOT (Day 28 ± 2 days).  Any 
temperature ≥ 38°C should be documented for CRS grading. 
The participant will be encouraged to use a TempTraq® device as a tool for temperature 
monitoring.  Additional instructions regarding the TempTraq device will be provided separately.  
If a participant in unable to wear the device at any point during the treatment period, this will not 
be considered a Protocol deviation. 
8.3.4. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status will be assessed as indicated in Table 3 according to the criteria 
in Table 14. 


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Table 14: 
Eastern Cooperative Oncology Group Performance Status Scoring 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 
8.3.5. 
Local Laboratory Assessments 
See Table 15 for the list of clinical laboratory tests to be performed and the SoA (see Table 3) for 
the timing and frequency.  A certified laboratory local to the investigative site will perform all 
clinical laboratory assessments except as identified in Table 16 and Table 17. 
The investigative site will enter the laboratory results and laboratory normal ranges into the 
eCRF.  Additional testing may be required by the sponsor based on emerging safety data.  
Additional tests may also be performed if clinically indicated. 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30 days after the last dose of itacitinib 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.  See Appendix D for management 
of potential Hy's Law cases. 
Screening laboratory assessments must be performed within 7 days of Day –3.  If performed 
more than 3 days before Day –3, then the tests must be repeated and eligibility confirmed before 
study treatment administration on Day –3.  Laboratory samples collected on study Day –3 must 
be performed before study treatment administration. 


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Table 15: 
Required Laboratory Analytes 
Chemistry 
Hematology 
Urinalysis With 
Microscopic 
Examination 
Serology 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Amylase 
Bicarbonate or CO2 
Blood urea nitrogen or 
urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated above 
ULN) 
Total protein 
Uric acid 
Complete blood 
count, including: 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell 
count 
 
Differential count, 
including: 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
 
Absolute values must 
be provided for: 
WBC differential 
laboratory results 
Color and 
appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Hepatitis B surface 
antigen 
Hepatitis B surface 
antigen antibody 
Hepatitis B core 
antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
PTT or aPTT 
INR 
Lipid Panel 
Ferritin Level 
Pregnancy Testing 
Total cholesterol 
Triglycerides 
LDL 
HDL 
Ferritin level 
Required for female 
participants of 
childbearing 
potential. 
See Section 8.3.5.1. 
C-Reactive Protein 
CRP 
aPTT = (activated) partial thromboplastin time; HDL = high-density lipoprotein; INR = international normalized ratio; 
LDL = low-density lipoprotein; PT = prothrombin time 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data. 
8.3.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during 
screening, the Day 28 visit, and the 30-day follow-up visit.  A urine or serum pregnancy test may 
be collected on Day –3 before administration of itacitinib.  If the participant is going to hospice, 
the Day 28 pregnancy test may be omitted.  Additionally, urine pregnancy tests should be 
performed as medically indicated (eg, in case of loss of menstrual cycle, when pregnancy is 
suspected).  If a urine pregnancy test is positive, the results should be confirmed with a serum 
pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume itacitinib and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.7 for reporting 
requirements. 


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8.3.5.2. 
Serology 
If hepatitis status is obtained within 60 days of the screening visit, that result may be used for 
this study.  HBV/HCV testing should be repeated if there is any clinical suspicion of active 
hepatitis during screening.  If hepatitis status is not known, hepatitis screening assessments will 
be performed at the screening visit to rule out hepatitis infection; required analytes are shown in 
Table 15.  Generally, hepatitis tests should be performed early in the screening process due to the 
length of time needed to obtain the results.  Additional tests may be performed if clinically 
indicated.  Hepatitis PCR assays only required if serology is positive.  HBV-DNA does not need 
to be performed if the anti-HBs is the only positive result (indicating immunity due to 
vaccination). 
The eligibility of any participant with positive viremia (eg, PCR assay targets detected) must be 
discussed with the medical monitor before participant enrollment. 
8.4. 
Hematologic Disease Status 
Participants are expected to have an objective assessment of disease status using PET/CT/MRI or 
bone marrow biopsy according to the institution's standard of care and the participant's 
hematologic disease.  The results of these assessments will be recorded in the eCRF at screening, 
Day 28, restaging of disease, and at post-treatment follow-up visits (90 days and 180 days 
post-IEC treatment).  If a disease assessment occurs at a different timepoint, per institutional 
guidelines, then this is acceptable.  Any hematologic disease assessments that are conducted 
during the study should be captured in the eCRF.   
A bone marrow assessment performed within 180 days of Day −3 can be used for the purpose of 
this study. 
Additional information with regard to response criteria that should be used for lymphoma is 
provided in Appendix E.  
Additional information with regard to response criteria that should be used for ALL is provided 
in Appendix F. 
 
 


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8.7. 
Unscheduled Visits 
Unscheduled study visits may occur at any time during the study if medically warranted.  Data 
from all assessments performed at unscheduled visits must be recorded in the eCRF. 
8.8. 
End of Treatment 
Per the Protocol, Day 26 is the last expected day of study treatment administration.  An EOT 
visit will be conducted at Day 28 (± 2 days). 
If the participant discontinues study treatment before Day 26, the EOT visit will still be 
conducted. 
Unless the participant withdraws consent, all study assessments should continue to be performed 
and captured in the eCRF. 
8.9. 
Follow-Up 
8.9.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the last dose of study treatment and the 
scheduled safety follow-up visit, which will occur approximately 30 days after the last dose of 
itacitinib.  Adverse events and SAEs must be reported up until 1) at least 30 days after the last 
dose of study treatment or 2) until toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer.  Reasonable efforts should be made to have the participant 
return for the 30-day safety follow-up visit and report any AEs that may occur during this period.  
If the participant cannot return to the site for the 30-day safety follow-up visit (eg, lives far 
away), the participant should be contacted by telephone for assessment of AEs and SAEs.  This 
contact should be documented in the source and eCRF. 


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8.9.2. 
Hematologic Disease Follow-Up 
All participants are expected to be followed, and hematologic disease status should be collected, 
until EOS (Day 180), unless informed consent is withdrawn. 
During the follow-up period, hematologic disease assessments should be conducted at Day 28, 
restaging of disease, Day 90, and Day 180.  However, if disease assessments are performed at 
different timepoints, based on institutional guidelines, then this is acceptable.  All disease 
assessments should be captured in the eCRF.  For additional guidance, see Section 8.4, 
Appendix E, and Appendix F. 
8.9.3. 
Electrocardiograms and Echocardiograms 
A 12-lead ECG will be obtained as outlined in the SoA (see Table 3) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.  All 
12-lead ECGs will be performed with the participant in a recumbent or semirecumbent position 
after 5 minutes of rest. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
participant management.  Additional 12-lead ECGs may be performed as clinically indicated to 
manage participant safety. 
The decision to include or exclude a participant or withdraw a participant from the study 
treatment based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the sponsor's medical monitor, as appropriate.  Clinically 
notable abnormalities that are considered clinically significant in the judgment of the investigator 
are to be reported as AEs. 
An assessment of LVEF will be performed locally by ECHO or multigated analysis to determine 
the cardiac function of the participant and to confirm study eligibility.  If cardiac functional 
status is obtained within 60 days of the screening visit, for the purposes of IEC therapy, that 
result may be used for this study. 
8.9.4. 
Survival Follow-Up 
Participants will be contacted by telephone, email, or with a visit to assess for survival.  All 
participants will be followed for survival until EOS (Day 180), unless informed consent is 
withdrawn. 
8.10. 
End of Study 
End of study is defined as participants who complete Day 180 or who withdraw their informed 
consent. 
The EOS will be recorded in the eCRF and will mark the end of the study for the participant. 


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9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition  
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline (Day –3), considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy, or require changes in study treatment.  
Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF 
rather than the abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though they may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses should be 
reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an 
AE or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as an AE or SAE 
if they fulfill the definition of an AE or SAE.  As an example, CRS or neurotoxicities will not be 
recorded as lack of efficacy but will be recorded as AEs/SAEs as appropriate. 
Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant's condition or 
considered to be treatment-related by the investigator. 
• Efficacy endpoints as outlined in Section 3 will not be reported as AE/SAEs, specifically, any event 
that is related to disease progression of the cancer under study.  Unblinded aggregated efficacy 
endpoint events and safety data will be monitored to ensure the safety of the participants in the study.  
Any suspected endpoint that upon review is not progression of the cancer under study will be 
forwarded to Incyte Pharmacovigilance as a SAE within 24 hours of determination that the event is 
not progression of the cancer under study. 


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• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing informed consent.  If present before entering the 
study, the condition should be captured as medical history. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an adverse drug experience that places 
the participant, in the opinion of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment or planned surgery (eg, stent replacement, hip surgery) is not 
considered an SAE. 
Hospitalization for medical interventions in which no unfavorable medical occurrence occurred 
(ie, elective procedures or routine medical visits) is not considered an SAE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person's ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance, such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle), that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e.  Is a congenital anomaly/birth defect 


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f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but 
may be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
the above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Event Form in the eCRF.  Conditions that were present at the time informed consent was 
given should be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records in 
lieu of completing the AE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, 
all participant identifiers, with the exception of the participant number, will be redacted on the copies 
of the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5).  See below for further instructions on the assessment of 
intensity. 
• Whether there is at least a reasonable possibility that the AE is related to the study treatment 
(including itacitinib(s) and/or reference therapy):  suspected (yes) or not suspected (no).  See below 
for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study treatment as a result of the AE/SAE(s) and/or reference 
therapy. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication 
or nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should 
be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug 
Therapy). 


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


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


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committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB, if appropriate according to local requirements. 
Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must report within 24 hours of learning of its occurrence any SAE by completing 
the Serious Adverse Event Report Form in English. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with 
an indication that it is follow-up to the previously reported SAE and the date of the original report.  
The follow-up report should include information that was not provided on the previous Serious 
Adverse Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study treatment because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or participant disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to that 
event, regardless of when it occurs. 
• Contacts for SAE reporting can be found in the investigator site file. 
9.5. 
Adverse Events of Special Interest 
Not applicable. 
9.6. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency, if knowledge of the treatment assignment is necessary to determine 
optimal medical management of the participant, the procedure for emergency unblinding is 
provided in the Pharmacy Manual.  This option may be used only if the participant's well-being 
requires the investigator to be aware of the participant's treatment assignment.  If a participant's 
treatment assignment must be unblinded, the sponsor must be notified immediately by telephone. 


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9.7. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study treatment 
may have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
treatment, the following procedures should be followed in order to ensure safety: 
• The study treatment must be discontinued immediately. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study treatment to any pregnancy outcome, as well as follow-up to the first 
well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.8. 
Warnings and Precautions 
Special warnings or precautions for the study treatment derived from safety information 
collected by the sponsor or its designee, are presented in the Section 2.4.  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications.  Any important new safety information should be discussed with the participant 
during the study, as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
9.9. 
Product Complaints 
The sponsor collects product complaints on itacitinib and drug delivery systems used in clinical 
studies in order to ensure the safety of study participants, monitor quality, and facilitate process 
and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 


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The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
9.10. 
Treatment of Overdose 
For this study, any dose of greater than 400 mg within a 24-hour time period will be considered 
an overdose. 
In the event of an overdose, the investigator or treating physician should: 
• Contact the medical monitor immediately. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities for at 
least 2 days. 
 
 
 
 
• Document the quantity of the excess dose as well as the duration of the overdose in 
the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 


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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Part 1 is a single-arm open-label study.  The sample size calculation is based on the primary 
endpoint of ≥ Grade 2 CRS rate by Day 14.  It was considered that 60% ≥ Grade 2 CRS by 
Day 14 is clinically relevant in this setting.  Based on a target rate of 60%, a sample size of 
62 will provide 90% power to exclude a higher limit of 79% of a 2-sided 95% CI.  The sample 
size calculation is based on an efficacy evaluable analysis set (see Section 10.2 for definition). 
Table 18 represents CRS Rates and CIs for a sample size of 62. 
Table 18: 
CRS Rates and 95% Confidence Intervals 
Sample Size 
Number of CRS 
CRS Rate (%) 
95% Confidence Interval (%) 
62 
36 
58.1 
44.8, 70.5 
62 
38 
61.3 
48.1, 73.4 
62 
40 
64.5 
51.3, 76.3 
62 
42 
67.7 
54.7, 79.1 
62 
44 
71.0 
58.1, 81.8 
Part 2 is a randomized expansion of the study; itacitinib 200 mg BID versus placebo. 
As in Part 1, the primary endpoint is Grade ≥ 2 CRS rate by Day 14.  Assuming Grade ≥ 2 CRS 
rate in the placebo arm is 50% (Nastoupil et al 2020) and a 20% in the treatment arm (~30% 
change in CRS rate), a sample size of 23 evaluable participants per group would provide 70% 
power based on a 1-sided Type-I error rate of 5%.  Sufficient number of participants will be 
enrolled to yield 23 evaluable participants in each group. 
A Bayesian interpretation for the selection and impact of the sample size can be provided in 
terms posterior probabilities.  As the response rate based on CRS grade has a binomial (n, p) 
distribution with s number of responders out of n participants, it is common to use a conjugate 
Beta (a, b) prior which will lead to a Beta(a + s, b + n − s) posterior distribution.  For this 
exercise, we will assume a noninformative Beta(1,1) (~ Uniform(0,1) prior). 
Table 19 presents scenarios of Bayesian posterior probability of demonstrating a treatment 
difference (≥ 30%) by Day 14 in response rates, between the itacitinib 200 mg BID group and 
the placebo group, under various response rates (number and percentage of responders). 


