Conditions: Lymphoma
Keywords: Diffuse large B-cell lymphoma Relapsed Diffuse large B-cell lymphoma Refractory Diffuse large B-cell lymphoma activated B cell germinal center B-cell non-Hodgkin lymphoma JAK1 inhibitor Bruton's tyrosine kinase (BTK) inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety/tolerability and efficacy of itacitinib in combination with ibrutinib in subjects with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: itacitinib intervention 2: ibrutinib
Intervention descriptions: intervention 1: Phase 1 will evaluate itacitinib at the protocol-specified starting dose, with a possible increase or decrease depending on tolerability. Phase 2 will evaluate the recommended dose determined in Phase 1. intervention 2: None

Protocol document:
Prot_000.pdf: 
Official Title: An Open-Label Phase 1/2 Study of Itacitinib (INCB039110) in Combination 
With Ibrutinib in Subjects With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma 
NCT Number: NCT02760485 
Document Date: Clinical Study Protocol Version 5: 18-June-2020 


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CONFIDENTIAL 
Clinical Study Protocol 
INCB 39110-206 
An Open-Label Phase 1/2 Study of INCB039110 in Combination 
With Ibrutinib in Subjects With Relapsed or Refractory Diffuse 
Large B-Cell Lymphoma 
Product: 
INCB039110 
IND Number: 
 
EudraCT Number: 
2017-002773-19 
Phase of Study: 
1/2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
30 MAR 2016 
Amendment (Version) 1: 
27 JUN 2016 
Amendment (Version) 2: 
11 MAY 2017 
Amendment (Version) 3: 
05 FEB 2018 
Amendment (Version) 4: 
01 MAR 2018 
Amendment (Version) 5: 
18 JUN 2020 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, Good Clinical Practices as defined in Title 21 of the US 
Code of Federal Regulations Parts 50, 54 56, 312, and Part 11 as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 


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INVESTIGATOR'S AGREEMENT 
I have read the INCB 39110-206 Protocol Amendment 5 (Version 5 dated 18 JUN 2020) 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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Dose cohorts are outlined in the table below: 
Cohort 
Subjects 
Regimen 
Subjects 
With 
DLT 
Action 
-1 
6 
INCB039110 200 mg 
QD + ibrutinib 560 mg 
QD 
≤ 1 
Begin expansion portion of the study 
2 
Enroll 3 additional subjects (9 subjects total) 
≥ 3 
Terminate study 
 
1 
(Starting 
dose) 
6 
INCB039110 300 mg 
QD + ibrutinib 560 mg 
QD 
≤ 1 
Escalate to Cohort 2 
2 
Enroll 3 additional subjects (9 subjects total); 
 if no new DLTs, escalate to Cohort 2 
≥ 3 
Reduce to Cohort -1 
 
2 
6 
INCB039110 400 mg 
QD + ibrutinib 560 mg 
QD 
≤ 1 
Begin Phase 2 
2 
Enroll 3 additional subjects (9 subjects total); 
 if no new DLTs, begin Phase 2 study 
≥ 3 
Begin Phase 2 of the study using Cohort 1 dose 
Phase 2: 
Subjects with ABC or unclassifiable DLBCL will receive the recommended Phase 2 dose of 
INCB039110 combination with ibrutinib as determined in Phase 1.  Phase 2 will use a Simon 2-stage 
design with a stopping rule to allow early termination of the study at the end of Stage 1 if there is lack 
of sufficient efficacy.  During Stage 1, if 9 or fewer of the first 22 evaluable subjects achieve an 
objective response (defined as a CR or PR), then the study may be terminated.  If 10 or more subjects 
achieve an objective response, then the study will continue and accrue 38 additional subjects to 
Stage 2.  Subjects who were enrolled but did not receive treatment will be excluded from the efficacy 
analysis and replaced.  A timely assessment of response will be made to avoid risk of overenrollment 
before accrual to Stage 2.  At the end of Stage 2, ORR will be assessed for sufficient efficacy to 
warrant further study.  The study will be considered successful if the total number of objective 
responders is 29 or more.  The study will end once all subjects have discontinued study treatment. 
Study Population: 
Key Inclusion Criteria: 
• Male or female, 18 years or older.  
• Histologically documented diagnosis of DLBCL. 
- For Phase 1, subjects may have any DLBCL subtype. 
- For Phase 2, subjects must have ABC or unclassifiable subtypes of DLBCL confirmed by 
immunohistochemistry using the Hans algorithm. 
Subjects having a computed tomography (CT) scan abnormality with uncertain interpretation 
following completion of the most recent treatment regimen must have biopsy confirmation of 
residual DLBCL before study entry. 
• Relapsed or refractory DLBCL, defined as having received at least 1 but no more than 3 prior 
treatment regimens and ineligible for high-dose chemotherapy/autologous stem cell transplant. 
• Fluorodeoxyglucose-avid disease (based on local evaluation) per the Lugano Classification.  
Fluorodeoxyglucose-avid disease is defined as disease with a 5-point scale score of 4 or 5. 
• Subjects must have archived tumor tissue (block or 15-20 unstained slides) available, or be willing to 
undergo an incisional or excisional lymph node biopsy of accessible adenopathy (or, in less 
accessible lymph nodes, 4 to 8 core biopsies). 


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• At least 1 measurable (≥ 2 cm in longest dimension) lesion on CT scan or magnetic resonance 
imaging (MRI). 
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. 
• Adequate bone marrow, renal, and hepatic function, per local reference laboratory ranges (values 
must not be achieved with growth factors) as follows: 
- Absolute neutrophil count ≥ 1.5 × 109/L. 
- Platelet count ≥ 75 × 109/L. 
- Hemoglobin ≥ 8.0 g/dL (transfusions are permitted to achieve required hemoglobin level). 
- Serum creatinine ≤ 2.0 g/dL or measured or calculated creatinine clearance ≥ 30 mL/min by the 
Cockcroft-Gault Equation. 
- Aspartate aminotransferase and ALT ≤ 2.5 × institutional upper limit of normal (ULN) or 
≤ 5 × ULN for subjects with known hepatic metastases. 
- Total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of liver 
metastases or presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia).  
Further evaluation should be performed to confirm and document origin of increase. 
• Prothrombin time/international normalized ratio < 1.5 × ULN and activated partial thromboplastin 
time < 1.5 × ULN. 
Key Exclusion Criteria: 
• Transformed DLBCL or DLBCL with coexistent histologies (eg, follicular or mucosa-associated 
lymphoid tissue lymphoma). 
• Primary mediastinal (thymic) large B-cell lymphoma. 
• Known central nervous system lymphoma (either primary or metastatic). 
• Autologous stem cell transplant within the previous 3 months, allogeneic stem cell transplant within 
the previous 6 months, or active graft versus host disease following allogeneic transplant. 
• Use of immunosuppressive therapy within 28 days of starting study treatment.  Immunosuppressive 
therapy includes but is not limited to cyclosporine A, tacrolimus, or high-dose corticosteroids.  
Subjects receiving corticosteroids must be at a dose level ≤ 10 mg/day within 7 days of initiating 
study treatment. 
• Prior or concurrent therapy with a Janus kinase inhibitor or Bruton's tyrosine kinase inhibitor. 
• Receipt of anticancer medications or investigational drugs within the following intervals before 
starting study treatment (unless otherwise approved by the sponsor): 
- < 6 weeks for mitomycin-C or nitrosoureas. 
- < 28 days for any investigational agent for any indication. 
- < 21 days or 5 half-lives (whichever is greater) for all other cytotoxic anticancer medications. 
- < 4 weeks for monoclonal antibodies used as anticancer treatment. 
- < 10 weeks or 5 half-lives from completion of any radio- or toxin-immunoconjugates. 
• Major surgery within 28 days before starting study treatment. 
• Prior treatment-related toxicities that have not resolved to Grade 1, with the exception of 
≤ Grade 2 neuropathy and any grade of alopecia. 
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral 
treatment. 


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• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction, and/or 
cardiac conduction issues within 6 months of Day 1; New York Heart Association Class II to IV 
congestive heart failure; uncontrolled arrhythmias. 
• Known bleeding disorders (eg, von Willebrand's disease) or hemophilia. 
• History of stroke or intracranial hemorrhage within 6 months of entering the study entry. 
• Significant concurrent, uncontrolled medical condition including, but not limited to renal, hepatic, 
hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral, or psychiatric disease. 
• Current or previous other malignancy within 3 years of study entry or not cured with treatment, 
except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial 
neoplasm, carcinoma in situ, or other noninvasive or indolent malignancy without sponsor approval. 
• Subjects who are currently receiving therapy with a strong cytochrome P450 3A4 inducer or 
inhibitor. 
• Subjects who are currently receiving therapy with warfarin or vitamin K antagonists such as 
coumarin-based anticoagulants (eg, fluindione and phenindione). 
• Unable to swallow oral medication, malabsorption syndrome, disease significantly affecting 
gastrointestinal function, resection of the stomach or small bowel, ulcerative colitis, symptomatic 
inflammatory bowel disease, or partial or complete bowel obstruction. 
• Known human immunodeficiency virus infection. 
• Known hepatitis B virus (HBV) or hepatitis C virus (HCV) or at risk for HBV reactivation.  
Hepatitis B virus DNA and HCV RNA must be undetectable.  At risk for HBV reactivation is 
defined as hepatitis B surface antigen–positive or anti–hepatitis B core antibody positive. 
Study Drug, Dosage, and Mode of Administration:   
The starting dose of INCB039110 in Phase 1 will be 300 mg QD (3 × 100 mg tablets); dose cohorts 
may be escalated to 400 mg QD or decreased to 200 mg QD depending on observed DLTs.  The 
recommended Phase 2 dose identified during Phase 1 will be the starting dose in Phase 2.  Subjects 
may have dose reductions of INCB039110 during the course of treatment based upon clinical and 
laboratory assessments. 
Reference Therapy, Dosage, and Mode of Administration: 
Ibrutinib will be administered at a dose of 560 mg QD (4 × 140 mg capsules).  Subjects may have dose 
reductions of ibrutinib during the course of treatment based upon clinical and laboratory assessments. 
Study Schedule/Procedures: 
During screening and every 28 days from the start of study treatment (Day 1), a study visit will be 
conducted that includes a physical examination, clinical laboratory tests, and assessments of vital 
signs, ECOG status, concomitant medications, and AEs.  
 
  Treatment compliance will also be assessed during the treatment 
portion of the study.  
During screening, subjects will have a bone marrow biopsy and an objective assessment of disease 
status performed by positron emission tomography (PET) using [18F] fluorodeoxyglucose and 
diagnostic quality CT scan or MRI.  Disease status will be subsequently assessed by CT/MRI at 
Week 8, Week 16, and every 16 weeks thereafter until disease progression.  On-treatment bone 
marrow biopsies will be required only if needed to confirm a CR.  PET-CT will be subsequently used 
to confirm CR/PR. 
Subjects withdrawn from study treatment for reasons other than disease progression will be assessed 
per standard of care until disease progression, initiation of new anticancer therapy, or death, whichever 
occurs first. 




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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................16 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Overview of Diffuse Large B-Cell Lymphoma ..........................................................19 
1.1.1. 
Treatment for Advanced DLBCL ...............................................................................20 
1.1.2. 
Treatment for Relapsed/Refractory DLBCL ..............................................................21 
1.2. 
Study Rationale ...........................................................................................................21 
1.2.1. 
Inhibition of Janus Kinase as a Target for Cancer Therapy .......................................21 
1.2.2. 
Inhibition of JAK With INCB039110 ........................................................................23 
1.2.3. 
Inhibition of Bruton's Tyrosine Kinase as a Target for Cancer Therapy ....................24 
1.2.4. 
Combined Inhibition of JAK and BTK in DLBCL ....................................................25 
1.3. 
Potential Risks and Benefits of the Treatment Regimen ............................................26 
1.3.1. 
INCB039110 ...............................................................................................................26 
1.3.2. 
Ibrutinib ......................................................................................................................27 
1.3.2.1. 
Summary of Clinical Safety ........................................................................................27 
1.3.2.2. 
Risks ...........................................................................................................................28 
1.3.2.3. 
Cytopenias ..................................................................................................................28 
1.3.2.4. 
Atrial Fibrillation ........................................................................................................28 
1.3.2.5. 
Second Primary Malignancies ....................................................................................28 
1.3.2.6. 
Tumor Lysis Syndrome ..............................................................................................28 
1.3.2.7. 
Diarrhea ......................................................................................................................29 
1.3.2.8. 
Rash ............................................................................................................................29 
1.3.2.9. 
Interstitial Lung Disease .............................................................................................29 
1.3.3. 
Potential Risks and Benefits for the Combination of INCB039110 and 
Ibrutinib ......................................................................................................................29 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
2.1. 
Study Objectives .........................................................................................................30 
2.1.1. 
Phase 1 ........................................................................................................................30 
2.1.1.1. 
Primary Objective .......................................................................................................30 
2.1.1.2. 
Secondary Objective ...................................................................................................30 
 
30 
2.1.2. 
Phase 2 ........................................................................................................................30 


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2.1.2.1. 
Primary Objective .......................................................................................................30 
2.1.2.2. 
Secondary Objectives .................................................................................................30 
 
30 
2.2. 
Study Endpoints ..........................................................................................................31 
2.2.1. 
Phase 1 ........................................................................................................................31 
2.2.1.1. 
Primary Endpoint ........................................................................................................31 
2.2.1.2. 
Secondary Endpoint ....................................................................................................31 
 
31 
2.2.2. 
Phase 2 ........................................................................................................................31 
2.2.2.1. 
Primary Endpoint ........................................................................................................31 
2.2.2.2. 
Secondary Endpoints ..................................................................................................31 
 
32 
3. 
SUBJECT ELIGIBILITY ...........................................................................................32 
3.1. 
Subject Inclusion Criteria ...........................................................................................32 
3.2. 
Subject Exclusion Criteria ..........................................................................................33 
4. 
INVESTIGATIONAL PLAN .....................................................................................35 
4.1. 
Overall Study Design ..................................................................................................35 
4.1.1. 
Phase 1 ........................................................................................................................35 
4.1.2. 
Phase 2 ........................................................................................................................36 
4.2. 
Measures Taken to Avoid Bias ...................................................................................37 
4.3. 
Number of Subjects ....................................................................................................37 
4.3.1. 
Planned Number of Subjects ......................................................................................37 
4.3.2. 
Replacement of Subjects .............................................................................................37 
4.4. 
Duration of Treatment and Subject Participation .......................................................37 
4.5. 
Overall Study Duration ...............................................................................................37 
4.6. 
Study Termination ......................................................................................................38 
5. 
TREATMENT ............................................................................................................38 
5.1. 
Treatment Assignment ................................................................................................38 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................38 
5.1.2. 
Randomization and Blinding ......................................................................................38 
5.2. 
INCB039110 ...............................................................................................................39 
5.2.1. 
Description and Administration ..................................................................................39 
5.2.2. 
Supply, Packaging, and Labeling ...............................................................................39 


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5.2.3. 
Storage ........................................................................................................................39 
5.2.4. 
Instruction to Subjects for Handling INCB039110 ....................................................39 
5.3. 
Ibrutinib ......................................................................................................................40 
5.3.1. 
Description and Administration ..................................................................................40 
5.3.2. 
Supply, Packaging and Labeling ................................................................................40 
5.3.3. 
Storage ........................................................................................................................40 
5.3.4. 
Instruction to Subjects for Handling Ibrutinib ............................................................41 
5.3.5. 
Overdose .....................................................................................................................41 
5.4. 
Treatment Compliance ................................................................................................41 
5.5. 
Treatment Interruptions and Adjustments ..................................................................42 
5.5.1. 
Dose Modifications .....................................................................................................42 
5.5.1.1. 
Dose Modification of INCB039110 ...........................................................................42 
5.5.1.2. 
Dose Modification for Ibrutinib ..................................................................................43 
5.5.2. 
Dose-Limiting Toxicity and Determination of Recommended Phase 2 Dose ...........44 
5.5.2.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................45 
5.5.2.2. 
Follow-Up of Dose-Limiting Toxicities .....................................................................45 
5.6. 
Withdrawal of Subjects From Study Treatment .........................................................45 
5.6.1. 
Withdrawal Criteria ....................................................................................................45 
5.6.2. 
Withdrawal Procedures ...............................................................................................46 
5.7. 
Concomitant Medications ...........................................................................................46 
5.7.1. 
Restricted Medications ...............................................................................................47 
5.7.2. 
Prohibited Medications and Measures ........................................................................48 
5.8. 
Procedural Restrictions ...............................................................................................48 
5.8.1. 
Minor Surgical Procedures .........................................................................................48 
5.8.2. 
Major Surgical Procedures .........................................................................................48 
5.8.3. 
Emergency Procedures ...............................................................................................48 
6. 
STUDY ASSESSMENTS ..........................................................................................49 
6.1. 
Screening ....................................................................................................................53 
6.2. 
Treatment ....................................................................................................................54 
6.3. 
End of Treatment ........................................................................................................54 
6.4. 
Follow-Up ...................................................................................................................54 
6.4.1. 
Safety Follow-Up ........................................................................................................54 
6.4.2. 
Disease Status Follow-Up ...........................................................................................54 


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6.5. 
Unscheduled Visits .....................................................................................................54 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................55 
7.1. 
Administration of Informed Consent Form ................................................................55 
7.2. 
Interactive Response Technology Procedure ..............................................................55 
7.3. 
Demography and History ............................................................................................55 
7.3.1. 
Demographics, Medical History, Disease History .....................................................55 
7.3.2. 
Prior and Concomitant Medications and Procedures ..................................................55 
7.4. 
Safety Assessments .....................................................................................................55 
7.4.1. 
Adverse Events ...........................................................................................................55 
7.4.2. 
Comprehensive Physical Examination .......................................................................56 
7.4.3. 
Targeted Physical Examination ..................................................................................56 
7.4.4. 
Vital Signs ..................................................................................................................56 
7.4.5. 
Twelve-Lead Electrocardiograms ...............................................................................56 
7.4.6. 
Laboratory Assessments .............................................................................................57 
7.4.6.1. 
Chemistry ....................................................................................................................57 
7.4.6.2. 
Hematology .................................................................................................................57 
7.4.6.3. 
Urinalysis ....................................................................................................................57 
7.4.6.4. 
Pregnancy Testing ......................................................................................................57 
7.4.6.5. 
Serology ......................................................................................................................57 
7.5. 
Efficacy Assessments .................................................................................................58 
7.5.1. 
Computed Tomography Scan or Magnetic Resonance Imaging ................................58 
7.5.2. 
FDG-PET or Combined PET-CT ...............................................................................58 
7.5.3. 
Bone Marrow Examination .........................................................................................58 
7.5.4. 
Response Criteria – the Lugano Classification ...........................................................58 
7.6. 
Performance Status Assessments ................................................................................61 
7.6.1. 
ECOG Performance Status .........................................................................................61 
 
61 
 
61 
 
62 
 
62 
 
62 
 
63 
 
63 
D
D


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63 
 
63 
7.9. 
Other Study Procedures ..............................................................................................63 
7.9.1. 
Distribution of Subject Reminder Cards .....................................................................63 
8. 
SAFETY MONITORING AND REPORTING .........................................................64 
8.1. 
Adverse Events ...........................................................................................................64 
8.1.1. 
Definitions ..................................................................................................................64 
8.1.2. 
Reporting ....................................................................................................................64 
8.2. 
Laboratory Test Abnormalities ...................................................................................66 
8.2.1. 
Definitions and Reporting ...........................................................................................66 
8.3. 
Serious Adverse Events ..............................................................................................66 
8.3.1. 
Definitions ..................................................................................................................66 
8.3.2. 
Reporting ....................................................................................................................67 
8.4. 
Adverse Events of Special Interest .............................................................................68 
8.4.1. 
Major Hemorrhage ......................................................................................................68 
8.5. 
Emergency Unblinding of Treatment Assignment .....................................................68 
8.6. 
Pregnancy ...................................................................................................................68 
8.7. 
Warnings and Precautions ..........................................................................................69 
8.8. 
Data Monitoring Committee .......................................................................................69 
8.9. 
Product Complaints ....................................................................................................69 
9. 
STATISTICS ..............................................................................................................70 
9.1. 
Study Populations .......................................................................................................70 
9.2. 
Selection of Sample Size ............................................................................................70 
9.2.1. 
Sample Size in Safety Run-in Phase ...........................................................................70 
9.2.2. 
Sample Size in Expansion Phase ................................................................................70 
9.3. 
Level of Significance ..................................................................................................71 
9.4. 
Statistical Analyses .....................................................................................................71 
9.4.1. 
Primary Analyses ........................................................................................................71 
9.4.2. 
Secondary Analyses ....................................................................................................71 
 
