A Phase 2, Multicenter, International, Open-Label, Safety and Efficacy Study of INCB050465 in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (CITADEL-202)
Phase: PHASE2
Conditions: Lymphoma
Sponsor: Incyte Corporation

Incyte Corporation 
Page 1 of 82 
Protocol INCB 50465-202 Am 4 
Version 4 
05 NOV 2019 
Clinical Study Protocol 
INCB 50465-202 / NCT02998476
A Phase 2, Multicenter, International, Open-Label, Safety and 
Efficacy Study of INCB050465 in Subjects With Relapsed or 
Refractory Diffuse Large B-Cell Lymphoma (CITADEL-202) 
Product: 
INCB050465 
IND Number: 
121,474 
EudraCT Number: 
2016-002205-19 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Date of Protocol: 
26 MAY 2016 
Date of Amendment (Version) 1: 30 AUG 2016 
Date of Amendment (Version) 2: 
09 NOV 2016 
Date of Amendment (Version) 3: 
23 FEB 2017 
Date of Amendment (Version) 4: 
05 NOV 2019 
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 11, 50, 54, 56, and 312, 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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Protocol INCB 50465-202 Am 4 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 50465-202 Protocol Amendment 4 (dated 05 NOV 2019) 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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Protocol INCB 50465-202 Am 4 
Version 4 
05 NOV 2019 
SYNOPSIS 
Name of Investigational Product:  INCB050465 
Title of Study:  A Phase 2, Multicenter, International, Open-Label, Safety and Efficacy Study of 
INCB050465 in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma 
Protocol Number:  INCB 50465-202 
Study Phase:  2 
Indication:  Diffuse large B-cell lymphoma 
Primary Objective: 
• To assess the efficacy of INCB050465 in terms of objective response rate (ORR) in subjects with 
relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in Group A. 
Secondary Objectives: 
• To assess the duration of response (DOR) in Group A. 
• To assess progression-free survival (PFS) in Group A. 
• To assess overall survival (OS) in Group A. 
• To characterize the safety of INCB050465 in Group A and Group B. 
Primary Endpoint: 
• Objective response rate in Group A, defined as the percentage of subjects with a complete 
response/complete metabolic response (CR/CMR) or partial response/partial metabolic response 
(PR/PMR) as defined by revised response criteria for lymphomas, as determined by an Independent 
Review Committee (IRC). 
Secondary Endpoints: 
• Duration of response in Group A, defined as the time from first documented evidence of CR/CMR or 
PR/PMR until disease progression or death from any cause among subjects who achieve an objective 
response, as determined by radiographic disease assessment provided by an IRC. 
• Progression-free survival in Group A, defined as the time from the date of the first dose of study drug 
until the earliest date of disease progression, as determined by radiographic disease assessment 
provided by an IRC, or death from any cause. 
• OS in Group A, defined as the time from the date of the first dose of study drug until death by any 
cause. 
• Safety as measured by clinical assessments, including vital signs and physical examinations, 12-lead 
electrocardiograms (ECG), chemistry and hematology laboratory values, and adverse events (AEs). 
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Overall Study Design:  This is a Phase 2, multicenter, international, open-label study designed to 
evaluate the safety and efficacy of INCB050465 20 mg once daily for 8 weeks followed by 20 mg once 
weekly, administered orally to subjects with relapsed or refractory DLBCL (see Section 1.4 for dose 
rationale).  The study consists of 2 groups:  Group A and Group B.  In Group A, 100 subjects who were 
not previously treated with a Bruton
's tyrosine kinase (BTK) inhibitor (eg, ibrutinib) will be enrolled.  In 
Group B, up to 20 subjects who were previously treated with a BTK inhibitor (eg, ibrutinib) will be 
enrolled.  Subjects will be evaluated for ORR by an independent review committee (IRC) and followed 
for DOR, PFS, and OS.  Subjects may receive treatment until disease progression, death, unacceptable 
toxicity, or consent withdrawal. 
An interim futility analysis is planned when the first 40 subjects in Group A have been treated and have 
been evaluated for response or have permanently discontinued study treatment because of disease 
progression, withdrawal of consent, or death.  Group A of the study will be terminated for futility if 
≤ 13 of the 40 subjects have responded (ie, CR/CMR or PR/PMR) based on assessments provided by the 
IRC; otherwise the study will continue.  A timely assessment of response will be performed to avoid the 
risk of overenrollment. No formal futility analysis will be conducted for Group B. 
Note:  With Amendment 4, Protocol-required procedures have been reduced for ongoing subjects.  
Study Population:  Subjects with histologically confirmed relapsed or refractory DLBCL who have 
received 2 to 5 prior therapies. 
Key Inclusion Criteria:  
• Men and women, aged 18 years or older (except in South Korea, aged 19 or older). 
• Relapsed or refractory DLBCL, which has been histologically documented, defined as having received 
at least 2 but no more than 5 prior treatment regimens (eg, an anti-CD20 antibody, an anti-CD20 
antibody with or without chemotherapy, or chemotherapy alone) and ineligible for high-dose 
chemotherapy supported by autologous stem cell transplant. 
• Must have ≥ 1 measurable (≥ 2 cm in longest dimension) or ≥ 1 measurable extranodal lesion (> 1 cm 
in longest dimension) lesion on computed tomography (CT) scan or magnetic resonance imaging 
(MRI). 
• Subjects must be willing to undergo an incisional or excisional lymph node biopsy of accessible 
adenopathy or provide the most recent, available archived tumor biopsy. 
• Eastern Cooperative Oncology Group performance status 0 to 2. 
Key Exclusion Criteria: 
• Primary mediastinal (thymic) large B-cell lymphoma. 
• Known brain or central nervous system metastases or history of uncontrolled seizures. 
• Allogeneic stem cell transplant within the last 6 months, or active graft versus host disease following 
allogeneic transplant, or autologous stem cell transplant within the last 3 months. 
• Use or expected use during the study of any prohibited medications, including potent cytochrome P450 
3A4 inhibitors or inducers within 14 days or 5 half-lives (whichever is longer) before the first dose of 
study drug. 
• Prior treatment with the following: 
− Group A:  Prior treatment with a selective phosphatidylinositol 3-kinase (PI3K) δ inhibitor (eg, 
idelalisib), a pan-PI3K inhibitor, or a BTK inhibitor (eg, ibrutinib). 
− Group B:  Prior treatment with a selective PI3Kδ inhibitor (eg, idelalisib) or a pan-PI3K inhibitor. 
INCB050465/Study Drug, Dosage, and Mode of Administration:  INCB050465 will be administered 
orally at a dose of 20 mg once daily for 8 weeks followed by 20 mg once weekly to subjects in a fasted 
state.  Subjects may have dose reductions or interruptions based upon clinical and laboratory assessments. 
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Reference Therapy, Dosage, and Mode of Administration:  Not applicable. 
Required concomitant medications:  All subjects must receive prophylaxis against Pneumocystis 
jirovecii pneumonia from the start of study treatment and should continue for 2 to 6 months after the last 
dose of study treatment. 
Study Schedule/Procedures:  During screening and every 21 days from the date of first study drug 
administration (Day 1), a study visit will be conducted that includes a physical examination, clinical 
laboratory tests, and an assessment of AEs. 
 
 
During screening, subjects will have an objective assessment of disease status performed by 
fluorodeoxyglucose (FDG) positron emission tomography (PET) and diagnostic quality CT scan or MRI.  
Subjects will also have a bone marrow biopsy performed at screening unless the subject has FDG-avid 
disease or has undergone a recent bone marrow biopsy.  Disease status will be subsequently assessed by 
PET-CT/MRI at Weeks 9, 18, 27, and every 18 weeks thereafter until disease progression.  On-study bone 
marrow biopsies will be required only if needed to confirm a CR/CMR. 
Subjects withdrawn from study treatment for reasons other than disease progression will be followed for 
disease assessment until either radiologic disease progression, the start of a new anticancer therapy, or 
death (whichever occurs first). 
Subjects withdrawn from study treatment because of disease progression will be followed approximately 
every 12 weeks for subsequent anticancer therapies and survival. 
Note:  With Amendment 4, Protocol-required procedures have been reduced for ongoing subjects. 
Estimated Duration of Participation:  Subject participation through safety follow-up is expected to 
average approximately 11 months, which includes the following: 
• A screening period lasting up to 28 days. 
• A treatment period lasting as long as the subject is receiving benefit, tolerating the regimen, and has not 
met withdrawal criteria (approximately 9 months). 
• A safety follow-up period lasting 30 to 35 days. 
Subjects will be followed for approximately 12 months after the safety follow-up period. 
Estimated Number of Subjects:  The target enrollment for this study is 100 to 120 subjects. 
Principal Coordinating Investigator:   
, MD, 
 
 
Statistical Methods:  Data from Group A and Group B will be analyzed separately.  Response data will 
be analyzed when all subjects have received at least 1 postbaseline disease assessment, or have 
progressed, withdrawn from the study, or died.  There will not be any statistical comparison between the 
2 groups.  
Sample Size: 
Group A:  100 subjects will be enrolled.  If the true ORR is 0.50, then there is about 90% probability of 
observing the lower bound of the 95% confidence interval of ORR ≥ 35%.    
Group B:  Up to 20 subjects will be enrolled.  There is 87% probability of observing ≥ 6 responders in 
20 subjects
.   
Primary Analysis:  Group A only:  The ORR as determined by the IRC and its 95% exact binomial 
confidence intervals (CIs) will be calculated.  The ORR as determined by the investigators and its 95% CI 
will be provided as a sensitivity analysis.   
Secondary Analyses:   
Group A:  The Kaplan-Meier estimation of median DOR and PFS (per IRC) and OS will be presented 
with respective 95% CIs.   
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All safety data, including AEs, laboratory data, vital signs, and ECGs, will be summarized descriptively. 
Level of Significance:  There will not be any statistical comparison between the 2 groups.  Within each 
group, 2-sided 95% CIs will be reported for all analyses when appropriate.      
Interim Analysis:   An interim futility analysis is planned for Group A.  The analysis will be conducted 
when 40 subjects have been treated and evaluated for response or have permanently discontinued study 
treatment because of disease progression, withdrawal of consent, or death.  Group A will be terminated 
for futility if ≤ 13 of the 40 subjects responded (ie, CR/CMR or PR/PMR) based on assessments provided 
by the IRC.  The futility boundary is calculated using a spending function of HSD(-4).  No formal futility 
analysis will be conducted for Group B. 
Independent Data Monitoring Committee: An independent Data Monitoring Committee (IDMC) will 
be established and will review data at predetermined intervals as specified in the IDMC charter. 
 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3
 
LIST OF ABBREVIATIONS 
........................................................................................................13 
1. 
INTRODUCTION 
......................................................................................................16
 
1.1. 
Diffuse Large B-Cell Lymphoma 
...............................................................................16
 
1.2. 
Treatment for Relapsed/Refractory DLBCL 
..............................................................16
 
1.3. 
INCB050465 
...............................................................................................................17 
1.4. 
Study Rationale 
...........................................................................................................18
 
1.5. 
Potential Risks and Benefits of the Treatment Regimen 
............................................19
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
..............................................................20
 
2.1. 
Study Objectives 
.........................................................................................................20
 
2.1.1. 
Primary Objective 
.......................................................................................................20
 
2.1.2. 
Secondary Objectives 
.................................................................................................20
 
 
20 
2.2. 
Study Endpoints 
..........................................................................................................20
 
2.2.1. 
Primary Endpoint 
........................................................................................................20 
2.2.2. 
Secondary Endpoints 
..................................................................................................20 
 
21 
3. 
SUBJECT ELIGIBILITY 
...........................................................................................21
 
3.1. 
Subject Inclusion Criteria 
...........................................................................................21
 
3.2. 
Subject Exclusion Criteria 
..........................................................................................22
 
4. 
INVESTIGATIONAL PLAN 
.....................................................................................24
 
4.1. 
Overall Study Design 
..................................................................................................24
 
4.2. 
Measures Taken to Avoid Bias 
...................................................................................25 
4.3. 
Number of Subjects 
....................................................................................................25 
4.3.1. 
Planned Number of Subjects and Sites 
.......................................................................25 
4.3.2. 
Replacement of Subjects 
.............................................................................................25
 
4.4. 
Duration of Treatment and Subject Participation 
.......................................................25
 
4.5. 
Overall Study Duration 
...............................................................................................26
 
4.6. 
Study Termination 
......................................................................................................26
 
5. 
TREATMENT 
............................................................................................................26
 
5.1. 
Treatment Assignment 
................................................................................................26
 
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5.1.1. 
Subject Numbering and Treatment Assignment 
.........................................................26 
5.1.2. 
Randomization and Blinding 
......................................................................................27 
5.2. 
INCB050465 
...............................................................................................................27 
5.2.1. 
Description and Administration 
..................................................................................27
 
5.2.2. 
Supply, Packaging, and Labeling ...............................................................................27 
5.2.3. 
Storage 
........................................................................................................................28
 
5.2.4. 
Instruction to Subjects for Handling INCB050465 
....................................................28 
5.3. 
Treatment Compliance 
................................................................................................28
 
5.4. 
Treatment Interruptions and Adjustments 
..................................................................28 
5.4.1. 
Criteria and Procedures for Dose Interruptions and Reductions of 
INCB050465 
...............................................................................................................28 
5.4.2. 
Supportive Care Guidelines for Diarrhea/Colitis .......................................................31 
5.4.3. 
Definition for Immune-Related Adverse Events 
........................................................31
 