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Table 19: 
Bayesian Posterior Probability of Demonstrating a Treatment Difference 
Na (%) 200 BID Group 
Nb (%) Placebo 
Posterior Probabilityc 
2 (8.7) 
9 (39.1) 
43.7 
12 (52.5) 
79.4 
14 (60.9) 
93.4 
5 (21.7) 
9 (39.1) 
13.9 
12 (52.5) 
45.9 
14 (60.9) 
67.9 
7 (30.4) 
9 (39.1) 
4.7 
12 (52.5) 
22.7 
14 (60.9) 
44.7 
a Number of participants with CRS ≥ Grade 2, out of 23 participants, in the 200 mg BID group. 
b Number of participants with CRS ≥ Grade 2, out of 23 participants, in the placebo group. 
c Bayesian posterior probability that the itacitinib group has at least 30% improvement over placebo, based on CRS 
≥ Grade 2. 
Based on the scenarios presented in Table 19, if we assume observed CRS rates (CRS ≥ Grade 2) 
of 2/23 (8.7%) and 12/23 (52.2%) in the itacitinib and placebo groups, respectively, then a 
Bayesian calculation is expected to yield a posterior probability of 79.4% of seeing an increase 
of at least 30% in the placebo group. 
10.2. 
Populations for Analysis 
Table 20 presents the populations for analysis. 
Table 20: 
Populations for Analysis 
Population 
Description 
Safety population 
The safety population includes all enrolled participants who received at 
least 1 dose of study treatment. 
All safety analyses will be conducted using the safety population. 
Efficacy evaluable 
analysis set (EAS) 
The EAS includes all participants who have received at least 1 dose of 
study treatment and have received IEC therapy. 
All efficacy analyses will be conducted using EAS. 
 
 
 
 
 
 
 
 


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10.3. 
Level of Significance 
Part 1:  There is no formal hypothesis testing in this study.  CRS rate as well as associated 95% 
exact CI by Clopper-Pearson method will be provided (Clopper and Pearson 1934). 
Part 2:  For the efficacy endpoints subjected to hypothesis testing, the 1-sided Type I error will 
be controlled at 0.05 for each individual cohort expansion.  For other endpoints, CIs will be 
reported at a 95% confidence level. 
10.4. 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses and procedures for accounting 
for missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.  Analysis will be summarized by IEC therapy 
and overall population in both efficacy and safety analysis.  
10.4.1. 
Primary Analysis 
10.4.1.1. CRS Rate by Day 14 
The primary endpoint of the study is CRS rate by Day 14, defined as the percentage of 
participants experiencing ≥ Grade 2 CRS by Day 14.  The primary analysis of CRS rate will be 
based on the EAS in overall population.  CRS rate and its exact 95% CI will be presented.  In 
addition, CRS rate will be provided separately for each IEC therapy.  
10.4.1.2. Cytokine Release Syndrome Rate by Day 14 – Part 2 
The primary endpoint of the study is CRS rate by Day 14, defined as the percentage of 
participants experiencing ≥ Grade 2 CRS by Day 14.  The primary analysis of CRS rate will be 
based on the EAS in overall population.  The primary hypothesis to be tested is to compare 
itacitinib 200 BID versus placebo.  CRS rates will be compared using a 1-sided (=0.05) test and 
will be complemented by a 95% CI. 
As sensitivity and supportive analysis, Bayesian posterior probabilities of crossing various 
thresholds of improvements over placebo (eg, 30%), as well as credible intervals will be 
computed using a noninformative Uniform (0,1) prior. 
10.4.2. 
Secondary Analysis 
10.4.2.1. Part 2 Analysis 
The secondary analysis in Part 2 will be conducted by first comparing the itacitinib 200 mg QD 
dose from Part 1 with the placebo group in Part 2, using a 95% CI.  This comparison will include 
participants who were treated with Yescarta, thus ensuring similarity in the underlying 
population.  A sensitivity analysis will also be conducted as an empirical comparison between 
treatment groups. 
Comparisons between treatment groups will be done at the summary level, based on rates and 
CIs, which will add to the determination of the optimal dose and schedule of itacitinib for 
subsequent trials.  Pairwise Cochran-Mantel-Haenszel tests and trend tests (eg, 


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  Final dose selection will include results from these tests as well as from other 
endpoints including safety, rescue medication required 
 
Similar comparisons between the treatment groups and placebo will also be conducted for other 
secondary endpoints explored in Part 1, as explained in sections below.  Evidence from these 
comparisons will also be used in selecting the optimal dose and schedule of itacitinib for 
subsequent trials. 
10.4.2.2. ICANS Incidence 
Incidence of ICANS, defined as the percentage of participants experiencing ICANS over 28-day 
period, will be presented together with its exact 95% CI.  In addition, the most severe ICANS 
within each participant will be summarized by frequency count.  There is no missing data 
imputation in calculation of ICE score or ICANS grading.  In addition, ICANS incidence will be 
provided separately for each IEC therapy. 
10.4.2.3. Onset and Duration of ICANS 
Time to first onset of ICANS from date of IEC infusion will be summarized within the first 
28 days.  Participants without ICANS will be considered as missing and not included in the 
summary.  Duration of multiple occurrence of ICANS within each participant will be added 
together regardless of grading.  Summary statistics including mean, median, standard deviation, 
minimum, and maximum will be provided for time to first onset of ICANS and duration of 
ICANS. 
10.4.2.4. Onset and Duration of CRS 
Time to first onset of CRS from date of IEC infusion will be summarized within the first 
28 days.  Participants without CRS will be considered as missing in the summary statistics.  
Duration of multiple occurrence of CRS within each participant will be added together regardless 
of grading.  Summary statistics including mean, median, standard deviation, minimum, and 
maximum will be provided for time to first onset of CRS and duration of CRS. 
10.4.2.5. Occurrence of CRS Within 48 Hours 
Percentage of participants who developed CRS within 48 hours of IEC infusion will be 
summarized.  Two-sided 95% exact CI will be provided. 
10.4.2.6. CRS Rate Within 28 Days 
Percentage of participants who developed CRS within 28 days of IEC infusion will be 
summarized.  Two-sided 95% exact CI will be provided.  
10.4.2.7. Hospitalization on Study 
Number of hospitalization associated with total duration of hospitalization will be summarized.  
Cause of hospitalization will be provided as well. 


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10.4.3. 
Safety Analyses 
Safety analyses will be conducted for the safety population.  All safety will be summarized by 
IEC therapy and overall population.  Specific safety may also be summarized by underlying 
disease as needed. 
Safety summaries will also be presented by the 2 dose groups and placebo for all the safety 
endpoints that are described below.  This additional information will be used to confirm the 
optimal dose selection. 
10.4.3.1. Adverse Events 
Adverse events will be coded by the Medical Dictionary for Regulatory Activities dictionary, 
and TEAEs (ie, AEs reported for the first time or worsening of a pre-existing event after first 
dose of study treatment) will be tabulated by preferred term and system organ class for all 
events, related events, and events of Grade 3 or higher. 
10.4.3.2. Clinical Laboratory Tests 
The clinical laboratory data will be analyzed using summary statistics.  In addition, distributions 
of key laboratory parameters may be plotted over time; these values will also be classified into 
CTCAE toxicity grades and tabulated. 
Laboratory test values outside the normal range will be assessed for severity based on the normal 
ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values and 
shift tables relative to baseline will be tabulated.  The following summaries will be produced for 
the laboratory data: 
• Number and percentage of participants with worst post baseline CTCAE grade 
(regardless of baseline value).  Each participant will be counted only for the worst 
grade observed postbaseline. 
• Shift tables from baseline to the worst post baseline value using CTCAE grade. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst post baseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
10.4.3.3. Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities, and participants exhibiting clinically 
notable vital sign abnormalities will be listed. 


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10.4.3.4. Dose Intensity 
Measures of exposure (eg, days of exposure, drug compliance, dose intensity) of study drug will 
be summarized by means of summary statistics. 
10.5. 
Interim Analysis 
For Part 1, an interim analysis is planned after approximately 24 participants are dosed with IEC 
therapy and complete the Day 28 (EOT) visit.  The results from the interim analysis will be 
reviewed by the DSMB.  The primary intent of this analysis is to minimize unnecessary exposure 
to itacitinib in the event of futility of preventing CRS.  The study may be stopped for futility at 
the interim analysis if the conditional power based on interim results is lower than 20%, which is 


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equivalent to more than 17 out of 24 participants experiencing ≥ Grade 2 CRS by Day 14.  More 
than 24 participants may be available in EAS at the time of interim analysis, and the stopping 
boundary will be re-evaluated at the time of the analysis.  
 
  Enrollment will continue 
while the analysis is being conducted, and the study Statistical Analysis Plan will describe the 
planned interim analysis in greater detail. 
No interim analysis is planned for Part 2. 


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


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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations. 
The sponsor will retain the original eCRF data and audit trail. 
11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided with eCRF completion guidelines for instructions on data entry in the 
eCRF.  The study monitor will reference the Monitoring Plan in order to ensure that each issue 
identified is appropriately documented, reported, and resolved in a timely manner in accordance 
with the plan's requirements.  Other data outside the EDC system required in the study conduct 
of the Protocol, such as documents or results transmitted to the sponsor via a central laboratory 
or specialized technical vendors, and as designated by the sponsor, will have their own data flow 
management plans, or study charters, or 
 plans, as applicable. 
The sponsor (or designee) will be responsible for the following: 
• Managing the integrity of the data and the quality of the conduct of the study, such as 
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved Protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated and/or collected, including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for the following: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (eg, laboratory data, imaging data, 
 photographs, diary data) 
or as otherwise specified in the Protocol. 
• Maintaining adequate and accurate source documents and trial records that include all 
pertinent observations on each of the site's trial participants. Source data should be 
attributable, legible, contemporaneous, original, accurate, and complete. Changes to 
source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (eg, via an audit trail). Source data are, in general, all 
information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source 
documents (original records or certified copies). 


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• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed and 
available at the investigator's site. Examples of source documents are original 
documents, data, and records (eg, hospital records; electronic hospital records; 
clinical and office charts; laboratory notes; memoranda; participants' diaries or 
evaluation checklists; pharmacy dispensing records; recorded data from 
automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiches; photographic negatives; microfilm or 
magnetic media; x-rays; participants' files; and e-records/records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial). 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Current applicable medical records must be available. 
• Sending participants' data, either as unique samples, copies, or photographs, to be 
evaluated centrally or analyzed centrally, or both, by a qualified vendor designated by 
the sponsor. 
− As required by privacy and data protection regulations and Incyte's privacy 
policies, if any photographs of participants are to be taken, the photographs must 
be limited to the area of the face or the body that is strictly necessary and the 
photographs should be masked (ie, identifying features such as eyes, mouth, scars, 
tattoos, or unique markings or features should be either obscured with a black bar 
or digitally pixelated so as to not permit the reidentification of the participants and 
preserve their confidentiality) by a specially designated photography vendor prior 
to sending the photographs to Incyte or any other third-party vendors for analysis 
or further processing. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring: Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan. The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 


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− Auditing: Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct. The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection: Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product. The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents. The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Quality Assurance 
The sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations).  The sponsor or designee is responsible for the data management of this 
study, including quality checking of the data.  Further, monitoring details describing strategy, 
including definition of study-critical data items and processes (eg, risk-based initiatives in 
operations and quality such as risk management and mitigation strategies and analytical 
risk-based monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues, Protocol deviations, and monitoring techniques (eg, central, remote, or 
on-site monitoring) are provided in the monitoring plan. 
Quality tolerance limits will be predefined in the operational manual to identify systematic issues 
that can impact participants' safety, efficacy results and analysis, and/or reliability of study 
results.  These predefined parameters will be monitored during the study and can be adjusted 
during the study upon data review.  Important deviations from the quality tolerance limits and 
remedial actions taken, including reporting to IRBs/IECs and health authorities if applicable, will 
be summarized in the CSR. 
11.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data protection laws 
and regulations.  The investigator and the sponsor or its designee are responsible for ensuring 
that personal information is handled in accordance with local data protection laws (including, but 
not limited to Health Insurance Portability and Accountability Act of 1996 and General Data 
Protection Regulation) as applicable, and the sponsor operates comprehensive data privacy and 
data security programs that are applicable to this study.  Appropriate notice, or notice and 
consent (as may be required by each applicable jurisdiction), for collection, use, disclosure, 
and/or transfer (if applicable) of personal information must be obtained in accordance with local 
data protection laws.  Appropriate data protection terms that comply with applicable laws will be 
included in relevant study agreements. 
To ensure confidentiality of records and protect personal data, participant names will not be 
supplied to the sponsor or its designee.  Only the participant number will be recorded in the 
eCRF; if the participant's name appears on any other document (eg, laboratory report), it must be 
obliterated on the copy of the document to be supplied to the sponsor or its designee.  Study 


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findings stored on a computer will be stored in accordance with appropriate technical and 
organizational measures as required by local data protection laws. 
In the event of a data breach involving participant data, the sponsor or its designee will follow 
the sponsor's incident response procedures.  The precise definition of a data breach varies in 
accordance with applicable law but may generally be understood as a breach of security leading 
to the accidental or unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, 
personal data.  In accordance with its incident response procedures, the sponsor will assess the 
breach to consider its notification and remediation obligations under applicable law. 
11.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research participants, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.6. 
Publication Policy 
By signing the study Protocol, the investigator and their institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals. Study results will be published in accordance with applicable local and national 
regulations. If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement. The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee. A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 


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Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.7. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
REFERENCES 
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Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and 
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Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
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Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
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Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
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European Medicines Agency. Guideline on the Investigation of Drug Interactions. 2012. 
Food and Drug Administration. Guidance for Industry: In Vitro Metabolism- and Transporter-
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Guschin D, Rogers N, Briscoe J, et al. A major role for the protein tyrosine kinase JAK1 in the 
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1995;14:1421-1429. 
 
 
Itacitinib Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
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Kymriah (tisagenlecleucel) [prescribing information]. Novartis Pharmaceuticals Corporation; 
May 2018. 
Le RQ, Li L, Yuan W, et al. FDA approval summary: tocilizumab for treatment of chimeric 
antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist 
2018;23:943-947. 
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of 
cytokine release syndrome. Blood 2014;124:188-195. 
Lee DW, Santomasso BD, Locke FL, et al. ASBMT Consensus Grading for Cytokine Release 
Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow 
Transplant 2018;18:31691-3164. 
Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol 
2007;178:2623-2629. 


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Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or 
refractory large B-cell lymphoma: results from the US Lymphoma CAR T consortium. J Clin 
Oncol 2020;38:3119-3128. 
Neelapu SS. Managing the toxicities of CAR T-cell therapy. Hematol Oncol 
2019;37(Suppl 1):48-52. 
Neelapu SS, Locke FL, Bartlett, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory 
large B-cell lymphoma. N Engl J Med 2017;377:2531-2544. 
Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment 
and management of toxicities. Nat Rev Clin Oncol 2018;15:47-62. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute 
lymphoblastic leukemia. N Engl J Med 2018;378:449-459. 
PRECLIN-19.16.1. Summary Report: Itacitinib (INCB039110) for the prevention of cytokine 
release syndrome (CRS) induced by Chimeric Antigen Receptor T-cells (CAR-T-cells) therapy. 
Wilmington, DE: Incyte Corporation. Approval Date:  15 JUL 2019. 
 