71 
9.4.4. 
Safety Analyses ..........................................................................................................72 
9.4.4.1. 
Adverse Events ...........................................................................................................72 
9.4.4.2. 
Clinical Laboratory Tests ...........................................................................................72 


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9.4.4.3. 
Vital Signs ..................................................................................................................72 
 
73 
9.5. 
Interim Analysis ..........................................................................................................73 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................74 
10.1. 
Investigator Responsibilities .......................................................................................74 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................75 
10.3. 
Data Management .......................................................................................................76 
10.4. 
Data Privacy and Confidentiality of Study Records ...................................................76 
10.5. 
Financial Disclosure ...................................................................................................77 
10.6. 
Publication Policy .......................................................................................................77 
11. 
REFERENCES ...........................................................................................................78 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................81 
APPENDIX B. CYTOCHROME P450 INHIBITORS AND INDUCERS ................................82 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................87 
 




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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Term 
Explanation 
5PS 
5-point scale 
aaIPI 
age-adjusted International Prognostic Index  
ABC 
activated B-cell 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ASCT 
autologous stem cell transplant 
 
 
BCL 
B-cell lymphoma 
BCR 
B-cell receptor 
BR 
bendamustine and rituximab 
BTK 
Bruton's tyrosine kinase 
CFR 
Code of Federal Regulations 
cHL 
classical Hodgkin lymphoma 
CLL 
chronic lymphocytic leukemia 
CNS 
central nervous system 
CI 
confidence interval 
CR 
complete response 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DFS 
disease-free survival 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EOT 
end of treatment 
FCR 
fludarabine, cyclophosphamide, and rituximab 


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Term 
Explanation 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
GCB 
germinal center B-Cell 
GCP 
Good Clinical Practice 
HBc 
hepatitis B core 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDC 
high-dose chemotherapy 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IL 
interleukin 
ILD 
interstitial lung disease 
IN 
Investigator Notification 
INR 
international normalized ratio 
IPI 
International Prognostic Index 
IRB 
Institutional Review Board 
ITT 
intent to treat 
IVRS 
Interactive Voice Response System 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
LDi 
longest transverse diameter of lesion 
MCL 
mantle cell lymphoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mTOR 
mammalian target of rapamycin 
MYD88 
myeloid differentiation primary response 88 
NCI 
National Cancer Institute 
NF-κB 
nuclear factor kappa light chain enhancer of activated B cells 
NHL 
non-Hodgkin lymphoma 
ORR 
objective response rate 
OS 
overall survival 


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Term 
Explanation 
PET 
positron emission tomography 
 
 
PFS 
progression-free survival 
PI3K 
phosphoinositide 3-kinase 
 
 
PMBL 
primary mediastinal (thymic) large B-cell lymphoma 
PO 
orally 
PP 
per protocol 
PPD 
cross product of the longest transverse diameter of lesion and 
perpendicular diameter 
PR 
partial response 
pSTAT3 
phosphorylated signal transducer and activator of transcription 3 
PT 
prothrombin time 
QD 
once daily 
RA 
rheumatoid arthritis 
R-CHOP 
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SDi 
shortest axis perpendicular to the LDi 
SEER 
Surveillance, Epidemiology, and End Results Program 
SPD 
sum of the product of the perpendicular diameters for multiple lesions 
STAT 
Signal transducer and activator of transcription 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TNF 
tumor necrosis factor 
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
WBC 
white blood cell 


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1. 
INTRODUCTION 
1.1. 
Overview of Diffuse Large B-Cell Lymphoma 
Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy, with over 
385,000 new cases diagnosed in 2012 (Torre et al 2015).  Incidence rates of NHL tend to be 
higher in North America, Western Europe, Northern Europe, and Australia compared with the 
rest of the world; it has been estimated that over 80,000 new cases of NHL and approximately 
20,000 deaths due to NHL will occur in the United States in 2015 (Siegel et al 2015).  Between 
1975 and 2011, the incidence of new cases of NHL in the United States has nearly doubled from 
11 to 20 cases per 100,000 people, but the proportion of deaths has slowly decreased 
(NCI 2015). 
Diffuse large B-cell lymphoma (DLBCL) is a clinically and pathologically heterogeneous group 
of lymphoid malignancies and is the most common subtype of NHL observed in adults.  Diffuse 
large B-cell lymphoma (BCL) accounts for approximately 25% of all NHLs in the developed 
world and up to 58% in some reports.  The incidence is higher in men than women and generally 
increases with age, with the median age at onset generally occurring within the sixth decade 
(Swerdlow et al 2008). 
Clinical presentation, histology, natural history, and prognosis are variable and are determined 
primarily by the site(s) of extranodal disease.  Approximately 60% of all patients have advanced 
disease, with bone marrow involvement reported in up to 30% of cases (Armitage and 
Weisenberger 1998).  The International Prognostic Index (IPI) and the age-adjusted IPI (aaIPI) 
are considered to be the most reliable prognostic benchmarks for all NHL subtypes and DLBCL 
in particular.  More recently, advances in molecular diagnostics have further defined DLBCL 
prognostic factors.  Gene expression profiling suggests the emergence of at least 3 distinct 
subtypes of DLBCL:  germinal center B-cell (GCB) type, activated B-cell (ABC) type, and 
Type 3 (primary mediastinal) DLBCL (Rosenwald et al 2002).  The ABC subtype has been 
associated with a particularly poor prognosis, suggesting that molecular subtyping may be a 
more relevant predictor than IPI.  Prognosis varies across patients with DLBCL; subtype, patient 
characteristics, disease burden, and response to therapy all affect clinical outcome, but all 
subtypes are considered aggressive and fatal if left untreated (Martelli et al 2013).  Survival 
outcomes for patients with GCB versus ABC subtypes are statistically different as shown below 
in Figure 1 and Table 1 (Roschewski et al 2013, Dunleavy et al 2013). 


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Figure 1: 
Using Biologic Predictive Factors to Direct Therapy of DLBCL 
 
Table 1: 
Progression-Free Survival and Overall Survival by DLBCL Subtype 
Molecular Subtype 
Regimen 
3-Year PFS Rate 
3-Year OS Rate 
ABC DLBCL 
R-CHOP 
40% 
Approximately 45% 
GCB DLBCL 
R-CHOP 
74% 
Approximately 80% 
PMBL 
DA-EPOCH-R 
100% 
97% (at 5 years) 
OS = overall survival; PFS = progression-free survival; PMBL = primary mediastinal B-cell lymphoma; 
R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. 
In addition, gene mutations and rearrangements have been associated with poorer prognosis.  
The combined frequency of BCL-6 mutations and rearrangements approaches 100% in DLBCL; 
increased expression of this gene results in downregulation of downstream tumor suppressor 
genes, allowing cells to avoid apoptosis (Phan and Dalla-Favera 2004, Migliazza et al 1995).  
B-cell lymphoma 6 and BCL-2 rearrangements have been reported in 22% of patients with 
Stage II to IV disease.  The presence of BCL-2 rearrangements did not significantly affect OS or 
disease-free survival (DFS); however, high BCL-2 protein expression did adversely affect both 
outcomes.  The p53 gene is responsible for inducing growth inhibition; deletions and mutations 
have been reported in 20% of DLBCL cases and have been associated with a poorer clinical 
prognosis when compared with that of patients with wild-type p53 (Ichikawa et al 1997).  
Overexpression of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), 
c-myc, and Ki-67 has also been associated with poor outcomes (Friedberg 2011). 
1.1.1. 
Treatment for Advanced DLBCL 
First-line treatment for DLBCL is based on the patient's IPI score and age using 3 major 
subgroups:  elderly patients (> 60 years, aaIPI = 0-3); young patients with low risk (< 60 years, 
aaIPI = 0-1); and young patients with high risk (<60 years, aaIPI = 2-3).  Rituximab, an 
anti-CD20 chimeric monoclonal antibody, has emerged as the standard of care for patients with 
DLBCL when administered in combination with cyclophosphamide, doxorubicin, vincristine, 


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and prednisone (R-CHOP) chemotherapy every 14 or 21 days.  Complete response rates of 76% 
to 78% have been reported in elderly patients (> 60 years) and up to 86% in younger (≤ 60 years) 
patients (Coiffier et al 2010, Pfreundschuh et al 2008, Feugier et al 2005, Satterthwaite and Witte 
2000, Sehn et al 2005, Coiffier et al 2002).  It is recommended that after completing systemic 
therapy, select patient subsets should receive additional therapy, patients with bulky disease 
should receive consolidation radiation therapy, and those with high lactate dehydrogenase (LDH) 
and multiple extranodal sites or orbital and testicular involvement should receive prophylactic 
central nervous system (CNS) radiation therapy.  The use of high-dose chemotherapy (HDC) 
supported by autologous stem cell transplant (ASCT) in the first-line setting was evaluated in a 
series of recent randomized studies, but results were not conclusive.  In some cases, HDC/ASCT 
has been recommended for young patients (< 65 years) diagnosed with DLBCL who did not 
achieve a complete response (CR) after first-line chemotherapy or for patients with 
chemosensitive DLBCL at relapse (Martelli et al 2013). 
1.1.2. 
Treatment for Relapsed/Refractory DLBCL 
Although the use of first-line rituximab has been associated with substantial reduction in relapse 
rates, up to 20% of patients with low IPI risk and up to 50% of patients with IPI score > 2 will 
relapse.  Relapsed patients and patients with disease that fails to respond to first-line therapy 
have a poor prognosis (Martelli et al 2013, Cultrera and Dalia 2012).  Patients in this setting are 
generally divided into 2 categories:  those with chemosensitive disease who are potentially 
eligible for HDC/ASCT, and those who are refractory to chemotherapy or are not medically fit 
for an aggressive chemotherapy regimen.  Salvage chemotherapy is generally inadequate; 
response rates range from 30% to 60%, but less than 10% of patients achieve long-term DFS.  
The PARMA study demonstrated the benefit of HDC/ASCT versus standard chemotherapy for 
relapsed or refractory DLBCL; OS and 5-year event-free survival were significantly improved in 
transplanted patients compared with nontransplanted patients (Philip et al 1991).  For patients 
ineligible for ASCT or relapsed after transplant, bendamustine in combination with rituximab 
demonstrated encouraging results; in a multicenter Phase 2 study, an overall response rate of 
59% was observed (Fischer et al 2011).  In addition, a number of novel agents are undergoing 
evaluation for DLBCL, including immunomodulating agents, mammalian target of rapamycin 
(mTOR) inhibitors, proteasome inhibitors, histone deacetylase inhibitors, and antiangiogenic 
agents. 
1.2. 
Study Rationale 
1.2.1. 
Inhibition of Janus Kinase as a Target for Cancer Therapy 
The Janus kinase (JAK) enzymes play an obligatory role in transducing intracellular signals 
generated by cytokine and growth factor receptors.  Upon cytokine and growth factor binding to 
their cognate receptors, tyrosine phosphorylation of the intracellular domains of the receptors by 
JAKs enables them to serve as docking sites for signal transducer and activator of transcription 
(STAT) factors, which are also phosphorylated.  Tyrosine-phosphorylated STATs are released 
from the receptors, form homodimers, and translocate to the nucleus where they bind canonical 
sequences and modulate transcription of genes that regulate a number of cellular functions.  In 
contrast to normal cells, in which STAT tyrosine phosphorylation occurs transiently, STAT 
proteins, especially STAT3, are persistently phosphorylated in most malignancies 


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(Sansone and Bromberg 2012).  The persistent or constitutive phosphorylation of STAT3 in 
cancers may occur via a variety of mechanisms, including increased expression of cytokines and 
cytokine receptors, decreased expression of the negative regulatory proteins such as suppressors 
of cytokine signaling through promoter methylation, and loss of tyrosine phosphatases that 
dephosphorylate JAKs and STATs. 
Neoplastic progression involves JAK/STAT pathway activity through cell autonomous and 
noncell autonomous mechanisms.  Cell autonomous mechanisms refer to tumor cell intrinsic 
alterations that facilitate the gain of neoplastic properties.  The ability of STAT3 to sustain cell 
proliferation and block apoptosis (Lesina et al 2011); mediate cell cycle progression during 
oncogenic stress (Toyonaga et al 2003, Thoennissen et al 2009); control invasiveness, metastasis, 
and angiogenesis; and confer chemotherapeutic resistance (Catlett-Falcone et al 1999) are major 
mechanisms contributing to cancer.  Noncell autonomous mechanisms refer to the extrinsic 
effects mediated by tumor microenvironment, stroma, immune system, and stellate cells 
(Masamune et al 2005); these play an integral role in many cancers and are substantially shaped 
to a great extent by JAK/STAT signaling.  In addition, JAK/STAT-dependent inflammatory 
cytokines such as interleukin (IL)-6 and interferon gamma are critical mediators of cancer 
cachexia, a significant cause for cancer morbidity and mortality.  Based on this evidence, we 
hypothesize that inhibition of JAK kinases may directly affect malignant cell proliferation and 
may suppress the inflammatory state leading to improvements in nutritional status, fatigue, 
tolerance to therapy, and prolonged survival in patients with advanced cancers that are driven by 
these intrinsic and extrinsic pathways influenced by STATs.  This hypothesis is supported by 
evidence that JAK/STAT inhibitors are able to slow tumor cell growth and prolong survival in 
in vivo models (Iwanski et al 2010, Thoennissen et al 2009, Toyonaga et al 2003). 
Aberrant activation of JAKs, through production of cytokines and growth factors, has also been 
associated with increased malignant cell proliferation and survival in a number of tumor types.  
JAKs activate a number of downstream pathways implicated in the proliferation and survival of 
malignant cells including the STATs, a family of important latent transcription factors.  In 
DLBCL, JAK pathway activation occurs through both autocrine and paracrine mechanisms.  In 
the tumor cells, B-cell receptor (BCR) signaling leads to increased IL-6 and IL-10 production 
through activation of the NF-κB pathway (Lam et al 2008).  A subset of DLBCLs has been 
characterized as having high expression of STAT3, IL-6, and/or IL-10, and it has been shown 
that JAK inhibition is cytotoxic in these DLBCL cell lines and synergizes with NF-κB inhibitors.  
In addition to JAK/STAT pathway activation through autocrine pathways, the stromal 
compartment can also provide a source of these cytokines in a paracrine manner (Hodge et al 
2005).  High phosphorylated STAT3 (pSTAT3) levels are associated with poor survival in 
DLBCL with difference more significant in non-GCB than GCB subtype.  Figure 2 shows gene 
expression profiling that identified an 11-gene signature of STAT3 activation in DLBCL.  
Survival differences based on STAT3 gene signature are similar to pSTAT3-based STAT-3 
activation. 


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Figure 2: 
STAT Activation Predicts Poor Prognosis in DLBCL 
 
Of clinical relevance, levels of serum IL-10 and IL-6, which signal through the JAKs, have been 
found to be elevated in patients with DLBCL when compared with normal controls.  Further, 
patients with high serum IL-10 levels were shown to have a shorter event-free survival 
(Gupta et al 2012).  Within the JAK family of kinases, JAK1 has been shown to cooperate with 
JAK2, JAK3, and tyrosine kinase (TYK) 2 and to play a dominant role in mediating the signaling 
of a number of inflammatory cytokines, including IL-6 and IL-10. 
Inhibiting the phosphoinositide 3-kinase (PI3K) or JAK-STAT pathways may also be therapeutic 
in B-cell malignancies due to their contribution to tumor growth and survival and effects on the 
tumor microenvironment.  Blocking both pathways may be synergistic due to JAK-STAT 
augmentation of BCR activation of the NF-κB pathway.  A Phase 1 study recently evaluated 
INCB039110 in combination with INCB040093, a PI3Kδ inhibitor, in 17 subjects with 
relapsed/refractory classical Hodgkin lymphoma (cHL).  In the dose-escalation portion of the 
study, responses were observed in 6 of the 9 evaluable subjects receiving INCB040093 and 
INCB039110.  In an expansion cohort, objective response rate (ORR) in the cHL cohort was 
50% in subjects treated with INCB040093 and 75% (1 CR) in subjects treated with INCB040093 
plus INCB039110 (Forero-Torres et al 2015). 
1.2.2. 
Inhibition of JAK With INCB039110 
INCB039110 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; aberrant production of cytokines and 
growth factors has been associated with a number of cancers.  Activated JAKs then 
phosphorylate tyrosine residues on cytokine receptors and are the principal kinases associated 
with phosphorylation and activation of the STAT.  Aberrant production of cytokines and growth 
factors has been associated with myeloproliferative neoplasms and other chronic inflammatory 
conditions; thus, inhibition of their signaling may represent a therapeutic option.  INCB039110 
potently inhibits JAK1 (IC50 = 3.6 nM at 1 mM adenosine triphosphate concentration), with 
22- to > 500-fold selectivity for the other JAK family members, JAK2, JAK3, and TYK2.  
Moreover, INCB039110 is potent (IC50 values of approximately 10-100 nM) in cytokine-driven 


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cell-based assays, such as IL-2–stimulated phosphorylation of JAKs and STATs, and IL-2–
induced proliferation of primary human T cells.  INCB039110 potently inhibits the 
phosphorylation of STAT proteins and the production of proinflammatory factors (eg, IL-17, 
monocyte chemotactic protein-1) induced by other cytokines, such as IL-23 and IL-6, with IC50 
values in the range of approximately 30 to 100 nM.  Additional preclinical and pharmacological 
details can be found in the Investigator's Brochure (IB). 
1.2.3. 
Inhibition of Bruton's Tyrosine Kinase as a Target for Cancer Therapy 
Ibrutinib (IMBRUVICA®) is a first-in-class, potent, orally administered, covalently binding 
inhibitor of Bruton's tyrosine kinase (BTK). 
Ibrutinib has been approved in many regions, including the United States and Europe, for the 
treatment of patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia 
(CLL) who have received at least 1 prior therapy, first-line treatment of patients with CLL with a 
deletion of the short arm of chromosome 17 (del17p) or a TP53 mutation, and patients with 
Waldenström's macroglobulinemia.  Ibrutinib is currently under investigation in various 
indications as a single agent and in combinations. 
B cells are lymphocytes with multiple functions in the immune response, including antigen 
presentation, antibody production, and cytokine release.  B cells express cell surface 
immunoglobulins comprising the BCR, which is activated by binding to antigen.  Antigen 
binding induces receptor aggregation and the clustering and activation of multiple TYKs, which 
in turn activate further downstream signaling pathways (Bishop et al 2003). 
The process of B-cell maturation, including immunoglobulin chain rearrangement and somatic 
mutation, is tightly regulated.  It is thought that BCLs and CLL result from mutations and 
translocations acquired during normal B-cell development (Shaffer et al 2002).  Several lines of 
evidence suggest that signaling through the BCR is necessary to sustain the viability of B-cell 
malignancies. 
The role of BTK in BCR signal transduction is demonstrated by the human genetic 
immunodeficiency disease X-linked agammaglobulinemia and the mouse genetic disease 
X-linked immunodeficiency, both caused by a mutation in the BTK gene.  These genetic diseases 
are characterized by a reduction in BCR signaling and a failure to generate mature B-cells.  The 
BTK protein is expressed in most hematopoietic cells with the exception of T-cells and natural 
killer cells, but the selective effect of BTK mutations suggests that its primary functional role is 
in antigen receptor signaling in B-cells (Satterthwaite and Witte 2000). 
In a Phase 1/2 study of 80 subjects with relapsed or refractory DLBCL, CRs or partial responses 
(PRs) were reported in 37% (14/38) of subjects with ABC DLBCL treated with ibrutinib, but in 
only 5% (1/20) of subjects with GCB DLBCL.  Subjects whose ABC tumors harbored BCR 
mutations responded to ibrutinib frequently (5/9; 55.5%), especially those with concomitant 
myeloid differentiation primary response 88 (MYD88) mutations (4/5; 80%).  This is consistent 
with the hypothesis of in vitro cooperation between the BCR and MYD88 pathways.  Responses 
also occurred in subjects whose ABC tumors lacked BCR mutations (9/29; 31%), suggesting that 
oncogenic BCR signaling in ABC does not require BCR mutations and might be initiated by 
other mechanisms (Wilson et al 2015). 


