A Phase 2 Multicenter, Randomized, Placebo Controlled, Double Blind Study to Assess the Safety and Efficacy of CC-486 (Oral Azacitidine) in Combination With Pembrolizumab (MK-3475) Versus Pembrolizumab Plus Placebo in Subjects With Previously Treated Locally Advanced or Metastatic Non-small Cell Lung Cancer
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Celgene

 
 
 
 
 
Protocol Title: A Phase 2 Multicenter, Randomized, 
Placebo Controlled, Double-Blind Study To Assess 
The Safety And Efficacy Of CC-486 (Oral Azacitidine) 
In Combination With Pembrolizumab (Mk-3475) 
Versus Pembrolizumab Plus Placebo In Subjects 
With Previously Treated Locally Advanced Or 
Metastatic Non-Small Cell Lung Cancer 
 
NCT Number:  NCT02546986 
Original Protocol Date:  15 May 2015 

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CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-NSCL-001 Final: 15 May 2015
TITLE PAGE
A PHASE 2 MULTICENTER, RANDOMIZED, PLACEBO 
CONTROLLED, DOUBLE-BLIND STUDY TO ASSESS 
THE SAFETY AND EFFICACY OF CC-486 (ORAL 
AZACITIDINE) IN COMBINATION WITH 
PEMBROLIZUMAB (MK-3475) VERSUS 
PEMBROLIZUMAB PLUS PLACEBO IN SUBJECTS 
WITH PREVIOUSLY TREATED LOCALLY ADVANCED 
OR METASTATIC NON-SMALL CELL LUNG CANCER
PROTOCOL NUMBER:
CC-486-NSCL-001
DATE FINAL:
15 May 2015
EudraCT NUMBER:
2014-005614-29
IND NUMBER:
123160
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
United States
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
2
CC-486-NSCL-001 Final: 15 May 2015
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: Route de Perreux 1, 
Boudry, Switzerland  2017
Phone:
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
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CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
3
CC-486-NSCL-001 Final: 15 May 2015
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
4
CC-486-NSCL-001 Final: 15 May 2015
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-NSCL-001 Final: 15 May 2015
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-NSCL-001 Final: 15 May 2015
PROTOCOL SUMMARY
Study Title
A Phase 2 multicenter, randomized, placebo controlled, double-blind study to assess the safety 
and efficacy of CC-486 (oral azacitidine) in combination with pembrolizumab (MK-3475) versus 
pembrolizumab plus placebo in subjects with previously treated locally advanced or metastatic 
non-small cell lung cancer
Indication  
Second-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). 
Objectives
Primary Objective:
!
To estimate the efficacy of CC-486 plus pembrolizumab versus pembrolizumab plus 
placebo based on progression-free survival (PFS) as measured using Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Secondary Objectives:
!
To estimate disease control rate (DCR) of CC-486 plus pembrolizumab versus 
pembrolizumab plus placebo
!
To estimate overall survival (OS) of CC-486 plus pembrolizumab versus 
pembrolizumab plus placebo
!
To estimate overall response rate (ORR) of CC-486 plus pembrolizumab versus 
pembrolizumab plus placebo
!
To evaluate safety and tolerability of CC-486 plus pembrolizumab versus 
pembrolizumab plus placebo
!
To evaluate the impact of pembrolizumab on the pharmacokinetics of CC-486 
Exploratory Objectives:
!
To determine the preliminary efficacy (immune-related [ir] PFS, irDCR, irORR) of 
CC-486 in combination with pembrolizumab versus pembrolizumab plus placebo
based on irRECIST criteria 
!
To explore mechanism and biomarkers associated with efficacy of CC-486 in 
combination with pembrolizumab versus pembrolizumab plus placebo,
Study Design
This is a Phase 2, multicenter, international, randomized, placebo controlled double-blind study 
to assess the safety and efficacy of the combination therapy of CC-486 plus pembrolizumab
versus placebo plus pembrolizumab in previously treated subjects with locally advanced or 
metastatic NSCLC who have received one prior platinum-based chemotherapy regimen. 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-NSCL-001 Final: 15 May 2015
Approximately 90 subjects will be randomized 1:1 to receive CC-486 plus pembrolizumab or 
placebo plus pembrolizumab. A safety analysis will be performed in the first 10 subjects in each 
arm after the completion of at least 1 cycle of treatment.
The randomization will be stratified by histology (non-squamous versus squamous).
An independent Data Monitoring Committee (iDMC) will be established to evaluate safety. 
Following the initial iDMC data review meeting, the iDMC will meet approximately every 6 
months per DMC charter (or more often if requested by the DMC Chairman) to assess safety 
data.  Details are outlined in the DMC charter.
The conduct of this trial will be overseen by a Steering Committee which will serve in an 
advisory capacity to the Sponsor.  
The study will be conducted in compliance with International Conference on Harmonisation 
(ICH) Good Clinical Practices (GCPs).
Study Population
Adult subjects with histologically confirmed diagnosis of locally advanced or metastatic 
NSCLC, lacking anaplastic lymphoma kinase (ALK) or endothelial growth factor receptor 
(EGFR) mutations, who have been treated with 1 prior platinum-based chemotherapy regimen
for locally advanced or metastatic disease.
Length of Study
Enrollment is expected to take approximately 12 months to complete.  The total length of this 
Phase 2 study with follow-up is estimated to be approximately 2 years. The primary analysis will 
be conducted when 70 PFS events have occurred. 
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol,
whichever is the later date.  
Study Treatments
CC-486/placebo will be administered at a dose of 300 mg orally daily on days 1-14 of a 21-day 
cycle. Pembrolizumab will be administered as a 30-minute intravenous (IV) infusion at a dose of 
200 mg (4 x 50 mg vials) on day 1 of a 21-day cycle. 
Subjects may remain on treatment until radiologic disease progression (for exceptions refer to 
Section 6.4.3 ), unacceptable toxicity, initiation of a new anticancer therapy, withdrawal of 
consent, subject refusal, physician decision, or death.
Overview of Efficacy Assessments
All subjects will be evaluated for tumor response and progression by Investigator assessment
according to RECIST 1.1 guidelines at screening and every 6 weeks (± 5 days) from 
randomization for the first 24 weeks, and every 9 weeks thereafter until documented disease 
progression (for exceptions refer to Section 6.4.3 ), start of new anticancer therapy, or 
withdrawal of consent. Subjects will also be evaluated according to irRECIST guidelines in cases 
of progressive disease (PD) per RECIST 1.1.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-NSCL-001 Final: 15 May 2015
Response assessments will include computed tomography (CT) scan or magnetic resonance 
imaging (MRI) of the chest and abdomen/pelvis. Bone scans will only be performed at baseline 
if clinically indicated. If the baseline bone scan is suggestive of metastasis, a CT or MRI should 
be performed and further follow-up of these lesions will follow the protocol schedule. Bone 
scans during the trial will only be performed if clinically indicated.  If suggestive of new lesions, 
a CT or MRI will be performed to confirm progression.
In the follow-up phase, anticancer treatment administered following the last dose of 
investigational product (IP) and survival will be followed every 8 weeks (± 5 days) until death, 
withdrawal of consent, or lost-to-follow-up, whichever occurs first, or the End of Trial.
Overview of Safety Assessments
All subjects will be monitored for adverse events, starting from the time the subject signs the 
informed consent form (ICF) until 30 days after the last dose of either study drug. A thorough 
evaluation of medical conditions will be conducted during screening for eligibility. Documented
physical examination (PE), vital signs, laboratory assessments, (eg, serum chemistry, 
hematology), 12-lead electrocardiogram (ECG), urinalysis, and Eastern Cooperative Oncology 
Group (ECOG) performance status will be monitored regularly. Preventative measures will be 
taken to avoid pregnancy in study subjects or their partners, and females of child-bearing 
potential will have regular pregnancy testing performed. The full schedule of assessments is 
described in Table 2 and Section 6.
Overview of Statistical Methods
This is a double-blind, placebo-controlled, randomized, phase 2 trial designed to evaluate the 
efficacy and safety/tolerability of  CC-486 plus pembrolizumab versus pembrolizumab plus 
placebo, in subjects with previously treated locally advanced or metastatic non-small cell lung 
cancer. The primary endpoint is PFS based on Investigator review.
Sample Size
The primary goal of this study is to provide estimates of the difference in efficacy and safety 
between CC-486 + pembrolizumab and placebo + pembrolizumab. Approximately 90 subjects 
will be randomized 1:1 to receive CC-486 plus pembrolizumab or placebo plus pembrolizumab. 
Primary analysis will be conducted when 70 PFS events occur. In this particular setting, a formal 
power calculation was not conducted.
Efficacy Analysis
Efficacy analyses will be performed using the intent-to-treat (ITT) population.
The median PFS in each stratum and treatment arm will be calculated based on Kaplan-Meier 
estimates along with corresponding two-sided 90% confidence interval (CI).  In addition, the 
Cox proportional hazards regression model with treatment and any stratification factors will be 
performed to obtain the point estimate of hazard ratio (HR) and two-sided 90% CI.  
The secondary efficacy endpoint of OS will be analyzed similarly to PFS.  Other secondary 
endpoints of overall response rate (ORR), and disease control rate (DCR) will be evaluated as 
well. A two-sided 90% CI of the difference in ORR and DCR between the two treatment arms 
will be provided. 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-NSCL-001 Final: 15 May 2015
Safety Analysis
Safety analysis will be performed using the safety population. Safety and tolerability will be 
monitored through continuous reporting of adverse events (AEs) and serious adverse events 
(SAEs), laboratory abnormalities, and incidence of subjects experiencing adverse events 
resulting in dose reductions, dose interruptions, and/or premature discontinuation of study drugs. 
Treatment-emergent adverse events (TEAEs), TEAEs leading to death or discontinuation from 
treatment, events assessed as Grade 3 or Grade 4,  vital signs, weight, clinical laboratory 
information, and concomitant medications/procedures will be tabulated and summarized.
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
All TEAEs will be summarized by system organ class and preferred term, frequency, severity 
grade based on the Common Terminology Criteria for Adverse Events (CTCAE) (Version 4.0) 
and relationship to treatment. Serious TEAEs, TEAEs of interest, and TEAEs leading to 
discontinuation, dose reduction, or interruption, or death will be summarized/ listed separately.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-NSCL-001 Final: 15 May 2015
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................18
1.1.
Disease Background ...............................................................................................18
1.2.
Treatment Options in Second-line Metastatic NSCLC ............................................18
1.3.
Overview of CC-486...............................................................................................20
1.3.1.
CC-486 Experience in Solid Tumors.......................................................................21
1.4.
Overview of Pembrolizumab ..................................................................................22
1.4.1.
Pembrolizumab Experience in Solid Tumors and Safety.........................................23
1.5.
Study Rationale ......................................................................................................24
2.
STUDY OBJECTIVES...........................................................................................26
2.1.
Primary Objective...................................................................................................26
2.2.
Secondary Objectives .............................................................................................26
2.3.
Exploratory Objectives ...........................................................................................26
3.
STUDY ENDPOINTS............................................................................................27
3.1.
Primary Endpoint....................................................................................................27
3.2.
Secondary Endpoints ..............................................................................................27
3.3.
Exploratory Endpoint(s)..........................................................................................27
4.
OVERALL STUDY DESIGN ................................................................................28
4.1.
Study Design ..........................................................................................................28
4.2.
Study Duration .......................................................................................................29
4.3.
End of Trial ............................................................................................................29
5.
TABLE OF EVENTS.............................................................................................30
6.
PROCEDURES......................................................................................................35
6.1.
Screening Period.....................................................................................................35
6.2.
Treatment Period ....................................................................................................36
6.2.1.
End of Treatment....................................................................................................37
6.3.
Follow-up Period....................................................................................................38
6.3.1.
Efficacy Follow-up.................................................................................................38
6.3.2.
Survival Follow-up.................................................................................................38
6.4.
Response Assessments............................................................................................38
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
11
CC-486-NSCL-001 Final: 15 May 2015
6.4.1.
Assessment of Response According to RECIST Version 1.1...................................39
6.4.2.
Assessment of Response According to irRECIST ...................................................39
6.4.3.
Assessment of Disease and Treatment after Initial Radiologic Progression .............39
6.5.
Pharmacokinetics....................................................................................................40
6.6.
Biomarkers .............................................................................................................41
6.7.
12-lead Electrocardiogram......................................................................................41
7.
STUDY POPULATION.........................................................................................42
7.1.
Number of Subjects and Sites .................................................................................42
7.2.
Inclusion Criteria....................................................................................................42
7.3.
Exclusion Criteria...................................................................................................43
8.
DESCRIPTION OF STUDY TREATMENTS........................................................46
8.1.
Description of Investigational Products...................................................................46
8.1.1.
CC-486 (Oral Azacitidine)/Placebo.........................................................................46
8.1.2.
Pembrolizumab.......................................................................................................46
8.2.
Treatment Administration and Schedule .................................................................46
8.2.1.
Dose Adjustment Guidelines...................................................................................47
8.2.1.1.
CC-486 (oral azacitidine)/Placebo ..........................................................................47
8.2.1.2.
Pembrolizumab.......................................................................................................49
8.2.2.
Overdose ................................................................................................................51
8.3.
Method of Treatment Assignment...........................................................................52
8.4.
Packaging and Labeling..........................................................................................52
8.5.
Investigational Product Accountability and Disposal ..............................................52
8.6.
Investigational Product Compliance........................................................................52
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................53
9.1.
Permitted Concomitant Medications and Procedures...............................................53
9.1.1.
CC-486 (oral azacitidine)........................................................................................53
9.1.2.
Pembrolizumab Supportive Care.............................................................................53
9.1.2.1.
Management of pneumonitis...................................................................................54
9.1.2.2.
Management of Diarrhea/Colitis.............................................................................54
9.1.2.3.
Management of type 1 diabetes mellitus (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) ................................................................54
9.1.2.4.
Management of hypophysitis ..................................................................................54
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9.1.2.5.
Management of hyperthyroidism or hypothyroidism...............................................55
9.1.2.6.
Management of hepatic abnormalities.....................................................................55
9.1.2.7.
Management of renal failure or nephritis.................................................................55
9.1.2.8.
Management of infusion reactions ..........................................................................55
9.2.
Prohibited Concomitant Medications and Procedures..............................................55
9.3.
Required Concomitant Medications and Procedures................................................56
10.
STATISTICAL ANALYSES..................................................................................57
10.1.
Overview................................................................................................................57
10.2.
Study Population Definitions ..................................................................................57
10.2.1.
Intent-To-Treat Population .....................................................................................57
10.2.2.
Safety Population....................................................................................................57
10.2.3.
PK Population ........................................................................................................57
10.2.4.
Biomarker Population.............................................................................................57
10.3.
Sample Size and Power Considerations...................................................................57
10.4.
Background and Demographic Characteristics........................................................58
10.5.
Subject Disposition.................................................................................................58
10.6.
Efficacy Analysis....................................................................................................58
10.6.1.
Primary Efficacy Endpoint......................................................................................58
10.6.2.
Secondary Endpoints ..............................................................................................59
10.6.2.1.
Overall Survival .....................................................................................................59
10.6.2.2.
Overall Response Rate (ORR) ................................................................................59
10.6.2.3.
Disease Control Rate (DCR)...................................................................................59
10.6.2.4.
irPFS, irORR and irDCR per irRECIST..................................................................59
10.6.3.
Subgroup Analysis..................................................................................................59
10.7.
Safety Analysis.......................................................................................................59
10.8.
Pharmacokinetic Analysis.......................................................................................60
10.8.1.
Plasma Concentrations............................................................................................60
10.8.2.
Pharmacokinetic Parameters...................................................................................61
10.8.3.
PK Analyses...........................................................................................................62
10.9.
Interim Analysis .....................................................................................................62
10.10.
Other Topics...........................................................................................................62
10.10.1.
Data Monitoring Committee ...................................................................................62
10.10.2.
Steering Committee ................................................................................................62
6
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10.9.
0.9.