 
 
Tecartus (brexucabtagene autoleucel) [prescribing information]. Kite Pharma, Inc.;2020. 
Xu XJ, Tang YM. Cytokine release syndrome in cancer immunotherapy with chimeric antigen 
receptor engineered T cells. Cancer Lett 2014;343:172-178. 
Yescarta (axicabtagene ciloleucel) [prescribing information]. Kite Pharma, Inc.;2021. 
 
 
 


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


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


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


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


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Potential Hy's Law Criteria Not Met 
If the participant has NOT had AST or ALT > 3 × ULN AND total bilirubin > 2 × ULN at any 
point in the study (the elevations do not have to be at the same time or within a specified 
timeframe), irrespective of ALP, please follow the instruction below: 
• Perform follow-up on subsequent laboratory results according to the guidance 
provided in Section 6.1.3 of the Protocol. 
Potential Hy's Law Criteria Met 
If the participant has had AST or ALT > 3 × ULN AND total bilirubin > 2 × ULN at any point in 
the study (the elevations do not have to be at the same time or within a specified timeframe), 
irrespective of ALP, please follow the instruction below: 
• Have participant discontinue study treatment. 
• Notify Incyte study team without delay. 
− The investigator, or designee, should contact the medical monitor to discuss and 
agree upon an approach for the study participant's follow-up and the continuous 
review of data. 
• Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as medically indicated. 
• Investigate the etiology of the event and perform any relevant diagnostic 
investigations as discussed with the medical monitor. 
• Enter the laboratory data into the laboratory CRF as soon as possible. 
• If at any time (in consultation with the medical monitor) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures. 
REVIEW AND ASSESSMENT 
No later than 3 weeks after the biochemistry abnormality was initially detected and the criteria 
for PHL was met, the medical monitor, Incyte pharmacovigilance physician, and investigator 
will discuss and review available data and agree on whether there is an alternative explanation 
for the elevations in liver biochemistry other than drug-induced liver injury caused by the study 
treatment.  Participant matter experts will be included in the review as appropriate. 
Evaluation of Alternative Causes 
In order to gather additional clinical information to seek other possible causes of the observed 
liver test abnormalities, the following alternative etiologies should be considered, including, but 
not limited to, 
• Active viral hepatitis 
• Alcoholic and autoimmune hepatitis 


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


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


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APPENDIX E. RESPONSE CRITERIA FOR LYMPHOMA – THE 
LUGANO CLASSIFICATION 
Site 
PET–Based Response 
CT/MRI-Based Response 
 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
Lymph nodes and 
extralymphatic 
sites 
Score 1, 2, or 3 with or without a residual 
mass on 5PS.a 
Target nodes/nodal masses must regress to 
≤ 1.5 cm in LDi. 
Nonmeasured 
lesion 
Not applicable. 
Absent. 
Organ enlargement 
Not applicable. 
Regress to normal. 
New lesions 
None. 
None. 
Bone marrow 
No evidence of FDG-avid disease in 
marrow. 
Normal by morphology; if indeterminate, IHC 
negative. 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic 
sites 
• Score 4 or 5a with reduced uptake 
compared with baseline and residual 
mass(es) of any size. 
• ≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites. 
• When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default 
value. 
• When no longer visible, 0 × 0 mm. 
For a node > 5 mm × 5 mm but smaller than 
normal, use actual measurement for 
calculation. 
Nonmeasured 
lesions 
Not applicable. 
Absent/regressed, but no increase. 
Organ enlargement 
Not applicable. 
Spleen must have regressed by > 50% in 
length beyond normal. 
New lesions 
None. 
None. 
Bone marrow 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from chemotherapy 
allowed).  If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consideration should be 
given for further evaluation with MRI or 
biopsy at interval scan. 
Not applicable. 
 
No metabolic response 
Stable disease 
Target nodes/ 
nodal masses, 
extranodal lesions 
Score of 4 or 5a with no significant 
change in FDG uptake from baseline at 
interim or EOT. 
< 50% decrease from baseline in SPD of up to 
6 dominant, measurable nodes and extranodal 
sites; no criteria for progressive disease are 
met. 
Nonmeasured 
lesions 
Not applicable. 
No increase consistent with progression. 
Organ enlargement 
Not applicable. 
No increase consistent with progression. 
New lesions 
None. 
None. 
Bone marrow 
No change from baseline. 
Not applicable. 


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Site 
PET-CT–Based Response 
CT-Based Response 
 
Progressive metabolic disease: 
Progressive disease (requires at least 1 of 
the following): 
Individual target 
nodes/nodal lesions 
Individual target nodes/nodal lesions: 
• Score 4 or 5a with an increase in 
intensity of uptake from baseline and/or 
• New FDG-avid foci consistent with 
lymphoma at interim or EOT 
assessment. 
 
Extranodal lesions: 
• New FDG-avid foci consistent with 
lymphoma at interim or end-of-
treatment assessment. 
 
New lesions: 
• New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation).  If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered. 
 
Bone marrow: 
• New or recurrent FDG-avid foci. 
PPD progression: 
• An individual node/lesion must be abnormal 
with all of the following:   
o LDi > 1.5 cm  
o Increase by ≥ 50% from PPD nadir 
o An increase in LDi or SDi from nadir 
▪ 0.5 cm for lesions ≤ 2 cm 
▪ 1.0 cm for lesions > 2 cm 
• In the setting of splenomegaly, the splenic 
length must increase by > 50% of the extent 
of its prior increase beyond baseline (eg, a 
15 cm spleen must increase to > 16 cm).  If 
no prior splenomegaly, must increase by at 
least 2 cm from baseline. 
• New or recurrent splenomegaly. 
• New or clear progression of pre-existing 
nonmeasured lesions. 
• Regrowth of any previously resolved 
lesions. 
• A new node > 1.5 cm in any axis. 
• A new extranodal site > 1.0 cm in any axis; 
if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma. 
• Assessable disease of any size 
unequivocally attributable to lymphoma. 
• New or recurrent involvement of the bone 
marrow. 


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APPENDIX F. RESPONSE CRITERIA FOR ACUTE LYMPHOBLASTIC 
LEUKEMIA 
Response Criteria for Blood and Bone Marrow 
Complete response (CR) 
• No circulating blasts or extramedullary disease. 
• No lymphadenopathy, splenomegaly, skin/gum 
infiltration/testicular mass/ central nervous system (CNS) 
involvement. 
• Trillneage hematopoiesis (TLH) and < 5% blasts. 
• Absolute neutrophil count (ANC) > 1.0 × 109/L. 
• Platelets > 100 × 109/L. 
• No recurrence for 4 weeks. 
Complete response with incomplete 
blood count recovery (CRi) 
• Meets all criteria for CR except platelet count and/or ANC. 
Overall response rate (ORR) 
• ORR = CR + CRi. 
Refractory disease 
• Failure to achieve CR at the end of the induction. 
Progressive disease (PD) 
• Increase of ≥ 25% in the absolute number of circulating or 
bone marrow blasts or development of extramedullary disease. 
Relapsed disease 
• Reappearance of blasts in the blood or bone marrow (> 5%) 
or in any extramedullary site after a CR. 
Response Criteria for CNS Disease 
CNS remission 
• Achievement of CNS-1 status in a participant with CNS-2 or 
CNS-3 status at diagnosis. 
CNS relapse 
• New development of CNS-3 status or clinical signs of CNS 
leukemia such as facial nerve palsy, brain/eye involvement, 
or hypothalamic syndrome without another explanation. 
Response Criteria for Lymphomatous Extramedullary Disease 
Computed tomography (CT) of neck/chest/abdomen/pelvis with intravenous (IV) contrast and positron 
emission tomography (PET)/CT should be performed to assess response for extramedullary disease. 
Complete response (CR) 
• Complete resolution of lymphomatous enlargement by CT.  
For participants with a previous positive PET scan, a 
post-treatment residual mass of any size is considered a CR 
as long as it is PET-negative. 
Partial response (PR) 
• > 50% decrease in the sum of the product of the greatest 
perpendicular diameters (SPD) of the mediastinal 
enlargement.  For participants with a previous positive PET 
scan, post-treatment PET must be positive in ≥ 1 previously 
involved site. 


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Progressive disease (PD) 
• > 25% increase in the SPD of the mediastinal enlargement.  
For participants with a previous positive PET scan, 
post-treatment PET must be positive in ≥ 1 previously 
involved site. 
No response (NR) 
• Failure to qualify for PR or PD. 
Relapse 
• Recurrence of mediastinal enlargement after achieving CR.  
For participants with a previous positive PET scan, 
post-treatment PET must be positive in ≥ 1 previously 
involved site. 
Response Criteria for Minimal Residual Disease 
The optimal sample for MRD assessment is the first pull or early pull of the bone marrow aspirate. 
• MRD in ALL refers to the presence of leukemic cells below the threshold of detection by 
conventional morphologic methods.  Participants who achieved a CR by morphologic assessment 
alone can potentially harbor a large number of leukemic cells in the bone marrow. 
• MRD is an essential component of participant evaluation over the course of sequential therapy.  If a 
participant is not treated in an academic center, there are commercially available tests available that 
should be used for MRD assessment. 
• Studies in both children and adults with ALL have demonstrated the strong correlation between 
MRD and risks for relapse, as well as the prognostic significance of MRD measurement during and 
after initial induction therapy. 
• The most frequently employed methods for MRD assessment include 6-color flow cytometry assays, 
specifically designed to detect abnormal MRD immunophenotypes, real-time quantitative 
polymerase chain reaction (RQ-PCR) assays, and next-generation sequencing based assays to detect 
fusion genes, clonal rearrangements in immunoglobulin (Ig) heavy chain genes, and/or T-cell 
receptor (TCR) genes. 
• Current 6-color flow cytometry, or PCR methods can detect leukemic cells at a sensitivity threshold 
of < 1 × 104 (< 0.01%) bone marrow mononuclear cells (MNCs).  The concordance rate for 
detecting MRD between these methods is generally high. 
− Timing of MRD assessment: 
▪ Upon completion of initial induction. 
▪ Additional timepoints should be guided by the regimen used. 


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APPENDIX G. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1 
22 APR 2020 
Amendment 2 
14 OCT 2020 
Amendment 3 
17 AUG 2021 
Amendment 4 
08 DEC 2022 
Amendment 4 (08 DEC 2022) 
Overall Rationale for the Amendment: 
The primary purpose of the amendment is to clarify the inclusion criteria for Part 2 (adult 
participants only) in order to ensure enrollment is consistent with the Yescarta label.  Additional 
changes are summarized below. 
1. Title Page 
Description of change:  The IND number was updated to 
 
Rationale for change:  To update the IND number. 
2. Section 1, Protocol Summary (Figure 1:  Study Design Schema Part 1; Figure 2:  
Study Design Schema Part 2) 
Description of change:  Updated the ECOG performance status scores to be consistent 
with enrollment criteria. 
Rationale for change:  To correct ECOG score in figures to coincide with Criterion 3. 
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities) 
Description of change:  Notes were added to FDG-PET CT/MRI, CRS assessments, and 
ICANS assessments. 
Rationale for change:  Clarification. 
 
 
 
 
 
 
 
 
 
 
 


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5. Section 5.1, Inclusion Criteria (Criterion 1) 
Description of change:  Added criteria associated with participant age eligibility for 
Part 2 of the study (ie, 18 years of age or older, as opposed to 12 and older in Part 1). 
Rationale for change:  Requested by the IRB to have study treatment guidance 
consistent with the Yescarta label. 
 
 
 
 
. 
 
 
7.  Section 9.6, Emergency Unblinding of Treatment Assignment 
Description of change:  Added text for emergency unblinding. 
Rationale for change:  Standard language for emergency unblinding is necessary for 
those participants under study treatment in Part 2. 
8. Section 9.10, Treatment of Overdose 
Description of change:  Changed the definition of overdose from 200 mg QD to 400 mg 
within a 24-hour period. 
Rationale for change:  To update the dose that denotes overdose for participants. 
 
 
 
 
 
10. Incorporation of administrative changes.  Other regulatory guidance and 
administrative changes have been incorporated throughout the Protocol and are noted in 
the redline version of the amendment. 


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Amendment 3 (17 AUG 2021) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to include an additional dosing regimen (Part 2) of 
itacitinib. 
1. Title page; Section 1, Protocol Summary 
Description of change:  Removed "Single Arm, Open Label" from the protocol title. 
Rationale for change:  An additional dosing regimen no longer supports the single arm, 
open label title. 
2. Section 1, Protocol Summary (Table 1:  Primary and Major Secondary Objectives 
and Endpoints); Section 3, Objectives and Endpoints (Table 7:  Objectives and 
Endpoints) 
Description of changes: 
• Added clarification to the objectives and endpoints for Part 1 and Part 2 to support 
selection of an optimal dose/schedule of itacitinib for subsequent trials. 
• Modified the secondary endpoint for ICANS regardless of CRS, after IEC therapy to 
include severity of ICANS in order to be consistent with the objective. 
• Modified the secondary endpoints for evaluating ICANS and CRS at Day 28 to 
include time to onset and duration. 
• Modified the secondary endpoint for characterizing the safety of itacitinib to include 
the evaluation for  Grade 3 cytopenias ongoing by Day 30. 
• Moved the objective and endpoint for evaluating tocilizumab treatment from 
exploratory to secondary and the language was clarified to assess intervention for CRS 
and ICANS and to include dexamethasone treatment. 
 
 
 
Rationale for changes:  To provide clarification for the evaluation of CRS and ICANS.  
To ensure the objective and endpoints for evaluating rescue medication is accurate.  
 