5.5. 
Study Treatment Discontinuation 
...............................................................................31
 
5.5.1. 
Criteria for Study Treatment Discontinuation 
............................................................32
 
5.5.2. 
Procedures for Study Treatment Discontinuation 
.......................................................32 
5.6. 
Concomitant Medications 
...........................................................................................33 
5.6.1. 
Pneumocystis Jirovecii Prophylaxis 
...........................................................................33
 
5.6.2. 
Supportive Care Measures 
..........................................................................................33
 
5.6.3. 
Restricted Medications 
...............................................................................................33
 
5.6.4. 
Prohibited Medications and Therapies .......................................................................34
 
6. 
STUDY ASSESSMENTS 
..........................................................................................34
 
6.1. 
Screening 
....................................................................................................................38
 
6.2. 
Treatment 
....................................................................................................................39
 
6.3. 
End of Treatment 
........................................................................................................39 
6.4. 
Follow-Up 
...................................................................................................................39
 
6.4.1. 
Safety Follow-Up 
........................................................................................................39
 
6.4.2. 
Disease Status Follow-Up 
...........................................................................................39
 
6.4.3. 
Survival Follow-Up 
....................................................................................................40
 
6.5. 
End of Study 
...............................................................................................................40 
6.6. 
Unscheduled Visits 
.....................................................................................................40 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
...........................40
 
7.1. 
Administration of Informed Consent Form 
................................................................40 
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7.2. 
Interactive Response Technology Procedure 
..............................................................40 
7.3. 
Demography and Medical History 
..............................................................................41 
7.3.1. 
Demographics and Medical History 
...........................................................................41
 
7.3.1.1. 
Prior and Concomitant Medications and Procedures 
..................................................41 
7.4. 
Safety Assessments 
.....................................................................................................41
 
7.4.1. 
Adverse Events 
...........................................................................................................41
 
7.4.2. 
Comprehensive Physical Examinations 
......................................................................42 
7.4.2.1. 
Disease-Specific Physical Examination .....................................................................42
 
7.4.3. 
Vital Signs ..................................................................................................................42
 
7.4.4. 
Twelve-lead Electrocardiograms 
................................................................................42
 
7.4.5. 
Laboratory Assessments 
.............................................................................................43
 
7.4.5.1. 
Chemistry and Hematology 
........................................................................................44
 
7.4.5.2. 
Pregnancy Testing ......................................................................................................44 
7.4.5.3. 
Serology 
......................................................................................................................44 
7.4.5.4. 
HIV Screening Test 
....................................................................................................44
 
7.5. 
Efficacy Assessments 
.................................................................................................44
 
7.5.1. 
FDG-PET or Combined PET-CT 
...............................................................................44
 
7.5.2. 
Computed Tomography Scan or Magnetic Resonance Imaging 
................................44 
7.5.3. 
Bone Marrow Examination 
.........................................................................................45 
7.5.4. 
Independent Review Committee 
.................................................................................45 
7.5.5. 
Response Criteria – The Lugano Classification .........................................................45
 
7.5.6. 
ECOG Performance Status 
.........................................................................................47
 
 
48 
 
48 
 
49 
 
49 
 
49 
 
49 
 
49 
 
50 
7.8. 
Other Study Procedures 
..............................................................................................50 
7.8.1. 
Administration of Study Drug 
....................................................................................50
 
7.8.2. 
Distribution of Subject Reminder Cards 
.....................................................................50 
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7.8.3. 
Data Collection for Survival Follow-Up 
....................................................................50
 
8. 
SAFETY MONITORING AND REPORTING 
.........................................................51
 
8.1. 
Adverse Events 
...........................................................................................................51
 
8.1.1. 
Definitions 
..................................................................................................................51
 
8.1.2. 
Reporting 
....................................................................................................................51 
8.2. 
Laboratory Test Abnormalities 
...................................................................................53
 
8.3. 
Serious Adverse Events 
..............................................................................................53 
8.3.1. 
Definitions 
..................................................................................................................53
 
8.3.2. 
Reporting 
....................................................................................................................54 
8.4. 
Adverse Events of Special Interest 
.............................................................................55
 
8.5. 
Pregnancy ...................................................................................................................55
 
8.6. 
Warnings and Precautions 
..........................................................................................56 
8.7. 
Independent Data Monitoring Committee 
..................................................................56
 
8.8. 
Product Complaints ....................................................................................................56 
9. 
STATISTICS 
..............................................................................................................57
 
9.1. 
Study Populations 
.......................................................................................................57 
9.2. 
Selection of Sample Size 
............................................................................................57
 
9.3. 
Level of Significance 
..................................................................................................57
 
9.4. 
Statistical Analyses 
.....................................................................................................58
 
9.4.1. 
Efficacy Analyses 
.......................................................................................................58
 
9.4.1.1. 
Primary Efficacy Analyses 
.........................................................................................58
 
9.4.1.2. 
Secondary Efficacy Analyses 
.....................................................................................58
 
 
59 
9.4.2. 
Safety Analyses ..........................................................................................................59
 
9.4.2.1. 
Adverse Events 
...........................................................................................................59
 
9.4.2.2. 
Clinical Laboratory Tests ...........................................................................................59
 
9.4.2.3. 
Vital Signs ..................................................................................................................59
 
9.4.2.4. 
Electrocardiograms 
.....................................................................................................60
 
 
60 
 
60 
9.5. 
Analyses for the Independent Data Monitoring Committee 
.......................................61 
9.6. 
Interim Analysis 
..........................................................................................................61
 
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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
..........................................................................................................62
 
10.1. 
Investigator Responsibilities 
.......................................................................................62
 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
.............................................63 
10.3. 
Data Management 
.......................................................................................................64
 
10.4. 
Data Privacy and Confidentiality of Study Records 
...................................................64 
10.5. 
Financial Disclosure 
...................................................................................................65
 
10.6. 
Publication Policy 
.......................................................................................................65
 
11. 
REFERENCES 
...........................................................................................................66
 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
...............................................................................68 
APPENDIX B. CYTOCHROME P450 AND P-GLYCOPROTEIN INHIBITORS 
AND CYTOCHROME P450 INDUCERS ................................................................69
 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
............................74
 
 
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LIST OF TABLES 
Table 1:
 Description and Administration 
..................................................................................27
 
Table 2:
 Guidelines for Interruption and Restarting Study Drug .............................................29 
Table 3:
 Dose Levels for INCB050465 
....................................................................................30
 
Table 4:
 Schedule of Assessments 
............................................................................................35
 
Table 5:
 Schedule of Laboratory Assessments 
.........................................................................36
 
Table 6:
 Schedule of Assessments for Ongoing Subjects in All Cohorts Upon 
Implementation of Protocol Amendment 4 
................................................................37 
Table 7:
 Schedule of Laboratory Assessments for Ongoing Subjects in All Cohorts 
Upon Implementation of Protocol Amendment 4 ......................................................37 
Table 8:
 Laboratory Tests:  Required Analytes (Not Applicable After Implementation 
of Protocol Amendment 4) 
.........................................................................................38 
Table 9:
 Lugano Classification for Response Assessment 
.......................................................46 
Table 10:
 Eastern Cooperative Oncology Group Performance Scores 
.......................................48 
 
 
48 
Table 12:
 Criteria for Clinically Notable Vital Sign Abnormalities 
...........................................60
 
Table 13:
 Criteria for Clinically Notable Electrocardiogram Abnormalities .............................60
 
 
LIST OF FIGURES 
Figure 1:
 Study Design 
...............................................................................................................25
 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
5PS 
5-point scale 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCT 
autologous stem cell transplant 
AST 
aspartate aminotransferase 
BTK 
Bruton
's tyrosine kinase 
CFR 
Code of Federal Regulations 
CL/F 
oral dose clearance 
CLL 
chronic lymphocytic leukemia 
CMR 
complete metabolic response 
CMV 
cytomegalovirus 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLBCL 
diffuse large B-cell lymphoma 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FL 
follicular lymphoma 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
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Abbreviation 
Definition 
HCV 
hepatitis C virus 
HDC 
high-dose chemotherapy 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
IB 
Investigator
's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IDMC 
independent Data Monitoring Committee 
IEC 
independent ethics committee 
IN 
Investigator Notification 
IPI 
International Prognostic Index 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRC 
independent review committee 
IV 
intravenous 
IWRS 
interactive web response system 
LDi 
longest transverse diameter of lesion 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin Lymphoma 
ORR 
objective response rate 
OS 
overall survival 
pAKT 
phosphorylated protein kinase B 
PCR 
polymerase chain reaction 
PD 
progressive disease  
PET 
positron emission tomography 
PFS 
progression-free survival 
PI3K 
phosphatidylinositol 3-kinase 
PJP 
Pneumocystis jirovecii pneumonia 
PK 
pharmacokinetic 
PMD 
progressive metabolic disease 
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Abbreviation 
Definition 
PMR 
partial metabolic response 
PPD 
cross-product of the longest transverse diameter and perpendicular diameter 
PR 
partial response 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SDi 
shortest axis perpendicular to the longest transverse diameter 
SPD 
sum of the product of the perpendicular diameters for multiple lesions 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
V/F 
volume of distribution 
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1. 
INTRODUCTION 
1.1. 
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 occurred 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 
(National Cancer Institute [NCI] 2014). 
Diffuse large B-cell lymphoma (DLBCL) is a subtype of NHL.  Diffuse large B-cell lymphoma 
is an aggressive form of NHL and is the most common NHL subtype, accounting for 
approximately 30% of all cases.  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).  Diffuse large B-cell lymphoma can develop as a transformation from a 
less aggressive form of lymphoma or as a first occurrence of lymphoma (called de novo).  
Prognosis varies across patients with DLBCL.  Subtype, patient characteristics, disease burden, 
and prior response to therapy affect clinical outcome, but all subtypes are considered aggressive 
and fatal if left untreated (Martelli et al 2013).  Despite significant progress in the management 
of patients with DLBCL, an unmet need still exists (Foon et al 2012). 
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 International Prognostic Index (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 high-dose chemotherapy (HDC)/autologous stem cell transplant 
(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 disease-free survival.  The 
PARMA study demonstrated the benefit of HDC/ASCT versus standard chemotherapy for 
relapsed or refractory DLBCL; overall survival (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, 
mechanistic target of rapamycin inhibitors, proteasome inhibitors, histone deacetylase inhibitors, 
and anti-angiogenic agents.  
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1.3. 
INCB050465 
Refer to the INCB050465 IB for current information on INCB050465. 
Phosphatidylinositol 3-kinases (PI3Ks) belong to a family of lipid signaling kinases that 
phosphorylate phosphoinositides of the inositol ring (Cantley 2002).  Phosphatidylinositol 
3-kinases are divided into 3 classes (Class I, II, and III) according to their structure, regulation, 
and substrate specificity.  Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ, are 
dual-specificity lipid and protein kinases that catalyze the phosphorylation of 
phosphatidylinositol-4,5-bisphosphate, giving rise to phosphatidylinositol-3,4,5-trisphosphate.  
Phosphatidylinositol-3,4,5-trisphosphate functions as a second messenger that controls a number 
of cellular processes, including growth, survival, adhesion, and migration.  The recognition that 
aberrant signal transduction occurs in malignant B-lymphocytes via the PI3K pathways resulting 
in disease progression has led to a focus on agents that modulate these signaling pathways.   
INCB050465 is a potent inhibitor of PI3Kδ (IC
50 value = 1.1 ± 0.5 nM), with approximately 
20,000-fold selectivity for the other PI3K family members.  INCB050465 does not significantly 
inhibit (< 30% inhibition) a broad panel of kinases when tested at a concentration of 100 nM 
(refer to the INCB050465 Investigator's Brochure [
IB; INCB050465 IB]).  INCB050465 is 
potent (IC50 values of ≤ 10 nM) in cell-based assays relevant to the pathogenesis of B-cell 
malignancies, such as PI3Kδ-mediated signaling and growth of human B-cell lines.  This effect 
is not due to general cytotoxicity.  Compared with inhibition of B-cell proliferation, 
INCB050465 is similarly potent in blocking helper T-cell differentiation but is > 100 times less 
potent in assays that measure effects on human T-cell and natural killer cell proliferation or 
monocyte function.  
 
  
 
 
 
  Inhibition of tumor growth and suppression of PI3K/protein kinase B 
signaling was observed at plasma concentrations that approximated the IC
90 (77 nM) for pAKT 
inhibition of Pfeiffer cells in human whole blood (INCB050465 IB).  Preclinical toxicology 
studies supported evaluation of INCB050465 in human clinical studies (INCB050465 IB). 
INCB050465 is being evaluated as a monotherapy in a Phase 1/2, dose-escalation and expansion 
study (INCB 50465-101, NCT02018861, Forero-Torres et al 2016).  As of 02 SEP 2016, data 
were available for 46 subjects who received INCB050465 administered orally at once daily QD) 
doses of 5 mg (n = 1), 10 mg (n = 3), 15 mg (n = 3), 20 mg (n = 15), 30 mg (n = 20), and 45 mg 
(n = 4).  The median duration of treatment was 104 days.  Adverse events (AEs) observed in 
≥ 20% of subjects were nausea, diarrhea, vomiting, neutropenia, fatigue, hypokalemia, and fever.  
No ≥ Grade 3 treatment-related AEs were reported in ≥ 10% of subjects.  Serious AEs (SAEs) 
that occurred in ≥ 2 subjects included colitis (n = 3), diarrhea (n = 3), and pyrexia, pneumonia, 
dehydration, exfoliative dermatitis, and hypotension (n = 2 each).  Eleven of the 46 subjects 
(24%) discontinued study treatment due to the following AEs:  colitis, diarrhea, pneumonitis, 
rash, exfoliative dermatitis, psoriasis, neutropenia, fatigue, pneumonia, and hypercalcemia.  All 
but 1 of these events occurred after the 9-week disease assessment.  No liver function test 
abnormalities > Grade 1 were reported while subjects were receiving study treatment.  No 
dose-limiting toxicities were identified, and the maximum tolerated dose was not reached. 
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As of 02 SEP 2016, 20 objective responses as reported by investigators were observed at doses 
≥ 10 mg QD in 41 evaluable subjects with DLBCL, follicular lymphoma (FL), Hodgkin 
lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia (CLL), and mantle cell 
lymphoma.  These results include 3 complete metabolic responses (CMRs) and 2 partial 
metabolic responses (PMRs) observed among the 14 evaluable subjects with DLBCL.  Objective 
responses for these 5 subjects occurred by the time of the 9-week disease assessment. The 
duration of treatment for these 5 subjects ranged from approximately 13 to 45 weeks, with 
1 subject remaining on study treatment at the time of the data cutoff. 
 