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11.
ADVERSE EVENTS..............................................................................................64
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................64
11.2.
Evaluation of Adverse Events.................................................................................65
11.2.1.
Seriousness.............................................................................................................65
11.2.2.
Severity / Intensity..................................................................................................66
11.2.3.
Causality ................................................................................................................66
11.2.4.
Duration .................................................................................................................67
11.2.5.
Action Taken..........................................................................................................67
11.2.6.
Outcome.................................................................................................................67
11.3.
Abnormal Laboratory Values..................................................................................67
11.4.
Pregnancy...............................................................................................................68
11.4.1.
Females of Childbearing Potential ..........................................................................68
11.4.2.
Male Subjects.........................................................................................................68
11.5.
Reporting of Serious Adverse Events......................................................................69
11.5.1.
Safety Queries ........................................................................................................69
11.6.
Expedited Reporting of Adverse Events..................................................................69
11.7.
Pembrolizumab Events of Clinical Interest .............................................................70
12.
DISCONTINUATIONS .........................................................................................72
12.1.
Treatment Discontinuations ....................................................................................72
12.2.
Study Discontinuation ............................................................................................72
13.
EMERGENCY PROCEDURES.............................................................................73
13.1.
Emergency Contact.................................................................................................73
13.2.
Emergency Identification of Investigational Products .............................................73
14.
REGULATORY CONSIDERATIONS...................................................................74
14.1.
Good Clinical Practice............................................................................................74
14.2.
Investigator Responsibilities...................................................................................74
14.3.
Subject Information and Informed Consent.............................................................75
14.4.
Confidentiality........................................................................................................75
14.5.
Protocol Amendments.............................................................................................75
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................75
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................76
14.8.
Termination of the Study ........................................................................................76
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14.6.
4.6.

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15.
DATA HANDLING AND RECORDKEEPING.....................................................77
15.1.
Data/Documents .....................................................................................................77
15.2.
Data Management...................................................................................................77
15.3.
Record Retention....................................................................................................77
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................79
16.1.
Study Monitoring and Source Data Verification......................................................79
16.2.
Audits and Inspections............................................................................................79
17.
PUBLICATIONS ...................................................................................................80
18.
REFERENCES.......................................................................................................81
19.
APPENDICES........................................................................................................84
19.1.
Appendix A: RECIST 1.1.......................................................................................84
19.1.1.
Definitions..............................................................................................................84
19.1.1.1.
Measurable Disease ................................................................................................84
19.1.2.
Tumor Response Evaluation ...................................................................................84
19.1.2.1.
Target Lesions........................................................................................................84
19.1.2.2.
Non-target Lesions .................................................................................................85
19.1.2.3.
Response Criteria....................................................................................................85
19.1.2.4.
Symptomatic Deterioration.....................................................................................87
19.2.
Appendix B: irRECIST...........................................................................................88
19.3.
Appendix C: Events of Clinical Interest (ECI) Guidance Document........................98
19.3.1.
Overview................................................................................................................98
19.3.1.1.
Dose Modification/Discontinuation ......................................................................100
19.3.2.
ECI Reporting Guidelines.....................................................................................100
19.3.3.
ECI Categories and Terms....................................................................................100
19.3.3.1.
Pneumonitis..........................................................................................................100
19.3.3.2.
Diarrhea/Colitis ....................................................................................................102
19.3.3.3.
Endocrine .............................................................................................................104
19.3.4.
Hematologic .........................................................................................................106
19.3.5.
Hepatic .................................................................................................................108
19.3.6.
Neurologic............................................................................................................109
19.3.7.
Ocular...................................................................................................................110
19.3.8.
Renal....................................................................................................................111
19.3.9.
Skin......................................................................................................................112
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19.3.6.
9.3.6.