  
3. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; Figure 1:  
Study Design Schema Part 1; Figure 2:  Study Design Schema Part 2); Section 4.1, 
Overall Design 
Description of change:  Added clarification to distinguish Part 1 from Part 2 and added 
language to describe the design for Part 2, which is a randomized portion of the study that 
has been added to evaluate itacitinib 200 mg BID versus placebo.  A study design schema 
for Part 2 was added as Figure 2. 
Rationale for change:  To describe Part 2 of the study. 


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5. Section 2.2.3, Itacitinib Clinical Safety Summary 
Description of change:  Updated the safety summary to include information from the 
data cutoff in APR 2021, since the previous information was from DEC 2019. 
Rationale for change:  To include a more recent total of the number of participants who 
have been treated with itacitinib. 
6. Section 2.3.3, Preliminary Results from Part 1 
Description of change:  Added a new section with the results from the interim analysis 
of Part 1 based on the data cutoff (08 JAN 2021). 
Rationale for change:  To provide a summary of preliminary results from Part 1 of the 
study. 
7. Section 2.3.4, Rationale for Part 2 
Description of change:  Added a new section to describe the rationale for Part 2, 
including population PK modeling and itacitinib concentration-time profiles.  Language 
was also included to provide a brief summary of the design for Part 2. 
Rationale for change:  To provide the rationale for evaluating a new dose schedule, 
itacitinib 200 mg BID, and a brief summary of the Part 2 design. 


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8. Section 5.1, Inclusion Criteria (Criterion #2); Section 6.2, Immune Effector Cell 
Therapy 
Description of change:  Updated inclusion criterion 2 to distinguish between Part 1 and 
Part 2.  The eligible participant population for Part 1 was not changed.  The eligible 
participant population for Part 2 includes only those receiving Yescarta for relapsed or 
refractory large B-cell lymphoma or follicular lymphoma. 
Rationale for change:  To clarify that the participant population in Part 2 will include 
only those receiving Yescarta. 
9. Section 6.1, Study Treatment Administered (Table 9:  Study Treatment 
Information) 
Description of change:  Added study treatment (itacitinib or placebo) and dose strength 
for Part 2. 
Rationale for change:  To add the study treatment for Part 2. 
10. Section 6.1.3, Dose Modifications for Itacitinib; Section 6.4.2, Restricted 
Medications and Procedures 
Description of change:  Added Part 2 treatment regimen and to indicate that if a dose 
reduction is required, participants may take 1 tablet instead of 2 (reduced to 100 mg BID 
or placebo). 
Rationale for change:  To provide dose modification guidance for participants in Part 2. 
11. Section 6.3, Measures to Minimize Bias:  Randomization and Blinding 
Description of change:  Added that Part 2 participants will be randomized to receive 
either itacitinib 200mg BID or placebo.  Investigators and participants will be blinded. 
Rationale for change:  To clarify randomization and blinding for Part 2. 
12. Section 6.4.2, Restricted Medications and Procedures; Section 6.4.3, Prohibited 
Medications and Procedures 
Description of change:  Moved language regarding rescue medication with Tocilizumab 
and/or corticosteroids for CRS Grade 1 from the prohibited medications to restricted 
medications and procedures. 
Rationale for change:  To provide guidance for when rescue medication is needed for 
CRS. 
 
 
 
 
 
 


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14. Section 9.4, Reporting of Serious Adverse Events 
Description of change:  Updated to clarify that the investigator must report SAEs within 
24 hours of learning of its occurrence, and removed the guidance with regard to faxing 
SAE reports. 
Rationale for change:  To be compliant with current guidance from Incyte 
Pharmacovigilance. 
15. Section 10.1, Sample Size Determination 
Description of change:  Added a sample size determination for Part 2 using a Bayesian 
approach, and added Table 19 to describe Bayesian posterior probability scenarios and 
provide rationale. 
Rationale for change:  To support the additional analyses that will be conducted for 
Part 2.  
16. Section 10.3, Level of Significance 
Description of change:  Modified the level of significance to include language for 
Part 2. 
Rationale for change:  To support the additional analyses that will be conducted for 
Part 2. 
17. Section 10.4.1.2, Cytokine Release Syndrome Rate by Day 14 – Part 2 
Description of change:  Added a new section to describe the primary, secondary, and 
safety analyses for Part 2. 
Rationale for change:  To support the additional analyses that will be conducted for 
Part 2. 
18. Section 10.4.2.1, Part 2 Analysis 
Description of change:  Added a new section to provide detail on treatment group 
comparisons. 
Rationale for change:  To support the additional analyses that will be conducted for 
Part 2. 
19. Section 10.4.3, Safety Analyses 
Description of change:  Updated to clarify that safety summaries will be presented by 
the 2 dose groups and placebo for all safety endpoints. 
Rationale for change:  To support the additional analyses that will be conducted for 
Part 2. 
20. Section 10.5, Interim Analysis 
Description of change:  Updated to clarify that no interim analysis is planned for Part 2. 
Rationale for change:  To clarify that an interim analysis will not be conducted for 
Part 2. 


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21. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Amendment 2 (14 OCT 2020) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise inclusion criterion 2, in order to allow for the 
use of any IEC therapy that is approved by the health authority in the country where the study is 
being conducted.  
1. Section 1, Protocol Summary (Table 2:  Key Study Design Elements; Treatment 
Groups and Duration); Section 4.1, Overall Design; Section 5.1, Inclusion Criteria; 
Section 6.2, Immune Effector Cell Therapy; Section 10.4, Statistical Analyses; 
Section 10.4.1.1, CRS Rate by Day 14; Section 10.4.2.1, ICANS Incidence; 
Section 10.4.3, Safety Analyses; Section 10.5, Interim Analysis 
Description of change:  Revised to allow IEC therapy that is approved by the health 
authority in the country where the study is being conducted.  
Rationale for change:  To allow additional options for IEC therapy.  
2. Section 2.1, Background; Section 2.4 Benefit/Risk Assessment 
Description of change:  Revised to include information regarding brexucabtagene 
autoleucel, a new FDA approved IEC therapy for MCL.   
Rationale for change:  To include new information regarding IEC therapy.  
3. Section 5.2, Exclusion Criteria (Table 8:  Exclusionary Laboratory Values) 
Description of change:  Corrected the unit for hemoglobin to g/dL. 
Rationale for change:  To correct the unit typo for hemoglobin. 
4. Section 6.4.3, Prohibited Medications and Procedures 
Description of change:  Added that participants who are administered tocilizumab 
should be discontinued from study treatment. 
Rationale for change:  To provide clarification with regard to use of tocilizumab. 
 
 
 
 
 
 
6. Section 9.4, Reporting of Serious Adverse Events 
Description of change:  Added clarification that if an SAE occurs more than 30 days 
after the last dose of study treatment, it is only required to be reported if it is considered 
to be related to itacitinib. 
Rationale for change:  To provide clarification with regard to SAE reporting.  


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Amendment 1 (22 APR 2020) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to clarify study procedures and provide more current 
information in response from sites and ethics committees. 
Additional changes from Administrative Change 1 were also included. 
1. Section 1, Protocol Summary (Table 3:  Schedule of Activities); Section 5.2, 
Exclusion Criteria (Table 8:  Exclusionary Laboratory Values); Section 8.9.3, 
Electrocardiograms and Echocardiograms 
Description of change:  Echocardiogram was added as a screening assessment. 
An assessment of LVEF will be performed locally by ECHO or multigated analysis to 
determine the cardiac function of the participant and to confirm study eligibility.  If 
cardiac functional status is obtained within 60 days of the screening visit, for the 
purposes of IEC therapy, that result may be used for this study. 
Rationale for change:  This assessment was inadvertently left out of the original 
Protocol.  The cardiopulmonary exclusion for LVEF should be confirmed by an ECHO. 
2. Section 1, Protocol Summary (Table 3:  Schedule of Activities); Section 8.3.2,  
Physical Examinations; Section 8.3.3, Vital Signs and Temperature Monitoring 
Description of change:  Height should be assessed at screening only.  Weight will be 
assessed at each visit where vital signs are assessed.  Temperature monitoring will being 
on Day −3.  Additionally, the participant will be encouraged to use a TempTraq device as 
a tool for temperature monitoring.  Additional instructions regarding the TempTraq 
device will be provided separately.  If a participant in unable to wear the device at any 
point during the treatment period, this will not be considered a Protocol deviation. 
Rationale for change:  To add a height assessment to the Protocol, to update the timing 
for weight assessments, and to clarify guidance and encourage the use of a tool that will 
provide consistency with regard to temperature monitoring.  The temperature monitoring 
time frame will be consistent with the start and stop of study treatment and will begin 
3 days before IEC in order to capture the participant's baseline temperature. 
 
 
 
 
 
 


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5. Section 2.2.1, Nonclinical Drug Metabolism and Pharmacokinetics 
Description of change:  The heading was updated to clarify that this section only 
contains nonclinical information.  Language was added to summarize the nonclinical 
data, including in vitro study results.  Previous information that is no longer relevant was 
removed. 
Rationale for change:  Response to ethics committees. 
6. Section 2.2.2, Clinical Drug Metabolism and Pharmacokinetics 
Description of change:  Section added to summarize the clinical PK data that are 
available. 
Description of change:  This information was inadvertently left out of the original 
Protocol. 
7. Section 2.2.3, Itacitinib Clinical Safety Summary 
Description of change:  The section was updated based on the most current IB, with a 
data cutoff date of 13 DEC 2019.  The number of participants and number of clinical 
studies have increased. 
Rationale for change:  To provide current information. 
8. Section 2.3.2, Justification for Dose 
Description of change:  A clarification was made with regard to the summary of the 
acute GVHD pilot study comparing 200 mg QD with 300 mg QD. 
Rationale for change:  To provide more accurate information. 
9. Section 6.4.2, Restricted Medication and Procedures 
Description of change:  The following were removed:  "No dose adjustment is 
recommended for concomitant administration of other less strong CYP3A inhibitors," 
and, "If administration of corticosteroids is required, the sponsor medical monitor should 
be consulted." 
Rationale for change:  To provide more accurate guidance with regard to restricted 
medication. 
10. Section 6.4.2, Prohibited Medications and Procedures 
Description of change:  The fourth bullet was revised to include corticosteroids. 
Rational for change:  To clarify that corticosteroids for Grade 1 CRS are prohibited. 


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11. Section 8.1.2, Screening Procedures 
Description of change:  The following sentence was removed, "Screening may not 
exceed 7 days." 
Rational for change:  To allow for flexibility in screening procedures that may be 
conducted prior to the screening period. 
12. Section 8.1.3, Interactive Response Technology Procedure 
Description of change:  Clarification added in regard to when IRT should be called. 
Rational for change:  To provide guidance with regard to IRT procedures. 
13. Section 8.2.2, ICANS Status 
Description of change:  The following sentence was added, "If the participant has no 
impairment (ICE score of 10), then Grade 0 may be entered in the EDC for ICANS 
Grade." 
Rational for change:  To provide guidance with regard to ICANS grading. 
14. Section 8.4, Hematologic Disease Status 
Description of changes: 
• Clarification regarding standard of care was added. 
• The following sentence was removed, "Only the response result and the date the 
assessment was performed will be captured in the eCRF." 
• The following sentence was added "A bone marrow assessment performed within 
180 days of Day −3 can be used for the purpose of this study." 
Rational for change:  To clarify procedures and add flexibility. 
 
 
 
 
 
 
 
 
 
 
. 
16. Section 8.9.3, Electrocardiograms and Echocardiograms 
Description of change:  QT was added to the text for ECG measurements. 
Rationale for change:  QT should be assessed. 


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17. Section 10.5, Interim Analysis 
Description of changes:  Text was added to indicate the results from the interim analysis 
will be reviewed by the DSMB, 
 
 
Rationale for Change:  Based on feedback from ethics committee. 
18. Appendix C, Instruction to Participants for Handling Itacitinib 
Description of change:  The last bullet was revised; if an itacitinib dose is missed by 
more than 8 hours, that dose should be skipped and the next scheduled dose should be 
administered at the usual time. 
Rationale for change:  The previous language indicated 4 hours, which is incorrect. 
19. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


Signature Page for VV-CLIN-001046 v5.0
Signature Page for VV-CLIN-001046 v5.0
Approval Task
08-Dec-2022 13:16:33 GMT+0000
Approval Task
08-Dec-2022 16:06:53 GMT+0000
Approval Task
08-Dec-2022 16:22:36 GMT+0000
Approval Task
08-Dec-2022 16:56:16 GMT+0000

SAP_001.pdf: 
NCT Number:   NCT04071366   
Document Date: Statistical Analysis Plan Amendment 1: 08 May 2023
Official Title: A Phase 2 Study of Itacitinib, for the Prevention of Cytokine Release Syndrome 
Induced by Immune Effector Cell Therapy


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................7 
2.1. 
Protocol and Case Report Form Version ......................................................................7 
2.2. 
Study Objectives and Endpoints ...................................................................................7 
3. 
STUDY DESIGN .........................................................................................................9 
3.1. 
Overall Study Design ....................................................................................................9 
3.1.1. 
Treatment Discontinuation .........................................................................................10 
3.1.2. 
Study Duration ............................................................................................................11 
3.2. 
Randomization ............................................................................................................11 
3.3. 
Control of Type I Error ...............................................................................................11 
3.4. 
Sample Size Considerations .......................................................................................11 
3.5. 
Schedule of Assessments ............................................................................................12 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................13 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................13 
4.1.1. 
Study Drug ..................................................................................................................13 
4.1.2. 
Study Treatment ..........................................................................................................13 
4.1.3. 
Day 1 ...........................................................................................................................13 
4.1.4. 
Study Day ...................................................................................................................13 
4.1.5. 
Baseline Value ............................................................................................................13 
4.1.6. 
Handling of Missing and Incomplete Data .................................................................13 
4.1.7. 
On-Treatment Assessment/Event ...............................................................................15 
4.2. 
Variable Definitions ....................................................................................................15 
4.2.1. 
Body Mass Index ........................................................................................................15 
4.2.2. 
Prior and Concomitant Medication .............................................................................15 
5. 
STATISTICAL METHODOLOGY ...........................................................................16 
5.1. 
General Methodology .................................................................................................16 
5.2. 
Treatment Groups .......................................................................................................16 
5.3. 
Analysis Populations ..................................................................................................16 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................18 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............18 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................18 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................18 
6.1.3. 
Prior Therapy ..............................................................................................................18 
6.1.4. 
Medical History ..........................................................................................................19 
6.2. 
Disposition of Participants ..........................................................................................19 
6.3. 
Protocol Deviations ....................................................................................................19 
6.4. 
Exposure .....................................................................................................................19 
6.5. 
Study Drug Compliance .............................................................................................19 
6.6. 
Prior and Concomitant Medication .............................................................................20 
7. 
EFFICACY .................................................................................................................21 
7.1. 
General Considerations ...............................................................................................21 
7.2. 
Analysis of the Primary Efficacy Parameter ..............................................................21 
7.2.1. 
Primary Efficacy Analysis ..........................................................................................21 
7.2.1.1. 
Handling of Missing Data in Primary Analysis ..........................................................22 
7.2.1.2. 
Sensitivity Analysis ....................................................................................................22 
7.2.1.3. 
Supportive Analysis ....................................................................................................22 
7.3. 
Analysis of the Secondary Efficacy Parameters .........................................................23 
7.3.1. 
Immune Effector Cell-Associated Neurotoxicity Syndrome Incidence .....................23 
7.3.2. 
Onset and Duration of Immune Effector Cell-Associated Neurotoxicity 
Syndrome ....................................................................................................................23 
7.3.3. 
Onset and Duration of Cytokine Release Syndrome ..................................................23 
7.3.4. 
Cytokine Release Syndrome-Free Survival ................................................................24 
7.3.5. 
Occurrence of Cytokine Release Syndrome Within 48 Hours ...................................24 
7.3.6. 
Cytokine Release Syndrome Rate Within 28 Days ....................................................24 
7.3.7. 
Intervention for CRS and ICANS ...............................................................................24 
 