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For the most comprehensive nonclinical and clinical information regarding ibrutinib background, 
safety, efficacy, and in vitro and in vivo preclinical activity and toxicology of ibrutinib, refer to 
the latest version of the ibrutinib IB. 
1.2.4. 
Combined Inhibition of JAK and BTK in DLBCL 
A number of B-cell malignancies, including DLBCL, have been shown to be particularly 
dependent upon BCR survival signals as evidenced by their sensitivity to genetic and 
pharmacological inhibition of BCR signaling components in vitro.  In DLBCL, JAK pathway 
activation also occurs through both autocrine and paracrine mechanisms.  In the tumor cells, 
BCR signaling leads to increased IL-6 and IL-10 production through activation of the NF-κB 
pathway (Lam et al 2008).  A subset of DLBCLs has been characterized as having high 
expression of STAT3, IL-6, and/or IL-10 and it has been shown that JAK inhibition is cytotoxic 
in these DLBCL cell lines and synergizes with NF-kB inhibitors.  In addition to JAK/STAT 
pathway activation through autocrine pathways, the stromal compartment can also provide a 
source of these cytokines in a paracrine manner (Hodge et al 2005).  Within the JAK family of 
kinases, JAK1 has been shown to cooperate with JAK2, JAK3, and TYK2 and to play a 
dominant role in mediating the signaling of a number of inflammatory cytokines, including IL-6 
and IL-10. 
Preclinical data demonstrate that the presence of IL-10, a cytokine shown to be elevated in 
DLBCL patients and correlated with decreased survival, reduces the potency of the BTK 
inhibitor, ibrutinib, to block cell growth.  The addition of a JAK1 inhibitor, although it has no 
inhibitory effect as a single agent, reverses this effect.  The combination of both inhibitors 
demonstrates marked synergy in blocking cell growth and inducing apoptosis by inhibiting 
multiple signaling pathways (Figure 3).  Together, these data suggest that both the JAK/STAT 
and BTK pathways may contribute to driving tumor growth and survival in DLBCL, and 
combination therapies that block both pathways may prove more beneficial in these diseases due 
to the central role that JAK-mediated cytokine signaling plays in augmenting BCR-mediated 
activation of the NF-κB pathway. 
Figure 3: 
Inhibition of JAK Synergizes With B-Cell Receptor Signaling Inhibition in 
DLBCL In Vitro 
 


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According to the Phase 1/2 study results for ibrutinib in DLBCL (Section 1.2.3), ABC subtype 
appears to be more driven by BCR signaling, and ibrutinib has demonstrated enhanced efficacy 
in this subtype.  The primary objective for Phase 1 of this study is to determine the safety and 
tolerability of the combination, INCB039110 and ibrutinib; thus, DLBCL subjects of all subtypes 
may be included in this part of the study.  However, in Phase 2 of the study, efficacy is the 
primary endpoint, and the selection of the sample size and response rate for continuation of the 
study into Stage 2 for the Simon 2-stage design are based on the objective response rate in 
DLBCL ABC subtype subjects treated in the above Phase 1/2 ibrutinib study.  
1.3. 
Potential Risks and Benefits of the Treatment Regimen  
1.3.1. 
INCB039110 
As of 13 DEC 2016, 9 Phase 1, 4 Phase 1/2, and 5 Phase 2 clinical studies with INCB039110, 
including studies of INCB039110 in combination with chemotherapeutic agents, corticosteroids, 
pembrolizumab (anti– programmed cell death 1 monoclonal antibody), and investigational 
PI3Kδ (INCB040093 and INCB050465) and indoleamine 2,3-dioxygenase 1 (epacadostat) 
inhibitors, have either been completed or are ongoing.  A total of 777 subjects were enrolled in 
these studies and received at least 1 dose of INCB039110.  In completed clinical pharmacology 
studies, INCB039110 has been administered to 197 healthy adult subjects as a single dose, repeat 
single doses, or multiple doses for up to 10 days. 
In the ongoing and completed clinical pharmacology studies, INCB039110 was generally safe 
and well tolerated in healthy subjects, with few discontinuations.  The majority of 
treatment-emergent adverse events (TEAEs) were mild in severity.  There have been no 
clinically significant, unanticipated safety findings or trends observed.  The main drug effect 
identified was a rapidly reversible dose related decrease in neutrophil counts presumably caused 
by neutrophil margination; neutrophil decreases generally resolved within 24 to 48 hours of dose 
discontinuation.  Other reversible hematologic abnormalities, including decreased reticulocyte 
count, were observed after multiple-dose administration of higher dose levels at which JAK2 
inhibition was noted. 
Adverse events (AEs) that have been reported by more than 5% of healthy subjects in an 
individual study receiving INCB039110 included fatigue, headache, neutropenia, nausea, contact 
dermatitis, ecchymosis, reticulocyte count decreased, excoriation, and nasal congestion.  Adverse 
events reported by more than 10% of subjects receiving INCB039110 in the psoriasis study 
included nasopharyngitis.  Adverse events reported by more than 10% of subjects in the MF 
study included fatigue, thrombocytopenia, nausea, diarrhea, upper respiratory tract infection, 
constipation, cough, dyspnea, peripheral edema, pyrexia, dizziness, abdominal pain, night 
sweats, pain in extremity, arthralgia, contusion, headache, pruritus, vomiting, and increased 
bilirubin/hyperbilirubinemia.  In the RA study, there were no TEAEs reported by more than 
10% of subjects.  
Events reported in ≥ 5 subjects in any study in which INCB039110 was given in conjunction 
with chemotherapy were as follows:  anemia, fatigue, thrombocytopenia, nausea, pyrexia, 
neutropenia, diarrhea, dysgeusia, peripheral edema, headache, alopecia, cough, dyspnea, 
constipation, decreased appetite, epistaxis, vomiting, and hypoalbuminemia.  


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In lymphoid malignancies where INCB039110 was given in combination with INCB040093, a 
PI3Kδ inhibitor (N = 71), TEAEs observed in ≥ 10% of subjects included nausea, cough, 
diarrhea, pyrexia, thrombocytopenia/platelet count decreased, vomiting, fatigue, 
neutropenia/neutrophil count decreased, chills, night sweats, aspartate aminotransferase 
increased, constipation, decreased appetite, headache, back pain, dyspnea, oropharyngeal pain, 
rash, alanine aminotransferase (ALT) increased, abdominal pain, anemia, asthenia, blood 
cholesterol increased, leukocytosis, upper respiratory tract infection, peripheral edema, dizziness, 
and pain in extremity.  Serious AEs reported in more than 1 subject included Pneumocystis 
jirovecii pneumonia (5 subjects), pyrexia (5 subjects), pneumonia (3 subjects), urinary tract 
infection (3 subjects), cardiac arrest (2 subjects), and respiratory failure (2 subjects). 
Because of the potential for myelosuppression, subjects will have hematologic parameters 
closely monitored during clinical studies.  If there are clinically relevant declines in hematology 
parameters, therapy may be interrupted until resolution or discontinuation.  As INCB039110 also 
has the potential to cause white blood cell (WBC) margination (ie, a transient decrease in 
absolute neutrophil count [ANC]), assessment of hematology parameters should be performed 
before study drug administration at all applicable study visits. 
Results from each of these studies are summarized in the INCB039110 IB. 
1.3.2. 
Ibrutinib 
1.3.2.1. 
Summary of Clinical Safety 
Pooled safety data for a total of 423 subjects treated with various therapies in combination with 
ibrutinib from 4 studies conducted in B-cell malignancies, which included 1 randomized control 
study, are summarized in Table 2.  Therapies used in combination with ibrutinib in these studies, 
included BR (bendamustine and rituximab), FCR (fludarabine, cyclophosphamide, and 
rituximab), ofatumumab, and R-CHOP. 
Table 2: 
Most Frequently Reported TEAEs in Subjects Receiving Ibrutinib in 
Combination Therapy (N = 423) 
Most Frequently Reported 
TEAEs > 10% 
Most Frequently Reported 
Grade 3 or 4 TEAEs > 2% 
Most Frequently Reported 
Serious TEAEs > 1% 
Neutropenia 
Neutropenia 
Febrile neutropenia 
Diarrhea 
Thrombocytopenia 
Pneumonia 
Nausea 
Febrile neutropenia 
Atrial fibrillation 
Thrombocytopenia 
Pneumonia 
Pyrexia 
Fatigue 
Hypertension 
 
For more detailed information, refer to the current version of the ibrutinib IB. 


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1.3.2.2. 
Risks 
1.3.2.2.1. Bleeding-Related Events 
There have been reports of hemorrhagic events in subjects treated with ibrutinib, both with and 
without thrombocytopenia.  These include minor hemorrhagic events, such as contusion, 
epistaxis, and petechiae, and major hemorrhagic events, some fatal, including gastrointestinal 
bleeding, intracranial hemorrhage, and hematuria.  Use of ibrutinib in subjects requiring other 
anticoagulants or medications that inhibit platelet function may increase the risk of bleeding.  
Subjects with congenital bleeding diathesis have not been studied.  See Section 5.7 for guidance 
on concomitant use of anticoagulants, antiplatelet therapy, and/or supplements.  See Section 5.8  
for guidance on ibrutinib management with surgeries or procedures. 
1.3.2.2.2. Infections 
Fatal and nonfatal infections have occurred with ibrutinib therapy.  At least 25% of subjects with 
MCL and 35% of subjects with CLL had Grade 3 or greater infections per NCI CTCAE v4.03 
(NCI 2010).  The most commonly reported infections include pneumonia, cellulitis, urinary tract 
infection, and sepsis.  Although causality has not been established, cases of progressive 
multifocal leukoencephalopathy have occurred in patients treated with ibrutinib. 
1.3.2.3. 
Cytopenias 
Treatment-emergent Grade 3 or 4 cytopenias (neutropenia, thrombocytopenia, and anemia) were 
reported in subjects treated with ibrutinib. 
1.3.2.4. 
Atrial Fibrillation  
Atrial fibrillation and atrial flutter have been reported in subjects treated with ibrutinib, 
particularly in subjects with cardiac risk factors, acute infections, and a previous history of atrial 
fibrillation.  For atrial fibrillation that persists, the risks and benefits of ibrutinib treatment should 
be considered, and the Protocol dose modification guidelines should be followed (see 
Section 5.5.1.2). 
1.3.2.5. 
Second Primary Malignancies 
Second primary malignancies, most frequently skin cancers, have occurred in subjects treated 
with ibrutinib.  Second primary malignancies, including nonskin carcinomas (SCC and BCC), 
have occurred in patients treated with ibrutinib.  The most frequent second primary malignancy 
was non-melanoma skin cancer. 
1.3.2.6. 
Tumor Lysis Syndrome 
There have been reports of tumor lysis syndrome events in subjects treated with single-agent 
ibrutinib or in combination with chemotherapy.  Subjects at risk of tumor lysis syndrome are 
those with comorbidities and/or risk factors, such as high tumor burden before treatment, 
increased uric acid (hyperuricemia), elevated LDH, bulky disease at baseline, and pre‐existing 
kidney abnormalities. 










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e. Aspartate aminotransferase (AST) and ALT ≤ 2.5 × institutional upper limit of 
normal (ULN) or ≤ 5 × ULN for subjects with known hepatic metastases. 
f. Total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of 
liver metastases or presence of documented Gilbert's syndrome (unconjugated 
hyperbilirubinemia).  Further evaluation should be performed to confirm and 
document the origin of increase. 
9. Prothrombin time (PT)/international normalized ratio (INR) < 1.5 × ULN and activated 
partial thromboplastin time (aPTT) < 1.5 × ULN. 
10. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and before the first dose on Day 1 and who agrees to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
up to 3 months after ending treatment.  Permitted methods that are at least 99% 
effective in preventing pregnancy (see Appendix A) should be communicated to the 
subject and their understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through up to 3 months after ending treatment.  
Permitted methods that are at least 99% effective in preventing pregnancy (see 
Appendix A) should be communicated to the subject and their understanding 
confirmed. 
11. Ability to comprehend and willingness to sign an informed consent form (ICF). 
3.2. 
Subject Exclusion Criteria 
If met, any of the following criteria will lead to subject exclusion from the study: 
1. Transformed DLBCL or DLBCL with coexistent histologies (eg, follicular or 
mucosa-associated lymphoid tissue lymphoma). 
2. PMBL. 
3. Known CNS lymphoma (either primary or metastatic). 
4. Autologous stem cell transplant within the previous 3 months, allogeneic stem cell 
transplant within the previous 6 months, or active graft versus host disease following 
allogeneic transplant. 
5. Use of immunosuppressive therapy within 28 days of starting study treatment.  
Immunosuppressive therapy includes, but is not limited to, cyclosporine A, tacrolimus, or 
high-dose corticosteroids.  Subjects receiving corticosteroids must be at a dose level 
≤ 10 mg/day within 7 days of initiating study treatment. 
6. Prior or concurrent therapy with a JAK inhibitor or BTK inhibitor. 


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7. Receipt of anticancer medications or investigational drugs within the following intervals 
before starting study treatment (unless otherwise approved by the sponsor): 
a. < 6 weeks for mitomycin-C or nitrosoureas. 
b. < 28 days for any investigational agent for any indication. 
c. < 21 days or 5 half-lives (whichever is greater) for all other cytotoxic anticancer 
medications. 
d. < 4 weeks for monoclonal antibodies used as anticancer treatment. 
e. < 10 weeks or 5 half-lives from completion of any radio- or toxin-immunoconjugates. 
8. Major surgery 28 days before starting study treatment. 
9. Prior treatment-related toxicities that have not resolved to ≤ Grade 1, with the exception 
of Grade ≤ 2 neuropathy and any grade of alopecia. 
10. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or 
antiviral treatment. 
11. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction, and/or cardiac conduction issues within 6 months of Day 1; New York Heart 
Association Class II to IV congestive heart failure; or uncontrolled arrhythmia. 
12. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia. 
13. History of stroke or intracranial hemorrhage within 6 months before study entry. 
14. Significant concurrent, uncontrolled medical condition including, but not limited to, 
renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, 
cerebral, or psychiatric disease. 
15. Current or previous other malignancy within 3 years of study entry or not cured with 
treatment, except cured basal or squamous cell skin cancer, superficial bladder cancer, 
prostate intraepithelial neoplasm, carcinoma in situ, or other noninvasive or indolent 
malignancy without sponsor approval. 
16. Subjects who are currently receiving therapy with a strong CYP3A4 inducer or inhibitor. 
17. Subjects who are currently receiving therapy with warfarin or vitamin K antagonists, 
such as coumarin-based anticoagulants (eg, fluindione and phenindione). 
18. Unable to swallow oral medication, malabsorption syndrome, disease significantly 
affecting gastrointestinal function, resection of the stomach or small bowel, ulcerative 
colitis, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction. 
19. Known human immunodeficiency virus infection. 
20. Known hepatitis B virus (HBV) or hepatitis C virus (HCV) or at risk for HBV 
reactivation.  Hepatitis B virus DNA and HCV RNA must be undetectable.  At risk for 
HBV reactivation is defined as hepatitis B surface antigen (HBsAg) positive or 
anti-hepatitis B core (HBc) antibody positive. 
21. Unwilling to be transfused with blood components. 


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22. Pregnant or breastfeeding women or subjects unwilling to take appropriate measures to 
avoid pregnancy. 
23. Any condition that would jeopardize the safety of the subject or compliance with the 
Protocol. 
24. Previous reaction to any component of or INCB039110 or ibrutinib, or known 
hypersensitivity to either active substance or any of their excipients. 
25. Prior radiotherapy within 2 weeks before starting study treatment.  A 1-week washout 
period is permitted for palliative radiation to non–central nervous system (CNS) disease 
with medical monitor approval. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, single-group, Phase 1/2 study of INCB039110 in combination with 
ibrutinib in subjects with relapsed or refractory DLBCL.  Phase 1 will evaluate the safety and 
tolerability of INCB039110 when combined with  ibrutinib in subjects with DLBCL (ABC, 
GCB, or unclassifiable) using a 6 + 3 design; Phase 2 will evaluate the efficacy of the 
combination in subjects with ABC or unclassifiable DLBCL at the dose determined in Phase 1 
using a Simon 2-stage expansion design.  Subjects may continue to receive study treatment until 
evidence of disease progression, unacceptable toxicity, or consent withdrawal. 
4.1.1. 
Phase 1 
The starting dose of INCB039110 will be 300 mg once daily (QD).  Depending on tolerability, 
the dose of INCB039110 in combination with ibrutinib (560 mg QD) could be increased to 
400 mg QD (Cohort 2) or decreased to 200 mg QD (Cohort -1).  The dose selected for study in 
Phase 2 will be the dose tolerated by at least two-thirds of subjects who did not require a dose 
reduction within the first 28 days of treatment.  In order to be included in the tolerability review, 
a subject must have received the cohort-specific dose of INCB039110 and ibrutinib for at least 
75% of the days during the 28-day DLT surveillance period or have experienced a DLT.  
Additional subjects may be enrolled to achieve a minimum cohort size of 6 should withdrawal or 
dose interruptions/reductions result in a subject being nonevaluable. 
Dose cohorts are outlined in Table 3, and the design is depicted in Figure 4. 


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Table 3: 
Phase 1 Dose Cohorts 
Cohort 
Number 
Regimen 
Subjects 
With 
DLT 
Action 
-1 
6 
INCB039110 200 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Begin expansion portion of the study 
2 
Enroll 3 additional subjects (9 subjects total) 
≥ 3 
Terminate study 
 
1 
(Starting 
dose) 
6 
INCB039110 300 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Escalate to Cohort 2 
2 
Enroll 3 additional subjects (9 subjects total); 
if no new DLTs, escalate to Cohort 2 
≥ 3 
Reduce to Cohort -1 
 
2 
6 
INCB039110 400 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Begin Phase 2 study 
2 
Enroll 3 additional subjects (9 subjects total); 
 if no new DLTs, begin Phase 2 study 
≥ 3 
Begin Phase 2 study using Cohort 1 dose  
Figure 4: 
Phase 1 Design Schema 
 
4.1.2. 
Phase 2 
Subjects with ABC or unclassifiable DLBCL will receive the recommended Phase 2 dose 
(RP2D) of INCB039110 in combination with ibrutinib as determined in Phase 1.  Phase 2 will 
use a Simon 2-stage design with a stopping rule to allow early termination of the study at the end 
of Stage 1 if there is lack of sufficient efficacy.  During Stage 1, if 9 or fewer of the first 
22 evaluable subjects achieve an objective response (defined as a CR or PR), then the study may 
be terminated.  If 10 or more subjects achieve an objective response, then the study will continue 
and accrue 38 additional subjects to Stage 2.  Subjects who were enrolled but did not receive 
treatment will be excluded from the efficacy analysis and replaced.  A timely assessment of 
response will be made to avoid risk of overenrollment before accrual to Stage 2.  At the end of 
Stage 2, ORR will be assessed for sufficient efficacy to warrant further study.  The study will be 
considered successful if the total number of objective responders is 29 or more.  The design is 
depicted in Figure 5. 