 
 
1.4. 
Study Rationale 
Aberrant activation of PI3Kδ has been associated with increased malignant B-cell proliferation 
and survival.  Another PI3Kδ inhibitor, idelalisib, received approval from the FDA  for the 
treatment of patients with relapsed CLL, in combination with rituximab, and also received 
accelerated approval from the FDA for the treatment of patients with relapsed follicular B-cell 
non-Hodgkin lymphoma (FL) or relapsed small lymphocytic lymphoma.  Idelalisib was also 
approved by the European Medicines Agency for patients with chronic CLL who have received 
at least 1 prior therapy or in certain first-line settings and for FL that is refractory to at least 
2 lines of treatment.  The approvals were based on objective response rate (ORR) and 
demonstrate that inhibition of PI3Kδ can be an effective strategy in the treatment of some B-cell 
malignancies. 
INCB050465 is a potent and selective inhibitor of PI3Kδ in enzyme and B-cell proliferation 
assays.  Based on emerging safety, efficacy, 
 data from the ongoing 
Study INCB 50465-101 (see Section 1.3), subjects with relapsed or refractory DLBCL who have 
received 2 to 5 prior regimens and who are ineligible for HDC/ASCT will receive INCB050465 
administered orally at a dose of 20 mg QD for 8 weeks followed by 20 mg once weekly.  This 
dose was chosen based on emerging efficacy and safety data from the ongoing Study 
INCB 50465-101 (see Section 1.3). 
 
  
Furthermore, 20 mg QD has demonstrated efficacy in DLBCL (2 CMRs in 2 subjects) and in 
other types of non-Hodgkin lymphomas (9 objective responses in 9 subjects with non-Hodgkin 
lymphoma).  However, 24% (n = 11) of all subjects in study INCB 50465-101 discontinued 
study treatment due to an AE.  All but 1 of these events occurred after the 9-week disease 
assessment. Among the subjects with an objective response (n = 20), 7 (35%) discontinued study 
treatment due to an AE.  Consequently, after administration of 20 mg QD for 8 weeks, the dosing 
regimen will be reduced to 20 mg once weekly.  This once-weekly regimen is proposed to 
maintain response while providing time off from pathway inhibition, which may reduce the 
frequency of AEs.  
 
 
 
  This once-weekly regimen is similar to 
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that of another PI3K inhibitor (copanlisib), which is administered intravenously on Days 1, 8, 
and 15 of a 28-day cycle, and which achieved 7 objective responses in 9 subjects with 
non-Hodgkin lymphoma (Patnaik et al 2016).  Among the 51 subjects who received study drug, 
4 discontinued treatment due to an AE.  There were 2 events of Grade 3 noninfectious 
pneumonitis, 1 event of Grade 3 diarrhea, and no events of colitis. 
The primary objective of this study is to evaluate the efficacy of INCB050465 in this patient 
population.  The ORR is an acceptable primary endpoint in this single-arm, Phase 2 study 
evaluating subjects who have received 2 to 5 prior lines of therapy and in which no comparator 
exists. 
1.5. 
Potential Risks and Benefits of the Treatment Regimen 
Nonclinical data supported an initial dose of 5 mg QD in the first-in-human study 
(INCB 50465-101) based on adequate exposure margins and the lack of findings in recovery 
animals after drug withdrawal (INCB050465 IB).  Potential risks with administration of 
INCB050465 based on preclinical findings include lymphoid depletion (INCB050465 IB).  This 
may result in infections, fever, or cytokine release resulting in fever, chills, hypotension, 
wheezing, and/or rash. 
Pneumonitis and colitis have been reported in subjects treated with the PI3Kδ inhibitor idelalisib 
(Gopal et al 2014), and these events have been observed for another PI3Kδ, INCB040093 
(INCB040093 IB).  In March 2016, several studies evaluating idelalisib administered in 
combination with several lymphoma standard-of-care therapies (eg, anti–CD20-containing 
regimens) were terminated because of an increased risk of death and SAEs due to infections and 
respiratory disorders in subjects administered the idelalisib combinations.  The relevance of these 
findings with respect to INCB050465 administered as a monotherapy is currently unknown.  To 
reduce the risk of infection with Pneumocystis jiroveci pneumonia (PJP), all subjects taking 
INCB050465 must also take a prophylactic antibiotic (see Section 5.6.1). 
There are no preclinical data available to date on the potential phototoxicity of INCB050465.  
Therefore, subjects enrolled in this study taking INCB050465 will be instructed by the site staff 
to take precaution to protect themselves from the sun/ultraviolet light.  This includes wearing 
long sleeves, long trousers, hats, and sunglasses. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
• To assess the efficacy of INCB050465 in terms of ORR in subjects with relapsed or 
refractory DLBCL in Group A. 
2.1.2. 
Secondary Objectives 
• To assess the duration of response (DOR) in Group A. 
• To assess progression-free survival (PFS) in Group A. 
• To assess OS in Group A. 
• To characterize the safety of INCB050465 in Group A and Group B. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
• Objective response rate in Group A, defined as the percentage of subjects with a 
CR/CMR or PR/PMR as defined by revised response criteria for lymphomas 
(Cheson et al 2014), as determined by an Independent Review Committee (IRC). 
2.2.2. 
Secondary Endpoints 
• Duration of response in Group A, defined as the time from first documented evidence 
of CR/CMR or PR/PMR until disease progression or death from any cause among 
subjects who achieve an objective response, as determined by radiographic disease 
assessment provided by an IRC. 
• Progression-free survival in Group A, defined as the time from the date of the first 
dose of study drug until the earliest date of disease progression, as determined by 
radiographic disease assessment provided by an IRC, or death from any cause. 
• OS in Group A, defined as the time from the date of the first dose of study drug until 
death by any cause. 
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• Safety as measured by clinical assessments, including vital signs and physical 
examinations, 12-lead electrocardiograms (ECG), chemistry and hematology 
laboratory values, and AEs. 
3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Men and women, aged 18 years or older (except in South Korea, aged 19 or older). 
2. Relapsed or refractory DLBCL, which has been histologically documented, defined as 
having received at least 2 but no more than 5 prior treatment regimens  (eg, an anti-CD20 
antibody, an anti-CD20 antibody with or without chemotherapy, or chemotherapy alone) 
and ineligible for HDC/ASCT. 
3. Group B only:  Must have received prior Bruton
's tyrosine kinase (BTK) inhibitor 
therapy (eg, ibrutinib). 
4. Subjects must be willing to undergo an incisional or excisional lymph node biopsy of 
accessible adenopathy or provide the most recent, available archived tumor biopsy. 
5. Must have ≥ 1 measurable nodal lesion (≥ 2 cm in longest dimension) or ≥ 1 measurable 
extranodal lesion (> 1 cm in longest dimension) on computed tomography (CT) scan or 
magnetic resonance imaging (MRI). 
6. ECOG performance status 0 to 2 (see Table 10). 
7. Adequate hematologic, hepatic, and renal function (values must not be achieved with 
growth factors): 
a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L. 
b. Hemoglobin ≥ 8.0 g/dL. 
c. Platelet count ≥ 50 × 109/L. 
d. Total bilirubin ≤ 1.5 × upper limit of normal (ULN). 
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e. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.0 × ULN or 
≤ 5 × ULN in the presence of liver metastases. 
f. Calculated creatinine clearance ≥ 50 mL/min by the Cockcroft-Gault Equation or the 
estimated glomerular filtration rate ≥ 50 mL/min/1.73 m
2 using the Modification of 
Diet in Renal Disease formula. 
8. 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 and at least 55 years of age). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and who agrees to take appropriate precautions to avoid pregnancy (with at 
least 99% certainty) from screening through safety follow-up.  Permitted methods that 
are at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the 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 at least 93 days after the last dose of 
study 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. 
9. Ability to comprehend and willingness to sign an informed consent form (ICF).  
3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Primary mediastinal (thymic) large B-cell lymphoma. 
2. Known brain or central nervous system metastases or history of uncontrolled seizures. 
3. Allogeneic stem cell transplant within the last 6 months, or active graft versus host 
disease following allogeneic transplant, or autologous stem cell transplant within the last 
3 months before the date of the first dose of study drug. 
4. Use of immunosuppressive therapy within 28 days of the date of study drug 
administration.  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 study drug 
administration. 
5. Prior treatment with the following: 
a. Group A:  Prior treatment with a selective PI3Kδ inhibitor (eg, idelalisib), a pan-PI3K 
inhibitor, or a BTK inhibitor (eg, ibrutinib). 
b. Group B:  Prior treatment with a selective PI3Kδ inhibitor (eg, idelalisib) or a 
pan-PI3K inhibitor. 
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6. Receipt of anticancer medications or investigational drugs within the following intervals 
before the date of the first dose of study drug: 
a. < 10 weeks from completion of any radio- or toxin-immunoconjugates.  
b. < 6 weeks for mitomycin-C or nitrosoureas. 
c. < 4 weeks for immunotherapy. 
d. < 3 weeks for radiotherapy.   
e. < 2 weeks for any investigational agent or other anticancer medications. 
7. Prior treatment-related toxicities that have not resolved to ≤ Grade 1 before the date of 
study drug administration date except for stable chronic toxicities (≤ Grade 2) not 
expected to resolve (eg, stable Grade 2 peripheral neurotoxicity). 
8. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor 
embolization). 
9. Use or expected use during the study of any prohibited medications, including potent 
cytochrome P450 (CYP) 3A4 inhibitors or inducers (see Appendix B) within 14 days or 
5 half-lives (whichever is longer) before the date of study drug administration. 
10. Significant concurrent, uncontrolled medical condition including, but not limited to, 
renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, 
cerebral, or psychiatric disease. 
11. Current or previous other malignancy within 3 years of study entry, except cured basal or 
squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, 
carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without 
sponsor approval. 
12. History of stroke or intracranial hemorrhage within 6 months of the date of study drug 
administration. 
13. Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or 
antiviral treatment, and exposure to a live vaccine within 30 days ofstudy drug 
administration. 
14. Known human immunodeficiency virus (HIV) infection or positivity on immunoassay.  
Note:  HIV screening test is optional for subjects enrolled in the United States, but 
subjects with known HIV infection enrolled in the United States will be excluded. 
15. Liver disease: 
a. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of 
reactivation:  HBV DNA and HCV RNA must be undetectable.  Subjects cannot be 
positive for hepatitis B surface antigen (HBsAg) or anti–hepatitis B core antibody.  
Subjects who have positive anti-HBs as the only evidence of prior exposure may 
participate in the study provided that there is both 1) no known history of HBV 
infection, and 2) verified receipt of hepatitis B vaccine. 
16. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction, and or cardiac conduction issues within 6 months of the date of study drug 
administration.  
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17. Current New York Heart Association Class II to IV congestive heart failure or 
uncontrolled arrhythmia. 
18. Presence of an abnormal ECG that is clinically meaningful.  Screening QTc interval 
> 450 milliseconds is excluded (corrected by Fridericia).  In the event that a single QTc is 
> 450 milliseconds, the subject may enroll if the average QTc for 3 ECGs is 
< 450 milliseconds.  
19. Unable to swallow oral medication, malabsorption syndrome, disease significantly 
affecting gastrointestinal function, total resection of the stomach or small bowel, 
ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel 
obstruction. 
20. Known hypersensitivity or severe reaction to INCB050465 or its excipients 
(INCB050465 IB).   
21. Currently pregnant or breastfeeding. 
22. Any condition that would, in the investigator
's judgment, interfere with full participation 
in the study, including administration of study drug and attending required study visits; 
pose a significant risk to the subject; or interfere with interpretation of study data. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a Phase 2, multicenter, international, open-label study designed to evaluate the safety and 
efficacy of INCB050465 20 mg QD for 8 weeks followed by 20 mg once weekly.  The study 
drug will be administered orally to subjects with relapsed or refractory DLBCL (see Figure 1).  
The study consists of 2 groups:  Group A and Group B.  In Group A, 100 subjects who were not 
previously treated with a BTK inhibitor (eg, ibrutinib) will be enrolled.  In Group B, up to 
20 subjects who were previously treated a BTK inhibitor (eg, ibrutinib) will be enrolled.  
Subjects will be evaluated for ORR by an independent review committee (IRC) and followed for 
DOR, PFS, and OS.  Subjects may receive treatment until disease progression, death, 
unacceptable toxicity, or consent withdrawal.  An interim futility analysis is planned when the 
first 40 subjects in Group A have been treated and have been evaluated for response or have 
permanently discontinued study treatment because of disease progression, withdrawal of consent, 
or death.  Group A of the study will be terminated for futility if ≤ 13 of the 40 subjects have 
responded (ie, CR/CMR or PR/PMR) based on assessments provided by the IRC; otherwise the 
study will continue.  A timely assessment of response will be performed to avoid the risk of 
overenrollment.  No formal futility analysis will be conducted for Group B. 
Subjects who have relapsed or refractory, histologically confirmed DLBCL will be screened for 
eligibility.  Those who meet the eligibility criteria will be administered study drug (see 
Section 5.2).  Subjects will be monitored for safety and efficacy periodically until disease 
progression, death, unacceptable toxicity, or withdrawal of informed consent.  An independent 
Data Monitoring Committee (IDMC) will review safety data periodically as stated in the IDMC 
charter. 
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After treatment discontinuation, subjects will be followed for safety and survival.  Subjects who 
have discontinued study treatment due to reasons other than disease progression will be followed 
for either radiologic disease progression, the start of a new anticancer therapy, or death, 
whichever comes first.  The study will be closed no later than 2 years after the first dose of 
INCB050465 is administered to the last patient enrolled, at which point an analysis of OS will be 
conducted. 
Note:  With Amendment 4, Protocol-required procedures have been reduced for ongoing 
subjects. 
Figure 1: 
Study Design 
 