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19.3.9.1.
Immediate Evaluation for Potential Skin ECIs ......................................................113
19.3.10.
Other ....................................................................................................................114
19.3.11.
Infusion Reactions ................................................................................................115
19.3.12.
Follow-up to Resolution .......................................................................................117
19.3.13.
References............................................................................................................117
19.4.
Appendix D: Table of Abbreviations ....................................................................119
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LIST OF TABLES
Table 1:
Main Data in Pretreated NSCLC Subjects...............................................................19
Table 2:
Table of Events.......................................................................................................30
Table 3:
Imaging and Treatment after Site-Assessed 1st Radiologic Evidence of PD............40
Table 4:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase..........................................................................................41
Table 5:
CC-486/Placebo Dose Adjustment and Dose Delays for Toxicity ...........................48
Table 6:
Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse 
Events.....................................................................................................................50
Table 7:
Hypothetical Power and Resulting Two-sided 90% CI of Hazard Ratio ..................58
Table 8:
Time Point Response: Subjects With Target (± Non-target) Disease .......................86
Table 9:
Time Point Response: Subjects With Non-target Disease Only ...............................87
Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) 
RECIST..................................................................................................................88
Table 11:
Events of Clinical Interest.......................................................................................98
Table 12:
Infusion Reactions................................................................................................116
Table 13:
Abbreviations and Specialist Terms.....................................................................119
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................29
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1.
INTRODUCTION 
1.1.
Disease Background
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in both men 
and women. Globally, approximately 1,825,000 new cases of lung cancer were diagnosed in
2012, and 1,590,000 deaths occurred due to this disease (Globocan, 2012). The World Health
Organization (WHO) divides lung cancer into 2 major classes based on its biology, therapy, and 
prognosis: NSCLC and small cell lung cancer. NSCLC accounts for more than 85% of all lung 
cancer cases and includes 2 major types: (1) non-squamous carcinoma (including 
adenocarcinoma, large-cell carcinoma, other cell types); and (2) squamous cell (epidermoid) 
carcinoma. Adenocarcinoma (40% of lung cancers) is the most common type of lung cancer seen 
in the United States (US) and is also the most frequently occurring cell type in nonsmokers 
(Speicher, 2000).
Cigarette smoking remains the most important risk factor for lung cancer, although 
approximately 15% of all lung cancers are diagnosed in patients who never smoked.
One reason for the high mortality rate of lung cancer is the advanced stage at diagnosis; only 25-
30% of new NSCLC cases are diagnosed with localized disease that is potentially curable with 
surgery (Fossella, 2000; Lang-Lazdunski, 2013). The majority of patients are diagnosed with 
locally advanced or metastatic disease and are not candidates for surgery.
1.2.
Treatment Options in Second-line Metastatic NSCLC
In patients with metastatic NSCLC who have experienced disease progression either during or 
after first-line therapy and have an Eastern Cooperative Oncology Group (ECOG) performance 
score of 0-2, single agent docetaxel, gemcitabine, or erlotinib is recommended if not previously 
given. Pemetrexed is another option for the non-squamous subtype of NSCLC (NCCN, 2014, 
ESMO, 2014).  
Docetaxel was shown to be superior to best supportive care (BSC), vinorelbine and ifosfamide; 
nevertheless, using either the weekly or three-weekly schedule in multiple randomized studies 
the observed response rate with docetaxel ranged from 3% to 12%, progression-free survival 
(PFS) from 1.9 to 3.4 months, and overall survival (OS) from 5.4 to 9.2 months (Shepherd, 2000; 
Fossella, 2000; Bria, 2006).
Recently, nintedanib, a triple angiokinase inhibitor, was approved in the European Union (EU) in 
combination with docetaxel as second-line therapy for NSCLC. The results showed that 
compared to docetaxel alone, nintedanib plus docetaxel significantly extended the median OS
from 10.3 to 12.6 months for patients with advanced adenocarcinoma, after first-line 
chemotherapy (P=0.0359; hazard ratio [HR]: 0.83) (Reck, 2014). In addition, ramucirumab was 
approved in the US in combination with docetaxel as second-line therapy. The phase 3 REVEL 
trial compared ramucirumab, a vascular endothelial growth factor (VEGFR)-2 antagonist, plus 
docetaxel with placebo plus docetaxel in NSCLC patients who experienced disease progression 
after treatment with platinum-based chemotherapy for locally advanced or metastatic disease.
Median OS was better in the ramucirumab group than in the placebo group (10.5 vs 9.1 months; 
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HR, 0.857; P = .0235), as was median PFS (4.5 vs 3.0 months; HR, 0.762; P < .0001) (Perol,
2014).
Gemcitabine showed modest activity in a phase II study with a 6.2% partial response and 17 
weeks median duration of survival in advanced NSCLC subjects who progressed on first-line 
cisplatin-containing therapy (Sculier, 2000).  Another phase II study found a partial response in
19% of subjects treated with gemcitabine as a second-line agent, and a median duration of 
response of 29 weeks (Crino, 1999).  In a third trial evaluating gemcitabine plus BSC versus 
BSC alone, tumor response was seen in 19% of gemcitabine-treated subjects while response was 
not measured in subjects treated with BSC alone (Anderson, 2000).  There was no difference in 
OS (5.7 versus 5.9 months, respectively).   The difference in the results between the trials may be 
due to the percentage of stage III versus stage IV subjects included in the trials.  In the study by 
Sculier et al. 96% of subjects had stage IV disease compared to 59% and 40% in Crino et al. and 
Anderson et al., respectively.
Erlotinib has been proven to be superior to BSC with significantly improved survival (6.7 vs. 4.7 
months), PFS (2.2 vs. 1.8 months), and delayed time to symptom deterioration (Shepherd, 2005).
Gefitinib is approved in the EU for the treatment of advanced and metastatic NSCLC with 
activating mutations of endothelial growth factor receptor (EGFR) only. Although a higher 
response rate was in favor of gefitinib compared to placebo (8% vs. 1%), median time to 
progression (TTP) (3.0 vs. 2.6 months) and survival (5.6 vs. 5.1 months) were similar in the 2
groups (Thatcher, 2005). A non-inferiority trial compared gefitinib to docetaxel in NSCLC 
patients after 1 or 2 lines of chemotherapy (Kim, 2008). A similar median survival (7.6 vs. 8 
months) and TTP (2.2 vs. 2.7 months) were observed, but less toxicity and better quality of life 
favored the gefitinib arm.
Pemetrexed showed clinically equivalent efficacy outcomes but better tolerability when 
compared to docetaxel in patients with the non-squamous subtype of NSCLC (Hanna, 2004; 
Peterson, 2007). 
An overview of the published data with the above described agents are summarized in Table 1.
Table 1:
Main Data in Pretreated NSCLC Subjects
Compound
Line of 
treatment
Histology
N
RR (%)
Median 
TTP/PFS 
(months)
OS 
(months)
Docetaxel
2nd
All
2557
2.7-12.6
1.9-3.4
5.4-9.2
Gemcitabine
2nd
All
65
6.21
--
4.22
Erlotinib
2nd 3rd
All
806
6.2-9
1.7-2.2
6.7-9.2
Gefitinib
2nd 3rd
All
1862
8.0-9.1
2.2-3.0
5.6-7.6
Pemetrexed
2nd
All3
871
4.3-9.1
2.6-2.9
6.7-8.3
1 This value represents partial response.
2 This value represents median duration of survival.
3 A retrospective analysis found that pemetrexed only showed significantly higher survival when compared to docetaxel in the 
non-squamous subgroup.  Docetaxel had statistically better survival in the squamous cell subgroup
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Personalized treatment based on molecular characteristics of the tumor has also become the 
standard of care.  In addition to the above guidelines, patients whose tumors are positive for the 
EGFR and/or anaplastic lymphoma kinase (ALK) mutation(s) should receive targeted therapy.  
The EGFR mutation which results in the activation of the EGFR tyrosine kinase domain has 
been reported in about 20-25% of non-squamous NSCLC cases and less than 5% in tumors with 
squamous histology.  Erlotinib and afatinib are EGFR tyrosine kinase inhibitors (TKIs) indicated 
for first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 
deletions or exon 21 (L858R) substitution mutations, the most commonly found mutations in 
NSCLC (Tarceva® Package Insert; Gilotrif® Package Insert; NCCN, 2014).  Patients who 
progress after first-line therapy are still recommended to be continued on erlotinib or afatinib as 
part of second-line therapy (NCCN, 2014).  Anaplastic lymphoma kinase translocation, another 
key driver mutation, occurs in roughly 5% of NSCLC cases (Shaw, 2013), and it is mostly 
associated with the adenocarcinoma subtype (Bang, 2011; Xalkori Package Insert).  Tumors with 
this mutation are amenable to treatment with crizotinib, an ALK, MET, and ROS1 tyrosine 
kinase inhibitor, and thus, crizotinib is used in first-line therapy for metastatic ALK-positive 
NSCLC patients.  For patients who progress after first-line therapy, crizotinib or the recently 
approved ALK inhibitor, ceritinib, is recommended as part of second-line therapy (NCCN, 
2014).  This trial will focus on second-line therapy for subjects who do not possess these 2 driver 
mutations.  Thus, EGFR-positive and ALK-positive subjects will be excluded from this trial.  
The reported response rate to second-line therapy has generally been less than 10% (NCCN, 
2014), and many patients who respond to second-line therapy eventually develop resistance.  The 
limited effective second-line therapy options available call for the investigation of novel 
approaches to drug therapy in advanced NSCLC.
1.3.
Overview of CC-486
CC-486 is an orally bioavailable formulation of azacitidine (AZA).  Azacitidine, an analog of the 
pyrimidine nucleoside cytidine, has effects on cell differentiation, gene expression, and 
deoxyribonucleic acid (DNA) synthesis and metabolism, and causes cytotoxicity.
Vidaza® (azacitidine injection) is approved by the US Food and Drug Administration (FDA) for 
five subtypes of the French American British (FAB) classification system of myelodysplastic 
syndrome (MDS) and chronic myelomonocytic leukemia (CMMoL). Vidaza is also approved by 
the European Commission for the treatment of adult MDS, acute myeloid leukemia (AML) and 
CMMoL patients who are not eligible for hematopoietic stem cell transplantation.  Vidaza can be 
administered by intravenous (IV) or subcutaneous (SC) routes as designated by country 
approval.
After its incorporation into a cell’s DNA during the S-phase of the cell cycle, AZA forms 
covalent adducts with DNA methyltransferase 1 (DNMT1) and depletes this enzyme required for 
the maintenance of DNA methylation patterns, thereby altering the epigenetic status of the cell.   
Epigenetic changes are covalent modifications of chromatin (DNA and histone proteins) that 
mediate the stable transmission of a gene’s transcriptional status through cell division.  One of 
the first recognized epigenetic alterations in cancer was DNA methylation.  The addition of a 
methyl group to cytosine in the dinucleotide CpG is catalyzed by DNA methyltransferases 
(DNMTs) and is associated with transcriptional suppresion of genes (Miranda, 2007). Genomic 
methylation patterns are precisely regulated during normal embryonic development and 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
21
CC-486-NSCL-001 Final: 15 May 2015
differentiation and have been found to be altered in specific ways in cancer.  Specifically, cancer 
cell genomes are typified by reduced methylation globally with focal areas of aberrant 
hypermethylation in the CpG islands of genes encoding known tumor suppressors such as PTEN 
and BRCA1 as well as genes encoding proteins required for apoptosis, including caspase 8, 
DAPK and Apaf-1.  DNA methylation-based gene silencing can thus contribute to the 
establishment and maintenance of the transformed state and limit the effectiveness of anticancer 
therapies.
CC-486 entered clinical testing in 2006 in subjects with MDS, CMMoL, and AML.  The AZA 
PH US 2007 CL 005 study has shown that CC-486 is bioavailable and a maximum tolerated dose 
(MTD) of 480 mg daily for 7 days of a 28-day cycle was defined based on dose-limiting diarrhea 
at the 600 mg dose (Garcia-Manero, 2011).  As expected, reversible and manageable 
myelosuppression was observed.  Pharmacodynamic activity (DNA hypomethylation) and 
clinical responses were observed with CC-486, although the cross-over design (with SC Vidaza 
administered during Cycle 1) confounded the interpretation of these responses in Part 1 of the 
study.
The second part of the AZA PH US 2007 CL 005 study explored both daily and twice daily 
extended dosing schedules of 14 and 21 days out of 28 days in a non-crossover design.  CC-486 
administered at 300 mg once daily (QD) for 14 or 21 days of a 28-day cycle produces cumulative 
exposures (area under the concentration-time curve [AUC] per cycle) that are approximately 
40% and 60% of the exposure achieved with the labeled dose and schedule of Vidaza, 
respectively.  Daily doses of 300 mg have proven to be tolerated on both the 14 and 21 out of 28-
day schedules with myelosuppression, gastrointestinal (GI) symptoms, and fatigue being the 
most common toxicities (Garcia-Manero, 2011).
In the AZA PH US 2007 CL 005 study, DNA methylation levels in blood were measured as a 
pharmacodynamic (PD) endpoint, to determine DNA hypomethylating activity of CC-486.  In 
summary, it was confirmed that CC-486 is biologically active, reducing DNA methylation when 
administered at low doses on extended schedules.
CC-486 is also under clinical investigation, either as monotherapy or in combination with other 
investigational products, for the treatment of lymphoma, multiple myeloma, and relapsed or 
refractory solid tumors (eg, urothelial carcinoma of the bladder, renal pelvis, ureter, or urethra; 
pancreatic carcinoma; breast cancer; ovarian cancer; nasopharyngeal carcinoma; cervical 
carcinoma; anal carcinoma; and merkel cell carcinoma).  
 
 There are 2 ongoing studies 
evaluating PK of CC-486 (AZA-ST-001 and CC-223-NSCL-001).
1.3.1.
CC-486 Experience in Solid Tumors
A Phase 1 study of CC-486 in combination with carboplatin or nab-paclitaxel, or as a single 
agent in subjects with relapsed or refractory solid tumors (AZA-ST-001) was initiated on 30 Nov 
2011.  In Part 1 of this two-part study, CC-486 at escalating doses of 200 or 300 mg was 
administered on Days 1 to 14 of a 21-day cycle in three separate arms of the study (Arm A, Arm 
B, Arm C). 
In Arm A of AZA-ST-001, subjects received carboplatin (AUC = 4) on Day 8 of each cycle and 
in Arm B, subjects received nab-paclitaxel 100 mg/m2 beginning on Day 8.  For Arm A, both 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
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22
CC-486-NSCL-001 Final: 15 May 2015
200 mg and 300 CC-486 mg were well tolerated with carboplatin AUC = 4.  For Arm B, 
initially, nab-paclitaxel was administered weekly starting on Cycle 1 Day 8 but dose-limiting 
neutropenia was encountered on this schedule at the first dose level of CC-486.  The protocol 
was amended to administer nab-paclitaxel on Days 8 and 15 of each cycle (ie, 2 out of 3 weeks) 
and this was well tolerated in combination with CC-486 at 200 mg.  When the CC-486 dose was 
escalated to 300 mg, dose-limiting neutropenia was again encountered, making the 200 mg the 
MTD of CC-486 in combination with nab-paclitaxel 100 mg/m2 on a 2- out of 3-week schedule.  
Arm C of study AZA-ST-001 assessed the safety of continuous administration of CC-486 on a 
21- out of 21-day schedule.  This schedule proved not to be tolerable, with profound 
granulocytopenia manifesting in 2 out of 6 subjects at the 300 mg dose level during Cycle 2.  
Single agent CC-486 was better tolerated in subjects when used at the dose of 300 mg daily for 
2- out of 3-week cycle with a manageable safety profile, and the recommended Phase 2 dose for 
Arm C was determined to be 300 mg on Days 1 to 14 of each 21-day cycle.
 