24 
 
24 
 
25 
 
25 
9. 
SAFETY AND TOLERABILITY ..............................................................................26 
9.1. 
General Considerations ...............................................................................................26 


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9.2. 
Adverse Events ...........................................................................................................26 
9.2.1. 
Adverse Event Definitions ..........................................................................................26 
9.2.2. 
Adverse Event Summaries ..........................................................................................27 
9.3. 
Eastern Cooperative Oncology Group Performance Status ........................................28 
9.4. 
Clinical Laboratory Tests ...........................................................................................28 
9.4.1. 
Laboratory Value Definitions .....................................................................................28 
9.4.2. 
Laboratory Value Summaries .....................................................................................28 
9.5. 
Vital Signs ..................................................................................................................29 
9.6. 
Electrocardiograms .....................................................................................................30 
9.7. 
Cytopenias Ongoing by Day 30 ..................................................................................30 
10. 
INTERIM ANALYSES ..............................................................................................31 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................32 
 
32 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................32 
11.2.1. 
Amendment 1 ..............................................................................................................32 
12. 
REFERENCES ...........................................................................................................33 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................34 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................7 
Table 2: 
Cytokine Release Syndrome Rates and 95% Confidence Intervals ...........................11 
Table 3: 
Bayesian Posterior Probability of Demonstrating a Treatment Difference ................12 
Table 4: 
Analysis Populations ..................................................................................................17 
Table 5: 
Baseline Laboratory Identification .............................................................................28 
Table 6: 
Normal Ranges for Vital Sign Values ........................................................................30 
Table 7: 
Normal Ranges for Electrocardiogram Intervals ........................................................30 
Table 8: 
Statistical Analysis Plan Versions ..............................................................................32 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema Part 1 .......................................................................................10 
Figure 2: 
Study Design Schema Part 2 .......................................................................................10 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
 
 
 
BID 
twice daily 
BMI 
body mass index 
CAR 
chimeric antigen receptor 
CI 
confidence interval 
 
 
 
 
 
 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRi 
complete response with incomplete blood count recovery 
CRS 
cytokine release syndrome 
CTCAE v5.0 
Common Terminology Criteria for Adverse Events version 5.0 
DLBCL 
diffuse large B-cell lymphoma 
DSMB 
Data Safety Monitoring Board 
EAS 
efficacy evaluable analysis set 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment  
ICANS 
immune effector cell–associated neurotoxicity syndrome 
ICE 
immune effector cell–associated encephalopathy 
ICF 
informed consent form  
IEC 
immune effector cell 
IRB 
institutional review board 


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Abbreviation 
Term 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIPI 
Mantle Cell Lymphoma International Prognostic Index 
 
 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
 
 
 
 
PT 
preferred term 
QD 
once daily 
QTcB 
QT interval corrected by Bazett 
QTcF 
QT interval corrected by Fridericia 
SAP 
Statistical Analysis Plan 
SoA 
schedule of activities 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
ULN 
upper limit of normal 
WHO 
World Health Organization  
 


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1. 
INTRODUCTION 
INCB 39110-211 is a Phase 2 study designed to assess the safety and efficacy of oral 
administration of itacitinib to participants planning to receive IEC therapy for any approved 
hematologic indication. This study will be conducted in 2 parts. In Part 1, participants are 
administered itacitinib 200 mg QD (open label). In Part 2, participants are randomized to receive 
either itacitinib 200 mg BID or placebo. According to Protocol Amendment 4, the study 
treatment itacitinib/placebo will begin on Day –3 (pre-IEC) and continue through Day 26 (study 
treatment period). Immune effector cell therapy will be administered on Day 0 (IEC infusion 
day). Protocol-defined assessments will be conducted on Days –3, –1, 0, 1, 3, 5, 7, 14, 21, and 
28. Additional post-therapy follow-up visits will be conducted at Day 90 and Day 180 (90 and 
180 days after IEC). End of study is met at Day 180 (6 months after IEC). 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the INCB 39110-211 Protocol. The scope of this plan includes the interim and final analyses that 
are planned and will be executed by the Department of Biostatistics or designee. 
 
 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 39110-211 Protocol Amendment 4 dated 08 DEC 2022 and the CRF 
was approved on 10 JUN 2022. Unless superseded by an amendment, this SAP will be effective 
for all subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of itacitinib as a 
preventative treatment for CRS associated with 
IEC therapy. 
Efficacy, as determined by the proportion of 
participants who develop ≥ Grade 2 CRS by 
Day 14 using ASBMT CRS Consensus Grading. 
Secondary 
To evaluate the proportion of participants with 
ICANS regardless of CRS, after IEC therapy. 
Incidence and severity of ICANS, as determined 
by the proportion of participants with ICANS by 
Day 28, after IEC therapy using the ICANS 
Consensus Grading. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Secondary (continued) 
To evaluate the onset and episode of ICANS 
using the ICANS Consensus Grading, regardless 
of CRS, by Day 28. 
Time to onset and duration of ICANS using the 
ICANS Consensus Grading, regardless of CRS, 
by Day 28. 
To evaluate the duration of all grades of CRS, by 
Day 28. 
Time to onset and duration of all grades of CRS 
by Day 28 using ASBMT CRS Consensus 
Grading. 
To evaluate the proportion of participants who 
develop any grade of CRS within 48 hours after 
IEC therapy. 
Proportion of participants with any grade of CRS 
at 48 hours, after IEC therapy using ASBMT CRS 
Consensus Grading. 
To evaluate the proportion of participants who 
develop ≥ Grade 2 CRS by Day 28 of 
administration after first IEC therapy. 
Proportion of participants with ≥ Grade 2 CRS by 
Day 28, after first IEC therapy. 
To characterize the safety of itacitinib, before and 
after IEC therapy, excluding CRS and ICANS. 
Safety of itacitinib assessed by the incidence of all 
AEs except CRS and ICANS, by collecting 
laboratory data, performing physical 
examinations, and collecting vital signs beginning 
at Day –3 and through the duration of safety 
follow-up.  
≥ Grade 3 cytopenias ongoing by Day 30. 
To evaluate the number of and length of hospital 
admissions for CRS and ICANS. 
Number of hospital admissions and duration of 
stay for participants with CRS and/or ICANS by 
EOS. 
To assess intervention for CRS and ICANS. 
Proportion of participants who were treated with 
tocilizumab for CRS. 
Proportion of participants requiring more than 
1 dose of dexamethasone (or equivalent) for 
ICANS. 


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Table 1: 
Objectives and Endpoints (Continued) 
3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is a 2-part Phase 2 study designed to assess the safety and efficacy of oral administration of 
itacitinib for the prevention of CRS in male or female participants planning to receive IEC 
therapy for any approved hematologic indication. 
• In Part 1, approximately 62 participants older than 12 years will be administered 
itacitinib 200 mg QD (open label). Based on the Protocol-defined analysis in Protocol 
Amendment 2, 10 participants with ALL will be included. 
• In Part 2, approximately 46 evaluable participants older than 18 years will be 
randomized to receive either itacitinib 200 mg BID or placebo. 
This study includes a 14-day screening period after apheresis. Apheresis will be per institutional 
standard of care. Conditioning chemotherapy will be administered at the discretion of the 
investigator. 
Participants will be administered study drug beginning at Day −3 to Day −1 before IEC infusion. 
Immune effector cell therapy will be administered on Day 0 along with study drug. Participants 
will continue to receive study drug through Day 26 to complete a 30-day study treatment period. 
During the treatment period, Protocol-defined assessments will be conducted on Day –3, Day –1, 
Day 0 (IEC infusion day), Day 1, Day 3, Day 5, Day 7, Day 14, Day 21, and Day 28. Restaging 
of hematologic disease will be conducted per institutional guidelines. Completers are defined as 
participants who complete 30 days of itacitinib administration (Day –3 to Day 26). An EOT 
assessment will be conducted at Day 28 ± 2 days. Additional post-therapy follow-up visits will 
be conducted 30 days after the last dose of itacitinib and 90 and 180 days after IEC infusion. End 
of study is met at Day 180. 
Safety will be monitored beginning at screening and will continue through to a 30-day 
post-treatment safety follow-up visit. 
Hematologic disease assessments should be conducted as indicated in the SoA. The date of the 
assessment as well as the results should be recorded in the eCRF. 
A planned interim analysis for CRS futility will be conducted when 24 participants in Part 1 are 
treated with an approved IEC therapy and complete the Day 28 (EOT) visit. The study may be 
stopped for futility at the interim analysis if the conditional power based on interim results is 
lower than 20%, which is equivalent to more than 17 out of 24 participants experiencing 
≥ Grade 2 CRS by Day 14. 


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See Figure 1 and Figure 2 for the study design. 
Figure 1: 
Study Design Schema Part 1 
 
Figure 2: 
Study Design Schema Part 2 
 
3.1.1. 
Treatment Discontinuation 
Participants must be withdrawn from study treatment for the following reasons: 
• The participant becomes pregnant. 
• Consent is withdrawn. 
Note: Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant. Participants may 
choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Unacceptable toxicity. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority and/or IRB. 


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3.1.2. 
Study Duration 
The study begins when the first participant signs the ICF. The end of the study is expected to 
occur when the last participant reaches their 180-day (6-month) follow-up visit. 
Completers (of treatment) are defined as participants who complete 30 days of itacitinib 
administration (Day –3 to Day 26). A participant is considered to have completed the study if 
he/she has completed all periods of the study including the 6-month follow-up for which a 
disease assessment is required. 
3.2. 
Randomization 
Part 1: Not applicable. 
Part 2: The planned 46 participants will be randomized 1:1 to receive either itacitinib or placebo, 
resulting in 23 participants in each cohort. 
3.3. 
Control of Type I Error 
For Part 1, analysis of CRS rate, 2-sided 95% exact confidence level by Clopper-Pearson method 
will be reported (Clopper and Pearson 1934). 
For Part 2, the analysis of the primary efficacy endpoint, a 2-sample t test with 1-sided Type I 
error of 0.05 will be conducted to test the difference between the 2 treatment groups. Two-sided 
95% CIs will be reported, for the primary efficacy endpoint for each treatment group and the 
difference between the 2 treatment groups. 
3.4. 
Sample Size Considerations 
Part 1 is a single-arm open-label study. The sample size calculation is based on the primary 
endpoint of ≥ Grade 2 CRS rate by Day 14. It was considered that 60% ≥ Grade 2 CRS by 
Day 14 is clinically relevant in this setting. Based on a target rate of 60%, a sample size of 62 
will provide 90% power to exclude a higher limit of 79% of a 2-sided 95% CI. The sample size 
calculation is based on an EAS (see Section 5.3 for definition). 
Table 2 represents CRS rates and CIs for a sample size of 62. 
Table 2: 
Cytokine Release Syndrome Rates and 95% Confidence Intervals 
Sample Size 
Number of CRS 
CRS Rate (%) 
95% CI (%) 
62 
36 
58.1 
44.8, 70.5 
62 
38 
61.3 
48.1, 73.4 
62 
40 
64.5 
51.3, 76.3 
62 
42 
67.7 
54.7, 79.1 
62 
44 
71.0 
58.1, 81.8 
Part 2 is a randomized expansion of the study; itacitinib 200 mg BID versus placebo. 
As in Part 1, the primary endpoint is Grade ≥ 2 CRS rate by Day 14. Assuming Grade ≥ 2 CRS 
rate in the placebo arm is 50% (Nastoupil et al 2020) and is 20% in the treatment arm (~30% 