4.2. 
Measures Taken to Avoid Bias 
This is an open-label study; no comparisons will be made between subjects or against historical 
controls.  Measurements of safety and efficacy are objective measurements, and only 
comparisons to pretreatment conditions will be made.  Safety will be objectively assessed using 
NCI CTCAE v4.03 (NCI 2009) guidelines; response will be assessed by an IRC using the 
Lugano classification (Cheson et al 2014). 
4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects and Sites 
The study will enroll 100 to120 subjects across approximately 80 sites. 
4.3.2. 
Replacement of Subjects 
No subjects will be replaced at any time during this study. 
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 in continuous 21-day 
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intervals.  If the subject discontinues INCB050465, the treatment period will end, and the subject 
will enter the 30-day safety follow-up period after which the subject will enter the survival 
follow-up period (see Section 6.4).  Study participation, excluding survival follow-up, is 
expected to average approximately 11 months per subject.  Survival follow-up may average 
approximately 12 months. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  It is estimated that the study will take 
approximately 1.5 years to accrue 120 subjects and that the study will be closed no later than 
2 years after the first dose of INCB050465 is administered to the last subject enrolled. 
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 or do so if required by a regulatory agency or 
upon advice from the IDMC.  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.  The IDMC will recommend termination of the study if warranted, as 
described in the IDMC charter. 
Upon study closure, subjects who are still receiving study treatment will have the option to 
transition to Study INCB 50465-214, in which they may continue to receive study treatment. 
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 web response 
system (IWRS) 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 IWRS 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 IWRS and dispense 
the study drug to the subject.  All subsequent dispensing of study drug should follow this 
process.  Refer to the IWRS manual for detailed information. 
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If a subject is mistakenly given a bottle of study drug that is not the bottle assigned by the IWRS, 
the IWRS 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. 
5.2. 
INCB050465 
5.2.1. 
Description and Administration 
The dose and regimen of INCB050465 is 20 mg QD for 8 weeks followed by 20 mg once 
weekly.  INCB050465 will be taken orally with water in a fasted state except on mornings of   
clinic visits (see Table 11).  Subjects should refrain from food consumption for 2 hours before 
and 1 hour after administration of INCB050465.  The dosage strengths and form are 5 mg and 20 
mg tablets (see Table 1).  
Table 1: 
Description and Administration 
Compound name 
INCB050465 
Dosage Strengths 
5 mg and 20 mg 
Form 
Tablet 
Active compound  
INCB050465  
Route of administration 
Oral 
Dose and Regimen 
20 mg QD for 8 weeks followed by 20 mg once weekly 
Instructions 
INCB050465 will be taken orally with water in a fasted state except on 
mornings of 
 clinic visits (see Table 11).  Subjects should refrain 
from food consumption for 2 hours before and 1 hour after 
administration of INCB050465. 
5.2.2. 
Supply, Packaging, and Labeling 
INCB050465 will be provided as 5-mg and 20-mg tablets packaged in high-density polyethylene 
bottles.  No preparation is required. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
Pneumocystis jirovecii pneumonia prophylaxis is required as coadministration with 
INCB050465; the prophylactic agents will be provided by Incyte.  Incyte will determine the most 
appropriate manner in which to supply a prophylactic agent per country based on regulatory 
considerations.  Further details are available in the study pharmacy manual. 
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5.2.3. 
Storage 
Bottles of INCB050465 tablets should be stored at ambient conditions (15°C-30°C or 
59°F-86°F). 
5.2.4. 
Instruction to Subjects for Handling INCB050465 
The subject must be instructed in the handling of study drug as follows: 
• To store study drug at room temperature. 
• To remove from the study drug bottle only the number of tablets needed at the time of 
administration. 
• Not to remove doses in advance of the next scheduled administration. 
• To make every effort to take doses on schedule. 
• To report any missed doses. 
• To keep INCB050465 in a safe place and out of reach of children. 
• To bring all used and unused study drug kits to the site at each visit. 
5.3. 
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 INCB040465 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 for site 
personnel to conduct tablet counts to assess study drug accountability.  The drug accountability 
documentation will be used by the sponsor to calculate treatment compliance. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Criteria and Procedures for Dose Interruptions and Reductions of INCB050465 
Treatment with INCB050465 may be interrupted for up to 14 days to allow for resolution of 
toxicity.  Subjects may resume treatment if no medical condition or other circumstance exists 
that, in the opinion of the investigator, would make the subject unsuitable for further 
participation in the study.  The treating investigator should contact the sponsor to discuss the 
case of any subject whose treatment has been interrupted for more than 14 days before restarting 
treatment with INCB050465. 
Because subjects may enter the study with extensive pretreatment and/or severe bone marrow 
infiltration by the primary disease, guidelines for dose interruption for hematologic AEs (see 
Table 2) are provided.  The starting dose and dose reduction levels of INCB050465 are provided 
(see Table 3).  Individual decisions regarding dose interruption and reduction should be made 
using clinical judgment and in consultation with the sponsor
's medical monitor, taking into 
account relatedness of the AE to the study drug and the subject's underlying condition.  Adverse 
events that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory 
values without associated clinically significant signs or symptoms may be exempt from 
dose-reduction guidelines. 
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Table 2: 
Guidelines for Interruption and Restarting Study Drug 
ADVERSE EVENT 
ACTION TAKEN 
Chemistry 
• AST and/or ALT is Grade 3 
(> 5.0 × ULN). 
Note:  In subjects with liver 
metastasis−related elevations at baseline, 
contact sponsor to discuss clinical 
management and possible dose reductions. 
Step 1:  Interrupt INCB050465 and monitor weekly until the 
toxicity has resolved to ≤ Grade 1. 
Step 2:  Restart INCB050465 at next lower dose with medical 
monitor approval.  Monitor as clinically indicated. 
Hematology 
• Grade 3 ANC (< 1.0 × 109/L). 
• Platelet count is Grade 2 (50 to 
< 75 × 109/L) for subjects who enrolled 
with platelets > 100 × 109/L. 
• Platelet count is Grade 3 (< 50 × 109/L) for 
subjects who enrolled with platelets 
≤ 100 × 109/L. 
Step 1:  Interrupt INCB050465 up to 14 days until the toxicity has 
resolved to ≤ Grade 1 or pretherapy baseline.  For Grade 3 ANC, 
monitor at least weekly. 
Step 2:  Restart INCB050465 at same dose; monitor as clinically 
indicated. 
• Grade 4 ANC (< 0.5 × 109/L). 
• Grade 3 or Grade 4 ANC with an oral 
temperature of at least 38.5°C OR with 
≥ Grade 3 infection. 
• Platelet count is Grade 4 (< 25 × 109/L). 
Step 1:  Interrupt INCB050465 up to 14 days until the toxicity has 
resolved ≤ Grade 1.  (For Grade 4 ANC, monitor ANC at least 
weekly.) 
Step 2:  Restart INCB050465 at same dose.  If assessed as related 
to INCB050465, restart at next lower dose.  Monitor as clinically 
indicated. 
Other toxicities 
• Diarrhea/colitis (Grade 1) 
Step 1:  Treat with antimotility agents (eg, 4 mg loperamide 
followed by 2 mg every 4 hours or after every unformed stool) and 
initiate supportive care (see Section 5.4.2).  If not improved after 
48 hours, treat per guidance for Grade ≥ 2. 
• Diarrhea/colitis (Grade ≥ 2) 
Step1:  Interrupt INCB050465.  Perform work-up for infection 
(including CMV, C. difficile, etc).  Initiate or continue supportive 
care (see Section 5.4.2).  Consider colonoscopy with biopsy for 
Grade ≥ 3. 
Step 2:  If infection is ruled out, start oral steroids, or consider IV 
steroids if subject is being given IV fluids.  If no improvement with 
oral steroids, switch to IV steroids. 
When diarrhea resolves to Grade ≤ 1, continue supportive care and 
taper steroids over 4 weeks.  When taper is complete and diarrhea 
is Grade ≤ 1, restart INCB050465 at next lower dose with approval 
of the medical monitor. 
If Grade ≥ 2 diarrhea reoccurs, permanently discontinue 
INCB050465.  
• Pneumonitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved.   
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
• Pneumonitis (Grade  ≥ 2) 
Permanently discontinue INCB050465. 
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Table 2: 
Guidelines for Interruption and Restarting Study Drug (Continued) 
ADVERSE EVENT 
ACTION TAKEN 
• Skin toxicity (eg, rash, pruritus, etc, unless 
otherwise specified) (Grade 2-3) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved to 
≤ Grade 1. 
Step 2: Restart INCB050465 at same dose.  If assessed as related 
to INCB050465, restart at next lower dose. 
• Exfoliative dermatitis (Grade 1) 
Step 1:  Interrupt INCB050465 until the toxicity has resolved. 
Step 2:  Restart INCB050465 at next lower dose.  Monitor as 
clinically indicated. 
• Exfoliative dermatitis (≥ Grade 2) 
Permanently discontinue INCB050465. 
• Intestinal perforation (any grade) 
Permanently discontinue INCB050465. 
• Pneumocystis jiroveci pneumonia infection Interrupt INCB050465.  Permanently discontinue INCB050465 if 
Pneumocystis jiroveci pneumonia infection is confirmed. 
• CMV infection 
Subjects with CMV viremia without associated clinical signs of 
CMV infection should be carefully monitored.  Consider 
interrupting INCB050465 for subjects with CMV viremia and 
clinical signs of infection until the infection has resolved.  Restart 
INCB050465 reduced by 1 dose level if approved by the medical 
monitor. 
• Varicella zoster infection 
Interrupt INCB050465.  Restart INCB050465 only by approval of 
the medical monitor. 
• Any Grade 1 or Grade 2 toxicity unless 
otherwise specified. 
Continue study treatment and treat the toxicity; monitor as 
clinically indicated. 
• Any Grade 3 toxicity, if clinically 
significant and not manageable by 
supportive care unless otherwise specified. 
Step 1:  Interrupt INCB050465 up to 14 days until the toxicity has 
resolved to ≤ Grade 1. 
Step 2:  Restart INCB050465 at same dose.  If assessed as related 
to INCB050465, restart at next lower dose.  If interrupted for 
> 14 days, contact the medical monitor for approval to restart 
INCB050465.  Monitor as clinically indicated. 
• Any recurrent Grade 3 toxicity after 2 dose 
reductions. 
Discontinue study drug administration and follow-up per Protocol.  
Exceptions require approval of sponsor. 
• Any other Grade 4 toxicity. 
Discontinue study drug administration and follow-up per Protocol.  
Exceptions require approval of sponsor. 
CMV = cytomegalovirus; IV = intravenous; PCR = polymerase chain reaction. 
Table 3: 
Dose Levels for INCB050465 
Timepoint 
Dose  
Starting dose 
20 mg once daily for 8 weeks 
Week 9, Day 1 
20 mg once weekly 
First dose reduction 
10 mg once weekly 
Second dose reduction 
5 mg once weekly 
Note that the first dose reduction is applicable for subject receiving either 20 mg QD or 20 mg 
once weekly. 
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5.4.2. 
Supportive Care Guidelines for Diarrhea/Colitis 
Subjects should be informed to immediately report to the investigator any event of diarrhea.  
Subjects should receive appropriate supportive care measures as deemed necessary by the 
investigator.  For any Grade ≥ 1 diarrhea, subjects should be advised to drink liberal quantities of 
clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  Subjects should try to eat: 5 to 6 small meals per day; low-fat, 
high-protein foods; and cooked instead of raw vegetables.  Subjects may supplement their diet 
with bananas, rice, applesauce, and toast to reduce the number of bowel movements, and may 
also try crackers, gelatin, noodles, or oatmeal.  Subjects should avoid fried, fatty, greasy, or spicy 
foods; milk, milk products, and acidic drinks; high-fiber foods and foods that cause gas; and 
alcohol, caffeine, and herbal supplements (Coutre et al 2015). 
For each occurrence, attempts should be made to rule out other causes, such as metastatic disease 
or bacterial or viral infection (including CMV), which might require additional supportive care. 
It may be necessary to perform conditional procedures such as colonoscopy with biopsy as part 
of evaluation of the event.  Note that several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased. 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain or cramping, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
5.4.3. 
Definition for Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology, or immune-related AEs (irAEs), may be 
defined as an AE consistent with an immune phenomenon associated with study drug exposure 
after all other etiologies have been eliminated.  Immune-related AEs may be expected based on 
previous experience with INCB050465 and other drugs (eg, idelalisib) that inhibit PI3Kδ.  
Special attention should be paid to AEs that may be suggestive of potential irAEs.  Based on 
emerging data from the ongoing Study INCB 50465-101, most irAEs occur after the first 
9 weeks of study drug administration.  However, an irAE could occur at any time.  Suspected 
irAEs should be discussed with the medical monitor when possible. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of drug-related 
AEs with potential immunologic etiology are outlined in Table 2 and Section 5.4.2.  For each 
AE, attempts should be made to rule out other causes, including but not limited to metastatic 
disease or bacterial or viral infection, which might require specific supportive care. 
5.5. 
Study Treatment Discontinuation 
The decision to discontinue study treatment will not constitute study completion.  In the event 
that study treatment is discontinued, the treatment phase will be considered complete, and the 
follow-up phases will begin. 
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5.5.1. 
Criteria for Study Treatment Discontinuation 
Subjects must permanently discontinue study treatment for any 1 the following: 
• The subject has experienced an unacceptable toxicity defined as follows: 
− Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor
's medical monitor, compromises the 
subject'
s ability to continue study-specific procedures or is considered to not be in 
the subject'
s best interest. 
− Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless 
a greater delay has been approved by the sponsor.  
• The subject is unable to tolerate INCB050465. 
• The subject has an objective radiographic tumor response of PD/PMD. 
• Further participation would be injurious to the subject
's health or well-being, in the 
investigator'
s medical judgment. 
• The subject becomes pregnant. 
• Informed consent is withdrawn.  Note:  Informed consent withdrawn means that the 
subject can no longer receive study treatment and can no longer be followed.   
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued 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.  (Note:  Not applicable in Canada.) 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then the sponsor should be consulted for instruction on 
handling the subject. 
5.5.2. 
Procedures for Study Treatment Discontinuation 
If a subject discontinues study treatment, then the following should occur: 
• The reason(s) for discontinuation must be documented in the subject
's medical record 
and in the eCRF. 
• The end-of-treatment (EOT) visit should be performed. 
• If the EOT visit coincides with a regular study visit, then the EOT evaluations will 
supersede those of that scheduled visit, and the data will be entered in the EOT visit 
in the eCRF. 
• The date of the EOT visit should be recorded in the IWRS. 
• Subjects must be followed for safety for no less than 30 days after the EOT visit or 
until study drug–related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
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If a subject actively withdraws from study treatment, then the subject will continue in the safety 
and survival follow-up periods of the study.  The study monitor or sponsor must be notified if a 
subject actively withdraws from study treatment or withdraws the informed consent.  If a subject 
withdraws informed consent, then the subject will have completed the study, and no additional 
data collection should occur. 
5.6. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 30 days before the date of study drug administration (Day 1) 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 e
CRF. 
5.6.1. 
Pneumocystis Jirovecii Prophylaxis  
All subjects are required to receive a standard PJP prophylaxis regimen determined by the 
investigator.  Examples of standard PJP prophylaxis therapies for this population include 
trimethoprim-sulfamethoxazole, atovaquone, dapsone with or without pyrimethamine, and 
pentamidine (NCCN 2016).  Due to reports of cross-sensitivity between sulfonamides and 
dapsone, all subjects who have a known or suspected allergy to sulfonamides must receive either 
inhaled pentamidine or atovaquone for PJP prophylaxis.  Prophylaxis should be given while 
subjects are receiving study treatment and should continue for 2 to 6 months after the last dose of 
study treatment. 
5.6.2. 
Supportive Care Measures 
Supportive care should be administered to subjects as per the institutional policy at the site for 
the standard therapy that the subject will receive.  Additional information may be available in the 
appropriate package inserts.  This includes the use of prophylactic growth factors, which should 
be based on American Society of Clinical Oncology guidelines for the use of white blood cell 
growth factors (Smith et al 2006) and the investigator
's clinical judgment. 
5.6.3. 
Restricted Medications 
• Use of systemic corticosteroid doses ≤ 10 mg/day prednisone (or equivalent) is 
permitted but discouraged from the screening visit through the EOT visit. 
• Use of weak or moderate inducers or inhibitors of CYP3A4 (Appendix B) is 
discouraged, and investigators should seek other options where possible. 
• P-glycoprotein substrates of clinical relevance should be used with caution (ie, 
aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, 
fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, 
saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan). 
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5.6.4. 
Prohibited Medications and Therapies 
• Use of potent inducers and inhibitors of CYP3A4 are prohibited (Appendix B).  
Based on the low overall bioavailability of topical ketoconazole, there are no 
restrictions on topical ketoconazole. 
• Use of any anticancer medications other than the study medication as described (see 
Section 3.2) through the 30-day follow-up is prohibited. 
• Use of systemic corticosteroid doses > 10 mg/day prednisone (or equivalent) is not 
permitted from the screening visit through the EOT visit. 
• Radiation therapy. 
6. 
STUDY ASSESSMENTS 
See the schedule of assessments (Table 4) and schedule of laboratory assessments (Table 5) for 
the timing of all assessments.  All assessments mandated throughout the study must be 
performed on a calendar schedule; delays in treatment administration will not delay performance 
of assessments.  A table of clinical laboratory analytes to be assessed (Table 8) is provided.  The 
order of assessments is suggested by the order listed within the Schedule of Assessments.  See 
Sections 6 and 7 for instructions on each assessment.  Further details of study procedures and 
assessments can be found in the study reference manual. 
Note:  Upon implementation of Protocol Amendment 4, only study assessments indicated in 
Table 6 and Table 7 will be performed. 
 