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Figure 5: 
Phase 2 Design Schema 
 
4.2. 
Measures Taken to Avoid Bias 
Measurements of safety and efficacy will be objectively assessed using NCI CTCAE v4.03 
(NCI 2010) and Lugano Classification (Cheson et al 2014), respectively. 
4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Up to 18 subjects will be enrolled in Phase 1, and approximately 60 subjects will be enrolled in 
Phase 2 (22 in Stage 1 and 38 in Stage 2). 
4.3.2. 
Replacement of Subjects 
Additional subjects may be enrolled in Phase 1 to achieve a minimum cohort size of 6 should 
withdrawal or dose interruptions/reductions result in a subject being nonevaluable. 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Each subject enrolled in the study may continue to receive study treatment until treatment 
discontinuation criteria are met.  If the subject discontinues all study treatment (INCB039110 
and ibrutinib), then the treatment period will end, and the subject will enter the follow-up period 
(see Section 6.4).  Study participation is expected to average approximately 6 months per 
individual subject. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of Phase 1 will occur when all 
subjects have completed the DLT surveillance period; Phase 2 will end once the last subject is 
assessed for response. 
Once the last subject is evaluable for response, a database lock of the study will occur to allow 
the analysis of the study data.  Any remaining subjects may continue to receive study treatment 
and be seen by the investigator per usual standard of care for this population.  Provisions will be 
made to ensure access to treatment for subjects who are continuing to benefit from study 
treatment at the time of study termination. 


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The investigator will be expected to monitor for and report any SAEs, AEs of special interest, 
and pregnancies, as detailed in Section 8.  The remaining subjects are considered to be on study 
until a discontinuation criterion is met and written notification is provided to the sponsor. 
The study will end once all subjects have discontinued study treatment and safety follow-up. 
4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the institutional review board 
(IRB)/independent ethics committee (IEC) in writing of the study's completion or early 
termination, send a copy of the notification to the sponsor or sponsor's designee, and retain 
1 copy for the site study regulatory file. 
The sponsor may terminate the study electively due to ethical concerns, insufficient subject 
recruitment, alterations in accepted clinical practice, emerging data, or if required by regulatory 
decision.  If the study is terminated prematurely, then the sponsor will notify the investigators, 
the IRBs and IECs, and regulatory bodies of the decision and reason for termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Study sites will enter subject demographic and baseline data into the interactive voice response 
system (IVRS) in order to receive a subject number and treatment allocation. 
All subject numbers will be 6 digits; the first 3 digits will be the site number, and the last 3 digits 
will be the subject's number.  This subject number will be maintained throughout the study and 
will not be reassigned.  Subjects who withdraw consent or discontinue from the study after being 
assigned a subject number will retain their initial number. 
Site staff will contact the IVRS to allocate the subject to treatment assignment and obtain the 
initial study drug assignment.  The investigator or designee will select the assigned bottles of 
study drug from their stock that correspond to the number provided by the IVRS and dispense 
the study drug to the subject.  All subsequent dispensing of study drug should follow this 
process.  Refer to the IVRS manual for detailed information. 
If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IVRS, 
then the IVRS help desk must be notified immediately.  The reason for the misallocation of the 
study drug must be documented by the study site and reported to the IRB/IEC. 
For subjects who signed an ICF but are not allocated study drug and for subjects who are 
allocated study drug but were not treated, refer to the electronic case report form (eCRF) 
Completion Guidelines for instruction on which eCRFs to complete. 
5.1.2. 
Randomization and Blinding 
Not applicable. 






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5.3.4. 
Instruction to Subjects for Handling Ibrutinib 
The subject must be instructed in the handling of ibrutinib as follows: 
• Store the study medication in accordance with the manufacturer's storage conditions. 
• Remove only the number of tablets from the study drug bottle needed at the time of 
administration. 
• Do not remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses. 
• Take study medication with a glass of water. 
• Do not open capsules nor dissolve them in water. 
• Do not take another dose if vomiting occurs after taking study medication. 
• If a dose of ibrutinib is not taken at the scheduled time, it should be taken as soon as 
possible on the same day with a return to the normal schedule the following day.   
• The subject should not take extra capsules to make up the missed dose. 
 
 
• Keep study drug in a safe place and out of reach of children. 
• Bring all used and unused ibrutinib kits to the site at each visit. 
5.3.5. 
Overdose 
Any dose of ibrutinib in excess of that specified in this Protocol is considered to be an overdose.  
Signs and symptoms of an overdose that meet any SAE criterion must be reported as a SAE in 
the appropriate timeframe and documented as clinical sequelae to an overdose.  There is no 
specific experience in the management of ibrutinib overdose in patients.  No maximum tolerated 
dose was reached in the Phase 1 study in which subjects received up to 12.5 mg/kg per day 
(1400 mg/day).  Healthy subjects were exposed up to a single dose of 1680 mg.  One healthy 
subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 
1680 mg.  Subjects who ingested more than the recommended dosage should be closely 
monitored and given appropriate supportive treatment. 
5.4. 
Treatment Compliance 
Compliance with all study-related treatments should be emphasized to the subject by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with INCB039110 and ibrutinib will be calculated by the sponsor based on the drug 
accountability documented by the site staff and monitored by the sponsor/designee (tablet 
counts).  Subjects will be instructed to bring all study drugs with them to the study visits in order 
for site personnel to conduct tablet counts to assess study drug accountability.  The drug 
accountability documentation will be used by the sponsor to calculate treatment compliance. 
P






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until resolved to moderate impairment (Child-Pugh Class B) or better and could be re-treated 
according to resolved hepatic conditions (ie, 140 mg or 280 mg for moderate or mild 
impairment, respectively).  Subjects should be monitored for signs of toxicity and follow dose 
modification guidance as needed. 
If the dose of ibrutinib is reduced, at the investigator's discretion, the dose of ibrutinib may be 
re-escalated after 56 days of a dose reduction in the absence of a recurrence of the toxicity that 
led to the reduction.  Dose changes must be recorded in the appropriate eCRF. 
Table 6: 
Dose Modifications for Ibrutinib 
Toxicity 
Occurrence 
Action to be Taken 
First 
Withhold study drug until recovery to Grade ≤ 1 or baseline; may restart at 
original dose level. 
Second 
Withhold study drug until recovery to Grade ≤ 1 or baseline; may restart at 
1 dose level lower (ie, 280 mg/day for 420 mg/day dose; 420 mg/day for 
560 mg/day dose). 
Third 
Withhold study drug until recovery to Grade ≤ 1 or baseline; may restart at 
1 dose level lower (ie, 140 mg/day for 420 mg/day dose; 280 mg/day for 
560 mg/day dose). 
Fourth 
Discontinue study drug. 
5.5.2. 
Dose-Limiting Toxicity and Determination of Recommended Phase 2 Dose 
A DLT will be defined as the occurrence of any toxicities in Table 7 occurring up to and 
including Study Day 28, except those with a clear alternative explanation (eg, disease 
progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically 
significant signs or symptoms based on investigator determination.  All DLTs will be assessed 
by the investigator using CTCAE v4.03 criteria (NCI 2010).  In order to be included in the 
tolerability review, subjects must have received the cohort-specific dose of INCB039110 and 
ibrutinib for at least 75% of the days during the 28-day surveillance period or have experienced a 
DLT.  Additional subjects may be enrolled to achieve a minimum cohort size should withdrawal 
or dose interruptions/reductions result in subjects being nonevaluable. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the RP2D, decisions will be made based on events that 
are observed from the first day of study drug administration through and including Day 28.  A 
lower RP2D may subsequently be determined based on relevant toxicities that become evident 
after Day 28. 




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• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The subject becomes pregnant. 
• Consent is withdrawn. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority or IRB or IEC. 
A subject may be withdrawn from study treatment in the following situations: 
• If a subject is found not to have met eligibility criteria, then the medical monitor and 
investigator will collaborate to determine whether the subject should be withdrawn 
from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
opinion of the investigator, then the sponsor should be consulted for instruction on 
handling the subject. 
5.6.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue study treatment, the subject 
will be withdrawn from the study, and the end-of-treatment (EOT) visit should be conducted.  
Reasonable efforts should be made to have the subject return for a follow-up visit as described in 
Section 6. 
Subjects who discontinue study treatment for reasons other than disease progression will be 
assessed per standard of care until disease progression, initiation of new anticancer treatment, or 
death, whichever occurs first. 
If a subject is withdrawn from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longer. 
5.7. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 30 days before enrollment will be recorded in the eCRF.  Concomitant 
treatments and/or procedures that are required to manage a subject's medical condition during the 
study will also be recorded in the eCRF. 
Supportive medications in accordance with standard practice (such as for emesis, diarrhea, etc.) 
are permitted.  Use of neutrophil growth factors (filgrastim and pegfilgrastim) or red blood cell 
growth factors (erythropoietin) is permitted per institutional policy and in accordance with the 


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American Society of Clinical Oncology guidelines (Smith et al 2015).  Transfusions may be 
given in accordance with institutional policy. 
Short courses (≤ 14 days) of steroid treatment for non–cancer related medical reasons (eg, joint 
inflammation, asthma exacerbation, rash, antiemetic use, infusion reactions) at doses that do not 
exceed prednisone 20 mg per day or equivalent are permitted. 
Localized hormonal or bone-sparing treatment for non–B-cell malignancies and localized 
radiotherapy for medical conditions other than the underlying B-cell malignancies may be 
considered if necessary.  Palliative (ie, nontherapeutic) radiotherapy for control of 
DLBCL-related symptoms is allowed. 
5.7.1. 
Restricted Medications 
The following medications have restrictions on use during the treatment phase of the study: 
• Aspirin in doses exceeding 81 mg/day is not permitted.  Low-dose aspirin 
(≤ 81 mg/day) is permitted.  Acetaminophen and nonsteroidal anti-inflammatory 
drugs (NSAIDs; eg, ibuprofen) are permitted. 
• Co-administration with strong CYP3A4 inhibitors; alternative agents with less 
CYP3A inhibition should be considered (Appendix B).  Differences in individual 
sensitivity and variation CYP enzyme inhibition may result in the need for dose 
reduction of INCB039110 and/or ibrutinib.  The sponsor medical monitor may be 
consulted for advice when using these agents. 
• Co-administration with CYP3A4 moderate/weak inducers (Appendix B). 
• If concomitant administration of an anticoagulant/antiplatelet medication is indicated, 
then caution and enhanced monitoring is required.  History of thrombocytopenia and 
any concurrent INCB039110-related thrombocytopenia should be a factor in the 
choice of anticoagulant and dose. 
• Systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per 
day are not permitted from the screening visit through the follow-up visit, except with 
medical monitor approval. 
• Any medications known to cause QT prolongation should be used with caution; 
periodic electrocardiogram (ECG) and electrolyte monitoring should be considered. 
• Supplements such as fish oil and vitamin E preparations should be avoided.  Ibrutinib 
should be used with caution in subjects requiring other anticoagulants or medications 
that inhibit platelet function. 


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• For subjects requiring the initiation of therapeutic anticoagulation therapy (eg, atrial 
fibrillation), the risks and benefits of continuing ibrutinib treatment should be 
considered.  If therapeutic anticoagulation is clinically indicated, then treatment with 
ibrutinib should be withheld and not restarted until the subject is clinically stable and 
has no signs of bleeding.  Subjects should be observed closely for signs and 
symptoms of bleeding.  No dose reduction is required when study drug is restarted.  
Warfarin or vitamin K antagonists should not be administered concomitantly with 
ibrutinib. 
5.7.2. 
Prohibited Medications and Measures 
The following medications are prohibited during the treatment: 
• Any concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, or tumor embolization) other 
than those specified in the Protocol. 
• Any investigational medication before withdrawing from the study. 
• Corticosteroids for the treatment of the underlying malignancy. 
• Potent inducers of CYP3A4. 
• Warfarin or vitamin K antagonists. 
5.8. 
Procedural Restrictions 
5.8.1. 
Minor Surgical Procedures 
For minor procedures (eg, a central line placement, needle biopsy, thoracentesis, paracentesis), 
ibrutinib should be withheld for at least 3 days before the procedure and should not be restarted 
for at least 3 days after the procedure.  For bone marrow biopsies that are performed while the 
subject is receiving ibrutinib, it is not necessary to withhold ibrutinib for these procedures. 
5.8.2. 
Major Surgical Procedures 
For any surgery or invasive procedure requiring sutures or staples for closure, ibrutinib should be 
withheld at least 7 days before the intervention until at least 7 days after the procedure.  Ibrutinib 
should be restarted at the discretion of the investigator when the surgical site is reasonably 
healed without serosanguineous drainage or the need for drainage tubes. 
5.8.3. 
Emergency Procedures 
For emergency procedures, ibrutinib should be withheld after the procedure until the surgical site 
is reasonably healed or for at least 7 days after the urgent surgical procedure, whichever is 
longer. 


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6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments in Table 8; 
the order of assessments is suggested by the order of mention within the schedule.  Laboratory 
assessments are shown in Table 9. 


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Table 8: 
Schedule of Assessments 
Procedure 
Section 
Screening 
Treatment 
EOT 
Follow-Up 
Comments 
Day 
-28 to -1 
Day 1 
Day 8 
(± 3 days) 
Day 15 
(± 3 days) 
Day 28/Q28D 
(± 3 days) 
EOT + 
30-35 Days 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
Contact IVRS 
7.2 
X 
X 
 
 
X 
X 
 
 
Inclusion and 
exclusion criteria 
3.1 
3.2 
X 
X 
 
 
 
 
 
 
Demography and 
medical history 
7.3.1 
X 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.3.2 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam/ 
weight/height 
7.4.2 
7.4.3 
X* 
X 
X 
X 
X 
X 
X 
*Comprehensive exam at screening; 
targeted physical exam thereafter.  
Height required at screening only. 
Vital signs 
7.4.4 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
7.4.5 
X* 
X* 
X** 
 
 
 
 
*Triplicate ECGs will be performed 
during screening and on Day 1 before 
starting study treatment. 
**Triplicate ECGs will be performed 
predose and 2 hours (± 15 minutes) after 
receiving INCB039110 on Day 8. 
Additional ECGs may be performed as 
clinically indicated. 
ECOG status 
7.6.1 
X 
X 
 
 
X 
X 
X 
 
AE assessment 
7.4.1 
X 
X 
X 
X 
X 
X 
X 
 
CT or MRI 
7.5.1 
X 
 
 
 
X* 
X 
 
*Week 8, Week 16, and then every 
16 weeks ± 1 week.  Also required to 
confirm CR. 
FDG-PET scan/PET-
CT 
7.5.2 
X 
 
 
 
X* 
 
 
*Required at baseline and to confirm 
CR or if clinically indicated. 


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Table 8: 
Schedule of Assessments (Continued) 
Procedure 
Section 
Screening 
Treatment 
EOT 
Follow-Up 
Comments 
Day 
-28 to -1 
Day 1 
Day 8 
(± 3 days) 
Day 15 
(± 3 days) 
Day 28/Q28D 
(± 3 days) 
EOT + 
30-35 Days 
Bone marrow exam 
7.5.3 
X* 
 
 
 
 
 
 
*Required as a screening assessment 
unless performed as per standard of care 
within 60 days of Day 1.  Repeat to 
confirm CR or if clinically indicated. 
Dispense study drug 
5.1 
 
X 
 
 
X 
 
 
 
Study drug 
accountability 
5.4 
 
X 
X 
X 
X 
X 
 
 
INCB039110 
administration 
5.2.1 
 
X* 
X* 
X* 
X* 
 
 
*Subjects should refrain from taking 
INCB039110 on clinic visit days until 
after local laboratory blood samples are 
collected. 
Ibrutinib 
administration 
5.3.1 
 
X* 
X* 
X* 
X* 
 
 
*Subjects should refrain from taking 
ibrutinib on clinic visit days until after 
local laboratory blood samples are 
collected. 
FDG = fluorodeoxyglucose; PET = positron emission tomography. 


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Table 9: 
Laboratory Assessments 
Laboratory Tests 
Section 
Screen 
Day 1 
Day 8 
(± 3 days) 
Day 15 
(± 3 days) 
Day 28/Q28D 
(± 3 days) 
EOT 
Follow-Up 
Details 
Local Laboratory Samples 
Serum chemistries 
7.4.6.1 
X 
X 
 
X 
X 
X 
X 
Day 1 laboratory tests may be omitted if the 
screening tests occurred in preceding 7 days. 
All lab draws should be performed before dose 
administration. 
Hematology 
7.4.6.2 
X 
X 
X 
X 
X 
X 
X 
Day 1 laboratory tests may be omitted if the 
screening tests occurred in preceding 7 days. 
All lab draws should be performed before dose 
administration. 
Coagulation panel 
7.4.6.2 
X 
X 
 
 
X* 
X 
 
Day 1 laboratory tests may be omitted if the 
screening tests occurred in preceding 7 days.  
All lab draws should be performed before dose 
administration. 
*After Day 28, should be repeated every 3 months, 
ie., Day 112, Day 196, etc. 
Serology 
7.4.6.5 
X 
 
 
 
 
 
 
 
Serum pregnancy 
7.4.6.4 
X 
 
 
 
 
X 
 
All female subjects of childbearing potential; 
negative pregnancy test must be obtained within 
7 days of first dose of study treatment. 
Urine pregnancy 
7.4.6.4 
 
X 
 
 
Only as medically indicated for females of 
childbearing potential. 
 


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Table 10: 
Table of Required Laboratory Analytes 
Serum Chemistries 
Serology 
Hematology  
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate 
Blood Urea Nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
LDH 
Phosphate  
Potassium  
Sodium  
Total bilirubina 
Direct bilirubina 
Indirect bilirubin 
Total serum protein 
Total cholesterol 
CRP 
HBsAg 
Anti-HBsAg 
Anti-HB core IgG 
HCV antibody 
HCV-RNA 
HBV-DNA 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Differential cell count: 
Basophils 
Eosinophils 
Lymphocytes (absolute) 
Monocytes 
Neutrophils (absolute) 
 
 
PT 
PTT 
aPTT 
INR 
CRP = C-reactive protein. 
a Only required if total bilirubin is elevated. 
6.1. 
Screening 
The screening period is the interval between the signing of the ICF and the day that the subject is 
enrolled in the study (Day 1).  Screening may not exceed 28 days.  Informed consent must be 
obtained before performing any study-specific procedures.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during this phase. 
Procedures conducted as part of the subject'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 that the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study.  Results from the screening visit evaluations will be 
reviewed to confirm subject eligibility before enrollment or the administration of study drug.  
Tests with results that fail eligibility requirements may be repeated once during the screening 
phase if the investigator believes the results to be in error.  For screening assessments that are 
repeated, the most recent available result before enrollment will be used to determine subject 
eligibility.  Treatment should start as soon as possible, but within 2 days after the date of 
enrollment.  Additionally, a subject who fails screening may repeat the screening process 1 time 
if the investigator believes there has been a change in eligibility status (eg, following recovery 
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6.2. 
Treatment 
The treatment period begins on the day that the subject receives the first dose of study drug 
(Day 1).  This day must be no more than 28 days after the subject has signed the ICF.  Dates for 
subsequent study visits will be determined based on this day and should occur within the visit 
windows outlined in the schedule of assessments (Table 8) unless delayed for safety reasons. 
6.3. 
End of Treatment 
There is no predefined EOT.  If a decision is made that the subject will permanently discontinue 
study treatment, then the EOT visit should be conducted.  If the EOT visit coincides with a 
regular study visit, then the EOT evaluations will supersede those of that scheduled visit, and the 
data should be entered in the EOT page in the eCRF.  The subject should be encouraged to return 
for follow-up visits. 
6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 35 days after the EOT visit (or after the last dose of study drug if 
the EOT visit was not performed).  Adverse events and SAEs must be reported up until at least 
30 days after the last dose of study drug, the date of the follow-up visit, or until toxicities 
resolve, return to baseline, or are deemed irreversible, whichever is longer.  Reasonable effort 
should be made to have the subject return for the follow-up visit and report any AEs that may 
occur during this phase. 
If a subject is scheduled to begin a new anticancer therapy before the end of the safety follow-up 
period, the safety follow-up visit should be performed before new anticancer therapy is started.   
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study treatment for a reason other than disease progression will move 
into the disease status follow-up period and should be assessed per standard of care to monitor 
disease status.  Every effort should be made to collect information regarding disease status until: 
• The start of new antineoplastic therapy. 
• Disease progression. 
• Death. 
• The end of the study. 
6.5. 
Unscheduled Visits 
Unscheduled visits may be held at any time at the investigator's discretion, and appropriate 
clinical and laboratory measurements performed based on AEs or other findings. 