 
 
 
The most promising hints of activity in AZA-ST-001 were observed in Arm B.  Of 8 evaluable
subjects with relapsed pancreatic carcinoma, 1 had a partial response (PR) and 3 others had 
stable disease (SD) > 16 weeks for a disease control rate (DCR) of 50%.  CC-486 has also shown 
promising efficacy in subjects with relapsed or refractory NSCLC (N = 20).  Although the 
efficacy data are not yet fully mature, objective responses were observed, including 2 PRs in 
NSCLC subjects. An additional 8 subjects with NSCLC had stable disease for periods ranging 
from 4 to 9 months. Furthermore, dramatic objective responses were observed in subjects with 
relapsed cervical and endometrial cancer.  These observations, although promissing, do not 
provide conclusive evidence of an epigenetic modifying effect by CC-486.
Please refer to the Azacitidine IB for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
the azacitidine/CC-486.
1.4.
Overview of Pembrolizumab
The programmed cell death protein-1 (PD-1) is an immune-checkpoint receptor expressed by T 
cells upon activation.  The normal function of PD-1 upon binding by its ligands, programmed 
death-ligand 1 (PD-L1) and PD-L2, is to moderate ongoing immune responses and prevent 
autoimmunity (Harvey, 2014).  Some tumor cells up-regulate the PD-1 ligands to evade active T-
cell immune surveillance. Pembrolizumab is a highly selective humanized monoclonal antibody 
(mAb) that binds to the PD-1 receptor and directly blocks the interaction between PD-1 and its 
ligands, thereby enhancing tumor regression and ultimately immune rejection (pembrolizumab
IB).  Pembrolizumab is being investigated in various oncology indications including melanoma, 
NSCLC, renal cell carcinoma (RCC), breast cancer, multiple myeloma (MM), microsatellite 
unstable tumors, and head and neck cancer. Pembrolizumab was recently approved in the US for 
the treatment of advanced, unresectable or metastatic malignant melanoma, and for use in 
melanoma patients with disease progression after prior treatment with (a) ipilimumab or (b) a 
BRAF inhibitor, in the case of BRAF V600-mutant disease (Nishimura, 2000). It is the first anti-
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
23
CC-486-NSCL-001 Final: 15 May 2015
PD-1 therapy to receive regulatory approval in the US, and pembrolizumab for the melanoma 
indication is currently under regulatory review in the EU.
1.4.1.
Pembrolizumab Experience in Solid Tumors and Safety
An open-label phase 1 trial (Keynote 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks, in subjects with 
advanced solid tumors. All 3 dose levels were well tolerated and no dose-limiting toxicities
(DLTs) were observed. Based on PK data showing a half-life of  21 days, the dosing frequency 
in the expansion cohort has been changed to every 3 weeks. 
The choice of the 200 mg every 3 weeks as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab showing that 
the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established in 
melanoma that are well tolerated and safe. 
The ongoing expansion cohort in Keynote 001 is enrolling subjects with NSCLC.
Keynote 001, Part C enrolled 38 subjects with NSCLC (adenocarcinoma, squamous cell 
carcinoma, and large cell carcinoma) who experienced progression of cancer after initiation of 
their second line of systemic therapy to receive monotherapy pembrolizumab. By Investigator-
assessed immune-related Evaluation Criteria in Solid Tumors (irRECIST), the overall response 
rate (ORR) (confirmed and unconfirmed) was 24%. Similar results were obtained using 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, yielding an ORR (confirmed and 
unconfirmed) of 21%. Most responses by irRECIST were observed by the time of first planned 
assessment at Week 9. The median duration of response by irRECIST has not been reached with 
a median duration of follow-up of 62 weeks. The median OS for all 38 patients treated with 
pembrolizumab was 51 weeks.
Pembrolizumab has been generally well-tolerated in subjects with solid tumors at doses up to 10 
mg/kg every other week without DLTs.  Of the 479 subjects for which preliminary data was 
available, the most commonly reported treatment-emergent AEs experienced were fatigue 
(43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhoea (22.3%), and rash (21.5%).   
466 subjects (97.3%) experienced treatment-emergent AEs of which 368 (76.8%) were 
considered drug-related. Serious adverse events (SAEs) were reported in 30.1% of patients, but 
SAEs that were attributed as potentially (possibly, probably, or definitely) drug-related by 
Investigators were reported in 6.7% of patients overall. Five patients died within 30 days of the 
last dose of pembrolizumab; none of the deaths were considered drug-related.
Preliminary results from Part C only (previously-treated NSCLC patients) reported the incidence 
of drug-related AEs to be 53%, usually Grade 1-2 in severity, and the AEs were most commonly 
rash (21.1%), pruritus (18.4%), fatigue (15.8%), diarrhea (13.2%), and arthralgia (10.5%). 
Serious AEs were reported in 34.2% of all NSCLC patients, but SAEs that were attributed as 
potentially drug-related by Investigators were reported in 2.6% of NSCLC patients. Most 
patients continued treatment in spite of adverse events; 21.1% discontinued due to an AE. The 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
24
CC-486-NSCL-001 Final: 15 May 2015
incidence of Grade 3/4 drug related AEs was 2.6%. Thus, the overall AE summary suggests that 
pembrolizumab is generally tolerable and AEs are generally manageable in NSCLC patients
(pembrolizumab IB).
In Part C of the study, 2 patients developed pneumonitis and 1 patient was reported with steroid-
responsive pulmonary edema. Two cases were Grade 2; the case of pulmonary edema was Grade 
3. These cases began as early as 4 days after the first dose to several cycles (Week 18) after the 
first dose. It is not clear the role of prior thoracic radiation to the development of this AE. The 
Grade 3 episode responded to steroids, whereas the Grade 2 cases did not. The Grade 3
pulmonary edema and a case of Grade 2 pneumonitis were considered drug-related; the third 
case was considered not drug-related. All 3 patients died from malignant neoplasm.
1.5.
Study Rationale
Both CC-486 and pembrolizumab have shown promising activity and acceptable tolerability in 
patients with relapsed or refractory NSCLC as detailed in Sections 1.3.1 and 1.4.1.
The reported response rate to second-line therapy in NSCLC has generally been less than 10% 
(NCCN, 2014), and many patients who do respond eventually develop resistance.  The limited 
availability of effective second-line therapy options call for the investigation of novel approaches 
to drug therapy in advanced NSCLC.  One potential strategy is the use of epigenetic agents, such 
as CC-486, to prime the tumor to become more responsive to immunotherapy. This approach is 
proposed by combining CC-486 with pembrolizumab in this trial.
Studies have shown that epigenetic events such as hypermethylation of the promoter sites on 
certain genes may play a role in tumor progression in lung cancer (Topaloglu, 2004).  
Importantly, unlike gene mutations, DNA methylation is reversible and can be inhibited by a 
DNMTi (Zeng, 2013).  There are currently 4 drugs targeting epigenetic changes that have been 
approved by the FDA for use in hematologic malignancies, i.e., 2 DNMT inhibitors for 
myelodysplastic syndrome (azacitidine and decitabine) and 2 histone deacetylase (HDAC) 
inhibitors for cutaneous T-cell lymphoma (vorinostat and romidepsin).  A recent study using the 
combination epigenetic therapy of azacitidine and entinostat, an HDAC inhibitor, in subjects 
with recurrent metastatic NSCLC who had extensive prior systemic therapy yielded some 
interesting results (Juergens, 2011).  Though only two of the 65 subjects had robust and durable
RECIST criteria responses to this therapy, a group of these subjects were observed during 
follow-up to have responded to various subsequent therapeutic regimens (Juergens, 2011). Five 
of these subjects received 1 of 2 investigational immunotherapy drugs, anti-PD1 or anti-PD-L1
antibody.  Preliminary data revealed that 3 subjects experienced durable partial responses for 
over a year while the other two subjects had stable disease on therapy for more than 6 months 
(Brahmer, 2013).  
Previous PD-1 immune-checkpoint targeting monotherapy studies in subjects with advanced 
NSCLC who received previous systemic therapy reported only a 16 to 17% response rate 
(Brahmer, 2012; Topalian, 2012, Brahmer, 2013 abstract, Garon 2014). 
The results of the above study led to the hypothesis that azacitidine may prime the tumor to 
become more responsive to immunotherapy.  There are several possible mechanisms as to how 
this may occur (Brahmer 2013): 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
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CC-486-NSCL-001 Final: 15 May 2015
!
Azacitidine induces the type I IFN pathway and subsequently upregulates suppressed 
antigen-presenting molecules, enhancing intratumoral inflammatory response.
!
Azacitidine reactivates the production of tumor antigens, such as cancer testes antigens, 
that are found in lung cancer.
!
Azacitidine activates silenced effector cytokine genes in anergized T cells.  
Further support for using CC-486 in combination with pembrolizumab is the fact that epigenetic 
treatment of NSCLC cell lines has been found to increase expression of PD-1 and PD-L1.  Co-
administration of a PD-1 pathway inhibitor would shift the balance in favor of the immune-
enhancing effects of epigenetic modulators on T cells (Brahmer, 2013).  Thus, the combination 
of azacitidine and a PD-1 pathway inhibitor would mechanistically complement each other for 
the purpose of cancer treatment.
Current treatment options for metastatic NSCLC patients who have progressed on first-line 
therapy are limited.  The use of epigenetic modifying agents such as CC-486 to overcome
immune resistance mechanisms of tumors is an interesting strategy.  Here we propose to evaluate
the ability of CC-486 to sensitize tumor cells to PD-1 inhibition with pembrolizumab.  
To explore the hypothesized mechanism of CC-486 priming to pembrolizumab efficacy, and 
potentially identify biomarkers to predict patients that would benefit from this therapeutic 
regimen, tissue samples will be collected from patients pre-therapy and during therapy for 
cellular and molecular analyses. Submission of archival or fresh tumor tissue pre-therapy is 
mandatory. Blood, serum and saliva will also be collected. 
 
 
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('06'RF1XPEHU
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Protocol CC-486-NSCL-001
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CC-486-NSCL-001 Final: 15 May 2015
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is:
!
To estimate the efficacy of CC-486 plus pembrolizumab versus pembrolizumab plus 
placebo based on PFS as measured using RECIST 1.1 criteria
2.2.
Secondary Objectives
The secondary objectives of the study are:
!
To estimate DCR of CC-486 plus pembrolizumab versus pembrolizumab plus 
placebo
!
To estimate OS of CC-486 plus pembrolizumab versus pembrolizumab plus placebo
!
To estimate ORR of CC-486 plus pembrolizumab versus pembrolizumab plus 
placebo
!
To evaluate safety and tolerability of CC-486 plus pembrolizumab versus 
pembrolizumab plus placebo
!
To evaluate the impact of pembrolizumab on the pharmacokinetics of CC-486
2.3.
Exploratory Objectives
The exploratory objectives of the study are:
!
To determine the preliminary efficacy (immune-related [ir] PFS, irDCR, irORR) of 
CC-486 plus pembrolizumab versus pembrolizumab plus placebo based on irRECIST
criteria 
!
To explore mechanism and biomarkers associated with efficacy of CC-486 plus 
pembrolizumab versus pembrolizumab plus placebo,
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('06'RF1XPEHU
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Celgene Corporation
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CC-486-NSCL-001 Final: 15 May 2015
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
!
PFS measured as time from randomization to progression according to RECIST 1.1 
(based on Investigator assessment) 
3.2.
Secondary Endpoints
!
Number (%) of subjects with SD for ≥ 18 weeks, complete response (CR) or PR 
(DCR). 
!
Overall survival.
!
Number (%) of subjects who achieve an objective CR or PR (ORR).
!
Safety to include the incidence of treatment-emergent adverse events (TEAEs), 
serious TEAEs, Grade 3-4 TEAEs, TEAEs of special interest, and laboratory 
abnormalities and other safety parameters.
!
Plasma PK parameters such as maximum observed concentration (Cmax), area under 
the concentration-time curve (AUC), time to maximum concentration (Tmax), terminal 
half-life (t1/2), apparent total body clearance (CL/F) and apparent volume of
distribution (Vz/F) for CC-486.
3.3.
Exploratory Endpoint(s)
!
Exploratory efficacy as measured by irPFS, irDCR, and irORR based on Investigator 
assessment using irRECIST.
 