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Table 4: 
Schedule of Assessments 
Note:  Upon implementation of Protocol Amendment 4, only the schedules of assessments in Table 6 and Table 7 should be 
followed. 
Procedure 
Section 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Disease 
Follow-Up 
Survival 
Follow-Up 
Day 
-28 to -1 Day 1 
Day 15 
(± 3 Days) 
Every 
3 Weeks 
(± 3 Days) 
Every 
12 Weeks 
(± 3 Days) 
EOT + 
30-35 Days 
 
Every 
12 Weeks 
(± 1 Week) 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
Contact IWRS 
7.2 
X 
X 
 
X 
 
X 
 
 
 
Inclusion & exclusion criteria 
3.1 
3.2 
X 
X 
 
 
 
 
 
 
 
Demography and medical history 
7.3.1 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
7.3.1.1 
X 
X 
X 
X 
 
X 
X 
 
 
Comprehensive physical exam  
7.4.2 
X
a 
 
 
 
 
X 
 
 
 
Disease-specific physical exam 
7.4.2.1 
 
X 
X 
X 
 
 
X 
 
 
Vital signs 
7.4.3 
X 
X 
X 
X 
 
X 
X 
 
 
12-lead ECG
 
7.4.4 
X 
X 
X 
 
X 
X 
X 
 
 
ECOG status 
7.5.6 
X 
X 
 
X 
 
X 
X 
 
 
AE assessment 
7.4.1 
X 
X 
X 
X 
 
X 
X 
 
 
FDG-PET/CT scan 
7.5.1 
7.5.2  
X 
Every 9 weeks (± 1 week) through Week 27, 
then every 18 weeks (± 1 week) thereafter.
b 
 
 
 
 
Bone marrow exam 
7.5.3 
X
c 
 
 
 
 
 
 
 
 
Study drug dispensing 
5.1 
 
X 
 
X
d 
 
 
 
 
 
Study drug accountability 
5.3 
 
X 
 
X 
 
X 
 
 
 
INCB050465 administration 
5.2.1 
 
X 
X 
X 
 
 
 
 
 
Disease follow-up 
6.4.2 
 
 
 
 
 
 
 
X
e 
 
Survival follow-up 
6.4.3 
 
 
 
 
 
 
 
 
X
f 
FDG = fluorodeoxyglucose; PET = positron emission tomography. 
a Height required at screening only. 
b If the PET-CT is of diagnostic quality, then a separate CT does not need to be performed.  If CT is not available, is not practicable, or is contraindicated, then an MRI may be 
substituted.  Every effort must be made to use the same modality for disease assessment throughout the study for each individual subject. 
c Required at baseline except for reasons provided in Section 7.5.3.  Also required if needed to confirm CR/CMR. 
d Study drug will be dispensed at Weeks 1, 4, 7, and 10, and every 12 weeks thereafter. 
e Only for subjects who discontinue study treatment for reasons other than disease progression. 
f May be conducted by phone or email. 
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Table 5: 
Schedule of Laboratory Assessments 
Note:  Upon implementation of Protocol Amendment 4, only the schedules of assessments in Table 6 and Table 7 should be 
followed. 
Laboratory Tests 
Section 
Screening 
Treatment 
EOT 
Safety 
Follow-Up 
Day 
-28 to -1 
Day 1 
Day 15 
(± 3 Days) 
Every 3 Weeks 
(± 3 Days) 
Other 
EOT + 
30-35 Days 
Serum chemistries 
7.4.5.1 
X 
X
a 
X 
X 
 
X 
X 
Hematology 
7.4.5.1 
X 
Xa 
X 
X 
 
X 
X 
Serology 
7.4.5.3  
X 
 
 
 
X
b 
 
 
Serum pregnancy  
7.4.5.2  
X
c 
 
 
 
 
X 
 
Urine pregnancy  
7.4.5.2  
 
 
 
X
d 
 
 
 
HIV testing 
7.4.5.4  
X
e 
 
 
 
 
 
 
a Day 1 tests may be omitted if the screening tests occurred in the preceding 7 days.  If needed, Day 1 blood draws should be performed before dose administration. 
b Samples for CMV DNA analysis only will be collected every 3 weeks for 10 weeks (Day 1 of Weeks 4, 7, and 10) and then every 12 weeks thereafter. 
c Only for female subjects of childbearing potential; negative pregnancy test must be obtained within 14 days before administration of study drug. 
d Only for females of childbearing potential. 
e Optional for subjects enrolled in the United States. 
 
 
 
 
 
 
 
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Table 6: 
Schedule of Assessments for Ongoing Subjects in All Cohorts Upon Implementation of Protocol Amendment 4 
Procedure 
Section 
At Least Every 12 Weeks 
in Clinic
a 
EOT 
Follow-Up 
Notes 
EOT + 30-35 Days 
Prior/concomitant medications 
7.3.1.1 
X 
X 
X 
Review to ensure no prohibited medications are 
being used.  Provide data to sponsor in regard to 
SAEs only. 
Study drug dispensing 
5.1 
X 
 
 
 
Study drug accountability 
5.3 
X 
X 
 
 
Distribute reminders 
7.8.2  
X 
X 
 
 
Laboratory tests 
Table 7  
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
AEs/SAEs 
7.4.1 
X 
X 
X 
AEs that lead to the discontinuation of study 
treatment and all SAEs must be recorded in the 
CRFs, regardless of the causal relationship. 
FDG-PET/CT scan 
7.5.1 
7.5.2 
 
 
 
Performed per standard-of-care guidelines. 
a Information related to concomitant medications and adverse events may also be collected between the required clinic visits (eg, by phone or email). 
Table 7: 
Schedule of Laboratory Assessments for Ongoing Subjects in All Cohorts Upon Implementation of Protocol 
Amendment 4 
Local Laboratory Tests 
Section 
At Least Every 12 Weeks 
in Clinic 
EOT 
Follow-Up 
Details 
EOT + 30-35 Days 
Serum chemistries 
N/A 
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
Hematology 
N/A 
X 
X 
X 
Performed at each site as per standard of care and 
monitored per investigator discretion. 
 
 
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Table 8: 
Laboratory Tests:  Required Analytes (Not Applicable After Implementation 
of Protocol Amendment 4) 
Serum Chemistries 
Hematology 
Serology 
Other 
Albumin 
Alkaline Phosphatase 
ALT 
AST 
Bicarbonate 
Blood urea nitrogen 
C-reactive protein 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate  
Potassium  
Sodium  
Total bilirubin 
Direct bilirubin
a 
Indirect bilirubin
a 
Total serum protein 
Total cholesterol 
Hemoglobin 
Hematocrit 
Platelet count (absolute) 
Red blood cell count 
White blood cell count 
Differential cell count: 
Basophils % 
Eosinophils % 
Lymphocytes (absolute) 
Monocytes 
Neutrophils (absolute) 
 