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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The IVRS will be contacted to obtain a subject ID number when a subject enters screening.  
Upon determining that the subject is eligible for study entry, the IVRS will be contacted to 
obtain treatment assignment.  Additionally, the IVRS will be contacted during visits when study 
drug is resupplied. 
7.3. 
Demography and History 
7.3.1. 
Demographics, Medical History, Disease History 
Demographic data and a complete medical and medication history, including date of diagnosis of 
DLBCL, histology, current staging, sites of disease, prior surgery, radiation, and other details 
related to the disease under study, will be collected at screening. 
7.3.2. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine study 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 30 days before enrollment and up to the 
safety follow-up visit will be recorded in the eCRF.  The medication record will be maintained 
after signing the ICF to document concomitant medications, including any changes to the dose or 
regimen.  Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF. 
7.4. 
Safety Assessments 
7.4.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF through the safety 
follow-up.  Subjects will be instructed to report all AEs during the study and will be assessed for 
the occurrence of AEs throughout the study.  In order to avoid bias in eliciting AEs, subjects will 
be asked general, nonleading questions such as "How are you feeling?"  All AEs (serious and 
nonserious) must be recorded on the source documents and eCRFs regardless of the assumption 


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of a causal relationship with the study drug.  The definition, reporting, and recording 
requirements for AEs are described in Section 8. 
7.4.2. 
Comprehensive Physical Examination 
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. 
The comprehensive physical examination will include the following organ or body system 
assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (liver, spleen); extremities; lymph nodes; a brief neurological examination (eg, 
reflexes, strength, Romberg's test, vibration sense, and gross sensory perception); and body 
weight (within 1 lb or 0.5 kg).  The initial comprehensive physical examination should include 
an accurate measurement of the subject's height. 
7.4.3. 
Targeted Physical Examination 
A targeted physical examination will be a symptom-directed evaluation conducted by the 
investigator or designee.  The targeted physical examination will include assessment(s) of the 
body systems or organs, as indicated by subject symptoms, AEs, subject's weight, or other 
findings. 
7.4.4. 
Vital Signs 
Vital sign measurements (blood pressure, pulse, respiratory rate, and body temperature) will be 
taken with the subject in the recumbent, semirecumbent, or sitting position after 5 minutes of 
rest.  Clinically notable abnormalities that are considered clinically significant in the judgment of 
the investigator are to be reported as AEs. 
7.4.5. 
Twelve-Lead Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  Triplicate ECGs will be performed during screening and on Day 1 before 
starting study treatment.  Triplicate ECGs will be performed predose and 2 hours (± 15 minutes) 
after receiving INCB039110 on Day 8.  When triplicate ECGs are being obtained, individual 
measurements should be performed 5 ± 3 minutes apart. 
All 12-lead ECGs obtained at subsequent timepoints will be compared with the baseline 12-lead 
ECGs as follows: 
• For ECG morphology, all postdose ECG recordings will be compared with Day 1 
predose ECGs. 
• For the calculation of changes in cardiac intervals (eg, QT interval), the intervals 
from the screening and Day 1 predose (triplicate) ECGs will be computed and 
averaged and used as the baseline for comparison of all postdose intervals. 
The investigator or another appropriately trained individual will perform the initial ECG analysis 
of the data collected for each subject.  Electrocardiogram data will be reviewed as necessary by a 
qualified cardiologist at the study site.  If a pattern of abnormalities is observed, the sponsor 


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reserves the right to have copies (electronic or hard) of any and all ECGs sent to a central ECG 
laboratory for review. 
Electrocardiograms that are identified as abnormal and clinically meaningful compared with the 
screening assessment should be reported as AEs.  For such AEs, the findings of the abnormal 
ECGs and the corresponding baseline ECG findings must be reported in the eCRF, and copies of 
the abnormal tracings and corresponding baseline tracings will also be sent to the sponsor and/or 
sponsor's designee as indicated in the study manual. 
Additional ECGs may be performed at the investigator's discretion as clinically indicated. 
7.4.6. 
Laboratory Assessments 
Blood draws for laboratory assessments will occur at study visits indicated in Table 9.  Blood 
draws will be completed before the subject receives the morning dose of INCB039110.  Specific 
laboratory assessments are listed in Table 10.  The screening portion of the study will require a 
maximum of 16 mL of blood, the first 28 days on study will require a maximum of 35 mL of 
blood, and each subsequent 28 days on study will require a maximum of 11 mL of blood for 
local safety laboratory assessments. 
All laboratory assessments will be performed at a local laboratory using institutional best 
practices.  Results and normal reference ranges will be entered into the eCRF. 
7.4.6.1. 
Chemistry 
All chemistry and coagulation panel assessments will be performed from blood samples 
collected using institutional best practices before administration of INCB039110.  Results and 
normal reference ranges will be entered to the eCRF. 
7.4.6.2. 
Hematology 
Hematology assessments, including complete blood count with differential, will be performed at 
a local (site) laboratory using institutional best practices before administration of INCB039110.  
Results and normal reference ranges will be entered to the eCRF. 
7.4.6.3. 
Urinalysis 
Not applicable. 
7.4.6.4. 
Pregnancy Testing 
A serum pregnancy test will be performed at screening and EOT.  Urine pregnancy test will be 
performed only if pregnancy is suspected during treatment; positive results must be confirmed 
with a serum pregnancy test.  Pregnancy testing will only be required for women of childbearing 
potential. 
7.4.6.5. 
Serology 
Serology will be performed by local laboratory using institutional best practices on samples 
drawn at the screening visit. 


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7.5. 
Efficacy Assessments 
Subjects will have an objective assessment of disease status using PET and diagnostic-quality 
computed tomography (CT) scan or MRI. 
7.5.1. 
Computed Tomography Scan or Magnetic Resonance Imaging 
Subjects will undergo a diagnostic-quality CT or MRI to evaluate measurable disease during the 
screening phase.  If CT/MRI assessment was performed as standard of care before signing of the 
ICF but within 28 days of Day 1, the results from that assessment may be recorded in the eCRF 
in lieu of a study-specific assessment. 
On-treatment assessments should be repeated at Week 8, Week 16, and every 16 weeks 
thereafter. 
This assessment schedule also applies to those subjects who discontinue study treatment for 
reasons other than disease progression until disease progression, start of new anticancer therapy, 
withdrawal of consent, end of the study, or death, whichever occurs first.  Scheduled assessments 
should always be calculated from the first dose of study treatment.  Imaging should not be 
delayed for delays in treatment. 
7.5.2. 
FDG-PET or Combined PET-CT 
Positron emission tomography (PET) using [18F] fluorodeoxyglucose (FDG), or combined 
PET-CT is required to evaluate disease burden during the screening phase.  If FDG-PET 
assessment was performed as standard of care before signing of the ICF but within 28 days of 
Day 1, then the results from that assessment may be recorded in the eCRF in lieu of a 
study-specific assessment. 
Subsequently, FDG-PET or PET-CT will be repeated in order to confirm response assessments 
of CR or if clinically indicated. 
This assessment schedule also applies to those subjects who discontinue study treatment for 
reasons other than disease progression until disease progression, start of new anticancer therapy, 
withdrawal of consent, end of the study, or death, whichever occurs first.  Scheduled assessments 
should always be calculated from the first dose of study treatment.  Imaging should not be 
delayed for delays in treatment. 
7.5.3. 
Bone Marrow Examination 
Bone marrow examination is required as a screening assessment unless performed as per 
standard of care within 60 days of Day 1.  Otherwise, a bone marrow biopsy will be performed 
only to confirm CR or as clinically indicated.  The pathology report result from the bone marrow 
examination will be captured in the eCRF. 
7.5.4. 
Response Criteria – the Lugano Classification 
The Lugano Classification (Cheson et al 2014) will be used to assess response to treatment (see 
Table 11).  As PET assessment is required to confirm CR or PR, PET-based response should be 
applied in most circumstances.  Computed tomography/MRI-based response criteria are provided 
in the event that PET scans cannot be interpreted. 






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7.6. 
Performance Status Assessments 
7.6.1. 
ECOG Performance Status 
ECOG performance status (Oken et al 1982; Table 12) will be required at screening to evaluate 
eligibility and will be assessed at other study visits per Table 8.  Performance status must be 
assessed by a medically qualified individual and recorded in the eCRF. 
Table 12: 
ECOG Performance Scores 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 


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7.9. 
Other Study Procedures 
7.9.1. 
Distribution of Subject Reminder Cards 
Subjects will be provided with a reminder card at each visit.  The subject reminder card will 
indicate the date/time of the next visit and will also remind the subject that they should not take 
their morning dose of study drug on Day 1, Day 8, and Day 15, as they will take it after blood 
draws have been completed for safety evaluation.  The reminder cards for the Day 1, 8, and 15 
visits will have an area on which the date and time of the last dose taken (from the previous 
evening) and the time of their last meal before the visit should be recorded. 


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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (AE) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related, 
that occurs after a subject provides informed consent.  Abnormal laboratory values or test results 
occurring after informed consent constitute AEs only if they induce clinical signs or symptoms, 
are considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study drug.  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE (eg, 
resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.  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. 


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Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
activities of daily living. 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
living. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (SAE) definition provided in 
Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an AE 
that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be reported 
as an AE with a start date equal to the day the event met the Grade 1 AE definition and a stop 
date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The Grade 3 
event will also be reported as an AE, with the start date equal to the day the event changed in 


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intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event either changed 
severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
8.2.1. 
Definitions and Reporting 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may 
be required (see Section 5.5) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization but 
may be considered serious when, based on appropriate medical judgment, the event 


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may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug. 
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to the study 
treatment. 
The investigator must also complete the Incyte Serious Adverse Event Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the study treatment:  suspected 
(yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the Serious 
Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. 


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All new malignant tumors including solid tumors, skin malignancies, and hematologic 
malignancies will be reported as SAEs, regardless of the treatment group that the subject is 
enrolled in. 
This includes any second primary malignancy, regardless of causal relationship to study drug(s), 
occurring at any time for the duration of the study, from the time of signing the informed consent 
to 5 years after the last study drug treatment. 
Events of second primary malignancy are to be reported using the SAE form; these events must 
also be documented in the appropriate page(s) of the eCRF and in the subject's source 
documents.  Documentation of the diagnosis of the second primary malignancy must be provided 
at the time of reporting as an SAE (eg, any confirmatory histology or cytology results, x-rays, 
CT scans). 
8.4. 
Adverse Events of Special Interest 
Specific AEs, or groups of AEs, will be followed as part of standard safety monitoring activities.  
These events (regardless of seriousness) will be reported per the SAE reporting timelines. 
8.4.1. 
Major Hemorrhage 
Major hemorrhage is defined as any of the following: 
• Any treatment-emergent hemorrhagic AEs of Grade 3 or higher. 
• Any treatment-emergent SAEs of bleeding of any grade. 
• Any treatment-emergent CNS hemorrhage/hematoma of any grade. 
All hemorrhagic events requiring transfusion of red blood cells should be reported as Grade 3 or 
higher per CTCAE Events meeting the definition of major hemorrhage will be captured as an AE 
of special interest according to Section 8.4. 
8.5. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
8.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.5 for the maximum permitted duration of study drug interruption). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of any 


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birth defects, congenital abnormalities, or maternal and/or newborn complications, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (IB).  Additional safety 
information collected between IB updates will be communicated in the form of Investigator 
Notifications (INs).  Any important new safety information should be discussed with the subject 
during the study, as necessary.  If new significant risks are identified, they will be added to the 
ICF. 
8.8. 
Data Monitoring Committee 
The sponsor will continuously monitor safety through frequent contact with the treating 
investigators, review of the clinical data, and formal study meetings.  Routine (at least biweekly) 
teleconferences will be held among participating study sites to provide subject-by-subject 
updates on current study status, interim toxicities reported, and any other pertinent information.  
Adverse event and laboratory data entered into the clinical database will be reviewed 
periodically for trends and evolving safety signals.  Lastly, formal review meetings will be 
conducted with investigators during the study to establish consensus on the safety and 
tolerability of a given dose, based on the collective experience of the group. 
8.9. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be reported as described in Section 8.1.2 of this Protocol. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 










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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study- related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
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study drug.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database provider's information security controls are aligned with ISO 27002.  
The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, laboratory report), it must be obliterated on the copy of the document to be 
supplied to the sponsor or its designee.  Study findings stored on a computer will be stored in 
accordance with local data protection laws.  The subjects will be informed that representatives of 


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the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
In the event of a serious breach, the sponsor should be notified immediately and will notify the 
licensing authority as per local regulations. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by 
Clinical Investigators (ie, "covered studies") are required to submit a completed Clinical 
Investigator Financial Disclosure form that sufficiently details any financial interests and 
arrangements that apply.  For the purpose of this regulation, "clinical investigator" is defined as 
any investigator or subinvestigator who is directly involved in the treatment or evaluation of 
research subjects, including the spouse and each dependent child of the clinical investigator or 
subinvestigator.  These requirements apply to both US and foreign clinical investigators 
conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national 
and international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 


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11. 
REFERENCES 
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: 
clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification 
Project. J Clin Oncol 1998;16:2780-2795. 
Bishop GA, Haxhinasto SA, Stunz LL, Hostager BS. Antigen-specific B-lymphocyte activation.  
Crit Rev Immunol 2003;23:149-197. 
Catlett-Falcone R, Dalton WS, Jove R. STAT proteins as novel targets for cancer therapy. Signal 
transducer and activator of transcription. Curr Opin Oncol 1999;11:490-496. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 2014;30:3059-3068. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15, 2014. http://www.hma.eu/ctfg.html. Accessed 
October 8, 2015. 
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP 
alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346:235-242. 
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the 
LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP 
chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. 
Blood 2010;116:2040-2045. 
Cultrera JL, Dalia SM. Diffuse large B-cell lymphoma: current strategies and future directions.  
Cancer Control 2012;19:204-213. 
Dunleavy K, Grant C, Wilson WH. Using biologic predictive factors to direct therapy of diffuse 
large B-cell lymphoma. Ther Adv Hematol 2013;4:43-57. 
Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment 
of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des 
Lymphomes de l'Adulte. J Clin Oncol 2005; 23:4117-4126. 
Fischer K, Cramer P, Busch R et al. Bendamustine combined with rituximab in patients with 
relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the 
german chronic lymphocytic leukemia study group. J Clin Oncol 2011; 29:3559-3566. 
Forero-Torres A, Barr PM, Magdid Diefenbach CS, et al. A phase 1 study of INCB040093, a 
PI3Kδ inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor: Interim 
results from patients (pts) with relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). 
J Clin Oncol 2015;33(suppl):abstr 8558. 
Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc Hematol 
Educ Program 2011;2011:498-505. 
Gupta M, Han JJ, Stenson M, et al. Elevated serum IL-10 levels in diffuse large B-cell 
lymphoma: a mechanism of aberrant JAK2 activation. Blood 2012;119:2844-2853. 


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Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in inflammation and cancer. Eur J 
Cancer 2005;41:2502-2512. 
Ibrutinib Investigator's Brochure (IB). Horsham, PA: Janssen Research & Development, LLC. 
Ichikawa A, Kinoshita T, Watanabe T, et al. Mutations of the p53 gene as a prognostic factor in 
aggressive B-cell lymphoma. N Engl J Med 1997;337:529-534. 
INCB039110 Investigator's Brochure (IB).  Wilmington, DE: Incyte Corporation. 
Iwanski GB, Lee DH, En-Gal S, et al. Cucurbitacin B, a novel in vivo potentiator of gemcitabine 
with low toxicity in the treatment of pancreatic cancer. Br J Pharmacol 2010;160:998-1007. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J 
Clin 2011;61:69-90. 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 
2008;27:3145-3154.  
Lam LT, Wright G, Davis RE, et al. Cooperative signaling through the signal transducer and 
activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell 
lymphoma. Blood 2008;111:3701-3713. 
Lesina M, Kurkowski MU, Ludes K, et al. Stat3/Socs3 activation by IL-6 transsignaling 
promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic 
cancer. Cancer Cell 2011;19:456-469. 
Martelli M, Ferreri AJ, Agnostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large 
B-cell lymphoma. Critical Rev Oncol Hematol 2013;87:146-171. 
Masamune A, Satoh M, Kikuta K, Suzuki N, Shimosegawa T. Endothelin-1 stimulates 
contraction and migration of rat pancreatic stellate cells. World J Gastroenterol 
2005;11:6144-6151. 
Migliazza A, Martinotti S, Chen W, et al.  Frequent somatic hypermutation of the 5' noncoding 
region of the BCL6 gene in B-cell lymphoma. Proc Natl Acad Sci USA. 1995;92:12520-12524. 
National Cancer Institute Surveillance, Epidemiology, and End Results Program (NCI SEER).  
SEER Stat Fact Sheets: Non-Hodgkin Lymphoma. 2015. 
http://seer.cancer.gov/statfacts/html/nhl.html. Accessed December 9, 2014. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events v4.03. 2010. 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed July 17, 2014. 
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. 
Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour 
(bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated 
with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the 
MabThera International Trial Group (MInT) study. Lancet Oncology 2008;9:435-444. 
Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in 
germinal-centre B cells. Nature 2004;432:635-639. 


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Philip T, Chauvin F, Armitage J, et al. Parma international protocol: pilot study of DHAP 
followed by involved-field radiotherapy and BEAC with autologous bone marrow 
transplantation. Blood 1991;77:1587-1592. 
Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in 
the molecular era. Nat Rev Clin Oncol 2014;11:12-23. 
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after 
chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 2002;346:1937-1947. 
Sansone P, Bromberg J. Targeting the interleukin-6/Jak/stat pathway in human malignancies. 
J Clin Oncol 2012;30:1005-1014. 
Satterthwaite AB, Witte ON. The role of Bruton's tyrosine kinase in B-cell development and 
function: a genetic perspective. Immunol Rev 2000;175:120-127. 
Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab 
therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. 
J Clin Oncol 2005;23:5027-5033. 
Shaffer AL, Rosenwald A, Staudt LM. Lymphoid malignancies: the dark side of B-cell 
differentiation. Nat Rev Immunol 2002;2:920-932. 
Siegel RL, Miller KD, Jemal AJ. Cancer Statistics, 2015. CA Cancer J Clin 2015;65:5-29. 
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: 
American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 
33:3199-3212. 
Swerdlow SH, Campo E, Harris NL, et al., eds. World Health Organization Classification of 
Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008. 
Thoennissen NH, Iwanski GB, Doan NB, et al. Cucurbitacin B induces apoptosis by inhibition of 
the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic 
cancer cells. Cancer Res 2009;69:5876-5884. 
Toyonaga T, Nakano K, Nagano M, et al. Blockade of constitutively activated Janus 
kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human 
pancreatic cancer. Cancer Lett 2003;201:107-116. 
Torre LA, Bray F, Siegel RL, et al.  Global Cancer Statistics, 2012.  Ca Cancer J Clin 
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Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in 
diffuse large B cell lymphoma. Nat Med 2015;21:922-926. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 


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APPENDIX B. CYTOCHROME P450 INHIBITORS AND INDUCERS 
University of Washington School of Pharmaceutics: Drug Interaction Database Program. 2002. 
http://www.druginteractioninfo.org.  Accessed May 2015.  Highlighted rows indicate recent 
additions to the lists at the time the database search was performed. 