!
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CC-486-NSCL-001 Final: 15 May 2015
4.
OVERALL STUDY DESIGN 
4.1.
Study Design
This is a Phase 2, multicenter, international, randomized, placebo controlled, double-blind study
to assess the safety and efficacy of CC-486 and pembrolizumab combination therapy versus 
pembrolizumab plus placebo in previously treated subjects with locally advanced or metastatic 
NSCLC who have received one prior platinum-based chemotherapy regimen.
Approximately 90 subjects will be randomized 1:1 to receive CC-486 plus pembrolizumab or 
placebo plus pembrolizumab as follows:
!
Arm A: CC-486 300 mg administered orally daily on days 1-14 plus pembrolizumab
200 mg administered as a 30-minute IV infusion on day 1 of a 21-day cycle 
!
Arm B: Placebo administered orally daily on days 1-14 plus pembrolizumab 200 mg
administered as a 30-minute IV infusion on day 1 of a 21-day cycle 
A safety analysis will be performed in the first 10 subjects in each arm after the last enrolled 
subject has completed 1 cycle of treatment.
Randomization will be stratified between treatment arms by:
!
Histology (non-squamous versus squamous)
The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, 
the Investigator may contact the medical monitor and forward appropriate supporting documents 
for review and discussion.
The study will be conducted in compliance with the International Council on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good 
Clinical Practice (GCP) and applicable regulatory requirements.
Primary analysis will be conducted when 70 PFS events have occurred.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
29
CC-486-NSCL-001 Final: 15 May 2015
Figure 1:
Overall Study Design
4.2.
Study Duration 
Enrollment is expected to take approximately 12 months to complete.  Completion of active 
treatment and post-treatment follow-up is expected to take an additional 12 months.  The entire 
study is expected to last approximately 2 years.
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, or the date of receipt of the last data point from the last subject that is 
required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol, 
whichever is the later date.
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('06'RF1XPEHU
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CC-486-NSCL-001 Final: 15 May 2015
5.
TABLE OF EVENTS
Table 2:
Table of Events
Screening 
Period
Treatment Perioda
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Follow-up 
Period
Day
-21 to -1
1b
14
1
14
1
EOT
Disease 
Progression/ 
Survival
Informed consent
X
Demographics
X
Prior cancer history
X
Prior cancer therapiesc
X
Complete medical history
X
Prior/ concomitant 
medication evaluationd
X (≤ 28d from 
screening)
Continuous, until 28 days after last dose
Prior/ concomitant 
procedures evaluatione
X (≤ 28d from 
screening)
Continuous, until 28 days after last dose
Inclusion/exclusion criteria
X
IRT registration
X
IRT randomization
Xf
Adverse event evaluation
Continuous after informed consent signature. See Section 11 for additional details on AE reporting 
timeframe
Physical examination 
(source documented only)
X
X
X
X
X
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('06'RF1XPEHU
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Table 2:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Follow-up 
Period
Day
-21 to -1
1b
14
1
14
1
EOT
Disease 
Progression/ 
Survival
Weight
X
X
X
X
X
Height
X
Vital signs
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Hematology laboratoryg
X
X
X
X
X
X
X
Coagulationh
X
HBV and HCV serologies 
(HBsAg, HBeAg, HBsAb, 
HBeAb, HBcAb, HCVAb)
X
X
Chemistry laboratoryi
X
X
X
X
X
X
X
Lipid panelj
X
Every 4th
cycle
X
Thyroid test
X
X
Cycle 3 Day 
1 then every 
6 weeks
Urinalysisk
X
X
X
X
X
12-lead electrocardiogram
X
X
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('06'RF1XPEHU
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CC-486-NSCL-001 Final: 15 May 2015
Table 2:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Follow-up Period
Day
-21 to -1
1b
14
1
14
1
EOT
Disease 
Progression/ 
Survival
Serum β-hCG (for all 
FCBP)l
X
Serum or Urine β-hCG (for 
all FCBP)l
X
(w/in72 hours)
X
X
X
X
PK blood draws sampling
(See Section 6.5 for 
timepoints)
X
X
Tumor biopsy for 
Biomarker Analyses
X
(Mandatory –
archival or 
fresh tumor 
collection)
X
(Optional)
Blood for Biomarker DNA 
Analyses
X 
X
Blood for Biomarker RNA 
Analyses
X
X
X
Serum for Biomarker 
Analyses
X 
X
Xm
X
Saliva for Germline DNA 
Analysis
X
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('06'RF1XPEHU
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Table 2:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Follow-up 
Period
Day
-21 to -1
1b
14
1
14
1
EOT
Disease 
Progression/ 
Survival
Tumor evaluation 
(CT/MRI)
X 
RECIST 1.1 algorithm: Every 6 weeks (± 5 days) from randomization for the first 24 
weeks then every 9 weeks until disease progression (for exceptions refer to Section 
6.4.3) or start of a new anticancer treatment, or withdrawal of consent
The irRECIST will be evaluated as exploratory efficacy assessment. For additional 
details, see Sections 6.4.2 , 6.4.3 and Appendix B, Section 19.1
Bone Scan 
Only if clinically indicated
CT Scan of the Head or 
Brain MRI
X
Only if clinically indicated
Administer                    
CC-486/placebo
Daily on Days 1-14
Administer 
pembrolizumab
Xn
X
On Day 1 
only
IP accountability
X
X
X
X
Survival follow-up
Every 8 weeks 
(+/- 5 days)
Anticancer therapy since 
IP discontinuation
At every survival 
follow-up visit
Abbreviations:  β-hCG = beta human chorionic gonadotropin; C1D1 = Cycle 1 Day 1; CT = computed tomography; ECOG = Eastern Cooperative Oncology 
Group; EOT = End of Treatment; FCBP = females of child bearing potential; IP = investigational product; irRECIST = immune-related Response Evaluation 
Criteria in Solid Tumors; IRT = interactive response technology; MRI = magnetic resonance imaging; PK = pharmacokinetic; RECIST = Response Evaluation 
Criteria in Solid Tumors
a All visits have a ± 2-day window, except Cycle 1 Day 1 which must occur within 21 days from Informed Consent Form signature, and survival follow-up 
which has a ±5-day window.
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('06'RF1XPEHU
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b Cycle 1 Day 1 evaluations can be omitted if Screening evaluations are performed within 72 hours of Cycle 1 Day 1.
c Prior cancer therapies include surgery, radiation, systemic or any other therapy (eg, hormonal, locoregional) for the subject's cancer
d Prior/concomitant medication evaluation ≤28 days before screening through 28 days after last dose.
e Prior/concomitant procedures evaluation ≤28 days before screening through 28 days after last dose.
f Prior to receiving first dose.
g Hematology includes complete blood count (CBC) with differential, including but not limited to red blood cell (RBC) count, hemoglobin, hematocrit, white 
blood cell (WBC) count with differential (neutrophil count including lymphocyte, monocyte, eosinophil, basophil counts and bands), absolute neutrophil count 
(ANC), and platelet count. ANC should be measured with automated count where available.
h Coagulation tests, including prothrombin time (PT), partial thromboplastin time (PTT), activated partial thromboplastin time (aPTT) and international 
normalized ration (INR)
I Chemistry includes (but is not limited to) sodium, potassium, calcium, phosphorus,  chloride, magnesium, bicarbonate, blood urea nitrogen (BUN) or urea, 
serum creatinine, fasting glucose, uric acid, albumin, total protein, alkaline phosphatase, lactate dehydrogenase, total bilirubin (indirect and direct), aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
j Lipid Panel parameters include total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides
k Urinalysis (a urine dipstick may be used) at screening and D1 of each cycle if abnormal at baseline.
l Serum β-hCG (for all FCPB) performed at screening; remaining pregnancy tests may be serum or urine at the Investigator’s discretion. Pregnancy testing (for 
all FCPB) must be done within 72 hours prior to the first administration of IP and prior to dosing on Day 1 of every cycle.  If the serum screening pregnancy 
test is performed > 72 hours before first dose, a serum or urine pregnancy test should be performed (Investigator’s discretion).  The subject may not receive IP 
until the Investigator has verified that the result of the pregnancy test is negative.
m Day 1 of Cycle 3 and every third cycle thereafter (C6D1, C9D1, C12D1)
n On Cycle 1 Day 1, pembrolizumab will be administered after the 6 hour CC-486 PK sample collection. For all subsequent pembrolizumab administration, 
pembrolizumab will be co-administered with CC-486.
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6.
PROCEDURES
Any questions regarding the study should be directed to the Celgene medical monitor or 
designee. 
6.1.
Screening Period
Screening evaluations will be performed for all subjects to determine study eligibility. These 
evaluations must be completed within 21 days of first dosing unless noted below.
Waivers to the protocol will not be granted during the conduct of this trial, under any 
circumstances.
Safety laboratory analyses will be performed centrally. Decisions with respect to investigational 
product (IP) dosing can be made based on a local lab draw if the central lab results have not been 
received. Central labs should be drawn at all times specified within the protocol. Screening 
laboratory values must demonstrate subject eligibility, but may be repeated within the screening 
window if necessary.
The following will be performed at screening as specified in the Table of Events (Table 2), after
informed consent has been obtained:
!
Demographics 
!
Prior cancer history (including specific information regarding diagnosis, staging, and 
histology)
!
Prior cancer therapies: includes surgery, radiation, systemic or any other therapy for
the subject’s cancer
!
Complete medical history (all relevant medical conditions occurring ≥ 28 days before
Screening should be included)
!
Prior and concomitant medication evaluation (including those taken ≤28 days before
screening, except for those taken for cancer which are recorded as part of prior cancer 
therapy)
!
Prior and concomitant procedures (including all procedures occurring ≤ 28 days 
before screening)
!
Interactive response technology (IRT) for subject number 
!
Adverse event evaluation (begins after the subject signs the informed consent form 
[ICF])
!
Physical examination (source documented only), weight, height
!
Vital signs (including blood pressure, temperature, respiratory rate, and heart rate)
!
Eastern Cooperative Oncology Group (ECOG) performance status
!
Hematology panel: Complete blood count (CBC) with differential, including but not 
limited to red blood cell (RBC) count, hemoglobin, hematocrit, white blood cell 
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('06'RF1XPEHU
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(WBC) count with differential (neutrophil count including lymphocyte, monocyte, 
eosinophil, basophil counts and bands), absolute neutrophil count (ANC), and platelet 
count.
!
Coagulation tests including, prothrombin time (PT), partial thromboplastin time 
(PTT), activated partial thromboplastin time (aPTT), international normalized ratio 
(INR).
!
Chemistry panel including, but not limited to sodium, potassium, calcium, 
phosphorus,  chloride, magnesium, bicarbonate, blood urea nitrogen (BUN) or urea, 
serum creatinine, fasting glucose, uric acid, albumin, total protein, alkaline 
phosphatase, lactate dehydrogenase (LDH), total bilirubin (indirect and direct), 
aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), 
alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)
!
Lipid panel including total cholesterol, high-density lipoprotein, low-density 
lipoprotein, and triglycerides
!
Thyroid test
!
Hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies (hepatitis B surface 
antigen [HBsAg], hepatitis B e antigen [HBeAg], hepatitis B surface antibody 
[HBsAb], hepatitis B e antibody [HBeAb], hepatitis B core antibody [HBcAb], 
hepatitis C virus antibody [HCVAb]
!
Urinalysis (a urine dipstick may be used) at screening (and Day 1 of each cycle if 
abnormal at baseline).
!
12-lead electrocardiogram (ECG)
!
Pregnancy test is required for all female subjects of childbearing potential. Serum
beta subunit of human chorionic gonadotropin (β-hCG) pregnancy test will be 
performed at screening. Urine (or serum) pregnancy test will be performed to assess 
subject eligibility within 72 hours prior to the first administration of IP, if the serum 
pregnancy test did not already occur within 72 hours of dosing (negative results 
required for IP administration).
!
Submission of archival or newly obtained tumor biopsy specimen for biomarker 
analysis is mandatory.
!
Response assessment/tumor evaluation (see Section 6.4)
6.2.
Treatment Period
The subjects must start treatment within 21 days of signing the ICF. For all subsequent visits, an 
administrative window of ± 2 days is permitted.
Treatment cycles are 21 days in duration, and will occur as described in Section 8.2.
The following evaluations will be performed at the frequency specified in Table 2.  The 
evaluations should be performed prior to dosing on the visit day, unless otherwise specified:
!
IRT for subject randomization (prior to first dose)
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('06'RF1XPEHU
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!
Concomitant medications evaluation (continuously)
!
Concomitant procedures evaluation (continuously)
!
Adverse event evaluation (continuously)
!
Physical examination (source documented only) including weight
!
Vital signs: on-treatment vital sign measurements will be source documented only.  
However, if an abnormal (out of range) value is reported at any given visit, that
parameter should be collected in the case report form (CRF) at every subsequent
scheduled visit until it returns to normal, and as an AE if appropriate.
!
ECOG Performance status
!
Hematology panel
!
Chemistry panel
!
Lipid panel
!
Thyroid test
!
Urinalysis
!
Urine (or serum) pregnancy test (prior to dosing on Day 1 of each cycle)
!
PK sampling
!
Tumor biopsy for biomarker analyses [Optional, but strongly recommended]
!
Blood for biomarker analyses
!
Serum for biomarker analyses
!
Saliva for Germline DNA Analysis
!
Response assessment/tumor evaluation (see Section 6.4)
!
IP accountability
6.2.1.
End of Treatment
An end of treatment (EOT) evaluation should be performed for subjects who are withdrawn from
treatment for any reason as soon as possible after the decision to permanently discontinue
treatment has been made. Subjects must also be discontinued in the IRT system.
The following evaluations will be performed as specified in the Table 2:
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Adverse event evaluation (monitored through 30 days after the last dose of either 
study drug)
!
Physical examination including weight
!
Vital signs
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('06'RF1XPEHU
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CC-486-NSCL-001 Final: 15 May 2015
!
ECOG performance status
!
Hematology panel
!
Hepatitis B virus (HBV) and HCV serologies (HBsAg, HBeAg, HBsAb, HBeAb, 
HBcAb, HCVAb
!
Chemistry panel
!
Lipid panel
!
Urinalysis
!
12-lead ECG
!
Urine (or serum) β-hCG level for females of childbearing potential
!
Blood for biomarker analyses
!
Serum for biomarker analyses
!
Response assessment/tumor evaluation will be continued at the schedule defined in
Table 2, and does not need to be performed specifically for the EOT visit except as 
specified in Section 6.4.
!
IP accountability
6.3.
Follow-up Period
6.3.1.
Efficacy Follow-up
All subjects who discontinue treatment for reasons other than disease progression, start of new
anticancer therapy, or withdrawal of consent from the entire study will be followed for tumor
response assessments and subsequent anticancer therapies as specified in Section 6.4.
6.3.2.
Survival Follow-up
After the end of treatment (EOT) visit, all subjects will be followed every 8 weeks (± 5 days) for 
survival until withdrawal of consent, death, or lost to follow-up, whichever occurs first, or until 
the End of Trial. Subsequent anticancer therapies should be collected at the same schedule. New 
anticancer therapy includes (but is not limited to) any systemic or local medication, surgery, 
radiation, or any other therapy intended to treat the subject’s cancer.
Survival follow-up may be conducted by record review (including public records) and/or
telephone contact with the subject, family, or the subject’s treating physician.
6.4.
Response Assessments
Response assessments (tumor evaluations) should be performed at Screening within 21 days 
before the start of IPs, and every 6 weeks (± 5 days) from randomization for the first 24 weeks, 
then every 9 weeks thereafter until disease progression (for exceptions refer to Section 6.4.3), 
start of a new anticancer therapy, or withdrawal of consent from the entire study. Tumor 
assessments should also be performed at any time, if clinically indicated.  Subjects with 
historical tumor scans evaluable per RECIST 1.1 performed ≤ 21 days before the first dose need 
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not repeat scans for the purposes of screening. Evaluation of response should be performed using 