HBsAg 
Anti-HBsAg 
Anti-HB core IgG 
HCV antibody 
HCV-RNA 
HBV-DNA 
CMV DNA 
HIV antibody 
(immunoassay)
b 
Pregnancy Test 
Female subjects of 
childbearing potential 
require serum 
pregnancy and urine 
pregnancy tests (see 
Table 5). 
Note:  Additional laboratory tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
a Only required if total bilirubin is > ULN. 
b Optional for subjects enrolled in the United States. 
6.1. 
Screening 
Screening is the interval between signing the ICF and the date that the study treatment is first 
administered (Day 1).  Screening may not exceed 28 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process.  Central laboratory results for serum chemistry, hematology, serology, and serum 
pregnancy will be used to determine eligibility.  
Procedures conducted as part of the subject
's routine clinical management (eg, 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 
screening interval.  All information associated with eligibility requirements must be entered into 
the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed by the investigator to confirm 
subject eligibility before enrollment or the administration of study drug.  Tests with results that 
fail eligibility requirements may be repeated during screening if the investigator believes the 
results to be in error.  For screening assessments that are repeated, the most recent available 
result before administration of study drug will be used to determine subject eligibility.  
Additionally, a subject who fails screening may repeat the screening process 1 time if the 
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investigator believes there has been a change in eligibility status (eg, after recovery from an 
infection).  Such subjects will be assigned a new subject ID number. 
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 (see Table 4) unless delayed for safety reasons.  
Subjects may receive treatment until disease progression, death, unacceptable toxicity, or consent 
withdrawal. 
6.3. 
End of Treatment 
There is no predefined EOT.  If a subject permanently discontinues study treatment, then the 
EOT visit should be conducted.  The subject should be encouraged to return for the safety 
follow-up visit. 
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, then the safety follow-up visit should be performed before new anticancer therapy is 
started.  Once new anticancer therapy has been initiated, the subject will move into the survival 
follow-up period. 
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study treatment for a reason other than disease progression will 
continue to be followed for disease assessments by radiologic imaging per the schedule of 
assessments (see Table 4).  Every effort should be made to collect information regarding disease 
status until any 1 of the following occurs: 
• The start of new antineoplastic therapy. 
• Disease progression. 
• Death. 
• The end of the study. 
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6.4.3. 
Survival Follow-Up 
Once a subject has received the last dose of study drug, confirmed disease progression, or started 
a new anticancer therapy, the subject moves into the survival follow-up period.  The site will use 
continuing subject records to supply data on subsequent treatment regimens, tumor assessments 
(if discontinued treatment for a reason other than progression), and OS in the eCRF. 
For subjects who do not intend to return to the study investigator for their ongoing care, 
follow-up should be maintained to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first. 
6.5. 
End of Study 
The study will continue up to 2 years after the first dose of study treatment is administered to the 
last subject enrolled, at which point the study will be closed. 
6.6. 
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. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Subjects ongoing after implementation of Protocol Amendment 4 will only have assessments 
performed as indicated in Table 6 and Table 7 and at a frequency determined by the investigator 
as guided by the standard of care.  Unless noted below, procedures listed in this section are 
not required to be performed or collected in the CRF after implementation of 
Amendment 4. 
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 IWRS will be contacted to obtain a subject ID number when a subject enters screening, upon 
determining that the subject is eligible for study entry to obtain the treatment assignment, 
throughout the study as indicated to update the study drug supply (see Table 4), and at the EOT 
visit.    
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7.3. 
Demography and Medical History 
7.3.1. 
Demographics and Medical 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. 
7.3.1.1. Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
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 end 
of study 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. 
Upon implementation of Amendment 4, use of concomitant medications should be monitored to 
verify that subjects are not taking any concomitant medication prohibited per Protocol 
(Section 5.6.4).  A concomitant medications is required to be entered in the SAE form if 
considered associated with an SAE or the eCRF if the concomitant medication led to study drug 
discontinuation. 
7.4. 
Safety Assessments 
Upon implementation of Amendment 4, only safety assessments (including laboratory analytes) 
that are consistent with standard of care and monitoring should be performed per the 
investigator
's discretion.  Subjects must be taken off study treatment if, in the opinion of the 
investigator, an unacceptable toxicity develops. 
7.4.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  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 of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
Upon implementation of Amendment 4, AEs that lead to the discontinuation of study treatment 
and all SAEs must be recorded in the CRFs, regardless of the assumption of a causal relationship 
with the study drug. 
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7.4.2. 
Comprehensive Physical Examinations 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
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 height (at screening only) and the 
following organ or body system assessments:  skin; head, eyes, ears, nose, and throat; thyroid; 
lungs; cardiovascular system; abdomen (liver, spleen); extremities; lymph nodes; and 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). 
7.4.2.1. Disease-Specific Physical Examination 
A disease-specific physical examination will be a symptom-directed evaluation and will include 
assessment(s) of the body systems or organs, as indicated by subject disease and symptoms, AEs, 
or other findings as determined by the investigator or designee.  A disease-specific physical 
examination must include a measurement of the subject's body w
eight (within 1 lb or 0.5 kg), 
and an evaluation of any AEs or symptoms that the subject has previously reported. 
7.4.3. 
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. 
7.4.4. 
Twelve-lead Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest.  Baseline ECGs will be obtained during screening using a single 
measurement, but can be done in triplicate if the single QTc measurement is > 450 milliseconds 
(corrected by Fridericia; see Section 3.2).  Electrocardiograms will also be obtained during the 
Day 1 visit (triplicate measurements) before the subject receives the first dose of study drug.  
Triplicate ECGs will be performed predose and 1.5 hours (± 15 minutes) after receiving 
INCB050465 on Day 15.  When triplicate ECGs are being obtained, individual measurements 
should be performed 5 minutes (± 3 minutes) apart.  All 12-lead ECGs obtained at subsequent 
timepoints (single measurements) 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. 
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If a single measurement demonstrates a QTc interval > 500 milliseconds, 2 more ECGs should 
be obtained over a brief period, and the averaged QTc intervals should be used to determine 
whether the study treatment should be interrupted. 
Twelve-lead ECGs will be acquired using an ECG analysis system with analysis and printing 
capabilities, as well as digital transmission capabilities to a central capture module at the ECG 
laboratory.  The investigator and research staff will receive adequate training by a qualified 
person on the use and operation of the analysis system.  The successful digital submission of a 
12-lead ECG, meeting quality standards, to the central ECG laboratory by the site must be 
ensured before enrollment of the first subject.  The study manual for procedures that must be 
followed for the recording and transmission of ECGs and the operator
's manual with instructions 
for operating the digital capture module will be shipped to the site along with the device.  The 
12-lead ECGs will be interpreted by the investigator at the site and will be used for immediate 
subject management.  The decision to include or exclude a subject or discontinue a subject
's 
participation in the study based on an ECG flagged as "Abnormal, Clinically Significant" is the 
responsibility of the investigator, in consultation with the sponsor
's medical monitor, as 
appropriate.  Twelve-lead ECGs that are identified by the investigator as "Abnormal, Clinically 
Significant" will be sent to the sponsor
's medical monitor for review.  
The overall ECG interpretation will be indicated by a flagging system that will help distinguish 
between a normal ECG, ECG abnormalities where no further investigation is required, and ECG 
abnormalities where study exclusion, further cardiovascular investigation, and/or prompt action 
may be necessary depending on the clinical context.  A suitable flag will be included in the 
"Overall ECG Interpretation" section of the report when an ECG is considered to be technically 
unacceptable or uninterpretable.  If several different abnormalities exist corresponding to 
different levels of flagging, then the label will reflect the most severe level.  Flagging by the 
central expert cardiologist of these significant abnormalities should only be regarded as a 
suggestion.  This service is intended to assist the investigator in his/her interpretation of the ECG 
and decision-making.  It is not intended to replace the investigator
's expert judgment and 
knowledge of the subject
's medical condition. 
7.4.5. 
Laboratory Assessments 
Blood draws for laboratory assessments will occur at study visits indicated (see Table 5).  Blood 
draws will be completed before the subject receives the daily dose of INCB050465.  Specific 
laboratory assessments are provided (see Table 8).   
All laboratory assessments will be performed at a central laboratory.  If a local laboratory 
assessment is deemed necessary by the investigator and results in a change in patient 
management (eg, dose modification) or an SAE, then the assessment data and reference ranges 
must be recorded in the subject'
s eCRF. 
Upon implementation of Amendment 4, laboratory assessments (Table 7) only need to be 
performed in accordance with standard of care at each investigational site and monitored as per 
the investigator’s discretion.  Laboratory results do not need to be reported in the CRF, but all 
laboratory results corresponding with an SAE must be reported on the SAE form. 
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7.4.5.1. Chemistry and Hematology 
All chemistry and hematology assessments (see Table 5 and Table 8) will be performed from 
blood samples collected using institutional best practices. 
7.4.5.2. Pregnancy Testing 
A serum pregnancy test will be performed at screening and EOT.  Urine pregnancy test will be 
performed per Table 5; positive results must be confirmed with a serum pregnancy test.  
Pregnancy testing will only be required for women of childbearing potential. 
7.4.5.3. Serology 
Serology assessments (see Table 8) will be performed at a central laboratory. 
7.4.5.4. HIV Screening Test 
Subjects enrolled outside of the United States must have an HIV immunoassay test during 
screening to ensure negative HIV status before Day 1.  This test is optional for subjects enrolled 
in the United States. 
7.5. 
Efficacy Assessments 
Subjects will have an objective assessment of disease status using PET and diagnostic quality CT 
scan or MRI. 
7.5.1. 
FDG-PET or Combined PET-CT 
Positron emission tomography using [18 F] 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, the results 
from that assessment may be recorded in the eCRF in lieu of a study-specific assessment.   
Scheduled assessments should always be calculated from the first dose of study treatment.  
Imaging should not be delayed for delays in treatment. 
Note:  Subjects who discontinue study treatment for any reason other than disease progression or 
withdrawal of consent will be followed according to the disease assessment schedule until either 
disease progression, the start of a new anticancer therapy, or death, whichever occurs first. 
Upon implementation of Amendment 4, FDG-PET or combined PET-CT assessments are only 
required to be performed as per standard of care guidelines and monitored.  Subjects must be 
taken off study if, in the opinion of the investigator, the disease has progressed and the subject is 
no longer having clinical benefit from the study treatment. 
7.5.2. 
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, then the results from that assessment must be recorded in the 
eCRF if used in lieu of a study-specific assessment.   
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The disease 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 interruption of study treatment. 
Upon implementation of Amendment 4, CT or MRI assessments are only required to be 
performed as per standard of care guidelines and monitored.  Subjects must be taken off study if, 
in the opinion of the investigator, the disease has progressed and the subject is no longer having 
clinical benefit from the study treatment. 
7.5.3. 
Bone Marrow Examination 
Bone marrow examination is required as a baseline assessment except in the following 
circumstances: 
• Subject had a bone marrow examination performed as per standard of care within 
approximately 60 days of the first dose of study drug. 
• Subject had a bone marrow examination performed after the last treatment for NHL 
and the results showed lymphoma involvement of the bone marrow. 
• Baseline PET scan shows that the subject does have FDG-avid disease in the bone 
marrow (PET + bone marrow). 
Subsequently, bone marrow biopsy will be performed only to confirm CR/CMR or as clinically 
indicated.  If the bone marrow does not have lymphoma involvement at baseline, a repeat 
marrow examination is not required to confirm indication of CR/CMR on imaging. 
All bone marrow examinations should include a unilateral aspiration and biopsy, when feasible. 
The pathology report result from the bone marrow examination will be captured in the eCRF.   
7.5.4. 
Independent Review Committee 
All imaging (PET and CT or MRI) will be submitted to the central radiology vendor for review.  
Imaging data and applicable clinical data will be reviewed and response assessed using the PET 
CT–based response criteria of the Lugano Classification (Cheson et al 2014) by independent 
reviewers as described in the Imaging Charter. 
7.5.5. 
Response Criteria – The Lugano Classification 
Sites will use the PET-CT–based response criteria of the Lugano Classification (Cheson et al 
2014) to assess response to treatment locally.  Details regarding response assessment per the 
Lugano Classification are provided (see Table 9).  Positron emission tomography is required and 
therefore the criteria for PET-based response should be applied in most circumstances.  
Computed tomography/MRI–based response criteria are provided for those subjects with PET 
scans that cannot be interpreted or who do not have FDG-avid disease.  Response per the 
PET-CT and CT/MRI criteria will be collected in the eCRF. 
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Table 9:  
Lugano Classification for Response Assessment 
Site 
PET-Based Response 
CT-Based Response 
 
Complete metabolic response 
Complete radiologic response 
(all of the following) 
Lymph nodes and 
extralymphatic sites  
Score 1, 2, or 3 with or without a residual 
mass on 5PS
a 
Target nodes/nodal masses must regress to 
≤ 1.5 cm in LDi 
Nonmeasured lesion  Not applicable 
Absent 
Organ enlargement  Not applicable 
Regress to normal 
New lesions  
None 
None 
Bone marrow  
No evidence of FDG-avid disease in 
marrow 
Normal by morphology; if indeterminate, 
IHC negative 
 
Partial metabolic response 
Partial remission (all of the following) 
Lymph nodes and 
extralymphatic sites  
• Score 4 or 5a with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
• At interim, these findings suggest 
responding disease 
• At EOT, these findings suggest residual 
disease 
• ≥ 50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites  
• When a lesion is too small to measure on 
CT, assign 5 mm × 5 mm as the default  
• When no longer visible, 0 × 0 mm 
For a node > 5 mm × 5 mm but smaller than 
normal, use actual measurement 
Nonmeasured lesions  Not applicable  
Absent/regressed, but no increase 
Organ enlargement  Not applicable  
Spleen must have regressed by > 50% in 
length beyond normal 
New lesions  
None 
None 
Bone marrow  
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (diffuse uptake compatible with 
reactive changes from chemotherapy 
allowed).  If there are persistent focal 
changes in the marrow in the context of a 
nodal response, consider further evaluation 
with MRI or biopsy  
Not applicable 
 
No metabolic response 
Stable disease 
Target nodes/nodal 
masses, extranodal 
lesions  
Score of 4 or 5a with no significant change 
in FDG uptake from baseline at interim or 
EOT 
< 50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and 
extranodal sites; no criteria for PD are met 
Nonmeasured lesions  Not applicable 
No increase consistent with progression 
Organ enlargement  Not applicable 
No increase consistent with progression 
New lesions  
None 
None 
Bone marrow  
No change from baseline 
Not applicable 
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Table 9:  
Lugano Classification for Response Assessment (Continued) 
Site 
PET-Based Response 
CT-Based Response 
 
Progressive metabolic disease 
Progressive disease 
(requires at least 1 of the following) 
Individual target 
nodes/nodal lesions  
Individual target nodes/nodal lesions:  
• Score 4 or 5a with an increase in 
intensity of uptake from baseline and/or  
• New FDG-avid foci consistent with 
lymphoma at interim or EOT assessment 
 