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In Vivo CYP3A Inhibitors 
 


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In Vivo CYP3A Inducers 
 


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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
27 JUN 2016 
Amendment (Version) 2: 
11 MAY 2017 
Amendment (Version) 3: 
05 FEB 2018 
Amendment (Version) 4: 
01 MAR 2018 
Amendment (Version) 5: 
18 JUN 2020 
Amendment 5 (18 JUN 2020) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to remove the Phase 2 secondary endpoint of overall 
survival. 
1. Synopsis; Section 2.1.2.2, Secondary Objectives; Section 2.2.2.2, Secondary 
Endpoints; Section 4.5, Overall Study Duration; Section 5.6.2, Withdrawal 
Procedures; Section 5.9, Study Completion; Section 6, Study Assessments (Table 8:  
Schedule of Assessments); Section 6.4.1, Safety Follow-Up; Section 6.4.3, Survival 
Follow-Up; Section 7.9.2, Data Collection for Survival Follow-Up; Section 9.4.2, 
Secondary Analyses 
Description of change:  Removed all references to survival follow-up from applicable 
sections. 
Rationale for change:  To discontinue the Phase 2 secondary endpoint of overall 
survival in the Protocol. 
2. Synopsis 
Description of change:  Updated to add 
, MD as the principal 
coordinating investigator for the study. 
Rationale for change:  To identify the principal coordinating investigator for the study. 


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Amendment 4 (01 MAR 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise the criteria for study termination; include 
blood volumes required for safety, 
 assessments; and clarify the methods used 
for estimating the rate of responders for the primary analysis. 
1. Section 4.6, Study Termination 
Description of change:  Revised to remove "etc" in the following sentence: 
"The sponsor may terminate the study electively due to ethical concerns, insufficient 
subject recruitment, alterations in accepted clinical practice, emerging data, etc, or if 
required by regulatory decision." 
Rationale for change:  To clarify the expected grounds for early termination of the study 
by the sponsor. 
2. Section 7.4.6, Laboratory Assessments; Section 7.7.1, Blood Sample Collection; 
 
Description of change:  All relevant sections were revised to include the blood volume 
required for safety, 
 assessments. 
Rationale for change:  To include blood volumes required for safety, 
 
assessments. 
3. Section 9.4.1, Primary Analyses; Section 11, References 
Description of change:  Updated to include additional detail regarding the methods for 
estimating the rate of responders. 
Rationale for change:  To provide clarification of the methods used to estimate the rate 
of responders for the primary analysis. 
4. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
 


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Amendment 3 (05 FEB 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to revise inclusion criteria, include additional 
rationale for the study population, and to clarify aspects of the study design, study duration, 
study drugs, data management, statistics, and study termination. 
1. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 8f was revised to include only those subjects 
with total bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of 
liver metastases or presence of documented Gilbert's syndrome (unconjugated 
hyperbilirubinemia). 
Rationale for change:  To provide a more appropriate upper limit for total bilirubin at 
study entry in this population. 
2. Section 1.2.4, Combined Inhibition of JAK and BTK in DLBCL 
Description of change:  The rationale for the DLBCL subpopulations included in both 
Phase 1 and 2 was added. 
Rationale for change:  To clarify the rationale for the difference in DLBCL 
subpopulations between Phase 1 and Phase 2. 
3. Section 1.3.3, Potential Risks and Benefits for the Combination of INCB039110 and 
Ibrutinib 
Description of change:  Potential benefits for the combination of INCB039110 and 
ibrutinib were added to the risks of the combination. 
Rationale for change:  To provide a more detailed risk-benefit assessment of the study 
drug combination. 
4. Section 3.1, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 10 was revised to extend the timeframe to 
avoid pregnancy or fathering children to 3 months after completion of study treatment. 
Rationale for change:  To align the Protocol with the ibrutinib SmPC. 
5. Section 4.5, Overall Study Duration 
Description of change:  Language was added to ensure access to treatment for subjects 
who continue to benefit from study treatment at the time of study termination. 
Rationale for change:  To clarify the sponsor's guarantee to provide study drug after 
study termination to those subjects continuing to benefit from the study treatment. 
6. Section 4.6, Study Termination 
Description of change:  Examples were added to demonstrate potential reasons for the 
sponsor to terminate the study electively. 
Rationale for change:  To provide examples of the most commonly expected grounds 
for early termination of the study by the sponsor. 


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7. Section 5.2.1, Description and Administration 
Description of change:  The administration instructions for INCB039110 were updated 
to indicate that the use of strong CYP3A inhibitors/inducers, grapefruit, and pomegranate 
should be avoided for the duration of the study .  The INCB039110 formulation used in 
the study was also added to this section. 
Rationale for change:  To align the Protocol with the most recent Investigator's 
Brochure and to clarify the formulation used in the study. 
8. Section 5.2.2, Supply, Packaging, and Labeling 
Description of change:  The language describing the product labels of INCB039110 was 
updated to be accurate for all countries participating in the study. 
Rationale for change:  Updated to accommodate the involvement of multiple countries. 
9. Section 9.4.3, Other Analyses 
Description of change:  Revised to clarify the statistical analysis planned for 
 
analysis. 
Rationale for change:  To clarify and ensure consistency in the Protocol regarding the 
statistical analysis of biomarkers. 
10. Section 10.3, Data Management 
Description of change:  Section was revised to include the information that the database 
provider's information security controls are aligned with ISO 27002.  
Rationale for change:  Clarify database alignment with ISO 27002. 
11. Section 10.4, Data Privacy and Confidentiality of Study Records 
Description of change:  Section was revised to include the process in place in the case of 
a serious breach in data privacy. 
Rationale for change:  To clarify measures that will be implemented in the case of a 
data security breach. 
12. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 


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Version 5 
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CONFIDENTIAL 
Amendment 2 (11 MAY 2017) 
The primary purpose of this amendment is to update several of the inclusion and exclusion 
criteria, correct inconsistencies with tissue sample requirements, and update restricted 
medications.   
1. Synopsis; Section 3.1, Subject Inclusion Criteria 
a. Description of change:  Inclusion criterion 8e was revised to indicate that aspartate 
aminotransferase and alanine aminotransferase must be ≤ 2.5 × institutional upper 
limit of normal (ULN) or ≤ 5 × ULN for subjects with known hepatic metastases. 
Rationale for change:  To provide appropriate requirements for subjects with hepatic 
metastases. 
b. Description of change:  Inclusion criterion 8f was revised to indicate that subjects 
can be included in the study if total bilirubin is < 2.0 × ULN if there are no liver 
metastases or < 3 × ULN in the presence of liver metastases or if bilirubin increase 
was due to presence of documented Gilbert's syndrome (unconjugated 
hyperbilirubinemia). 
Rationale for change:  To provide appropriate requirements for subjects with liver 
metastases. 
2. Synopsis; Section 3.2, Subject Exclusion Criteria; Section 5.7.1, Restricted 
Medications 
Description of change:  Exclusion criterion 5 was revised to indicate that subjects can be 
included in the study if they are receiving corticosteroids at a dose level ≤ 10 mg/day 
within 7 days of initiating study treatment.  Section 5.7.1 was revised to indicate that 
systemic corticosteroid doses greater than the equivalent of 10 mg prednisolone per day 
are not permitted from the screening visit through the follow-up visit, except with 
medical monitor approval. 
Rationale for change:  To provide appropriate requirements for subjects receiving 
corticosteroids. 
3. Synopsis; Section 3.2 Subject Exclusion Criteria 
a. Description of change:  Exclusion criterion 6 was revised to remove lenalidomide.  
Subjects can be included in the study if they received prior or concurrent therapy with 
lenalidomide. 
Rationale for change:  To provide appropriate requirements for eligibility following 
prior therapy. 
b. Description of change:  Exclusion criterion 7d was revised to indicate that subjects 
will be excluded from the study if they received monoclonal antibodies used as 
anticancer treatment < 4 weeks before starting study treatment. 
Rationale for change:  To provide appropriate washout requirements for eligibility 
following prior therapy with monoclonal antibodies. 
c. Description of change:  Exclusion criterion 25 was added to indicate that subjects 
will be excluded from the study if they received prior radiotherapy within 2 weeks 




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Amendment 1 (27 JUN 2016) 
The primary purpose of this amendment is to provide clarifications around 
 sample 
collection requirements, eligibility, and assessment of dose-limiting toxicities. 
1. Synopsis; Section 3.2, Subject Exclusion Criteria 
Description of change:  Exclusion criterion #4 was revised to include autologous stem 
cell transplant within the previous 3 months. 
Rationale for change:  Clarification per external feedback. 
Description of change:  Exclusion criteria #7c, 7d, and 7e (receipt of anticancer 
medications) were revised to indicate c. < 21 days or 5 half-lives (whichever is greater) 
for all other cytotoxic anticancer medications, d. < 8 weeks for monoclonal antibodies 
used as anticancer treatment, and e. < 10 weeks or 5 half-lives from completion of any 
radio- or toxin-immunoconjugates. 
Rationale for change:  Clarification per external feedback, as certain monoclonal 
antibodies have longer half-lives. 
2. Synopsis; Section 4.1.1, Phase 1 (Table 1) 
Description of change:  In Table 1 (Phase 1 Dose Cohorts), column header was revised 
from "DLTs" to "Subjects With DLT." 
Rationale for change:  Clarification that DLT assessments are made based on the 
number of subjects with a DLT, not the number of DLTs, as 1 subject could have 
multiple DLTs. 
3. Section 6, Study Assessments (Table 8, Table 9, and Table 10) 
Description of change:  In Table 8 (Schedule of Assessments), a note was added for the 
12-lead ECG assessment to indicate that triplicate ECGs will be performed predose and 
2 hours (± 15 minutes) after receiving INCB039110 on Day 8. 
Rationale for change:  To indicate the timing for Day 8 ECG assessments and to align 
with the text in Section 7.4.5 (Twelve-Lead Electrocardiograms). 
Description of changes:  Table 9 (Laboratory Assessments) was revised to include 
2 ambient correlative blood samples (for BTK receptor occupancy and cell population 
analysis) and 1 frozen correlative blood sample, and to include correlative plasma 
samples.  The optional on-study tumor biopsy sample was revised to span from Day 1 
through end of treatment (instead of the Day 28/Q28D column only). 
Rationale for changes:  Clarification of sample collection requirements 
4. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

SAP_001.pdf: 
Official Title: An Open-Label Phase 1/2 Study of Itacitinib (INCB039110) in Combination 
With Ibrutinib in Subjects With Relapsed or Refractory Diffuse Large B-Cell 
Lymphoma 
NCT Number: NCT02760485 
Document Date: Statistical Analysis Plan: 29-Nov-2022 


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STATISTICAL ANALYSIS PLAN 
 
 
 
 
INCB 39110-206 
An Open-Label Phase 1/2 Study of INCB039110 in Combination 
With Ibrutinib in Subjects With Relapsed or Refractory Diffuse 
Large B-Cell Lymphoma 
 
 
 
 
 
IND Number: 
 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 5 dated 18 JUN 2020 
CRF Approval Date: 
02 NOV 2016 
SAP Version: 
Amendment 2 
SAP Author:  
 
, Biostatistics 
Date of Plan: 
29 NOV 2022 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Study Objectives ...........................................................................................................8 
2.2.1. 
Phase 1 ..........................................................................................................................8 
2.2.1.1. 
Primary Objective .........................................................................................................8 
2.2.1.2. 
Secondary Objective .....................................................................................................8 
 
9 
2.2.2. 
Phase 2 ..........................................................................................................................9 
2.2.2.1. 
Primary Objective .........................................................................................................9 
2.2.2.2. 
Secondary Objectives ...................................................................................................9 
 
9 
2.3. 
Study Endpoints ............................................................................................................9 
2.3.1. 
Phase 1 ..........................................................................................................................9 
2.3.1.1. 
Primary Endpoint ..........................................................................................................9 
2.3.1.2. 
Secondary Endpoints ....................................................................................................9 
 
10 
2.3.2. 
Phase 2 ........................................................................................................................10 
2.3.2.1. 
Primary Endpoint ........................................................................................................10 
2.3.2.2. 
Secondary Endpoints ..................................................................................................10 
 
10 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Overall Study Design ..................................................................................................11 
3.1.1. 
Phase 1 ........................................................................................................................11 
3.1.2. 
Phase 2 ........................................................................................................................12 
3.1.3. 
Definition of Dose-Limiting Toxicities ......................................................................12 
3.2. 
Level of Significance ..................................................................................................13 
3.3. 
Sample Size Considerations .......................................................................................13 


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3.3.1. 
Sample Size for Phase 1 .............................................................................................13 
3.3.2. 
Sample Size for Phase 2 .............................................................................................13 
3.4. 
Schedule of Assessments ............................................................................................14 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................14 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................14 
4.1.1. 
Day 1 ...........................................................................................................................14 
4.1.2. 
Study Day ...................................................................................................................14 
4.1.3. 
Scheduled Visits .........................................................................................................14 
4.1.4. 
Baseline Assessments .................................................................................................14 
4.1.5. 
Last Available Value ..................................................................................................14 
4.2. 
Variable Definitions ....................................................................................................14 
4.2.1. 
Prior and Concomitant Medication .............................................................................14 
5. 
STATISTICAL METHODOLOGY ...........................................................................16 
5.1. 
General Methodology .................................................................................................16 
5.2. 
Treatment Groups .......................................................................................................16 
5.3. 
Analysis Populations ..................................................................................................16 
5.3.1. 
Intent-to-Treat Population ..........................................................................................16 
5.3.2. 
Per Protocol Population ..............................................................................................16 
5.3.3. 
Safety Population ........................................................................................................16 
 
17 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................17 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............17 
6.2. 
Disposition of Subjects ...............................................................................................17 
6.3. 
Protocol Deviations ....................................................................................................17 
6.4. 
Exposure .....................................................................................................................18 
6.5. 
Study Drug Compliance .............................................................................................18 
6.6. 
Medical History ..........................................................................................................18 
6.7. 
Prior and Concomitant Medication .............................................................................18 
7. 
EFFICACY .................................................................................................................19 
7.1. 
General Considerations ...............................................................................................19 
7.2. 
Efficacy Hypotheses ...................................................................................................19 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................19 


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7.3.1. 
Primary Efficacy Analysis ..........................................................................................19 
7.4. 
Analysis of the Secondary Efficacy Parameter ..........................................................19 
7.4.1. 
Duration of Response .................................................................................................19 
7.4.2. 
Durable Response Rate ...............................................................................................19 
7.4.3. 
Progression-Free Survival ..........................................................................................20 
7.4.4. 
Overall Survival ..........................................................................................................20 
7.4.5. 
Other Efficacy Analyses .............................................................................................21 
7.4.5.1. 
Eastern Cooperative Oncology Group Performance Status ........................................21 
7.4.5.2. 
Weight .........................................................................................................................21 
 
21 
 
21 
8. 
SAFETY AND TOLERABILITY ..............................................................................22 
8.1. 
General Considerations ...............................................................................................22 
8.2. 
Adverse Events ...........................................................................................................22 
8.2.1. 
Adverse Event Definitions ..........................................................................................22 
8.2.2. 
Adverse Event Summaries ..........................................................................................23 
8.3. 
Clinical Laboratory Tests ...........................................................................................25 
8.3.1. 
Laboratory Value Definitions .....................................................................................25 
8.3.2. 
Laboratory Value Summaries .....................................................................................25 
8.4. 
Vital Signs ..................................................................................................................26 
8.5. 
Electrocardiograms .....................................................................................................27 
9. 
INTERIM ANALYSES ..............................................................................................27 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................28 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................28 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................28 
10.2.1. 
Original to Amendment 1 ...........................................................................................28 
10.2.2. 
Amendment 1 to Amendment 2 ..................................................................................29 
11. 
REFERENCES ...........................................................................................................30 
APPENDIX A. CLINICAL LABORATORY TESTS ...............................................................31 
APPENDIX B. PLANNED TABLES, FIGURES, AND LISTINGS.........................................32 
 


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LIST OF TABLES 
Table 1: 
Phase 1 Dose Cohorts .................................................................................................11 
Table 2: 
Criteria for Defining Dose-Limiting Toxicity ............................................................13 
Table 3: 
Evaluation and Censoring of Progression-Free Survival ............................................20 
Table 4: 
Identification of Records for By-Visit Summaries .....................................................25 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................27 
Table 6: 
Criteria for Clinically Notable Electrocardiogram Abnormalities .............................27 
Table 7: 
Statistical Analysis Plan Versions ..............................................................................28 
 
LIST OF FIGURES 
Figure 1: 
Phase 1 Design Schema ..............................................................................................12 
Figure 2: 
Phase 2 Design Schema ..............................................................................................12 
 


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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this statistical analysis plan. 
Abbreviation 
Definition 
ABC 
activated B-cell 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
 
 
 
 
 
CI 
confidence interval 
 
 
CLL 
chronic lymphocytic leukemia 
 
 
 
 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
diffuse large B-cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
FDA 
Food and Drug Administration 
GCB 
germinal center B-Cell 
HBc 
hepatitis B core 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
IgG 
immunoglobulin G 
INR 
international normalized ratio 


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Abbreviation 
Definition 
ITT 
intent to treat 
JAK 
Janus kinase 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
 
 
PP 
per protocol 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
TEAE 
treatment-emergent adverse event 
 
 


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1. 
INTRODUCTION 
INCB 39110-206 is an open-label, single-group, Phase 1/2 study of INCB039110 in combination 
with ibrutinib in subjects with relapsed or refractory DLBCL.  Phase 1 will evaluate the safety 
and tolerability of INCB039110 when combined with ibrutinib in subjects with DLBCL (ABC, 
GCB, or unclassifiable); Phase 2 will evaluate the efficacy of the combination in subjects with 
ABC or unclassifiable DLBCL at the dose determined in Phase 1.  INCB039110 is a small 
molecule inhibitor of the JAK family of protein tyrosine kinases, 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; aberrant production of cytokines and growth factors has 
been associated with a number of cancers.  Ibrutinib (IMBRUVICA®) is a first-in-class, potent, 
orally administered, covalently binding inhibitor of Bruton's tyrosine kinase.  Ibrutinib has been 
approved in many regions, including the United States and Europe, for the treatment of patients 
with mantle cell lymphoma and CLL who have received at least 1 prior therapy, first-line 
treatment of patients with CLL with a deletion of the short arm of chromosome 17 (del17p) or a 
TP53 mutation, and patients with Waldenström's macroglobulinemia.  Ibrutinib is currently 
under investigation in various indications as a single agent and in combinations. 
A detailed description of the investigational product, target patient population, rationale for doses 
to be examined, and potential risks and benefits of treatment with INCB039110 and ibrutinib is 
provided in the Protocol, Section 1.  The purpose of this SAP is to define the methodology for 
analyzing and summarizing the data collected during the conduct of Study INCB 39110-206.  
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 39110-206 Protocol Amendment 5 dated 18 JUN 2020 and CRFs 
approved on 02 NOV 2016.  Unless superseded by an amendment, this SAP will be effective for 
all subsequent Protocol Amendments and eCRF versions. 
2.2. 
Study Objectives 
2.2.1. 
Phase 1 
2.2.1.1. 
Primary Objective 
The primary objective of Phase 1 is to evaluate the safety and tolerability of INCB039110 in 
combination with ibrutinib in subjects with relapsed or refractory DLBCL. 
2.2.1.2. 
Secondary Objective 
The secondary objective of Phase 1 is to evaluate the efficacy of INCB039110 in combination 
with ibrutinib in terms of ORR. 