RECIST 1.1 and irRECIST guidelines by Investigator assessment.  
6.4.1.
Assessment of Response According to RECIST Version 1.1
Response assessments include computed tomography (CT) scan or MRI.  The regions to be 
imaged are the chest and abdomen/pelvis, including whole liver and kidney. In case of 
metastases to other organs not covered with these scans, the regions need to be included in the 
scans as well. If brain metastases are documented at baseline, brain imaging should be continued 
throughout the study. Bone scans will only be performed at baseline if clinically indicated. If at 
baseline, the bone scan is suggestive of bone lesions, CT or MRI will be used both at baseline 
and subsequent scans. Bone scans during the trial will only be performed if clinically indicated 
and if suggestive of new lesions, a CT or MRI will be performed to confirm the new lesion. Any 
skeletal lesions identified at baseline should be followed at the same schedule. The same mode of 
imaging for lesion evaluation at Screening must be used consistently throughout the study. 
Adherence to the planned imaging schedule is critical regardless of dose delays or unscheduled 
or missed assessments; scans must follow the calendar and not be adjusted for delays in 
treatment.
The CT imaging should include contrast unless medically contraindicated. Conventional CT 
should be performed with contiguous cuts of 5 mm or less in slice thickness. Spiral CT should be 
performed by use of a 5 mm contiguous reconstruction algorithm.
All subjects with evidence of objective tumor response (CR or PR) should have the response 
confirmed with repeat assessments at the next scheduled scan, but after no less than 4 weeks.  
6.4.2.
Assessment of Response According to irRECIST
Evaluation of response will also be performed using irRECIST guidelines as an exploratory 
assessment.  Additional details and definitions of irRECIST are found in Appendix B in Section
19.2.
6.4.3.
Assessment of Disease and Treatment after Initial Radiologic Progression
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses.  The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with cytotoxic 
agents, and can manifest as a clinical response after an initial increase in tumor burden or even 
the appearance of new lesions.  
If radiologic imaging shows PD by RECIST 1.1, tumor assessment should be repeated ≥4 weeks 
later in order to confirm PD (per irRECIST) with the option of continuing treatment per below 
while awaiting radiologic confirmation of progression.  If repeat imaging shows a reduction in 
the tumor burden compared to the initial scan demonstrating PD, treatment may be continued as 
per treatment calendar.  If repeat imaging confirms progressive disease, subjects will be 
discontinued from study therapy (exception noted in Table 3).  In determining whether or not the 
tumor burden has increased or decreased, Investigators should consider all target lesions as well 
as non-target lesions. Refer to Appendix B for additional information.
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When feasible, subjects should not be discontinued until progression is confirmed; however, the 
decision to continue study treatment after the 1st evidence of disease progression is at the 
Investigator’s discretion based on the clinical status of the subject as described in Table 3.  
Subjects may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria:
!
Absence of signs and symptoms indicating disease progression
!
No decline in ECOG performance status
!
Absence of rapid progression of disease
!
Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
Table 3:
Imaging and Treatment after Site-Assessed 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Site based 
assessment 
indicates PD
Repeat imaging at 
≥4 weeks at site to 
confirm PD
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan 
by site
Repeat imaging at 
≥4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging required
Exceptions as per 
note*
Discontinue 
treatment
Exceptions as per 
note*
No additional 
imaging required
N/A
Repeat scan shows 
SD, PR or CR
Continue regularly 
scheduled imaging 
assessments
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion
* Note:  If progression is confirmed per irRECIST, the subject remains clinically stable and per the Principal 
Investigator is achieving extraordinary clinical benefit, the Principal Investigator may discuss with the Sponsor to 
consider a potential exception.
6.5.
Pharmacokinetics
At specific sites, for the first 10-12 subjects randomized to each Arm, mandatory 
pharmacokinetics will be collected. Blood samples for CC-486 PK assessment will be collected 
on Day 1 of Cycle 1 and Cycle 2 prior to the dose administration of CC-486/placebo, known as 
predose, and over the 8-hour period following each dose administration of CC-486/placebo at 
0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose (see Table 4).  These samples will be 
analyzed centrally.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-NSCL-001 Final: 15 May 2015
Table 4:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase
Nominal Times
Acceptable Deviation Window
Predose
≤ 60 min
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± 3 min
0.5 hr
± 3 min
1 hr
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2 hr
± 3 min
2.5 hr
± 3 min
Nominal Times
Acceptable Deviation Window
3 hr
± 3 min
3.5 hr
± 3 min
4 hr
± 3 min
6 hr
± 20 min
8 hr
± 20 min
6.6.
Biomarkers
Tumor, blood and serum will be collected to explore the hypothesized mechanism of CC-486 
priming to pembrolizumab efficacy, and potentially identify biomarkers to predict patients that 
would benefit from this therapeutic regimen. Fresh tumor biopsy is the preferred tissue for these 
analyses; however archival formalin fixed, paraffin embedded (FFPE) blocks may be provided 
instead. Archival or fresh tumor tissue is mandatory at screening, but it is optional at Cycle 2 
Day 14 -/+ 7 days. Blood, serum and saliva will also be collected at time point detailed in the 
schedule of events.
Details regarding the collection, storage, and shipment of the samples are provided in the 
Laboratory Manual. A separate consent will be provided.
6.7.
12-lead Electrocardiogram
Triplicate 12-lead ECGs will be recorded at screening and EOT and will be assessed locally.  
The 12-lead ECGs (12-lead at 25 mm/sec reporting rhythm, ventricular rate, PR-interval, QRS 
complex, QT interval, and QTc interval) will be performed after the subject has been in the 
supine position for at least 5 minutes.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-NSCL-001 Final: 15 May 2015
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
A total of approximately 90 adult subjects with locally advanced or metastatic NSCLC who have 
been treated with one prior platinum-based chemotherapy regimen will be randomized. The 
study will be conducted at sites globally.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the informed consent form.
2. Subject has histologically or cytologically confirmed squamous or non-squamous 
NSCLC.
3. Subject has stage IIIB or IV NSCLC (American Joint Committee on Cancer [AJCC] 
Staging Manual, 7th edition [Edge, 2009])  and was pretreated with 1 prior systemic
platinum based chemotherapy.
4. Subject has provided a formalin fixed tumor tissue sample from a biopsy of a tumor 
lesion either at the time of or after the diagnosis of metastatic disease has been made 
AND from a site not previously irradiated to assess for PD-L1 status. Fine needle 
aspirates, endobronchial ultrasound (EBUS) or cell blocks are not acceptable. Needle or 
excisional biopsies, or resected tissue is required.  Archival tissue may be acceptable. 
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to 
the testing laboratory within 14 days from site slide sectioning date otherwise a new 
specimen will be requested.
5. Subject has radiographically-documented measurable disease, as per RECIST 1.1.
6. Subject has an ECOG performance status of 0 to 1.
7. Subject has adequate organ functions, evidenced by the following:
a.
AST (SGOT), ALT (SGPT) ≤ 2.5 x upper limit of normal range (ULN), or ≤ 5 x ULN 
range if liver metastasis present
b. Total bilirubin ≤ 1.5 x ULN
c.
Serum creatinine ≤ 1.5 x ULN
d. Potassium within normal range, or correctable with supplements
8. Subject has adequate bone marrow function, evidenced by the following:
a.
Absolute neutrophil count ≥ 1.5 x 109 cells/L
b. Platelets ≥ 100 x 109 cells/L 
c.
Hemoglobin ≥ 9 g/dL
d. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 x ULN unless 
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-NSCL-001 Final: 15 May 2015
e.
Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants
9. Female of childbearing potential (FCBP) (defined as a sexually mature woman who 1) 
has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) or, 2) if ≥ 45 years old has not been 
naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any 
time during the preceding 24 consecutive months)) must:
a.
Have two negative pregnancy tests as verified by the Investigator prior to starting 
study therapy. She must agree to ongoing pregnancy testing during the course of the 
study, and after end of study treatment. This applies even if the subject practices true 
abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be 
reviewed on a monthly basis) or agree to use, and be able to comply with two 
effective methods of contraception without interruption, 28 days prior to starting IP, 
during the study therapy (including dose interruptions), and for 120 days after 
discontinuation (or longer if required by local requirements) of study therapy. The 
two methods of contraception can either be two barrier methods or a barrier method 
plus a hormonal method to prevent pregnancy.
10. Male subjects must practice true abstinence* (which must be reviewed on a monthly 
basis) or agree to the use a condom during sexual contact with a pregnant female or a 
female of childbearing potential while participating in the study, during dose 
interruptions and for at least 3 months following investigational product discontinuation 
(or longer if required by local requirements), even if he has undergone a successful 
vasectomy. 
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle 
of the subject. Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation  methods) and withdrawal are not acceptable methods of contraception.
11. Subject is willing to adhere to the study visit schedule and other protocol requirements.
12. Subject understands and voluntarily signs an informed consent document prior to any 
study related assessments/procedures are conducted.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has known sensitizing EGFR and/or positive ALK mutation.
2. Subject has been previously treated with azacitidine (any formulation), decitabine, or any 
other hypomethylating agent.
3. Subject has received prior therapy with any other anti-PD-1, or PD-L1 or PD-L2 agent or 
an antibody targeting other immuno-regulatory receptors or mechanism, including 
participation in any other pembrolizumab trial and treatment with pembrolizumab.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-NSCL-001 Final: 15 May 2015
a.
Examples of such antibodies include (but are not limited to) antibodies against 
indoleamine 2,3-dioxygenase (IDO), PD-L1, IL-2R, glucocorticoid-induced 
tumor necrosis factor receptor (GITR).
4. Subject has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who 
has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.
5. Subject is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an investigational 
device within 4 weeks prior to administration of pembrolizumab and CC-486
6. Subject has previous severe hypersensitivity reaction to another monoclonal antibody 
(mAb).
7. Subject has a known or suspected hypersensitivity to azacitidine, mannitol, or any other 
ingredient used in the manufacture of CC-486 (see the Azacitidine IB).
8. Subject has had radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks 
prior to starting IP, and/or from whom ≥ 30% of the bone marrow was irradiated.
9. Subject has received radiation therapy to the lung that is > 30 Gy within 6 months of the 
first dose of trial treatment
10. Subject has received a live-virus vaccination within 30 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted.
11. Subject has not recovered from the acute toxic effects of prior anticancer therapy, 
radiation, or major surgery/significant trauma.
12. Subject has an active infection requiring therapy.
13. Subject has had an allogenetic tissue/solid organ transplant.
14. Subject has active autoimmune disease that has required systemic treatment within the 
past 2 years (eg, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.
15. Subject has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B is 
defined as a known positive HBsAg result.  Active Hepatitis C is defined by a known 
positive Hep C Ab result and known quantitative HCV ribonucleic acid (RNA) results 
greater than the lower limits of detection of the assay.
16. Subject has had any other malignancy within 5 years prior to randomization, with the 
exception of adequately treated in situ carcinoma of the cervix, uterus, or non-
melanomatous skin cancer (all treatment of which should have been completed 6 months 
prior to enrollment).
17. Subject has a history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative 
colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other 
gastrointestinal disorder or defect that would interfere with the absorption, distribution, 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-NSCL-001 Final: 15 May 2015
metabolism, or excretion of the IP and/or predispose the subject to an increased risk of 
gastrointestinal toxicity.
18. Subject has persistent diarrhea or clinically significant malabsorption syndrome or known 
sub-acute bowel obstruction ≥ Grade 2, despite medical management
19. Subject has significant active cardiac disease within the previous 6 months including 
unstable angina or angina requiring surgical or medical intervention, significant cardiac 
arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart 
failure.
20. Subject has history of interstitial lung disease (ILD) OR a history of pneumonitis that has 
required oral or IV steroids. Subjects whose pneumonitis was solely as a result of 
radiation therapy for their NSCLC would not be excluded from the study unless they 
received oral/IV steroids to manage the pneumonitis.
21. Subject has a known history or current diagnosis of human immunodeficiency virus 
(HIV) infection, regardless of treatment status.
22. Subject has any other concurrent severe and/or uncontrolled medical condition that 
would, in the Investigator’s judgment, contraindicate patient participation in the clinical 
study (eg, chronic pancreatitis, etc.).
23. Subject with uncontrolled or symptomatic central nervous system (CNS) metastases
and/or carcinomatous meningitis
!
Subjects with controlled and asymptomatic CNS metastases may participate in this 
trial. The patient must have completed any prior treatment for CNS metastases (must 
include radiotherapy and/or surgery) ≥ 28 days (≥ 14 days for stereotactic 
radiosurgery) and, if on corticosteroid therapy, should be receiving a stable dose of no 
greater than 4 mg/d dexamethasone (or equivalent anti-inflammatory potency of 
another corticosteroid) for at least 14 days before start of study treatment
24. Subject has not recovered from the acute toxic effects (Common Terminology Criteria for 
Adverse Events [CTCAE] grade ≤ 1) of prior anticancer therapy, radiation, or major 
surgery/significant trauma (except alopecia or other toxicities not considered a safety risk 
for the subject at the Investigator’s discretion).
25. Subject has an impaired ability to swallow oral medication.
26. Subject is pregnant or breast feeding.
27. Subject has any condition that confounds the ability to interpret data from the study.
28. Subject is or has an immediate family member (spouse or children) who is investigational 
site or sponsor staff directly involved with this trial, unless prospective Institutional 
Review Board (IRB) approval (by chair or designee) is given allowing exception to this 
criterion for a specific subject.
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-NSCL-001 Final: 15 May 2015
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Products
Subjects will receive CC-486 plus pembrolizumab or pembrolizumab plus placebo during the 
study.  CC-486 and matching placebo will be double blind whereas pembrolizumab will be open 
label. CC-486 and pembrolizumab are designated as IPs.  All IPs must be stored in an area free 
of environmental extremes and a secured area to prevent unauthorized access, as directed on the 
package label. A temperature log must be maintained.
8.1.1.
CC-486 (Oral Azacitidine)/Placebo
The study sponsor, Celgene Corporation will supply CC-486 and placebo 150 and 200-mg 
tablets for oral administration. Sufficient quantities of IP will be supplied by Celgene and should 
be stored as directed on the label. All tablets will be packaged in blister packs. Each tablet is 
formulated using excipients that are generally regarded as safe and used in marketed drug 
products.  A list of excipients included in the formulations is provided in the azacitidine IB.  
8.1.2.
Pembrolizumab
Pembrolizumab (50 mg lyophilized powder in single-use vial for reconstitution) for IV 
administration will be sourced by the study sponsor (Celgene Corporation) from 
 