Extranodal lesions:  
• New FDG-avid foci consistent with 
lymphoma at interim or EOT assessment 
 
New lesions:  
• New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(eg, infection, inflammation).  If 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered 
 
Bone marrow:  
• New or recurrent FDG-avid foci 
PPD progression:  
• An individual node/lesion must be 
abnormal with all of the following: 
- LDi > 1.5 cm  
- Increase by ≥ 50% from PPD nadir  
- Increase in LDi or SDi from nadir: 
o 0.5 cm for lesions ≤ 2 cm  
o 1.0 cm for lesions > 2 cm  
• In the setting of splenomegaly, the splenic 
length must increase by > 50% of the 
extent of its prior increase beyond 
baseline (eg, a 15 cm spleen must increase 
to > 16 cm).  If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline 
• New or recurrent splenomegaly 
• New or clear progression of pre-existing 
nonmeasured lesions 
• Regrowth of any previously resolved 
lesions 
• A new node > 1.5 cm in any axis 
• A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its presence 
must be unequivocal and must be 
attributable to lymphoma 
• Assessable disease of any size 
unequivocally attributable to lymphoma 
• New or recurrent involvement of the bone 
marrow 
5PS = 5-point scale; LDi = longest transverse diameter of lesion; PPD = cross-product of the longest transverse diameter and 
perpendicular diameter; SDi = shortest axis perpendicular to the longest transverse diameter; SPD = sum of the product of the 
perpendicular diameters for multiple lesions. 
a PET 5-point scale:  1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to 
lymphoma. 
7.5.6. 
ECOG Performance Status 
Eastern Cooperative Oncology Group performance status (Oken et al 1982; Table 10) will be 
assessed (see Table 4).  Performance status must be assessed by a medically-qualified individual 
and recorded in the eCRF. 
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Table 10:  
Eastern Cooperative Oncology Group 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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7.8. 
Other Study Procedures 
7.8.1. 
Administration of Study Drug 
See Section 5.2.1 for complete details regarding study drug administration. 
After implementation of Amendment 4, subjects will be dispensed the appropriate amount of 
medication to self-administer study drug as per protocol until their next scheduled visit 
(scheduled no more than 12 weeks later).  Subjects will continue to self-administer study 
medication, and compliance will continue to be assessed. 
7.8.2. 
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 
subjects of which days they should not take their morning dose before coming to the clinic (see 
Section 7.6).  The reminder cards for the Day 15 visit will have an area on which the date and 
time of the last dose taken (from the previous day) and the time of their last meal before the visit 
should be recorded. 
After implementation of Amendment 4, subjects will receive reminder cards that will include the 
date and time of the next visit and instructions for study drug administration. 
7.8.3. 
Data Collection for Survival Follow-Up 
For subjects having entered the survival follow-up period of the study, the site will collect data 
as described (see Section 6.4.3). 
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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: 
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. 
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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 intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event 
either changed severity again or resolved. 
Upon implementation of Amendment 4, AEs leading to treatment discontinuation and all SAEs 
regardless of causal relationship must be reported on the AE form in the eCRF. 
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8.2. 
Laboratory Test Abnormalities 
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 5.4) 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 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
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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. 
Upon implementation of Amendment 4, all SAEs regardless of causal relationship will be 
reported as described above. 
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8.4. 
Adverse Events of Special Interest 
Specific adverse events, or groups of adverse events, will be followed as part of standard safety 
monitoring activities.  These events (regardless of seriousness) will be reported per the SAE 
reporting timelines (see Section 8.3.2). 
• ALT ≥ 5 × ULN 
• AST ≥ 5 × ULN 
• Colitis 
• Diarrhea ≥ Grade 2  
• Rash ≥ Grade 2 
• Intestinal perforation 
• Pneumonitis 
• Pneumocystis jirovecii infection 
• CMV infection 
• Herpes simplex virus infection 
• Varicella zoster virus infection 
• Exfoliative dermatitis 
8.5. 
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 5.4 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 
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. 
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Any SAE occurring during pregnancy must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
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 (INCB050465 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. 
8.7. 
Independent Data Monitoring Committee 
An IDMC will be formed and will consist of qualified individuals who are not involved with the 
conduct of the study.  The establishment, composition, roles, duties, and responsibilities of the 
IDMC are addressed in the approved IDMC charter. 
8.8. 
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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9. 
STATISTICS 
9.1. 
Study Populations 
The full analysis set includes all subjects enrolled in the study who received at least 1 dose of 
INCB050465.  The full analysis set will be used for the summary of demographics, baseline 
characteristics, subject disposition, and analyses of all efficacy data. 
The per protocol (PP) population includes all subjects in the full analysis set who were 
sufficiently compliant with the Protocol.  The following procedures will be performed to identify 
those subjects who are to be excluded from the PP population before the database freeze: 
• Clinical review of Protocol deviations/violations 
• Clinical review of concomitant medications as defined in Section 5.6 of the Protocol 
• Clinical review of the dose administration and drug accountability listing 
The determination of subjects being considered for exclusion from the PP population by the 
clinical team will be prepared and signed before database freeze.  
The safety population includes all subjects enrolled in the study who received at least 1 dose of 
INCB050465.  This population will be used for all safety analyses.  
9.2. 
Selection of Sample Size 
The study will enroll 100 subjects into Group A.  If the true ORR is 0.50, then there is 
approximately 90% probability of observing the lower bound of the 95% CI of the ORR ≥ 35%. 
 
 
 
9.3. 
Level of Significance 
There will not be any statistical comparison between the 2 groups.  Within each group, 2-sided 
95% CIs will be reported for all analyses when appropriate. 
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9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. Primary Efficacy Analyses 
Objective response rate is defined as the percentage of subjects with a CR/CMR or PR/PMR as 
determined by revised response criteria for DLBCL (Cheson et al 2014). 
The ORR as determined by the IRC and its 95% exact binomial CIs will be calculated for 
subjects in Group A.  This is considered the primary efficacy analysis of the study.  
The ORR as reported by the investigator and its 95% exact binomial CIs will also be calculated 
for subjects in Group A. 
Response data will be analyzed when all subjects have received at least 1 postbaseline disease 
assessment, or have progressed, withdrawn from the study, or died.  
9.4.1.2. Secondary Efficacy Analyses 
Duration of response is defined as the time from first documented evidence of CR/CMR or 
PR/PMR until disease progression or death due to any cause among subjects who achieve an 
overall response (ie, CR/CMR or PR/PMR) as determined by revised response criteria for 
lymphomas (Cheson et al 2014).  For subjects who have not progressed and are still alive at the 
time of the analysis, DOR will be censored on the day of last evaluable disease assessment.  For 
subjects who have discontinued study or have started other anticancer treatment, DOR will be 
censored on the day of last evaluable disease assessment documenting absence of PD/PMD 
before the discontinuation or the start of the new anticancer treatment. 
Progression-free survival is defined as the time from the date of first dose of the study drug to the 
first documented disease progression as determined by revised response criteria for lymphomas 
(Cheson et al 2014), or death due to any cause, whichever occurs first.  For subjects who have 
not progressed and are still alive at the time of the analysis, PFS will be censored on the day of 
last evaluable disease assessment.  For subjects who have discontinued study or have started 
other anticancer treatment, PFS will be censored on the day of last evaluable disease assessment 
documenting absence of PD/PMD before the discontinuation or the start of the new anticancer 
treatment.  For subjects who have no baseline or no postbaseline disease assessment, PFS will be 
censored with censored duration of 1 day. 
The Kaplan-Meier estimation of median DOR and PFS as determined by the IRC and its 
95% CIs will be provided for subjects in Group A. 
The Kaplan-Meier estimation of median DOR and PFS as reported by the investigator and its 
95% CIs will also be provided for subjects in Group A. 
Overall survival is defined as the time from the date of first dose of study drug to death due to 
any cause.  For subjects who are still alive at the time of the analysis, OS will be censored on the 
date the subjects is last known to be alive.  The Kaplan-Meier estimation of median OS and its 
95% CIs will be provided for subjects in Group A. 
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9.4.2. 
Safety Analyses 
9.4.2.1. Adverse Events 
A treatment-emergent adverse event (TEAE) is any AE either reported for the first time or 
worsening of a pre-existing event after first dose of study drug.  Analysis of AEs 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 based on the NCI CTCAE v4.03 using Grades 1 through 4. 
The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
An overall summary of AEs will include number (%) of subjects reporting any TEAEs, any 
SAEs, any Grade 3 or 4 TEAEs, any treatment-related TEAEs, any fatal TEAE, and any TEAEs 
leading to treatment interruption/dose reduction/discontinuation. 
Number (%) of subjects reporting any TEAEs, any SAEs, any Grade 3 or 4 TEAEs, any 
treatment-related TEAEs, any treatment-related SAEs, any treatment-related Grade 3 or 4 
TEAEs, any fatal TEAE, and any TEAEs leading to treatment interruption/dose 
reduction/discontinuation will be tabulated by system organ class and preferred term. 
9.4.2.2. Clinical Laboratory Tests 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03 when applicable.  
The following summaries will be produced for the laboratory data: 
• Descriptive statistics of the value and change from baseline at each assessment time 
will be provided. 
• For laboratory parameters that have CTC grading, shift tables will be provided 
showing change in CTC grade from baseline to the worst grade postbaseline. 
• For laboratory parameters where CTC grades are not defined, shift tables from 
baseline to the worst postbaseline value will be produced using the low/normal/high 
classifications based on laboratory reference ranges. 
Categorical laboratory data will be tabulated by visit at baseline and postbaseline visits when 
necessary. 
9.4.2.3. Vital Signs 
Descriptive statistics and mean change from baseline will be summarized for vital signs (weight, 
blood pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital 
sign results will be reviewed for clinically notable abnormalities (see Table 12), and subjects 
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exhibiting clinically notable vital sign abnormalities will be listed.  A value will also be 
considered an "alert" value if it is outside the established range and shows a > 25% change from 
baseline.  The abnormal values for subjects exhibiting alert vital sign abnormalities will be listed 
Table 12: 
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 
> 38ºC 
< 35ºC 
Respiratory rate 
> 24/min 
< 12/min 
9.4.2.4. Electrocardiograms 
Descriptive statistics and mean change from baseline will be summarized for the ECG parameter 
at each assessment time.  Average of all values before the first dose of study drug will be used as 
the baseline value.  Criteria for clinically notable ECG abnormalities are defined (see Table 13).  
The abnormal values for subjects exhibiting clinically notable ECG abnormalities will be listed.  
Alert ECG values are defined as an absolute value outside the defined range and absolute 
percentage change > 25% (30% for QRS) interval.  The abnormal values for subjects exhibiting 
alert ECG abnormalities will be listed.  Outliers of QT, QTcB, and QTcF, defined as absolute 
values > 450 milliseconds or change from baseline > 30 milliseconds, will also be listed.   
Table 13: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF 
> 460 msec 
< 295 msec 
PR 
> 220 msec 
< 75 msec 
QRS 
> 120 msec 
< 50 msec 
QT 
> 500 msec 
< 300 msec 
RR 
> 1330 msec 
< 600 msec 
QTcF = Fridericia correction. 
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9.5. 
Analyses for the Independent Data Monitoring Committee 
Preplanned analyses of safety will be provided to the IDMC as specified in the IDMC charter.  In 
addition, the IDMC will make recommendations to the sponsor at the planned interim futility 
analysis in Group A (see Section 9.6).  The process by which the IDMC will make 
recommendations and decisions will be documented in the IDMC charter. 
9.6. 
Interim Analysis 
An interim futility analysis is planned when the first 40 subjects in Group A have been treated 
and have been evaluated for response or have permanently discontinued study treatment because 
of disease progression, withdrawal of consent, or death.  Group A of the study will be terminated 
for futility if ≤ 13 of the 40 subjects have responded (ie, CR/CMR or PR/PMR) based on 
assessments provided by the IRC; otherwise the study will continue.  The futility boundary is 
determined using a spending function of HSD(-4).  A timely assessment of response will be 
performed to avoid the risk of overenrollment. 
 