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2.2.2. 
Phase 2 
2.2.2.1. 
Primary Objective 
The primary objective of Phase 2 is to evaluate the efficacy of INCB039110 in combination with 
ibrutinib in subjects with relapsed or refractory non-GCB DLBCL as demonstrated by ORR. 
2.2.2.2. 
Secondary Objectives 
The secondary objectives of Phase 2 are as follows: 
• To evaluate efficacy in terms of DOR, durable response rate, PFS, and OS. 
• To evaluate the safety and tolerability of the treatment combination. 
 
 
 
 
 
 
 
 
 
 
2.3. 
Study Endpoints 
2.3.1. 
Phase 1 
2.3.1.1. 
Primary Endpoint 
Safety and tolerability will be assessed by evaluating the frequency, duration, and severity of 
AEs (including SAEs and DLTs), and changes in clinical and laboratory assessments. 
2.3.1.2. 
Secondary Endpoints 
Efficacy will be assessed by ORR, defined as the percentage of subjects achieving either a CR 
or PR. 


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2.3.2. 
Phase 2 
2.3.2.1. 
Primary Endpoint 
Efficacy will be assessed by ORR, defined as the percentage of subjects achieving either a CR 
or PR. 
2.3.2.2. 
Secondary Endpoints 
• DOR, defined as the time from earliest date of disease response until earliest date of 
disease progression. 
• Durable response rate, defined as the percentage of subjects achieving a CR or PR for 
> 16 weeks. 
• PFS, defined as the time from enrollment until the earliest date of disease progression 
determined by objective radiographic disease assessments, or death due to any cause. 
• OS, defined as the date of enrollment until death due to any cause. 
• Safety and tolerability via assessment of the frequency, duration, and severity of AEs and 
SAEs, and changes in clinical and laboratory assessments. 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Overall Study Design 
This is an open-label, single-group, Phase 1/2 study of INCB039110 in combination with 
ibrutinib in subjects with relapsed or refractory DLBCL.  Phase 1 will evaluate the safety and 
tolerability of INCB039110 when combined with  ibrutinib in subjects with DLBCL (ABC, 
GCB, or unclassifiable) using a 6 + 3 design; Phase 2 will evaluate the efficacy of the 
combination in subjects with ABC or unclassifiable DLBCL at the dose determined in Phase 1 
using a Simon 2-stage expansion design.  Subjects may continue to receive study treatment until 
evidence of disease progression, unacceptable toxicity, or consent withdrawal. 
3.1.1. 
Phase 1 
The starting dose of INCB039110 will be 300 mg QD.  Depending on tolerability, the dose of 
INCB039110 in combination with ibrutinib (560 mg QD) could be increased to 400 mg QD 
(Cohort 2) or decreased to 200 mg QD (Cohort -1).  The dose selected for study in Phase 2 will 
be the dose tolerated by at least two-thirds of subjects who did not require a dose reduction 
within the first 28 days of treatment.  In order to be included in the tolerability review, a subject 
must have received the cohort-specific dose of INCB039110 and ibrutinib for at least 75% of the 
days during the 28-day DLT surveillance period or have experienced a DLT.  Additional subjects 
may be enrolled to achieve a minimum cohort size of 6 should withdrawal or dose 
interruptions/reductions result in a subject being nonevaluable.  Dose cohorts are outlined in 
Table 1, and the design is depicted in Figure 1. 
Table 1: 
Phase 1 Dose Cohorts 
Cohort 
Number 
Regimen 
Subjects 
With 
DLT 
Action 
-1 
6 
INCB039110 200 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Begin expansion portion of the study 
2 
Enroll 3 additional subjects (9 subjects total) 
≥ 3 
Terminate study 
 
1 
(Starting 
dose) 
6 
INCB039110 300 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Escalate to Cohort 2 
2 
Enroll 3 additional subjects (9 subjects total); 
if no new DLTs, escalate to Cohort 2 
≥ 3 
Reduce to Cohort -1 
 
2 
6 
INCB039110 400 mg QD 
+ ibrutinib 560 mg QD 
≤ 1 
Begin Phase 2 study 
2 
Enroll 3 additional subjects (9 subjects total); 
if no new DLTs, begin Phase 2 study 
≥ 3 
Begin Phase 2 study using Cohort 1 dose 


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Figure 1: 
Phase 1 Design Schema 
 
3.1.2. 
Phase 2 
Subjects with ABC or unclassifiable DLBCL will receive the recommended Phase 2 dose of 
INCB039110 in combination with ibrutinib as determined in Phase 1.  Phase 2 will use a Simon 
2-stage design with a stopping rule to allow early termination of the study at the end of Stage 1 if 
there is lack of sufficient efficacy.  During Stage 1, if 9 or fewer of the first 22 evaluable subjects 
achieve an objective response (defined as a CR or PR), then the study may be terminated.  If 
10 or more subjects achieve an objective response, then the study will continue and accrue 
38 additional subjects to Stage 2.  Subjects who were enrolled but did not receive treatment will 
be excluded from the efficacy analysis and replaced.  A timely assessment of response will be 
made to avoid risk of overenrollment before accrual to Stage 2.  At the end of Stage 2, ORR will 
be assessed for sufficient efficacy to warrant further study.  The study will be considered 
successful if the total number of objective responders is 29 or more.  The design is depicted in 
Figure 2. 
Figure 2: 
Phase 2 Design Schema 
 
3.1.3. 
Definition of Dose-Limiting Toxicities 
A DLT will be defined as the occurrence of any toxicities in Table 2 occurring up to and 
including Study Day 28, except those with a clear alternative explanation (eg, disease 
progression) or transient (≤ 72 hours) abnormal laboratory values without associated clinically 
significant signs or symptoms based on investigator determination.  All DLTs will be assessed 
by the investigator using CTCAE v4.03 criteria (NCI 2010).  In order to be included in the 
tolerability review, subjects must have received the cohort-specific dose of INCB039110 and 
ibrutinib for at least 75% of the days during the 28-day surveillance period or have experienced a 
DLT.  Additional subjects may be enrolled to achieve a minimum cohort size should withdrawal 
or dose interruptions/reductions result in subjects being nonevaluable. 




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3.4. 
Schedule of Assessments 
All study assessments will be performed as indicated in the schedule of assessments in Table 8 of 
Protocol Amendment 5 (dated 18 JUN 2020); the order of assessments is suggested by the order 
of mention within the schedule.  Laboratory assessments are shown in Table 9 of Protocol 
Amendment 5 (dated 18 JUN 2020). 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date of first dose of INCB039110 or ibrutinib. 
4.1.2. 
Study Day 
The study day at a visit or reporting date will be calculated by the visit or reporting date minus 
the Day 1 date plus 1 (visit date – Day 1 date + 1).  This study day will be subtracted by 1 if it is 
≤ 0, so that a study day of 0 will never occur.  A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Scheduled Visits 
Study evaluations in weeks or days from Day 1 are presented in the Schedule of Assessments. 
4.1.4. 
Baseline Assessments 
Baseline is defined as the last nonmissing measurement obtained before the first dose of 
INCB039110 or ibrutinib is administered. 
4.1.5. 
Last Available Value 
The last available value is the last nonmissing measurement obtained after starting INCB039110 
or ibrutinib and within 90 days after the last dose of INCB039110 or ibrutinib. 
4.2. 
Variable Definitions 
4.2.1. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy drug started before the first dose of INCB039110 or 
ibrutinib. 
Concomitant medication is defined as any nonstudy drug that is started accordingly: 
• Before the date of first administration of INCB039110 or ibrutinib 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 INCB039110 or ibrutinib and is ongoing or 
ends during the course of study drug administration. 


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Note:  A prior medication could also be classified as "both prior and concomitant medication" if 
the end date is on or after first dose of INCB039110 or ibrutinib.  In the listing, it will be 
indicated whether a medication is prior-only, concomitant-only, or both prior and concomitant 
medication. 
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, then 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 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, the incomplete date will be imputed as if it is the first day of the 
year. 


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5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; version 9.1 or later) will 
be used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries 
for continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
For the Phase 1 portion of the study, the safety run-in population (defined in Section 5.3.3) will 
be used for all safety analyses.  For the Phase 2 portion of the study, the safety evaluable 
population will be used for all safety analyses, and the ITT population will be used for all 
efficacy analyses.  
 
 
5.2. 
Treatment Groups 
Subjects will be summarized overall and based on the dose regimen initially assigned: 
• Ibrutinib 560 mg QD + INCB039110 200 mg QD 
• Ibrutinib 560 mg QD + INCB039110 300 mg QD 
• Ibrutinib 560 mg QD + INCB039110 400 mg QD 
Table summaries, unless otherwise indicated, will be provided by treatment group.  Note that 
1 of the above 3 treatments will be recommended for Phase 2 of the study, and separate 
summaries will be provided for the Phase 1 and Phase 2 portions of the study. 
5.3. 
Analysis Populations 
5.3.1. 
Intent-to-Treat Population 
The ITT population will include all subjects enrolled into the Phase 2 portion of the study.  This 
population will be used for analyses of all efficacy data. 
5.3.2. 
Per Protocol Population 
The PP population for efficacy data will include subjects in the ITT population who are 
considered to be compliant with the Protocol and will be defined for supportive sensitivity 
analyses for the primary and secondary efficacy endpoints.  This population will include subjects 
in the ITT population who received at least 80% of the assigned study drug regimen, met all 
inclusion/exclusion criteria, and had no significant Protocol violations as determined by sponsor.  
A subject who is discontinued because of disease progression is considered to be evaluable for 
the PP population. 
5.3.3. 
Safety Population 
The safety run-in population will include all subjects enrolled in the Phase 1 portion of the study 
who received at least 1 dose of study drug.  The safety evaluable population will include all 
subjects enrolled in the Phase 2 portion who received at least 1 dose of study drug.  Treatment 


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groups for this population will be determined according to the actual treatment that the subject 
receives on Day 1.  All safety analyses in Phase 1 and 2 will be conducted using the safety run-in 
population and safety evaluable population, respectively. 
 
 
 
 
 
  
 
 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
A list of planned tables, figures, and listings is provided in Appendix B. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
The following demographic and baseline characteristics will be summarized for the safety 
run-in/safety evaluable populations:  age, sex, race, ethnicity, weight, height, ECOG 
performance status, prior radiation (yes/no), prior surgery (yes/no), prior treatment regimens, 
number of prior treatment regimens, subtype of DLBCL, B symptoms, and bulky disease 
(≥ 10 cm). 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled and who were withdrawn from the 
study (with a primary reason for withdrawal) will be summarized for the ITT and safety 
run-in/safety evaluable populations. 
6.3. 
Protocol Deviations 
Protocol deviations captured on the Protocol Deviation Log will be presented in the subject data 
listings. 


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6.4. 
Exposure 
For subjects in the ITT and safety run-in/safety evaluable populations, exposure to INCB039110 
and ibrutinib will be summarized descriptively as follows: 
• Duration of treatment (days):  The duration of treatment will be number of study 
days between Day 1 and the last nonzero dose administration record of INCB039110 
or ibrutinib taken by the subject. 
• Average daily dose of INCB039110 or ibrutinib (mg/day):  Average daily dose of 
study drug (mg/day) = [total actual study drug taken (mg)] / [duration of treatment 
with study drug (days)]. 
6.5. 
Study Drug Compliance 
For subjects in the ITT and safety run-in/safety evaluable populations, overall compliance (%) 
for INCB039110 or ibrutinib will be calculated for all subjects as follows: 
overall compliance (%) = 100  (total dose taken) / (intended dose) 
The intended dose will be determined up to the earliest study day of permanent discontinuation 
of INCB039110 or ibrutinib (ie, AE discontinuation is the first AE with action taken being "drug 
withdrawn"), last study drug record in the database, or subject death.  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. 
6.6. 
Medical History 
For subjects in the ITT and safety run-in/safety evaluable populations, medical history will be 
summarized by assigned treatment group.  This summation will include the number and 
percentage of subjects with significant medical history for each body system/organ class and 
documented on the Medical History eCRF. 
6.7. 
Prior and Concomitant Medication 
For subjects in the safety run-in/safety population, prior medications and concomitant 
medications will be coded using the WHO Drug Dictionary and summarized by WHO drug class 
and WHO drug term.  In the data listing, each medication will be recorded as prior, concomitant, 
or both prior and concomitant.  Results will be summarized as number and percentage of subjects 
with prior and concomitant medications by preferred term and WHO drug class. 
Prior medication information will also be used to identify anticancer medication received by 
subjects before enrollment into the study.  Prior anticancer medication data will be summarized 
and presented by treatment group as well as listed. 


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7. 
EFFICACY 
A list of planned tables, figures, and listings is provided in Appendix B. 
7.1. 
General Considerations 
Not applicable. 
7.2. 
Efficacy Hypotheses 
Objective response rate (primary endpoint):  Administration of INCB039110 in combination 
with ibrutinib increases ORR in subjects with relapsed or refractory non-GCB DLBCL compared 
with historical rate. 
7.3. 
Analysis of the Primary Efficacy Parameter 
7.3.1. 
Primary Efficacy Analysis 
The primary variable for the Phase 2 of the study is ORR, which is defined as the proportion of 
subjects with best response (CR or PR) by modified Lugano Classification (Cheson et al 2014) 
for DLBCL.  The proportion of responders within each treatment group will be estimated with 
90% CIs by treatment group.  Confidence intervals will be calculated based on the method of 
Koyama and Chen (2008) that accounts for early termination rules of the Simon 2-stage design.  
Within each treatment group, 1- sample binomial test will be used to test the null hypothesis.  
In general, best response is determined on the subject level using the highest overall response 
achieved postbaseline.  In the case of SD, measurements must meet the SD criteria at least once 
after study entry at a minimum interval of 56 days.  Subjects who fail to meet these criteria will 
have best response of PD if the next available Lugano Classification evaluation after the initial 
scan indicates PD or NE if no additional evaluations are available. 
7.4. 
Analysis of the Secondary Efficacy Parameter 
7.4.1. 
Duration of Response 
For objective responders, the DOR is the time from the first overall response contributing to an 
objective response (CR or PR) to the earlier of the subject's death and first overall response of 
PD (by Lugano Classification for DLBCL) occurring after the first overall response contributing 
to the objective response.  Median DOR and 90% CIs will be estimated using the Kaplan-Meier 
method.  Subjects who are still responding at the time of database freeze or discontinuation will 
be right-censored at the time of last valid radiologic assessment.  The DOR evaluation will be 
performed separately for each treatment group, and no statistical comparison will be made. 
7.4.2. 
Durable Response Rate 
For objective responders, the durable response rate is defined as the percentage of subjects 
achieving a CR or PR (as determined by Lugano Classification) for ≥ 16 weeks since the time 
from the first overall response contributing to an objective response (CR or PR).  Confidence 
intervals will be calculated based on the Clopper-Pearson method for binomial distributions. 


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7.4.3. 
Progression-Free Survival 
Progression-free survival is defined as the number of days from the date of first dose (which is 
not necessarily Day 1) to the earlier of death or disease progression.  Date of death will be 
determined using the Death Report, the Survival Follow-Up, and the Subject Status eCRFs.  
Disease progression is measured by investigator assessment of objective radiographic disease 
assessments per Lugano Classification.  Censoring for PFS will follow the algorithm outlined in 
Table 3, which is based on FDA guidance (FDA 2007).  The analyses will be based on the ITT 
population, according to treatment assignment.  Time-to-event data will be analyzed by the 
Kaplan-Meier method, treating subjects with no observed death or progression as censored at the 
last valid radiologic assessment visit.  Median PFS and 90% CI will be estimated. 
Table 3: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Date of enrollment 
Progression documented between 
scheduled visits 
Progressed 
Earliest of: 
• Date of radiological assessment showing new 
lesion (if progression is based on new 
lesion); or  
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions)  
No progression 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
Treatment discontinuation for 
undocumented progression 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
Treatment discontinuation for 
toxicity or other reason 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
Death before first 
pharmacodynamic assessment 
Progressed 
Date of death 
Death between adequate 
assessment visits 
Progressed 
Date of death 
Death or progression after more 
than 1 missed assessment 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
7.4.4. 
Overall Survival 
Overall survival will be determined from the date of first dose until death.  Survival data will be 
analyzed using Kaplan-Meier method, treating subjects with no observed death as censored at 
their last date known to be alive.  Median survival and 90% CI will be estimated.  Overall 
survival data will continue to be collected until 75% of subjects have died, have withdrawn 
consent, or are lost to follow-up. 


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7.4.5. 
Other Efficacy Analyses 
7.4.5.1. 
Eastern Cooperative Oncology Group Performance Status 
Subjects' ECOG performance status and changes in status at scheduled assessment times will be 
summarized. 
7.4.5.2. 
Weight 
Subjects' body weight and change from baseline in body weight at scheduled assessment times 
will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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8. 
SAFETY AND TOLERABILITY 
A list of planned tables, figures, and listings is provided in Appendix B. 
8.1. 
General Considerations 
The analyses for this section will be provided mainly for the Phase 2 portion using the safety 
evaluable population.  Data from the Phase 1 portion using the safety run-in population will be 
summarized separately where appropriate.  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 preferred terms reported on relatively few subjects.  Additional summaries 
for specific subgroups may be included on an ad hoc basis. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug and until 30 days after the last 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 to study drug administration. 
Adverse events will be tabulated by the MedDRA preferred term and system organ class.  
Severity of AEs will be described and graded using the NCI CTCAE v4.03.  The CTCAE 
reporting guidelines and grading details are available on the Cancer Therapy Evaluation Program 
website (NCI 2010).  
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, then it will be rated on a scale of 1 to 4 as follows:  1 = mild, 
2 = moderate, 3 = severe, and 4 = life-threatening.  All toxicities will be graded based on the 
worst level reached, not the level that they may have reached if they had not been treated.  When 
the intensity of an AE changes over time for a reporting period (eg, between visits), each change 
in intensity will be collected as an AE until the event resolves.  Only the worst grade will be 
reported in AE summaries.  Also, the Grade 3 or higher AEs will be reported in the listing to 
display all higher intensity AEs. 
The subset of AEs considered by the investigator to be related to INCB039110 or ibrutinib will 
be considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered to be treatment-related.  The incidence of 
AEs and treatment-related AEs will be tabulated.  Serious adverse events will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unsolved missing 
values will be handled according to the following rules: 
• An unsolved missing causality will be considered treatment-related. 
• An unsolved missing severity will be identified as an unknown severity. 