 and labeled for clinical trial use.  Sufficient quantities of IP will be supplied by 
Celgene and should be stored as directed on the label.  Pembrolizumab will be administered in 
the clinic.
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
8.2.
Treatment Administration and Schedule
Subjects will be randomized 1:1 to receive CC-486 plus pembrolizumab or pembrolizumab plus 
placebo. CC-486/placebo will be administered at a dose of 300 mg orally daily on days 1-14 of a 
21-day cycle.
During scheduled site visits the subjects must arrive to the clinic in the fasting state (ie, no food 
or drink [except water] for approximately 8 - 10 hours) for all predose safety laboratory 
evaluations. Dose administration should take place after all scheduled predose safety assessments 
are completed.
Subjects will ingest CC-486/placebo with approximately 240 mL (8 ounces) of room temperature 
water.  CC-486/placebo may be taken on an empty stomach or with food (a light breakfast or 
meal of up to approximately 600 calories).
If following CC-486/placebo administration an emesis event occurs, subjects should not take 
additional drug on that same day. It is recommended that the subject receives an antiemetic 30 
minutes prior to all subsequent CC-486 doses.
Pembrolizumab will be administered as a 30-minute IV infusion at a dose of 200 mg (4 x 50 mg 
vials) on Day 1 of a 21-day cycle. Sites should make every effort to target infusion timing to be 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-NSCL-001 Final: 15 May 2015
as close to 30 minutes as possible. However, given the variability of infusion pumps from site to 
site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time of 24-40 minutes).
Pembrolizumab should be co-administered with CC-486.
For subjects enrolled in the PK population, the treatment administration on PK days (i.e., Day 1 
of Cycle 1 and Cycle 2) is described below:
!
After performing the required overnight fast, taking antiemetic premedication with 
240 mL of water for nausea and vomiting (eg, ondansetron), and completing the 
required predose assessments (including the predose PK sample), subjects will ingest 
CC-486/placebo with 240 mL of room temperature water in the clinic approximately 
30 minutes after antiemetic administration on each PK dosing day.  Each dose of   
CC-486/placebo should be given at approximately the same time each day.  The exact 
date and time of dosing will be recorded in the source documents and appropriate 
CRF.
!
On Day 1 of Cycle 1 only, pembrolizumab will be administered as described above, 
but administration will start after the 6 hour CC-486 PK sample collection time-point.
Dietary restrictions on PK days (i.e., Day 1 of Cycle 1 and Cycle 2): 
!
Subjects should be instructed to limit their coffee intake to one 8-ounce cup of black 
coffee (no cream or sugar) and to not consume alcohol, tea, chocolate, or cola 
beverages within 2 hours prior to collecting PK samples.
!
Subjects should not ingest food for a minimum of 8 hours prior and 2 hours after CC-
486/placebo is administered.  Water can be allowed as desired except for 1 hour 
before and after CC-486/placebo administration.  The only water permitted in the 1-
hour period before CC-486/placebo administration is the 240 mL of water for 
antiemetic ingestion.
8.2.1.
Dose Adjustment Guidelines
8.2.1.1.
CC-486 (oral azacitidine)/Placebo
For CC-486/placebo, a maximum of 1 dose reduction will be allowed from the original dose (eg, 
patients can dose reduce from 300 mg/placebo oral daily dose to 200 mg/placebo oral daily 
dose). Re-escalation to the higher dose is not permitted. If a subject requires more than 1 dose 
reduction for CC-486/placebo, they will be discontinued from CC-486/placebo, however, they 
may continue to receive pembrolizumab (and conversely, subjects who discontinue 
pembrolizumab may continue to receive CC-486/placebo) but must continue to undergo all 
safety and efficacy assessments as per  Table 2.
CC-486/placebo may be withheld for up to 7 days between the end of 1 cycle and the start of the 
next cycle to allow hematologic criteria to recover sufficiently for the next cycle to begin.
The maximum number of days that a dose may be withheld without requiring a dose reduction is 
7 days.
The maximum number of days that a dose may be withheld due to unacceptable toxicity before a 
subject is permanently discontinued from CC-486 is 14 days.For the purposes of dose 
adjustments, unacceptable toxicity will be defined as any AE that is deemed by the Investigator 
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('06'RF1XPEHU
CC-486
Protocol CC-486-NSCL-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-NSCL-001 Final: 15 May 2015
to be related to CC-486/placebo that poses a medical risk or substantial discomfort to the subject 
including, but not limited to, Grade 3 or 4 hematologic or non-hematologic toxicity. Subjects 
should be discontinued after the 3rd episode.
See Section 8.2.1.2 and Table 6 for dose modification guidelines for pembrolizumab drug-related 
adverse events for overlapping toxicity events for all IPs.
Please refer to Table 5 for the Dose Adjustment Guidelines.
Table 5:
CC-486/Placebo Dose Adjustment and Dose Delays for Toxicity
Toxicity
Recommendation
Grade 2 hematologic toxicity causing delay to the 
planned start of a Cycle
Absolute Neutrophil Count (ANC) < 1.5 x 109/L
Platelets < 75 x 109/L
Hold CC-486/placebo until ANC & Platelets 
≤ Grade 1
Delay ≤ 7 days, resume CC-486/placebo at same 
dose
Delay 8 – 14 days, reduce CC-486/placebo by 100 
mg
Delay > 14 days, permanently discontinue from 
study
Grade 3 neutropenia or thrombocytopenia causing 
delay to the planned start of a Cycle ANC 0.5-0.99 
x 109/L
Platelets 25-49 x 109/L
Hold CC-486/placebo until ANC & Platelets 
recover to ≤Grade 1 (ANC ≥ 1.5 x 109/L, Platelets 
≥ 75 x 109/L)
Recovery in ≤ 7 days, resume CC-486/placebo at 
same dose
Recovery in 8–14 days, reduce CC-486/placebo by 
100 mg
No recovery by 14 days, permanently discontinue 
from study
Grade 4 neutropenia or thrombocytopenia causing 
delay to the planned start of a Cycle
ANC < 0.5 x 109/L
Platelets < 25 x 109/L
For ANC < 0.5 x 109/L
The initiation of G-CSF is left at the Investigator’s 
discretion. If initiated administer G-CSF per 
institutional practice or package insert and continue 
until ANC recovers to ≥ 2.0 x 109/L
Hold CC-486/placebo until ANC & Platelets 
recover to ≤Grade 1
(ANC ≥ 1.5 x 109/L, Platelets ≥ 75 x 109/L)
Recovery in ≤ 7 days, reduce CC-486/placebo by 
100 mg
No recovery by 7 days, permanently discontinue 
from study
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pla
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rmanently d
manently d
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placebo
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≤Grade 1 
Grade 1
109/L)
/L)
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Table 5:
CC-486/Placebo Dose Adjustment and Dose Delays for Toxicity (Continued)
Toxicity
Recommendation
Grade 3 or 4 Nausea or Vomiting
Grade 3 or 4 Diarrhea
Grade 3 or 4 Fatigue/Asthenia
Hold until resolution to ≤ Grade 1 and provide 
optimal medical management
If response ≤72 hours (3 days), and recovery ≤ 7 
days, reintroduce CC-486/placebo at 200 mg
If event recurs after re-challenge at 200 mg, 
discontinue CC-486/placebo
If no recovery by 7 days, discontinue CC-
486/placebo
Grade 3 or 4 any other non-hematologic toxicity
Hold until resolution to ≤ Grade 1 and provide 
optimal medical management
If recovery ≤ 7 days, reintroduce CC-486/placebo 
at 200 mg
If event recurs after re-challenge at 200 mg, 
discontinue CC-486/placebo
If no recovery by 7 days, discontinue CC-
486/placebo
Renal dysfunction - For any unexplained 
reductions in serum bicarbonate levels to < 20 
mEq/L or unexplained elevations of BUN and/or 
serum creatinine (> 20%) from baseline
Hold until resolution to ≤ baseline level (+/- 20%) 
Reduce CC-486 dose in the next cycle of treatment 
to the next lower dose level 
If similar unexplained renal and/or electrolyte 
disturbances subsequently persist or recur, 
discontinue CC-486
ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; BUN = blood urea nitrogen; ESMO =
European Society for Medical Oncology; G-CSF = granulocyte colony stimulating factor.
Note: The initiation of G-CSF is left at the Investigator’s discretion.
Note: Granulocyte colony stimulating factor (G-CSF) should only be utilized in accordance to ASCO or ESMO 
recommendations.
Note: If Grade 3 or 4 neutropenia associated with fever or Grade ≥ 3 thrombocytopenia with clinically significant bleeding 
occurs at any time, the dose adjustment guidelines for Grade 4 hematological toxicity should be enacted.
Note: If neutropenia is associated with fever and severe diarrhea, subject should be managed appropriately according to the local 
practice. In case of recurrence of the diarrhea with neutropenia and fever, the continuation of the subject in the study should be 
discussed on a case-by-case basis with the sponsor’s study monitor.
8.2.1.2.
Pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology.  These adverse events may occur shortly after the first dose or several months after the 
last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or 
life-threatening AEs as per Table 6 below. Dose reductions are not permitted for pembrolizumab.
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Table 6:
Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse 
Events
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to 
Grade 0-1.
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased Bilirubin
2
Toxicity resolves to 
Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose.
3-4
Permanently discontinue
(see exception below)1
Permanently discontinue
Type 1 diabetes 
mellitus (T1DM), if 
new onset, or 
Hyperglycemia
T1DM or
3-4
Hold pembrolizumab for 
new onset Type 1 
diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence 
of beta cell failure.
Resume pembrolizumab when 
patients are clinically and 
metabolically stable.
Hypophysitis
2-4
Toxicity resolves to 
Grade 0-1. Therapy with 
pembrolizumab can be 
continued while 
endocrine replacement 
therapy is instituted
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.
Hyperthyroidism 
3
Toxicity resolves to 
Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with 
pembrolizumab can be 
continued while thyroid 
replacement therapy is 
instituted
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted.
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
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nfusion R
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Table 6:
Dose Modification Guidelines for Pembrolizumab Drug-Related Adverse 
Events (Continued)
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Pneumonitis
2
Toxicity resolves to 
Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per
day within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
Renal Failure or 
Nephritis
2
Toxicity resolves to 
Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
All Other Drug-
Related Toxicity2
3 or Severe
Toxicity resolves to 
Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per 
day within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued.
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold IP at physician discretion.  Permanently 
discontinue IP for persistent Grade 2 adverse reactions for which treatment with IP has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose.
After the first cycle, each drug may be given independently on a cyclical regimen according to 
the protocol-defined dose interruptions/delays for CC-486/placebo or pembrolizumab as defined 
in Section 8.2.1 above. Dosing interruptions are permitted in the case of medical / surgical events 
or logistical reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
patient vacation, and/or holidays). Subjects should be placed back on study therapy within 3 
weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record.
8.2.2.
Overdose
Overdose, as defined for this protocol, refers to blinded CC-486 and/or pembrolizumab. 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater.
For CC-486, on a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of blinded CC-486 assigned to a given subject, regardless of any 
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associated adverse events or sequelae. On a schedule or frequency basis, an overdose is defined 
as anything more frequent than the protocol required schedule or frequency.
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form. See Section 
11.1 for the reporting of adverse events associated with overdose.
8.3.
Method of Treatment Assignment
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will be randomized by IRT to receive CC-486 plus pembrolizumab or placebo plus 
pembrolizumab. Treatment assignment will be performed centrally.
All IP will be managed by the IRT system as a central subject number assignment and 
accountability tool only.
8.4.
Packaging and Labeling
The labels for IPs may include, but are not limited to, sponsor name, address and telephone 
number, the protocol number, IP name, dosage form and strength (where applicable), amount of 
IP per container, lot number, expiry date (where applicable), medication identification/kit 
number, dosing instructions, storage conditions, and required caution statements and/or 
regulatory statements as applicable. Additional information may be included on the label as 
applicable per local regulations.
8.5.
Investigational Product Accountability and Disposal 
Celgene (or designee) will review with the Investigator and relevant site personnel the process 
for Investigational Product return, disposal, and/or destruction including responsibilities for the 
site versus the responsibilities of Celgene (or designee).
8.6.
Investigational Product Compliance
Accurate recording of all IPs administered will be made in the appropriate section of the 
subject’s case report form (CRF) and source documents. The Investigator or designee is 
accountable for the compliance of all study-specific IPs either administered or in their custody 
during the course of the study.
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9.
CONCOMITANT MEDICATIONS AND PROCEDURES
9.1.
Permitted Concomitant Medications and Procedures
9.1.1.
CC-486 (oral azacitidine)
In general, the use of any concomitant medication/therapies deemed necessary for the care of the 
subject is permitted.
All concomitant treatments, including blood and blood products, must be reported on the CRF. 
Subjects may be administered supportive and palliative care (eg, pain control, anti-nausea, anti-
diarrheal) as clinically indicated throughout the study. 
Myeloid growth factors (granulocyte colony stimulating factor [G-CSF] and granulocyte 
macrophage colony-stimulating factor [GM-CSF]) should be administered according to 
American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology 
(ESMO) guidelines only for the treatment of neutropenic infections.
Antiemetics are not required during the study, except for subjects enrolled in the PK population; 
at the Investigator’s discretion, subjects not enrolled in the PK population may also receive 
prophylactic antiemetic therapy (eg, a serotonin [5-HT3] receptor antagonist such as  
ondansetron) approximately 30 minutes prior to each dose of CC-486.  
Treatment with antidiarrheal medications should be prescribed at the first sign of diarrhea.  Pre-
medication with antidiarrheal medication for subsequent doses of CC-486 may be appropriate at 
the Investigator’s discretion.
9.1.2.
Pembrolizumab Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below and in greater detail in the events of 
clinical interest (ECI) guidance in Appendix C. Where appropriate, these guidelines include the 
use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.  Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The
treatment guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the Investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance). Refer to Table 6 for dose modification guidelines 
for pembrolizumab. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance.
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9.1.2.1.
Management of pneumonitis
These guidelines may also be used for cases of pneumonitis that may not be related to 
pembrolizumab.
!
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.
!
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
!
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration
9.1.2.2.
Management of Diarrhea/Colitis
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  
!
All subjects who experience diarrhea/colitis 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
!
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
!
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.  
!
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
9.1.2.3.
Management of type 1 diabetes mellitus (if new onset, including diabetic 
ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA)
!
For type 1 diabetes mellitus (T1DM) or Grade 3-4 Hyperglycemia
o
Insulin replacement therapy is recommended for type 1 diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.
o
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.
9.1.2.4.
Management of hypophysitis
!
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.
nged 
ed 
lit
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advised to
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ake is not f
ake is no
n.  For Gra
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hat persi
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to Grade 1 
to Grad
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ype 1 diab
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DKA]) or
KA]) or ≥
or metabo
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Insulin 
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9.1.2.4.
9.1.2.4.