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change in CRS rate), a sample size of 23 evaluable participants per group would provide 70% 
power based on a 1-sided Type I error rate of 5%. Sufficient number of participants will be 
enrolled to yield 23 evaluable participants in each group. 
A Bayesian interpretation for the selection and impact of the sample size can be provided in 
terms posterior probabilities. As the response rate based on CRS rate has a binomial (n, p) 
distribution with s number of responders out of n participants, it is common to use a conjugate 
Beta (a, b) prior which leads to a Beta(a + s, b + n − s) posterior distribution. For this exercise, 
we assume a noninformative Beta(1,1) (~ Uniform(0,1) prior). 
Table 3 presents scenarios of Bayesian posterior probability of demonstrating a treatment 
difference (≥ 30%) by Day 14 in CRS rates, between the itacitinib 200 mg BID group and the 
placebo group, under various CRS rates assumption (number and percentage of participants 
experiencing > = Grade 2 CRS). 
Table 3: 
Bayesian Posterior Probability of Demonstrating a Treatment Difference 
Na (%) 200 BID Group 
Nb (%) Placebo 
Posterior Probabilityc 
2 (8.7) 
9 (39.1) 
43.7 
12 (52.5) 
79.4 
14 (60.9) 
93.4 
5 (21.7) 
9 (39.1) 
13.9 
12 (52.5) 
45.9 
14 (60.9) 
67.9 
7 (30.4) 
9 (39.1) 
4.7 
12 (52.5) 
22.7 
14 (60.9) 
44.7 
a Number of participants with CRS ≥ Grade 2, out of 23 participants, in the 200 mg BID group. 
b Number of participants with CRS ≥ Grade 2, out of 23 participants, in the placebo group. 
c Bayesian posterior probability that the itacitinib group has at least 30% improvement over placebo, based on CRS ≥ Grade 2. 
Based on the scenarios presented in Table 3, if we assume observed CRS rates (CRS ≥ Grade 2) 
of 2/23 (8.7%) and 12/23 (52.2%) in the itacitinib and placebo groups, respectively, then a 
Bayesian calculation is expected to yield a posterior probability of 79.4% of seeing an reduction 
of at least 30% in the itacitinib group. 
3.5. 
Schedule of Assessments 
Refer to Protocol Amendment 4 dated 08 DEC 2022 for a full description of all study procedures 
and assessment schedules for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Study Drug 
Itacitinib and placebo are the study drugs in this study. 
4.1.2. 
Study Treatment 
Itacitinib, placebo, and IEC therapy are all considered as the study treatments in this study. 
4.1.3. 
Day 1 
Day 1 is the date of first dose of itacitinib/placebo, which is given 3 days to 1 day before IEC 
infusion. 
4.1.4. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (Visit/Reporting Date – Day 1 date). 
A study day of −1 indicates 1 day before Day 1. 
4.1.5. 
Baseline Value 
Baseline is the last nonmissing assessment obtained before the first administration of study drug 
for safety analysis. For efficacy endpoints related to IEC therapy, the last nonmissing assessment 
prior to IEC therapy may be taken as baseline depending on the specific analysis to be 
conducted. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.6. 
Handling of Missing and Incomplete Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 


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Missing or partial disease diagnosis date will be handled as follows: 
• If only the day is missing, then the imputed day will be the first of the month. 
• If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
• No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows: 
• If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the participant discontinued 
treatment. 
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose. 
For relevant efficacy endpoints, partial death date will be imputed as follows: 
• If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date. 
• If mmyyyy for the last contact date < mmyyyy for the death date, then the death date 
will be set to the first day of the death month. 
• Otherwise, the partial death date will not be imputed. 
For prior and concomitant medications: 
The start/stop dates recorded in the eCRF by the investigator and his or her research staff will be 
used to identify when a concomitant medication was taken during the study. Any missing start 
date must be queried for resolution. Unresolved missing start dates will be handled as follows: 
• If the date is completely missing, the medication will be considered both prior and 
concomitant. 
• If only the day is missing, and the last day of the month is before the first dose date 
on Day 1, then the concomitant medication will be considered as starting before 
Day 1, and the incomplete date will be imputed as the last day of the month. 
• If only the day is missing, and the first day of the month is on or after the first dose 
date on Day 1, then the concomitant medication will be considered as starting after 
Day 1, and the incomplete date will be imputed as the first day of the month. 
• If only the day is missing, and the month is equal to the month of the first dose date 
on Day 1, then the incomplete date will be imputed as the first day of the month. 
• If both the month and day are missing, and the last day of the year is before the first 
dose date on Day 1, then the concomitant medication will be considered as starting 
before Day 1, and the incomplete date will be imputed as if it is the last day of the 
year. Otherwise, if the last day of the year is on or after the first dose date Day 1, the 
incomplete date will be imputed as if it is the first day of the year. 


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• If the imputed start date through the above procedure is after the stop date recorded in 
the eCRF, then the imputed start date will be set equal to the stop date. 
4.1.7. 
On-Treatment Assessment/Event 
Safety data can be summarized for itacitinib and IEC therapy, respectively. For itacitinib, 
on-treatment assessment/event is defined as any assessment/event obtained in the following time 
interval: 
Date of first administration of study drug through the date of last administration of study 
drug + 30 days. 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. 
If the last date of study drug is missing, on-treatment assessments/events include any 
assessment/event recorded in the database that occurred after the start date of study drug. 
For IEC therapy, any safety data reported after IEC therapy would be considered as on-treatment 
assessment/event without cutoff. 
To simplify data reporting, any safety data collected after Day 1 will be presented in summary 
table. Data listings will include all assessments/events, and those which are not on-treatment 
assessments/events to itacitinib will be flagged. 
4.2. 
Variable Definitions 
The following variables will only be calculated. 
4.2.1. 
Body Mass Index 
Body mass index will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any non-study medication started before the first dose of itacitinib. 
Concomitant medication is defined as any non-study medication that is started accordingly: 
• Before the date of first administration of itacitinib and is ongoing throughout the 
study or ends on/after the date of first study drug administration. 
• On/after the date of first administration of itacitinib and is ongoing or ends during the 
course of study drug administration. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of itacitinib. In the listing, it will be indicated whether a medication 
is prior-only, concomitant-only, or both prior and concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant, that is, if the start date and end 
date are all missing, then the medication is considered as concomitant medication. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9.4 or later) will be used 
for the generation of all tables, figures, and statistical analyses. Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum. Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
Interim analyses are planned for this study as defined in Section 10. 
5.2. 
Treatment Groups 
In Part 1, all participants will take itacitinib. Participants may receive any of the 3 IECs approved 
for hematologic indications at the time of study conduct. Thus, the treatment groups in this study 
are as the following: 
• Itacitinib 200 mg QD + Kymriah® (tisagenlecleucel) 
• Itacitinib 200 mg QD + Yescarta® (axicabtagene ciloleucel) 
• Itacitinib 200 mg QD + Tecartus® (brexucabtagene autoleucel) 
In this part, 3 different disease populations are planned to be enrolled in this study (ie, B-cell 
lymphoma, MCL, and ALL). 
In Part 2, the participants will be randomized 1:1 into 2 groups (ie, itacitinib 200 mg BID and 
placebo). The study population will include participants who are receiving Yescarta for relapsed 
or refractory large B-cell lymphoma or follicular lymphoma. Thus, the treatment groups in this 
part are as the following: 
• Itacitinib 200 mg BID + Yescarta (axicabtagene ciloleucel) 
• Placebo + Yescarta (axicabtagene ciloleucel) 
For all summary tables, results from Parts 1 and 2 will be displayed in the same table for each 
analysis, unless otherwise specified. This will apply for all analyses in this study. For analysis 
purpose, efficacy and safety will be presented separately for Part 1 and Part 2 by treatment 
group. Specific analysis such as disease history and baseline characteristics and response of 
underlying disease will be summarized by treatment group and disease population. Further split 
or combination may be considered in analysis. 
5.3. 
Analysis Populations 
Table 4 presents the populations for analysis. 


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Table 4: 
Analysis Populations 
Population 
Description 
Safety population 
The safety population includes all enrolled participants who received at 
least 1 dose of study drug. 
All safety analyses will be conducted using the safety population.  
Efficacy evaluable 
analysis set (EAS) 
The EAS includes all participants who have received at least 1 dose of 
study drug and have received IEC therapy. 
All efficacy analyses will be conducted using EAS. 
 
 
 
 
 
 
 
 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of planned tables, figures, and listings. 
Unless otherwise specified, for Part 1 of the study, the information specified in this section will 
be summarized by treatment group as well as overall using the safety population. 
 
 
 For Part 1 of the study, if any of the subgroups include less 
than 10% of the overall sample size for that part, the information for that subgroup will only be 
listed. For Part 2 of the study, the information will be summarized by treatment group using the 
safety population. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be listed in detail. The following will be 
summarized using safety population: age, sex, race, ethnicity, body weight, height, BMI, and 
ECOG status, all at baseline. Qualitative data will be summarized by contingency tables while 
quantitative data will be summarized by descriptive summary statistics. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
Baseline disease characteristics will be separately summarized in participants with ALL, B-cell 
lymphoma, and MCL. According to data collected in the eCRF, the following information will 
be summarized for participants with ALL: time since diagnosis, which is from diagnosis date to 
the first dose date of study drug; CNS status; morphology % blast; marrow morphology 
category; number of prior lines of therapy; and whether or not prior radiation was given. For 
participants with B-cell lymphoma, the following information will be summarized: time since 
diagnosis, which is from diagnosis date to the first dose date of study drug; B-cell lymphoma 
disease type; NCCN prognostic index; DLBCL type and subtype; number of prior lines of 
therapy; Philadelphia chromosome status; and whether or not prior radiation was given. For 
participants with MCL, the following information will be summarized time since diagnosis, 
which is from diagnosis date to the first dose date of study treatment; number of prior systemic 
treatment regimens; current Ann Arbor staging; whether or not current B-symptoms are present; 
current MIPI risk category; prior radiation therapy; and prior surgery. Tumor marker information 
may be summarized if sufficient data are collected. 
6.1.3. 
Prior Therapy 
For prior medication therapy, the number and percentage of participants who received each drug 
will be summarized by WHO drug class and preferred name. The term for the 
medication/therapy taken; the start and stop dates; best response; reason for discontinuation; date 
of relapse/progression; and the route, collected on the prior therapy page of the CRF, will be 
listed. 


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For prior radiotherapy, the radiotherapy type; the start and stop dates; the reason for regimen; the 
number of fractions received; total dose; and best response, collected on the prior radiotherapy 
page of the CRF, will be listed. 
6.1.4. 
Medical History 
Medical history will be summarized for all participants in the safety population. This summary 
will be presented by primary SOC and PTs. 
6.2. 
Disposition of Participants 
The number and percentage of participants who are on treatment, who discontinued any study 
drug with a primary reason for discontinuation, who are on study, and who withdrew from the 
study with a primary reason for study withdrawal will be summarized for all participants in the 
safety population. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be presented in the participant data listings and 
summarized descriptively. 
6.4. 
Exposure 
For participants in the safety population, exposure to itacitinib, placebo, and IEC therapy will be 
summarized descriptively as follows: 
• Total dose administered of study drug (mg): total actual study drug taken (mg) 
• Average daily dose of study drug (dose intensity) (mg): Total dose administered 
(mg) / duration of treatment 
• Duration of treatment of study drug (days): Date of last dose of study drug – date 
of first dose of study drug + 1 
• Total cell count of IEC and CAR-positive viable T cells will be summarized for 
IEC therapy 
6.5. 
Study Drug Compliance 
Overall compliance (%) for itacitinib will be calculated for all participants as follows: 
Overall compliance (relative dose intensity) (%) = 100%  (total dose administered) / 
(intended dose) 
Intended dose is defined as the sum of the doses prescribed by the investigator accounting both 
for planned dose reductions as well as those reductions or increases mandated by the 
investigator. 
For IEC infusions, compliance calculations are not applicable. Infusion information collected in 
eCRF may be listed as needed, including any temporary infusion interruption. 


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6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary 
and summarized by ATC drug class and WHO drug term. Results will be summarized as number 
and percentage of participants with prior and concomitant medications by ATC class and WHO 
drug class in the safety population. For the summary of concomitant medication, only 
medications starting on or after the first dose of study drug will be included. Medications with 
missing start/end dates will be considered as concomitant medication in the summary. Other 
medications will be provided in the listing. 


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7. 
EFFICACY 
A list of planned tables, figures, and listings is provided in Appendix A. 
7.1. 
General Considerations 
Unless otherwise specified, for Part 1 of the study, all efficacy analyses will be summarized by 
treatment group as well as overall using the EAS. For Part 1 of the study, if any of the subgroup 
includes less than 10% of the overall sample size for that part, the information for this subgroup 
will only be listed. For Part 2 of the study, all efficacy analyses will be summarized by treatment 
group using the EAS. 
7.2. 
Analysis of the Primary Efficacy Parameter 
7.2.1. 
Primary Efficacy Analysis 
The primary endpoint of the study is CRS rate by Day 14, defined as the percentage of 
participants experiencing ≥ Grade 2 CRS by Day 14 after IEC therapy. 
In Part 1, the CRS rate will be calculated for each treatment group as follows: 
𝐶𝑅𝑆 𝑟𝑎𝑡𝑒= 𝑥
𝑛 
where n is the number of efficacy evaluable participants, and x is the number of efficacy 
evaluable participants who experience ≥ Grade 2 CRS by Day 14. 
The exact 95% CI (2-sided) will be calculated using the Clopper-Pearson method (Clopper and 
Pearson 1934), as the following: 
(𝐵(𝛼
2 ; 𝑥, 𝑛−𝑥+ 1) , 𝐵(1 −𝛼
2 ; 𝑥+ 1, 𝑛−𝑥)) 
where B (p; v, w) is the pth percentile from a beta distribution with shape parameters v and w, 
and α is 5%. 
In Part 2, the CRS rate and the associated 95% CI will also be calculated for each treatment 
group, itacitinib 200 mg BID and placebo, in the same way as the analysis for Part 1. The 
primary efficacy endpoint analysis will be the comparison of the percentage of efficacy 
evaluable participants experiencing ≥ Grade 2 CRS by Day 14 between the 2 treatment groups. 
The CRS rates will be compared using a 1-sided Z-test at the significance level of 0.05, and a 
95% CI (2-sided) for the difference in the CRS rate will be calculated. The following statistical 
hypothesis will be tested for the primary efficacy endpoint analysis: 
H0: CRSA ≥ CRSB versus H1: CRSA < CRSB 
where CRSA and CRSB will be the CRS rates for itacitinib 200 mg BID and placebo, 
respectively. The Z-test for the difference between the 2 treatment groups will be based on the 
following test statistic: 
𝑧=
𝐶𝑅𝑆
̂ 𝐴−𝐶𝑅𝑆
̂ 𝐵
√𝐶𝑅𝑆
̂ (1 −𝐶𝑅𝑆
̂ )( 1
𝑛1 + 1
𝑛2)
 


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where n1 and n2 are the numbers of efficacy evaluable participants for itacitinib 200 mg BID and 
placebo, respectively, and 
𝐶𝑅𝑆
̂ 𝐴= 𝑥1
𝑛1
 