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For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent.  Therefore, an unsolved missing onset date will be considered 
treatment-emergent, with the following exceptions: 
• 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. 
• 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. 
8.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include the following: 
• Number (%) of subjects reporting any TEAEs 
• Number (%) of subjects reporting any DLTs (would be Phase 1 only) 
• Number (%) of subjects reporting any treatment-related TEAEs 
• Number (%) of subjects reporting any serious TEAEs 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs 
• Number (%) of subjects with INCB039110 dose reductions because of TEAEs  
• Number (%) of subjects who temporarily interrupted INCB039110 because of TEAEs 
• Number (%) of subjects who permanently discontinued INCB039110 because of 
TEAEs 
• Number (%) of subjects with ibrutinib dose reductions because of TEAEs  
• Number (%) of subjects who temporarily interrupted ibrutinib because of TEAEs 
• Number (%) of subjects who permanently discontinued ibrutinib because of TEAEs 
• Number (%) of subjects with dose reductions of any study drug because of TEAEs  
• Number (%) of subjects who temporarily interrupted any study drug because of 
TEAEs 
• Number (%) of subjects who permanently discontinued any study drug because of 
TEAEs 
• Number (%) of subjects who had a fatal TEAE 
• Number (%) of subjects reporting any AEs related to reference therapy 


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The following summaries will be produced by MedDRA term (if ≤ 10 subjects appear in a table, 
then a listing may be appropriate): 
• Number (%) of subjects reporting TEAEs by system organ class and preferred term 
• Number (%) of subjects reporting TEAEs by preferred term in decreasing order of 
frequency 
• Number (%) of subjects reporting TEAEs by system organ class, preferred term, and 
highest CTCAE grade 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting any Grade 3 or 4 TEAEs by preferred term in 
decreasing order of frequency 
• Number (%) of subjects reporting treatment-related TEAEs by system organ class and 
preferred term 
• Number (%) of subjects reporting treatment-related TEAEs by preferred term in 
decreasing order of frequency 
• Number (%) of subjects reporting treatment-related TEAEs by system organ class, 
preferred term, and highest CTCAE grade 
• Number (%) of subjects reporting any Grade 3 or 4 treatment-related TEAEs by 
system organ class and preferred term 
• Number (%) of subjects reporting any Grade 3 or 4 treatment-related TEAEs by 
preferred term in decreasing order of frequency 
• Number (%) of subjects reporting TEAEs leading to death by system organ class and 
preferred term 
• Number (%) of subjects reporting serious TEAEs by system organ class and preferred 
term 
• Number (%) of subjects reporting serious TEAEs by preferred term in decreasing 
order of frequency 
• Number (%) of subjects reporting treatment-related serious TEAEs by system organ 
class and preferred term 
• Number (%) of subjects reporting TEAEs leading to dose reduction by system organ 
class and preferred term 
• Number (%) of subjects reporting TEAEs leading to dose interruption by system 
organ class and preferred term 
• Number (%) of subjects reporting TEAEs leading to discontinuation of medication by 
system organ class and preferred term 
• Number (%) of subjects reporting TEAEs requiring concomitant medications by 
system organ class and preferred term 


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8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
The baseline value will be determined using the last nonmissing values collected before the first 
dose.  For baseline laboratory candidates with the same date and time, additional rules may be 
provided after consultation with the medical monitor to delineate which value will be defined as 
baseline. 
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. 
8.3.2. 
Laboratory Value Summaries 
Clinical laboratory tests, including hematology and serum chemistry (see Appendix A), will be 
performed for each subject during the study in accordance with Table 9 of Protocol 
Amendment 5 (dated 18 JUN 2020). 
If specific safety issues arise, then additional unscheduled laboratory tests or analyses may be 
performed at the discretion of the investigator. 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  All tests with numeric values will have a unique unit per test.  Any laboratory test results 
and associated normal ranges from local laboratories will be converted to SI units.  For the 
limited number of cases where the associated normal ranges from a local laboratory cannot be 
obtained despite due diligence, a set of standard normal ranges based on documented reference 
ranges will be applied to facilitate reporting the test results. 
When there are multiple nonmissing laboratory values for a subject's particular test within a visit 
window, the convention shown in Table 4 will be used to determine the record used for by-visit 
tabulations and summaries. 
Table 4: 
Identification of Records for By-Visit Summaries 
Priority 
Laboratory Visit 
Central or Local 
Laboratory 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
Central 
In-window 
Use smallest 
laboratory sequence 
number 
2 
Scheduled 
Local 
In-window 
3 
Unscheduled 
Central 
In-window 
4 
Unscheduled 
Local 
In-window 
5 
Scheduled 
Central 
Out-of-window 
6 
Scheduled 
Local 
Out-of-window 
Laboratory parameters will be summarized.  Shift tables based on worst postbaseline value 
recorded will use all postbaseline values.  Other laboratory parameters collected will only be 
listed in an appendix to the CSR in their original units without SI conversions.  A detailed listing 
of the serum chemistry, hematology, and urinalysis tests is provided in Appendix A. 


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Numeric laboratory values will be summarized descriptively, and non-numeric test values will be 
tabulated.  In addition, line graph and box-and-whisker plots will be provided for prespecified 
laboratory parameters. 
For test results that will be summarized with available normal ranges, the number and percentage 
of subjects 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 will be produced for each test for the safety run-in/safety evaluable 
population as well as the subset of subjects treated at the maximum tolerated dose.  The 
denominator for the percentage calculation will use the number of subjects 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 all gradable laboratory parameters, the values will be classified into grade levels 
corresponding to CTCAE v4.03 criteria.  For specific laboratory values requiring clinical 
intervention to grade, the classification according to the quantitative component will be provided. 
The number and percentage of subjects with the laboratory values of Grade 1, 2, 3, or 4 will be 
calculated for each treatment according to the largest treatment-emergent worsening of 
laboratory grade.  Separate summaries for abnormally high and abnormally low laboratory 
values will be provided when the laboratory in question has both high and low grading criteria.  
For instance, if a subject has a baseline fasting glucose of 210 mg/dL, maximum fasting glucose 
after starting treatment of 245 mg/dL, and minimum fasting glucose after starting treatment of 
52 mg/dL, then the subject will be counted as follows: 
• The subject will be counted as a Grade 2 "Glucose decreased" in summaries of 
hypoglycemia because the subject was not hypoglycemic at study entry but became 
hypoglycemic after treatment. 
• The subject will not count as a "Glucose increased" in summaries of hyperglycemia 
because the subject met the numeric requirements for Grade 2 hyperglycemia at 
baseline (fasting glucose value > 160 to 250 mg/dL) and did not increase in grade 
after starting treatment. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Vital signs, including systolic blood pressure, diastolic blood pressure, pulse, respiration rate, 
and body temperature, will be taken with subjects in the seated position during the study in 
accordance with Table 8 of Protocol Amendment 5 dated 18 JUN 2020.  Change and percentage 
change from baseline will be calculated using the last nonmissing value before first dose of study 
drug (Day 1) as the baseline value. 
Incidences of clinically notable vital sign abnormalities are defined in Table 5.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed along with 


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their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change > 25%. 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38°C 
< 35.5°C 
Respiratory rate 
> 24/min 
< 8/min 
8.5. 
Electrocardiograms 
Twelve-lead ECGs will be obtained for each subject during the study in accordance with Table 8 
of Protocol Amendment 5 dated 18 JUN 2020.  The baseline for each parameter is the average of 
all available values collected at screening, Day -1, and Day 1 predose.  Electrocardiogram results 
will be reviewed for clinically notable abnormalities according to predefined criteria (see 
Table 6).  Number and percentage of subjects with alert ECG values (outliers), defined as the 
absolute value outside the defined range (see Table 6) and percentage change > 25% (30% for 
QRS interval) will be summarized and listed if applicable.  Electrocardiogram abnormalities, 
both at baseline and postbaseline visits, will be tabulated by treatment group.  Incidences of 
abnormalities will be listed with study visit, assigned treatment group, and a description of the 
abnormality. 
Table 6: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcFa 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1500 msec 
< 600 msec 
a QTcF (Fridericia correction). 
9. 
INTERIM ANALYSES 
No interim analysis is planned. 


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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 7. 
Table 7: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
17 APR 2017 
Amendment 1 
10 OCT 2017 
Amendment 2 
29 NOV 2022 
10.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
10.2. 
Changes to the Statistical Analysis Plan 
10.2.1. 
Original to Amendment 1 
Updates to the original SAP include the following: 
• In Section 6.1, baseline disease staging was removed, prior systemic therapy other 
than radiation was changed to prior treatment regimens, and number of lines of 
previous anticancer therapies was changed to number of prior treatment regimens.  In 
Appendix B, the summary table for prior medications for cancer was revised to prior 
therapies for cancer, and the listing for systemic cancer medication history was 
revised to prior treatment regimens. 
• In Section 6.4 and Appendix B, references to study cycles were removed, and 
analyses summarized by cycles were updated to be summarized by day.  Average 
daily dose (mg/day) of study drug was added. 
• In Appendix B, summary tables including QTcB and RR interval values were 
removed or revised to exclude those values.  Shift summary tables of laboratory 
values in CTC grade (both one and two directional) were removed.  The standard 
summary table for clinically significant ECG abnormalities was removed.  Shift 
summary tables and listings of laboratory hematology and chemistry values were 
added.  Standard summary tables for ECOG status and 12-lead ECG QT interval 
values were added.  Sample table shells were removed in accordance with new 
standard operating procedures.  Formatting changes were applied as necessary, and 
table numbering was modified as a result of the changes listed above. 
• Other minor, administrative changes have been incorporated throughout the SAP and 
are noted in the redline version of the amendment. 


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10.2.2. 
Amendment 1 to Amendment 2 
Updates to Amendment 1 of the SAP include the following: 
• In Section 4.2, age was removed from the variable definitions as the latest CRF 
design does not collect birth date. 
• In Section 5.3.2, the definition of the PP population was revised to be consistent with 
Protocol Amendment 5. 
• In Section 8.2.1, the definition of TEAE was updated. 
• In Section 8.2.2 and Appendix B, the summary tables for TEAEs leading to study 
withdraw, nonserious TEAEs, and clinically notable vital signs were removed; a 
summary table for body weight was added. 
• Other minor, administrative changes have been incorporated throughout the SAP and 
are noted in the redline version of the amendment. 


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11. 
REFERENCES 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 2014;32:3059-3068. 
Food and Drug Administration (FDA). Guidance for Industry: Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics. 2007. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
cm071590.pdf. Accessed July 22, 2016. 
Koyama T, Chen H. Proper inference from Simon's two-stage designs. Stat Med 2008;27:3145-
3154. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events version 4.0. 
2010. http://ctep.cancer.gov/reporting/ctc.html. Accessed July 15, 2016. 


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APPENDIX A. CLINICAL LABORATORY TESTS 
Serum Chemistries 
Serology 
Hematology  
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate 
Blood Urea Nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
LDH 
Phosphate  
Potassium  
Sodium  
Total bilirubina 
Direct bilirubina 
Indirect bilirubin 
Total serum protein 
Total cholesterol 
CRP 
HBsAg 
Anti-HBsAg 
Anti-HBc IgG 
HCV antibody 
HCV-RNA 
HBV-DNA 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
White blood cell count 
Differential cell count: 
Basophils 
Eosinophils 
Lymphocytes (absolute) 
Monocytes 
Neutrophils (absolute) 
PT 
PTT 
aPTT 
INR 
a Only required if total bilirubin is elevated. 


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APPENDIX B. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the CSR.  Standard 
tables will follow the conventions in the Standard Safety Tables Shells initial version.  In-text 
tables are identical in structure and content as appendix tables, but follow a Rich Text Format. 
Note:  Data from the Phase 1 portion will be summarized separately where appropriate. Table 
and listing numbers that end in ".x" below will end in ".1" for Phase 1 and ".2" for Phase 2. 
Tables 
Table No. 
Title 
Populationa 
Standard In-Text 
Baseline and Demographic Characteristics 
1.1.1.x 
Analysis Populations 
 
X 
X 
1.1.2.x 
Summary of Subject Disposition 
Safety Run-in / ITT 
X 
X 
1.1.4.x 
Summary of Protocol Deviations 
Safety Run-in / ITT 
X 
X 
1.2.1.x 
Summary of Demographics and Baseline Characteristics Safety Run-in / ITT 
X 
X 
1.3.1.x 
Summary of Baseline Disease Characteristics 
Safety Run-in / ITT 
 
X 
1.4.1.x 
Summary of General Medical History 
Safety Run-in / ITT 
 
X 
1.5.1.x 
Summary of Prior Medications 
Safety Run-in / ITT 
 
X 
1.5.2.x 
Summary of Concomitant Medications 
Safety Run-in / ITT 
 
X 
1.5.3.x 
Summary of Prior Therapies for Cancer 
Safety Run-in / ITT 
 
X 
Efficacy 
2.1.1.x 
Summary of Best Response per Lugano Classification 
Safety Run-in / ITT 
 
X 
2.1.2 
Summary of Best Response per Lugano Classification 
(Phase 2) 
PP 
 
X 
2.4.1 
Summary of Duration of Response per Lugano 
Classification (Phase 2) 
ITT 
 
X 
2.4.2 
Summary of Durable Response Rate (Phase 2) 
ITT 
 
X 
2.5.1 
Kaplan-Meier Analysis of Progression-Free Survival per 
Lugano Classification (Phase 2) 
ITT 
 
X 
2.6.1 
Kaplan-Meier Analysis of Overall Survival (Phase 2) 
ITT 
 
X 
2.8.1.x 
Summary of ECOG Status 
Safety Run-in / ITT 
X 
X 
Safety 
3.1.1.x 
Summary of Exposure and Duration of Exposure to 
INCB039110 and Ibrutinib 
Safety Run-in / ITT 
X 
X 
3.1.2.x 
Summary of INCB039110 and Ibrutinib Compliance 
Safety Run-in / ITT 
X 
X 
3.2.1.x 
Overall Summary of Treatment-Emergent Adverse 
Events 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.2.x 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.3.x 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.4.x 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
Safety Run-in / 
Safety Evaluable 
X 
X 


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Table No. 
Title 
Populationa 
Standard In-Text 
3.2.5.x 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.6.x 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in 
Decreasing Order of Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.7.x 
Summary of INCB039110 Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.8.x 
Summary of Ibrutinib Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.9.x 
Summary of INCB039110 Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.10.x 
Summary of Ibrutinib Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.11.x 
Summary of INCB039110 Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.12.x 
Summary of Ibrutinib Treatment-Related, 
Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum 
Severity 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.13.x 
Summary of Grade 3 or Higher INCB039110 
Treatment-Related, Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.14.x 
Summary of Grade 3 or Higher Ibrutinib 
Treatment-Related, Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.15.x 
Summary of Grade 3 or Higher INCB039110 
Treatment-Related, Treatment-Emergent Adverse Events 
by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.16.x 
Summary of Grade 3 or Higher Ibrutinib 
Treatment-Related, Treatment-Emergent Adverse Events 
by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.17.x 
Summary of Treatment-Emergent Adverse Events With a 
Fatal Outcome by MedDRA System Organ Class and 
Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.18.x 
Summary of Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.19.x 
Summary of Serious Treatment-Emergent Adverse 
Events by MedDRA Preferred Term in Decreasing Order 
of Frequency 
Safety Run-in / 
Safety Evaluable 
X 
X 


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Table No. 
Title 
Populationa 
Standard In-Text 
3.2.21.x 
Summary of INCB039110 Treatment-Related, 
Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.22.x 
Summary of Ibrutinib Treatment-Related, 
Treatment-Emergent Serious Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
 
3.2.24.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Dose Reduction of INCB039110 by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.25.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Dose Reduction of Ibrutinib by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.26.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Dose Interruption of INCB039110 by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.27.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Dose Interruption of Ibrutinib by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.28.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of INCB039110 by 
MedDRA System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.29.x 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of Ibrutinib by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.2.30.x 
Summary of Treatment-Emergent Adverse Events 
Requiring Concomitant Medications by MedDRA 
System Organ Class and Preferred Term 
Safety Run-in / 
Safety Evaluable 
X 
X 
Laboratory 
3.3.1.x 
Summary of Laboratory Values – Hematology 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.3.3.x 
Summary of Laboratory Values – Chemistry 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.3.5.x 
Shift Summary of Laboratory Hematology Values in 
CTC Grade - To the Worst Abnormal Value 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.3.6.x 
Shift Summary of Laboratory Chemistry Values in CTC 
Grade - To the Worst Abnormal Value 
Safety Run-in / 
Safety Evaluable 
X 
X 
Vital Signs 
3.4.1.x 
Summary of Systolic Blood Pressure 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.4.2.x 
Summary of Diastolic Blood Pressure 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.4.3.x 
Summary of Pulse 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.4.4.x 
Summary of Body Temperature 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.4.5.x 
Summary of Respiration Rate 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.4.6.x 
Summary of Body Weight 
Safety Run-in / 
Safety Evaluable 
X 
X 


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Table No. 
Title 
Populationa 
Standard In-Text 
ECGs 
3.5.1.x 
Summary of 12-Lead ECG:  PR Interval Values 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.5.2.x 
Summary of 12-Lead ECG:  QRS Interval Values 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.5.3.x 
Summary of 12-Lead ECG:  QT Interval Values 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.5.4.x 
Summary of 12-Lead ECG:  QTcF Interval Values 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.5.5.x 
Outliers of QT and QTcF Interval Values 
Safety Run-in / 
Safety Evaluable 
X 
X 
3.5.6.x 
Summary of Clinically Significant ECG Abnormalities 
Safety Run-in / 
Safety Evaluable 
X 
X 
a For table numbers ending in " x" the populations will be the safety run-in population for all Phase 1 tables and the ITT or safety 
evaluable population for Phase 2 tables. 
Figures 
Figure No. 
Title 
4.6.1 
Kaplan-Meier Plot of Progression-Free Survival (Phase 2) 
4.7.1 
Kaplan-Meier Plot of Overall Survival (Phase 2) 
4.9.1.1.1 
Line Graph of Mean and STD for Hemoglobin (G/L) by Visit (Phase 1) 
4.9.1.1.2 
Line Graph of Mean and STD for Neutrophils (GI/L) by Visit (Phase 1) 
4.9.1.1.3 
Line Graph of Mean and STD for Platelets (GI/L) by Visit (Phase 1) 
4.9.1.1.4 
Line Graph of Mean and STD for Leukocytes (GI/L) by Visit (Phase 1) 
4.9.1.2.1 
Line Graph of Mean and STD for Hemoglobin (G/L) by Visit (Phase 2) 
4.9.1.2.2 
Line Graph of Mean and STD for Neutrophils (GI/L) by Visit (Phase 2) 
4.9.1.2.3 
Line Graph of Mean and STD for Platelets (GI/L) by Visit (Phase 2) 
4.9.1.2.4 
Line Graph of Mean and STD for Leukocytes (GI/L) by Visit (Phase 2) 
Listings 
Listing No. 
Title 
2.1.1.x 
Subject Enrollment and Disposition Status 
2.2.1.x 
Protocol Deviations 
2.3.1.x 
Analysis Populations  
2.3.2.x 
Subject Inclusion and Exclusion Criteria 
2.4.1.x 
Demographics and Baseline Characteristics 
2.4.2.x 
Medical History 
2.4.3.x 
Prior Treatment Regimens 
2.4.4.x 
Prior Surgery 
2.4.5.x 
Prior Radiotherapy 
2.4.6.x 
Flow Cytometry 
2.4.7.x 
Hematopoietic Stem Cell Transplant History 
2.4.8.x 
DLBCL History 
2.4.9.x 
Prior and Concomitant Drug Treatments 
2.4.10.x 
PRBC/Platelet Transfusions 
2.4.11.x 
Procedures and Non-Drug Therapy 


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Listing No. 
Title 
2.5.1.x 
Study Drug Administration of INCB039110 
2.5.2.x 
Study Drug Administration of Ibrutinib 
2.5.3.x 
INCB039110 Compliance 
2.5.4.x 
Ibrutinib Compliance 
2.6.1.x 
Investigator Response 
2.6.2 
PFS Events and Assessments (Phase 2) 
2.6.3 
OS Events and Assessments (Phase 2) 
2.6.4 
Duration of Response and Durable Response (Phase 2) 
2.6.5.x 
Target Lesions 
2.6.6.x 
Non-Target Lesions 
2.6.7.x 
New Lesions 
2.6.8.x 
Bone Marrow Testing 
2.6.9.x 
ECOG Status 
2.6.10.x 
Deaths 
2.7.1.x 
Adverse Events 
2.7.2.x 
Dose-Limiting Toxicities 
2.7.3.x 
Serious Adverse Events 
2.7.4.x 
Grade 3 and Higher Adverse Events 
2.7.5.1.x 
Adverse Events Leading to Discontinuation of INCB039110 
2.7.5.2.x 
Adverse Events Leading to Discontinuation of Ibrutinib 
2.7.6.x 
Fatal Adverse Events 
2.7.7.x 
Deaths 
2.7.8.x 
Adverse Events of Special Interest 
2.8.1.x 
Clinical Laboratory Values - Hematology 
2.8.2.x 
Clinical Laboratory Values - Chemistry 
2.8.3.x 
Abnormal Clinical Laboratory Values - Hematology 
2.8.4.x 
Abnormal Clinical Laboratory Values - Chemistry 
2.9.1.x 
Vital Signs 
2.9.2.x 
Abnormal Vital Sign Values 
2.9.3.x 
Body Weight 
2.10.1.x 
12-Lead ECG Values 
2.10.2.x 
Abnormal 12-Lead ECG Values 
2.10.3.x 
Clinically Significant ECG Abnormality