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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 
direct access to subject records. 
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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 
will also maintain records adequately documenting that the subjects were provided the specified 
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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 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 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
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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. 
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 
Cantley LC.  The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657. 
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. 
Coutre S, Barrientos JC, Brown JR, et al. Management of adverse events associated with 
idelalisib treatment: expert panel opinion. Leuk Lymphoma 2015;56:2779-2786. 
Cultrera JL, Dalia SM. Diffuse large B-cell lymphoma: current strategies and future directions.  
Cancer Control 2012;19:204-213. 
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, Wertheim MS, Phillips TJ, et al. Preliminary safety, efficacy and 
pharmacodynamics of a highly selective PI3Kδ inhibitor, INCB050465, in patients with 
previously treated B-cell malignancies. Presented at: American Association of Cancer Research; 
April 16-20, 2016; New Orleans, LA. 
Foon KA, Takeshita K, Zinzani PL. Novel therapies for aggressive B-cell lymphoma. Adv 
Hematol 2012;2012:302570. 
Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed 
indolent lymphoma. N Engl J Med 2014;370:1008-1018. 
INCB040093 Investigator
's Brochure (IB). Wilmington, DE: Incyte Corporation. 
INCB050465 Investigator's Brochure (IB). Wilmington, DE: Incyte Corporation. 
Martelli M, Ferreri AJ, Agnostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large 
B-cell lymphoma. Crit Rev Oncol Hematol 2013;87:146-171. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events Version 
4.03. 2009. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. Accessed May 21, 2016. 
National Cancer Institute (NCI). Surveillance, Epidemiology, and End Results Program. 2016. 
http://seer.cancer.gov/statfacts/html/nhl.html. Accessed May 21, 2016. 
National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: 
Non-Hodgkin
's Lymphomas Version 4.2014. 2014. https://www.nccn.org/about/nhl.pdf. 
Accessed February 23, 2017. 
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. 
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Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib 
(BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients 
with advanced solid tumors andnon-Hodgkin’s lymphomas. Ann Oncol 2016;27:1928-1940. 
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. 
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A.  Global Cancer Statistics, 
2012. CA Cancer J Clin 2015;65:87-108. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29. 
Smith TC, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of 
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24:3187-3205. 
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. 
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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 ovulation
1 
− oral 
− injectable 
− implantable
2 
• Intrauterine device (IUD)
2 
• Intrauterine hormone-releasing system (IUS)
2 
• Bilateral tubal occlusion2 
• Vasectomised partner
2,3 
• 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 of avoiding pregnancy provided 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 AND P-GLYCOPROTEIN 
INHIBITORS AND CYTOCHROME P450 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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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
30 AUG 2016 
Amendment (Version) 2: 
09 NOV 2016 
Amendment (Version) 3: 
23 FEB 2017 
Amendment (Version) 3-CAN: 
12 DEC 2017 
Amendment (Version) 4: 
05 NOV 2019 
Amendment 4 (05 NOV 2019) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to reduce 
Protocol-required procedures for subjects who remain on study treatment.  Subjects should be 
monitored per the standard of care for their condition as determined by the investigator. 
1. Synopsis; Section 4.1, Overall Study Design; Section 6, Study Assessments 
(including new Table 6 and Table 7); Section 7, Conduct of Study Assessments and 
Procedures; Section 7.3.1.1, Prior and Concomitant Medications and Procedures; 
Section 7.4, Safety Assessments; Section 7.4.1, Adverse Events; Section 7.4.5, 
Laboratory Assessments; Section 7.5.1, FDG-PET or Combined PET-CT; 
Section 7.5.2, Computed Tomography Scan or Magnetic Resonance Imaging; 
Section 7.8.1, Administration of Study Drug; Section 7.8.2, Distribution of Subject 
Reminder Cards 
Description of change:  The sections were updated to include information on reduced 
Protocol-required assessments for subjects who are ongoing in the study. 
Rationale for change:  To reduce the burden of unnecessary procedures for the ongoing 
remaining subjects and the sites. 
2. Synopsis 
Description of change:  The coordinating PI for the study was added (
 
MD, 
). 
Rationale for change:  To identify the study
's coordinating PI. 
3. Section 1.3, INCB050465 
Description of change:  Added a statement to refer to the IB for current information on 
INCB050465. 
Rationale for change:  The IB has been updated and is a better source for this 
information. 
4. Section 4.6, Study Termination 
Description of change:  Statement added indicating that upon study closure, subjects 
who are still receiving study treatment will have the option to transition to Study 
INCB 50465-214, in which they may continue to receive study treatment. 
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Rationale for change:  To include a crossover option for subjects to continue treatment 
after study closure. 
5. Section 7.4.1, Adverse Events; Section 8.1.2, Reporting; Section 8.3.2, Reporting 
Description of change:  Serious adverse events (SAEs) and adverse events leading to 
discontinuation from study treatment will be collected by the sponsor. 
Rationale for change:  Collection of all SAEs and AEs leading to discontinuation is 
sufficient for safety monitoring of the study treatment at this point in the study. 
6. 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-CAN (12 DEC 2017) 
Overall Rationale for the Amendment:  To remove a criterion for study treatment 
discontinuation per Health Canada
's request. 
1. Section 5.5.1, Criteria for Study Treatment Discontinuation 
Description of change:  The following bullet has been deleted from Section 5.5.1: 
• 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. 
Rationale for change:  To meet Health Canada requirements. 
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Amendment 3 (23 FEB 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to address changes requested by the European 
Regulatory Agency. 
This amendment includes the changes to Protocol INCB 50465-202 Amendment 2 (09 NOV 
2016) summarized below.  A redline version of the amendment depicting updated and previous 
text is also provided. 
1. Synopsis; Section 1.4, Study Rationale; Section 3.1, Subject Inclusion Criteria 
Description of change:  Change the minimum number of allowed prior systemic 
therapies from 1 to 2 and provide types of prior therapies. 
Rationale for change:  Requested by European Regulatory Agency. 
2. Synopsis; Section 1.5, Potential Risks and Benefits of the Treatment Regimen; 
Section 5.2.2, Supply, Packaging, and Labeling; Section 5.6.1, Pneumocystis Jirovecii 
Prophylaxis 
Description of change:  Require that all subjects receive prophylaxis against 
Pneumocystis jirovecii pneumonia. 
Rationale for change:  Requested by European Regulatory Agency. 
3. Section 1.4, Study Rationale 
Description of change:  The dose rationale was moved from Section 1.5, Potential Risks 
and Benefits of the Treatment Regimen, to Section 1.4, Study Rationale. 
Rationale for change:  To relocate the dose rationale to the appropriate section of the 
Protocol. 
4. Section 1.5, Potential Risks and Benefits of the Treatment Regimen 
Description of change:  A paragraph was added stating that subjects should avoid 
sun/ultraviolet light. 
Rationale for change:  Requested by European Regulatory Agency. 
5. Section 3.1, Subject Inclusion Criteria; Section 6, Study Assessments (Table 5) 
Description of change:  The amount of time that men should avoid fathering a child was 
increased to 93 days in inclusion criterion 8c; an administrative error was corrected by 
removing the pregnancy test on Day 1 in inclusion criterion 8b.  Pregnancy test for 
women of childbearing potential was added at each 3-week visit in Table 5. 
Rationale for change:  Requested by European Regulatory Agency. 
6. Section 3.2, Subject Exclusion Criteria 
Description of change:  Exclusion criterion 13 was modified to exclude subjects that had 
exposure to a live vaccine within 30 days of study drug administration.  
Rationale for change:  Requested by European Regulatory Agency. 
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7. Section 3.2, Subject Exclusion Criteria (criterion 14); Section 6, Study Assessments 
(Tables 5 and 6); Section 7.4.5.4, HIV Screening Test 
Description of change:  Require that subjects enrolled outside the United States have an 
HIV test at screening. 
Rationale for change:  Requested by European Regulatory Agency. 
8. Section 5.4.1, Criteria and Procedures for Dose Interruptions and Reductions of 
INCB050465 (Table 2) 
Description of change:  Provide guidance that all subjects with Grade 3 ANC 
(< 1.0 × 10
9/L) should have INCB050465 administration interrupted. 
Rationale for change:  Requested by European Regulatory Agency. 
9. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
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Amendment 2 (09 NOV 2016) 
Overall Rationale for the Amendment:  
The primary purpose of this amendment is to change the dose of INCB050465. 
This amendment includes the changes to Protocol INCB 50465-202 Amendment 1 
(30 AUG 2016) summarized below.  A redline version of the amendment depicting updated and 
previous text is also provided. 
1. Synopsis; Section 1.4, Study Rationale; Section 4.1, Overall Study Design; Section 
5.2.1, Description and Administration 
Description of change:  The dose of INCB050465 has been changed from 30 mg once 
daily to 20 mg once daily for 8 weeks followed by 20 mg once weekly. 
Rationale for change:  As of 02 SEP 2016, among all subjects (n = 46) in study 
INCB 50465-101, 11 (24%) have discontinued study drug due to an adverse event (AE).  
Among the subjects with an objective response (n = 20), 7 (35%) discontinued study 
treatment due to an AE.  The dose has been changed in an effort to reduce the frequency 
of AEs that lead to study drug discontinuation. 
2. Synopsis; Section 3.1, Subject Inclusion Criteria 
Description of change:  Inclusion criterion 1 was modified to allow only subjects aged 
19 years or older to enroll in South Korea. 
Rationale for change:  The legal adult age in South Korea is 19 years. 
3. Section 1.3, INCB050465 
Description of change:  Safety and efficacy data have been updated based on a data cut 
of 02 SEP 2016. 
Rationale for change:  These changes were made to provide the most recent emerging 
data to support the need for a dose change and the new dose rationale. 
4. Section 1.5, Potential Risks and Benefits of the Treatment Regimen 
Description of change:  The potential risks and benefits of the treatment regimen were 
updated based on the 02 SEP 2016 data cut, and the dose rationale was provided. 
Rationale for change:  The changes were made to provide a current interpretation based 
on the most recent data.  The dose rational was changed to support the new dose. 
5. Section 5.4, Treatment Interruptions and Adjustments 
Description of change:  Table 2 (Guidelines for Interruption and Restarting Study Drug) 
and Table 3 (Dose Levels for INCB050465) were updated, and the term "immune-related 
adverse event" was defined. 
Rationale for change:  New guidance was provided for AEs that have caused treatment 
discontinuation in Study INCB 50465-101 to assist physicians manage these AEs.  The 
term "immune-related adverse event" was defined so investigators can consistently 
answer the following question in the eCRF:  "Is this event an immune-related adverse 
event?" 
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6. Section 6, Study Assessments (Table 4:  Schedule of Assessments) 
Description of change:  The frequency of drug dispensing was altered. 
Rationale for change:  Because the dose schedule changed from daily to weekly at 
Week 9, the dose dispensing schedule was changed to reduce the amount of drug that 
would otherwise be discarded. 
7. Section 8.4, Adverse Events of Special Interest 
Description of change:  Rash ≥ Grade 2 was added to the list of adverse events of 
special interest, and diarrhea was changed to ≥ Grade 2. 
Rationale for change:  Rash was added because this is an AE that has led to study 
treatment discontinuation and has occurred with some frequency in Study 
INCB 50465-101.  The change in diarrhea reporting was made to reduce the amount of 
expedited reporting for this event. 
8. 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 1 (30 AUG 2016) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to fulfill a request from the FDA to 1) add an 
Independent Data Monitoring Committee and 2) Conduct an interim analysis for futility in 
Group A. 
This amendment includes the changes to Protocol INCB 50465-202 (26 MAY 2016) summarized 
below.  A redline version of the amendment depicting updated and previous text is also provided. 
1. Synopsis; Section 4.1, Overall Study Design; Section 9.2, Selection of Sample Size; 
Section 9.6, Interim Analysis 
Description of change:  An interim futility analysis has been added.  The analysis is 
planned when the first 40 subjects in Group A have been treated and have been evaluated 
for response or have permanently discontinued study treatment because of disease 
progression, withdrawal of consent, or death.  Group A of the study will be terminated for 
futility if ≤ 13 of the 40 subjects have responded (ie, complete response [CR]/complete 
metabolic response [CMR] or partial response [PR]/partial metabolic response [PMR]) 
based on assessments provided by the independent review committee; otherwise the 
study will continue. A timely assessment of response will be performed to avoid the risk 
of overenrollment. No formal futility analysis will be conducted for Group B.  
Section 9.2 (Selection of Sample Size) was updated to be consistent with the numbers 
used in the added interim analysis. 
Rationale for change:  Requested by the FDA. 
2. Synopsis; Section 4.1, Overall Study Design; Section 4.6, Study Termination; 
Section 8.7, Independent Data Monitoring Committee; Section 9.5, Analyses for the 
Independent Data Monitoring Committee 
Description of change:  An independent Data Monitoring Committee (IDMC) was 
included in the study to review safety and perform the futility analysis. 
Rationale for change:  Requested by the FDA. 
3. Synopsis; Section 2, Study Objectives and Endpoints 
Description of change:  The primary objective was updated to clarify that efficacy will 
be assessed in terms of objective response rate (ORR) in Group A, and study endpoints 
were updated to indicate Group A or Group B where applicable. 
Rationale for change:  For clarity and to make the objectives and endpoints consistent.  
4. Synopsis; Section 2.2, Study Endpoints; Section 4.1, Overall Study Design; Section 
5.5.1, Criteria for Study Treatment Discontinuation; Section 6, Study Assessments; 
Section 7.5.3, Bone Marrow Examination; Section 7.5.5, Response Criteria – The 
Lugano Classification; Section 9.4.1, Efficacy Analyses 
Description of change:  Complete response (CR), partial response (PR), and progressive 
disease (PD) were changed throughout the document to complete response/complete 
metabolic response (CR/CMR), partial response/partial metabolic response (PR/PMR), 
and progressive disease/progressive metabolic disease (PD/PMD). 
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Rationale for change:  The change was made to be consistent with the endpoints of the 
Lugano Criteria, which are being used to evaluate the disease assessments. 
5. Section 5.4.1, Criteria and Procedures for Dose Interruptions and Reductions of 
INCB050465 (Table 2); Section 5.4.2, Supportive Care Guidelines for 
Diarrhea/Colitis; Section 11, References 
Description of change:  Guidance for management of diarrhea and colitis was added, 
and guidance for ALT/AST elevation and Grade 3 toxicities was modified. 
Rationale for change:  To support investigators whose subjects experience 
diarrhea/colitis, which has been observed in the ongoing INCB050465 Phase 1 study. 
 
8. 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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Signature Manifest
Document Number:IC-DEV-PROT-AMEND-0524
Revision:1
Title:50465-202 Protocol Amendment 4
All dates and times are in Eastern Standard Time.
APPROVAL: 50465-202 Am 4 Revised
Approval and Release
Name/Signature
Title
Date
Meaning/Reason
05 Nov 2019, 06:04:48 PM
Approved
 
06 Nov 2019, 08:33:58 AM
Approved
06 Nov 2019, 03:58:47 PM
Approved
07 Nov 2019, 12:47:22 PM
Approved