𝐶𝑅𝑆
̂ 𝐵= 𝑥2
𝑛2
 
𝐶𝑅𝑆
̂ = 𝑥1 + 𝑥2
𝑛1 + 𝑛2
 
where x1 and x2 are the number of efficacy evaluable participants experiencing CRS ≥ Grade 2 
by Day 14 for the treatment group, itacitinib 200 mg BID and placebo, respectively. 
For the 1-sided test specified above, the p-value will be calculated as the probability of Z ≤ z, 
where Z is the random variable for the standard normal distribution. If the p-value is smaller than 
or equal to the significance level at 0.05, the null hypothesis will be rejected. It could be 
concluded that the ≥ Grade 2 CRS rate by Day 14 after Yescarta for itacitinib 200 mg BID is 
significantly lower than that for placebo. 
The 95% CI (2-sided) of the difference in the CRS rate between the 2 treatment groups can be 
calculated as follows: 
𝐶𝑅𝑆
̂ 𝐴−𝐶𝑅𝑆
̂ 𝐵± 1.96 ∗√
𝐶𝑅𝑆
̂𝐴(1−𝐶𝑅𝑆
̂𝐴)
𝑛1
+
𝐶𝑅𝑆
̂𝐵(1−𝐶𝑅𝑆
̂𝐵)
𝑛2
. 
7.2.1.1. 
Handling of Missing Data in Primary Analysis 
For the primary analysis, if a participant drops out of the study prior to reaching Day 14 after 
IEC without experiencing a CRS event of ≥ Grade 2, the participant will be considered as not 
experiencing ≥ Grade 2 CRS by Day 14. See Section 7.2.1.2 for the sensitivity analysis that is 
planned in this regard. 
7.2.1.2. 
Sensitivity Analysis 
A sensitivity analysis will be performed on the primary efficacy endpoint. For this analysis, 
participants who dropped out of the study prior to reaching Day 14 after IEC without 
experiencing any CRS event of ≥ Grade 2 will be excluded. If there is no participant in this 
situation, the sensitivity analysis will not be performed. The same method for the primary 
efficacy endpoint analysis specified in Section 7.2.1 will be used for this analysis, except that no 
hypothesis testing will be conducted here. 
7.2.1.3. 
Supportive Analysis 
A supportive analysis will be conducted by comparing the itacitinib 200 mg QD dose in Part 1 
with the placebo group in Part 2, using a 95% CI (2-sided), for participants with B-cell 
lymphoma and treated with Yescarta as the IEC therapy. For the itacitinib 200 mg QD treatment 
group, only participants with B-cell lymphoma and treated with Yescarta from Part 1 will be 
considered; whereas all participants in the placebo treatment group from Part 2 are considered 
for this analysis. This analysis is performed in the same way as the primary efficacy endpoint 
analysis for Part 2, except that no hypothesis testing is conducted.  


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As another supportive analysis, comparison between the itacitinib 200 mg QD dose from Part 1 
and the itacitinib 200 mg BID treatment group from Part 2 will be conducted in the same way as 
the analysis specified above, for participants with B-cell lymphoma and treated with Yescarta as 
the IEC therapy, except that no hypothesis testing is conducted.  
7.3. 
Analysis of the Secondary Efficacy Parameters 
7.3.1. 
Immune Effector Cell-Associated Neurotoxicity Syndrome Incidence 
Incidence of ICANS, defined as the percentage of participants experiencing ICANS by Day 28 
(over the first 28-day period) after IEC therapy, will be summarized and presented together with 
its exact 95% CI (2-sided). The 95% CIs will be calculated in the same way as for the CRS rate 
in Section 7.2.1. 
There will be no missing data imputation in calculation of ICE score or ICANS grading. In 
addition, ICANS incidence will be provided separately for each IEC therapy. 
7.3.2. 
Onset and Duration of Immune Effector Cell-Associated Neurotoxicity 
Syndrome 
Time to first onset of ICANS from date of IEC infusion is summarized within the first 28 days. 
Participants without ICANS will be considered as missing and not included in the summary. 
The duration of ICANS is defined as the number of days where a participant has a non-zero 
ICANS grade. Duration of ICANS by Day 28 after IEC as the secondary analysis will be 
summarized. For investigational purpose, duration of all ICANS including events after Day 28 
may also be conducted. 
For ICANS that occurs prior to or on Day 30, refer to the information collected on the ICANS 
assessment log of the CRF; for ICANS that occur after Day 30, refer to the information collected 
on the ICANS page of the CRF. 
Summary statistics including mean, median, standard deviation, minimum, and maximum will be 
provided for time to first onset of ICANS and duration of ICANS. 
7.3.3. 
Onset and Duration of Cytokine Release Syndrome 
Time to first onset of CRS from date of IEC infusion will be summarized within the first 
28 days. Participants without CRS will be considered as missing in the summary. 
Duration of CRS is defined as the number of days where a participant has a CRS event. Duration 
of multiple occurrence of CRS within each participant will be added together regardless of 
grading. The duration of CRS by Day 28 as the secondary analysis will be summarized. For 
investigational purposes, a summary of the overall duration may be conducted.. 
Summary statistics including mean, median, standard deviation, minimum, and maximum are 
provided for time to first onset of CRS and duration of CRS by treatment group. 


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7.3.4. 
Cytokine Release Syndrome-Free Survival 
The CRS-free survival analysis will be performed using the Kaplan-Meier method, with the 
following events considered as the events of interest: 
• CRS of ≥ Grade 2 
• Death 
• Initiation of tocilizumab with the indication of CRS treatment 
• Initiation of corticosteroids with the indication of CRS treatment 
For participants who experience any of the events of interest mentioned above, the time-to-event 
variable will be calculated as the number of days from IEC therapy to the first occurrence of the 
events of interest. For participants who do not experience any of the events of interest, they will 
be treated as censored observations, and the time-to-event variable will be calculated as the 
number of days from Day 0 to the date of the last available CRS assessment by Day 28. The 
numbers of participants who do and do not experience any of the events of interest will be 
summarized. The median CRS-free survival in days, and the CRS-free survival rates on Days 7, 
14, 21, and 28 will be included in the summary. 
7.3.5. 
Occurrence of Cytokine Release Syndrome Within 48 Hours 
Percentage of participants who developed CRS within 48 hours of IEC infusion as well as the 
maximum grade of CRS will be summarized, using the same method as for the analysis of the 
CRS rate specified in Section 7.2.1. 
7.3.6. 
Cytokine Release Syndrome Rate Within 28 Days 
Percentage of participants who developed CRS within 28 days of IEC infusion as well as the 
maximum grade of CRS will be summarized, using the same method as for the analysis of the 
CRS rate specified in Section 7.2.1. 
7.3.7. 
Intervention for CRS and ICANS 
To assess intervention for CRS, the use of tocilizumab and corticosteroid for CRS treatment will 
be summarized. All use of tocilizumab and corticosteroid are listed including ICANS as the 
indication. 


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9. 
SAFETY AND TOLERABILITY 
A list of planned tables, figures, and listings is provided in Appendix A. 
9.1. 
General Considerations 
The clinical safety data (eg, vital signs, ECGs, routine laboratory tests, physical examinations, 
and AEs) will be summarized using descriptive statistics (eg, mean, frequency) using the safety 
population. The safety analyses will be performed separately for different treatment groups. 
Specific safety analyses may also be summarized by underlying disease as needed. Summary 
tables may be replaced with listings when appropriate. For instance, an AE frequency table may 
be replaced with a listing if it only contains a few unique PTs reported on relatively few 
participants. 
Safety summaries are also presented by the 2 dose groups and placebo for all the safety 
endpoints that are described below. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study drug. Analysis of AEs (as discussed below) will be limited to TEAEs, but data 
listings will include all AEs regardless of their timing in relation to study drug administration. 
Adverse events will be tabulated by MedDRA PT and SOC. Severity of AEs will be graded 
using the NCI CTCAE v5.0. The CTCAE reporting guidelines and grading details are available 
on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs. If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related. The incidence of AEs and 
treatment-related AEs will be tabulated. 
In addition, serious TEAEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution. Unresolved missing 
causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
• If the stop/resolution date is before the first dose administration date on Day 1, then 
the AE will be considered as not being treatment-emergent. 
• If both the month and day are missing, and the last day of the year is before the first 
dose administration date on Day 1, then the AE will not be considered 
treatment-emergent. 


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• If only the day is missing, and the last day of the month is before the first dose 
administration date on Day 1, then the AE will not be considered treatment-emergent. 
• If only the day is missing, and the first day of the month is after the first dose 
administration date on Day 1, then the AE will be considered treatment-emergent. 
9.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of participants who had any TEAEs 
• Number (%) of participants who had any serious TEAEs 
• Number (%) of participants who had any Grade 3 or higher TEAEs 
• Number (%) of participants who had any TEAEs related to study drug 
• Number (%) of participants who had any serious TEAEs related to study drug 
• Number (%) of participants who had any Grade 3 or higher TEAEs related to study 
drug 
• Number (%) of participants who temporarily interrupted study drug because of 
TEAEs 
• Number (%) of participants who permanently discontinued study drug because of 
TEAEs 
• Number (%) of participants who had study drug dose reductions because of TEAEs 
• Number (%) of participants who had a fatal TEAE 
• Number (%) of participants who had any AEs related to IEC therapy 
The following summaries will be produced by MedDRA term (if 10 or fewer participants appear 
in a table, a listing may be appropriate): 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of ≥ Grade 3 TEAEs by SOC and PT 
• Summary of ≥ Grade 3 TEAEs by PT in decreasing order of frequency 
• Summary of ≥ Grade 3 TEAEs by SOC, PT, and maximum severity 
• Summary of serious TEAEs by SOC and PT 
• Summary of serious TEAEs by PT in decreasing order of frequency 
• Summary of study drug treatment-related TEAEs by SOC and PT 
• Summary of study drug treatment-related TEAEs by SOC, PT, and maximum 
severity 


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• Summary of IEC therapy treatment-related TEAEs by SOC and PT 
• Summary of IEC therapy treatment-related TEAEs by SOC, PT, and maximum 
severity 
• Summary of treatment-related ≥ Grade 3 study drug TEAEs by SOC and PT 
• Summary of treatment-related ≥ Grade 3 IEC therapy TEAEs by SOC and PT 
• Summary of study drug treatment-related serious TEAEs by SOC and PT 
• Summary of IEC therapy treatment-related serious TEAEs by SOC and PT 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of TEAEs leading to study drug dose interruptions by SOC and PT 
• Summary of TEAEs leading to IEC therapy interruptions by SOC and PT 
• Summary of TEAEs leading to study drug dose reduction by SOC and PT 
• Summary of TEAEs leading to withdrawal of study drug 
• Summary of Deaths 
9.3. 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status at scheduled assessment times are summarized by treatment group 
and in overall population. The changes in ECOG status from the baseline may also be 
summarized. 
9.4. 
Clinical Laboratory Tests 
9.4.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit. 
Baseline will be determined according to Table 5. If there are multiple values that meet the 
criteria for baseline, Table 5 may be referred to as tiebreaker to delineate which value will be 
defined as baseline. 
Table 5: 
Baseline Laboratory Identification 
Priority 
Laboratory Visit 
Proximity to Visit Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade or similar criteria where clinical intervention is required for CTCAE grading. The 
incidence of abnormal laboratory values and shift tables relative to baseline will be tabulated. 
9.4.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from laboratories will be reported in SI units. Any 
laboratory test results and associated normal ranges from local laboratories will be converted to 


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SI units. For test results that will be summarized with available normal ranges, the number and 
percentage of participants with the laboratory values being low (but never high), normal, high 
(but never low), and both low and high will be calculated for each test. This shift summary may 
be produced for each test for the safety population. The denominator for the percentage 
calculation will use the number of participants in the baseline category (ie, low, high, normal, 
missing) as the denominator for the percentage in each of the categories during the treatment 
period. For numeric laboratory values, baseline value, postbaseline value, change from baseline, 
and percentage change from baseline will be summarized by visit. 
Shift tables will be presented showing change in CTC grade from baseline to worst postbaseline 
grade. Separate summaries for abnormally high and abnormally low laboratory values will be 
provided when the laboratory parameter has both high and low grading criteria. The denominator 
for the percentage calculation will be the number of participants in the baseline category. 
The following summaries will be produced for laboratory data (by laboratory parameter) 
reported on treatment. All laboratory assessments will be listed, and those collected later than 
30 days after the last treatment/exposure date will be flagged in the listings. 
• Number and percentage of participants with worst postbaseline CTC grade 
(regardless of the baseline status) will be summarized. Each participant will be 
counted only for the worst grade observed after baseline. 
• Shift tables using CTC grades comparing baseline with the worst postbaseline value 
will be produced for hematology, chemistry, and some other laboratory parameters 
with CTC grades. 
• For laboratory parameters where CTC grades are not defined, shift tables to the worst 
postbaseline value will be produced using the low/normal/high classifications based 
on laboratory reference ranges. 
• Number and percentage of participants meeting categorical liver function test criteria, 
including ALT, AST, and ALT or AST (≥ 3 ×, 5 ×, 8 ×, 10 ×, 20 × ULN); total 
bilirubin (≥ 1 ×, 2 × ULN); ALP (≥ 1.5 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 × ULN); combined 
categories of ALT/AST and total bilirubin (eg, ALT/AST ≥ 3 × ULN and total 
bilirubin ≥ ULN); combined categories of ALT/AST total bilirubin; and ALP (ALT 
or AST ≥ 3 × ULN and total bilirubin ≥ 2 × ULN and ALP < 2 × ULN at the same 
visit; potential drug induced liver injury). The worst values observed postbaseline for 
each participant will be used for each of the categories. 
9.5. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, temperature, and respiratory 
rate will be summarized descriptively. 
Normal ranges for vital sign values are defined in Table 6. The abnormal values for participants 
exhibiting vital sign abnormalities will be listed along with their assigned treatment group. Alert 
vital signs are defined as an absolute value outside the defined normal range and percentage 
change greater than 25%. Note that the definition of alert vital signs does not apply for body 


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temperature. The abnormal values for participants exhibiting alert vital sign abnormalities will be 
listed. 
Table 6: 
Normal Ranges for Vital Sign Values 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
≤ 155 mmHg 
≥ 85 mmHg 
Diastolic blood pressure 
≤ 100 mmHg 
≥ 40 mmHg 
Pulse 
≤ 100 bpm 
≥ 45 bpm 
Temperature 
≤ 38ºC 
≥ 35.5ºC 
Respiratory rate 
≤ 24 breaths/min 
≥ 8 breaths/min 
9.6. 
Electrocardiograms 
Twelve-lead ECGs including PR, QT, QRS, QTcB, and QTcF intervals will be obtained for each 
participant during the study. Baseline will be determined as the last nonmissing ECG 
measurements taken on or before the first administration of study drug. 
Normal ranges for ECG values are defined in Table 7. ECG values will also be considered 
abnormal if the absolute percentage change from baseline is more than 25%. Participant 
exhibiting ECG abnormalities will be listed with study visit and assigned treatment group. 
Abnormal values for participant with alert ECG values, defined as both the absolute value and 
the percentage change from baseline being outside normal ranges, will be identified and listed. 
Outliers of QT, QTcB, and QTcF values, defined as absolute values > 450 ms, > 500 ms, or 
change from baseline > 30 ms, will be summarized. 
Table 7: 
Normal Ranges for Electrocardiogram Intervals 
Parameter 
High Threshold 
Low Threshold 
PR 
≤ 220 ms 
≥ 75 ms 
QT 
≤ 500 ms 
≥ 300 ms 
QRS 
≤ 120 ms 
≥ 50 ms 
QTcF, QTcB 
≤ 460 ms 
≥ 295 ms 
QTcB = Bazett's correction; QTcF = Fridericia's correction. 
In addition to ECG, echocardiogram may also be conducted, and data collected will be 
summarized and listed as appropriate. 
9.7. 
Cytopenias Ongoing by Day 30 
All the cytopenias ≥ Grade 3 by Day 30 will be summarized. The laboratory tests on neutrophils, 
hemoglobin, and platelets will be included. 
 
  


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10. 
INTERIM ANALYSES 
For Part 1, an interim analysis is planned after approximately 24 participants are dosed with IEC 
therapy and complete the Day 28 (EOT) visit. The results from the interim analysis will be 
reviewed by the DSMB. The primary intent of this analysis is to minimize unnecessary exposure 
to itacitinib in the event of futility of treating CRS. The study may be stopped for futility at the 
interim analysis if the conditional power based on interim results is lower than 20%, which is 
equivalent to more than 17 out of 24 participants experiencing ≥ Grade 2 CRS by Day 14. More 
than 24 participants may be available in EAS at the time of interim analysis, and the stopping 
boundary will be re-evaluated at the time of the analysis.
 Enrollment will continue while the analysis 
is being conducted. 
No interim analysis is planned for Part 2. 


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11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 8. 
Table 8: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
06 JAN 2021 
Amendment 1 
08 MAY 2023 
 
 
 
 
11.2. 
Changes to the Statistical Analysis Plan 
11.2.1. 
Amendment 1 
The primary purpose of SAP Amendment 1 is to implement Protocol Amendments 3 and 4 by 
adding the analyses for the randomized placebo-controlled Part 2 of the study using a 200 mg 
BID regimen. 
Other minor updates include: 
• Replaced previous IND number with a new IND number. 
• Revised Section 7.2.1 to provide explanation of calculations. 
• Additional analyses were added to Section 7.2.1 and Section 7.3. 
• Liver function test criteria was updated to align with the new version of standard. 
• Format changes were applied to Appendix A. Additional tables and listings were 
added. 
• In Appendix A, ECG tables were deleted due to data collection, the corresponding 
listings will still be created. 
• Editorial changes have been made for better clarity and accuracy. 


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12. 
REFERENCES 
Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26:404-413. 
Nastoupil LJ, Jain MD, Feng L, et al. Standard-of-care axicabtagene ciloleucel for relapsed or 
refractory large B-cell lymphoma: results from the US Lymphoma CAR T consortium. J Clin 
Oncol 2020;38:3119-3128. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report. The lists of tables, figures, and listings are to be used as guidelines. Modifications of the 
lists that do not otherwise affect the nature of the analysis will not warrant an amendment to the 
SAP. 
Tables 
Table No. 
Title 
Population 
Baseline and Demographic Characteristics 
1.1 Disposition 
1.1.1 
Analysis Populations 
Enrolled 
1.1.2 
Summary of Participant Disposition 
Safety 
1.1.3 
Summary of Number of Participants Enrolled by Site 
Enrolled 
1.1.4 
Summary of Protocol Deviations 
Safety 
1.2 Demography and Baseline Characteristics 
1.2.1 
Summary of Demographics and Baseline Characteristics 
Safety 
1.3 Baseline Disease Characteristics (refine per data collection) 
1.3.1 
Summary of Underlying Disease History and Baseline Disease Characteristics 
for B-Cell Lymphoma 
Safety 
1.3.2 
Summary of Underlying Disease History and Baseline Disease Characteristics 
for Mantle Cell Lymphoma 
Safety 
1.3.3 
Summary of Underlying Disease History and Baseline Disease Characteristics 
for Acute Lymphoblastic Leukemia 
Safety 
1.3.4 
Summary of Cancer Types 
Safety 
1.3.5 
Summary of Prior Therapy 
Safety 
1.4 Prior Medication and Concomitant Medication (refine per data collection) 
1.4.1 
Summary of Prior Medications 
Safety 
1.4.2 
Summary of Concomitant Medications 
Safety 
1.5 Others 
1.5.1 
Summary of General Medical History 
Safety 
1.5.2 
Summary of Death 
 
2 Efficacy (add subgroup analysis as needed) 
2.1.1 
Summary of CRS Rate by Day 14 After IEC Therapy 
EAS 
2.1.1.1 
Sensitivity Analysis: Summary of CRS Rate by Day 14 After IEC Therapy – 
Excluding Participants Who Drop Out of the Study Prior to Day 14 Without 
Experiencing ≥ Grade 2 CRS 
EAS 
2.2.1 
Summary of ICANS Rate by Day 28 After IEC Therapy 
EAS 
2.2.2.1 
Summary of Onset and Duration of ICANS by Day 28 After IEC Therapy 
EAS 
2.2.2.2 
Summary of Onset and Duration of ICANS During the Lifetime of the Study 
EAS 
2.2.3.1 
Summary of Onset and Duration of CRS by Day 28 After IEC Therapy 
EAS 
2.2.3.2 
Summary of Onset and Duration of CRS During the Lifetime of the Study 
EAS 
2.2.4.1 
Summary of CRS-Free Survival by Day 28 After IEC Therapy 
EAS 
2.2.4.2 
Summary of CRS Rate Within 48 Hours and by Day 28 After IEC Therapy 
EAS 
2.2.4.3 
Summary of Tocilizumab and Corticosteroid Use for CRS Treatment 
EAS 
 
 
 
 
 
 


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Table No. 
Title 
Population 
 
 
 
 
 
E
 
 
 
 
 
 
 
 
 
Safety 
3.1 Dose Exposure 
3.1.1 
Summary of Exposure to Study Drug 
Safety 
3.1.2 
Summary of Exposure to IEC Therapy 
EAS 
3.2 Adverse Events  
3.2.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
3.2.2.1 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term  
Safety 
3.2.3.1 
Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term 
in Decreasing Order of Frequency 
Safety 
3.2.4.1 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ 
Class, Preferred Term, and Maximum Severity 
Safety 
3.2.5.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.6.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and Maximum Severity 
Safety 
3.2.7.1 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.8.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term 
Safety 
3.2.9.1 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
3.2.10.1 
Summary of Study Drug Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.11.1 
Summary of Study Drug Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum Severity 
Safety 
3.2.12.1 
Summary of IEC Therapy Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.13.1 
Summary of IEC Therapy Treatment-Related Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum Severity 
Safety 
3.2.14.1 
Summary of Grade 3 or Higher Study Drug Treatment-Related Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.15.1 
Summary of Grade 3 or Higher IEC Therapy Treatment-Related Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.16.1 
Summary of Study Drug Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.17.1 
Summary of IEC Therapy Treatment-Related Serious Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.18.1 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term 
Safety 
3.2.19.1 
Summary of Treatment-Emergent Adverse Events Leading to Study Drug  Dose 
Interruption by MedDRA System Organ Class and Preferred Term 
Safety 


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Table No. 
Title 
Population 
3.2.20.1 
Summary of Treatment-Emergent Adverse Events Leading to IEC Therapy 
Interruption by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.21.1 
Summary of Treatment-Emergent Adverse Events Leading to Study Drug Dose 
Reduction by MedDRA System Organ Class and Preferred Term 
Safety 
3.2.22.1 
Summary of Treatment-Emergent Adverse Events Leading to Withdrawal of 
Study Drug  
Safety 
3.3 Laboratory (update per data collection) 
3.3.1.1 
Summary of Laboratory Hematology Values  
Safety 
3.3.1.2 
Summary of Laboratory Chemistry Values 
Safety 
3.3.1.3 
Summary of Laboratory Coagulation Values  
Safety 
3.3.1.4 
Summary of Laboratory Urinalysis Values 
Safety 
3.3.1.5 
Summary of Laboratory Lipid Values 
Safety 
3.3.2.1 
Shift Summary of Hematology Laboratory Values to the Worst Abnormal Value 
Safety 
3.3.2.2 
Shift Summary of Chemistry Laboratory Values to the Worst Abnormal Value 
Safety 
3.3.2.3 
Shift Summary of Coagulation Laboratory Values to the Worst Abnormal Value 
Safety 
3.3.3.1 
Shift Summary of Hematology Laboratory Values in CTC Grade to the Worst 
Abnormal Value 
Safety 
3.3.3.2 
Shift Summary of Chemistry Laboratory Values in CTC Grade to the Worst 
Abnormal Value 
Safety 
3.3.3.3 
Shift Summary of Coagulation Laboratory Values in CTC Grade to the Worst 
Abnormal Value 
Safety 
3.3.3.4 
Treatment-Emergent Worsening of Laboratory Abnormalities - Hematology 
Safety 
3.3.3.5 
Treatment-Emergent Worsening of Laboratory Abnormalities - Chemistry 
Safety 
3.3.3.6 
Treatment-Emergent Worsening of Laboratory Abnormalities - Coagulation 
Safety 
3.3.6 
Summary of Liver Chemistry 
Safety 
3.3.7 
Summary of Grade 3 or Higher Cytopenias Rate 
EAS 
3.4 Vital Signs 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
3.4.2 
Summary of Diastolic Blood Pressure 
Safety 
3.4.3 
Summary of Pulse 
Safety 
3.4.4 
Summary of Respiration Rate 
Safety 
3.4.5 
Summary of Body Temperature 
Safety 
3.4.6 
Summary of Weight 
Safety 
 
 
 
 
 
 
 
 
Figures 
Figure No. 
Title 
Efficacy (Lab figures may be added as needed) 
4.1.1 
Kaplan-Meier Estimates of CRS-Free Survival by Study Part and Treatment Group 
Listings 
Listing No. 
Title 
2.1 Discontinued Participants (Participant Disposition) 
2.1.1 
Participant Enrollment and Disposition Status 


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Listing No. 
Title 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 Protocol Deviations 
2.2 
Protocol Deviations 
2.3 Data Excluded From 
 Efficacy, and/or Safety Analyses 
2.3 
Analysis Populations 
2.4 Demography and Baseline (Including Prior and Concomitant Medications) 
2.4.1 
Demographic and Baseline Disease Characteristics 
2.4.2 
Underlying Disease History and Baseline Disease Characteristics for B-Cell Lymphoma 
2.4.2.1 
Underlying Disease History and Baseline Disease Characteristics for Mantle Cell Lymphoma 
2.4.2.2 
Underlying Disease History and Baseline Disease Characteristics for  Acute Lymphoblastic 
Leukemia 
2.4.3 
Prior Radiotherapy 
2.4.4 
Prior Medication Therapy 
2.4.5 
Medical History 
2.4.6 
Prior and Concomitant Medications 
2.5 Drug Exposure 
2.5.1 
Study Drug Exposure 
2.5.2 
IEC Exposure 
2.5.3 
Itacitinib Administration 
2.5.4 
IEC Therapy Administration 
2.6 Efficacy 
2.6.1.1 
CRS Assessments by Day 30 After IEC Therapy and at Post-Treatment Follow-Up 
2.6.1.2 
CRS Assessments After Day 30 After IEC Therapy 
2.6.2.1 
ICANS Assessments by Day 30 After IEC Therapy and at Post-Treatment Follow-Up 
2.6.2.2 
ICANS Assessments After Day 30 After IEC Therapy 
2.6.3 
All Response Assessment in Lymphoma 
2.6.4 
All Response Assessment in Acute Lymphoblastic Leukemia 
2.6.5 
Use of Tocilizumab and Corticosteroid 
2.7 Adverse Events 
2.7.1 
Adverse Events 
2.7.2 
Serious Adverse Events 
2.7.3 
Fatal Adverse Events 
2.7.4 
Adverse Events Leading to Study Drug Interruption, Reduction, or Withdrawal 
2.7.5 
Study Drug Treatment-Related Adverse Events 
2.7.7 
Adverse Events ≥ Grade 3 
2.8 Laboratory Data (update per data collection) 
2.8.1 
Clinical Laboratory Values – Hematology 
2.8.2 
Clinical Laboratory Values – Chemistry 
2.8.3 
Clinical Laboratory Values – Urinalysis  
2.8.4 
Clinical Laboratory Values – Coagulation 
2.8.5 
Clinical Laboratory Values – Lipid 
2.8.6.1 
Abnormal Clinical Laboratory Values – Hematology 
2.8.6.2 
Abnormal Clinical Laboratory Values – Chemistry 
2.8.6.3 
Abnormal Clinical Laboratory Values – Urinalysis 
2.8.6.4 
Abnormal Clinical Laboratory Values – Coagulation 
2.8.6.5 
Abnormal Clinical Laboratory Values – Lipid 
2.8.7 
Clinical Laboratory Values – Pregnancy 


Incyte Corporation 
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INCB 39110-211 Statistical Analysis Plan Am 1 
08 MAY 2023 
VV-CLIN-013309 
CONFIDENTIAL 
Listing No. 
Title 
2.8.10 
Clinical Laboratory Values – Liver Chemistry 
 
 
2.9 Vital Signs 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 
2.10 Electrocardiograms 
2.10.1 
ECG Values 
2.10.2 
Abnormal ECG Values 
2.11 Physical Examinations 
2.11.1 
Physical Examinations 
2.11.2 
ECOG Performance Status