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!
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.
9.1.2.5.
Management of hyperthyroidism or hypothyroidism
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
!
Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism):
o
In hyperthyroidism, non-selective beta-blockers (eg, propranolol) are 
suggested as initial therapy.
o
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyroinine, is indicated per standard of care.
!
Grade 3-4 hyperthyroidism 
o
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.
9.1.2.6.
Management of hepatic abnormalities
!
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
o
Treat with IV or oral corticosteroids
!
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
!
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
9.1.2.7.
Management of renal failure or nephritis
!
For Grade 2 events, treat with corticosteroids.
!
For Grade 3-4 events, treat with systemic corticosteroids.
!
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
9.1.2.8.
Management of infusion reactions
See Appendix C for guidelines for subjects who experience an infusion reaction associated with 
administration of pembrolizumab.
9.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are prohibited during the course of the study:
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!
Cytotoxic, chemotherapeutic, targeted, hormonal, or investigational agents/therapies 
or any other anticancer treatment.
!
Vidaza (azacitidine injection), decitabine, or other demethylating agents.
!
Other PD-1 or PD-L1 inhibitors
!
Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be considered on an exceptional case by case basis after consultation with 
Sponsor.  The subject must have clear measurable disease outside the radiated 
field.  Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS.
!
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 
flu, rabies, bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. However, 
intranasal influenza vaccines (eg, Flu - Mist®) are live attenuated vaccines, and are 
not allowed.
!
Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest, use as a pre-medication for chemotherapeutic agents specified in the 
protocol, or for use as a pre-medication in subjects with a known history of an IV 
contrast allergy administered as part of CT radiography. Replacement doses of 
steroids (for example, prednisone 5-7.5 mg daily) are permitted while on study. 
Subjects who, in the assessment by the Investigator, require the use of corticosteroids 
for any other clinical management should be discussed with medical monitor.
9.3.
Required Concomitant Medications and Procedures
Not applicable.
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10.
STATISTICAL ANALYSES
10.1.
Overview
This is a placebo-controlled, double-blind, randomized, phase 2 trial designed to estimate the 
efficacy and safety/tolerability of CC-486 plus pembrolizumab and placebo plus pembrolizumab, 
in subjects with previously treated metastatic non-small cell lung cancer. The primary endpoint is 
PFS based on Investigator review. 
The sections below lay out the proposed statistical considerations and analyses. The detail
statistical analysis methods will be documented in the statistical analysis plan (SAP).
10.2.
Study Population Definitions
10.2.1.
Intent-To-Treat Population
The intent-to-treat (ITT) population will consist of all randomized subjects.  All efficacy 
analyses will be based on the ITT population, unless otherwise specified.  The efficacy analyses 
will be performed according to treatment assigned at randomization.
10.2.2.
Safety Population
The safety population will consist of any enrolled subjects who received at least 1 dose of IP.  
All safety analyses will be based on the Safety population, unless otherwise specified.  The 
treatment groups for the safety analyses are based on the treatment as received if different from 
the pre-planned randomization.
10.2.3.
PK Population
The PK analysis population will include all randomized subjects who have evaluable 
concentration data to determine the pharmacokinetic parameters from at least 1 dose of CC-486.
10.2.4.
Biomarker Population
The biomarker analysis population will include all randomized subjects who received at least 1
dose of IP, provided consent for exploratory biomarker studies, and had at least 1 predose 
biomarker tissue collected and deemed of adequate quality for biomarker analysis. 
10.3.
Sample Size and Power Considerations
The primary goal of this study is to provide estimates of the difference in efficacy and safety 
between CC-486 plus pembrolizumab and placebo plus pembrolizumab. 
Approximately 90 subjects will be randomized 1:1 to receive CC-486 plus pembrolizumab or 
placebo plus pembrolizumab. Primary analysis will be conducted when 70 PFS events occur.
Selected hypothetical scenarios are presented in Table 7 with confidence interval and power 
estimates, when approximately 70 PFS events have occurred.
The table below demonstrates the hypothetical power of testing the null hypothesis H0: λT/ λC=1, 
against the two sided alternative H0: λT/ λC≠1,assuming that time to PFS events in both treatment 
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on.n.
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Celgene Corporation
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CC-486-NSCL-001 Final: 15 May 2015
arms follow exponential distributions, and λC is the monthly hazard rate of the survival 
distribution in the control arm, and  λT is the monthly hazard rate of the survival distribution in 
the experimental arm (CC-486+pembrolizumab).
Table 7:
Hypothetical Power and Resulting Two-sided 90% CI of Hazard Ratio
Combo Treatment Median PFS (month) 
5.5
5.0
4.6
Total PFS events
74
75
76
Power (%) w/two-sided α=0.10
1
82.4
71.7
59.4
HR with [two-sided 90% CI] 
0.55 [0.38,0.81]
0.60 [0.41,0.88]
0.65 [0.45,0.95]
1 These calculations assume the median PFS in pembrolizumab alone is 3.0 months (Garon, 2014). And lost to 
follow-up (to assess PFS events) rate is 10% at the end of study. 
The power calculations are conducted with East 5.4. 
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race and other categorical variables will be provided using frequency 
tabulations.  Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site will be provided. Protocol 
deviations will be summarized using frequency tabulations.
10.6.
Efficacy Analysis
10.6.1.
Primary Efficacy Endpoint
The primary endpoint PFS will be defined as the time from the randomization date to disease 
progression assessed by Investigator according to RECIST version 1.1 guideline or death due to 
any cause, whichever occurs first.  
Subjects who are alive and progression-free at the cut-off date of the PFS analyses will be 
censored at the date of the last tumor evaluation.  If subjects  begin new anti-cancer therapy prior 
to documented progression, PFS will be censored at the last assessment prior to receiving the 
anti-cancer therapy. Subjects with 2 or more missing response assessments prior to a visit with 
documented disease progression (or death) will be censored at the last visit where the subject 
was documented to be PFS event-free.  A sensitivity analysis will be performed with censoring 
rules that follow the principles of assigning the date of event based on the time of the first 
evidence of objective progression or death regardless of violations, discontinuation of IP or 
change of therapy. 
PFS will be summarized by median progression-free survival time (including two-sided 90% 
confidence interval [CI]) for each treatment group and within each strata.  The hazard ratio and a 
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two-sided 90% CI will be estimated by using Cox proportional hazard model with treatment, and 
any stratification factors as model covariates.  The Kaplan-Meier curve for PFS will be presented
for each treatment group and strata.
10.6.2.
Secondary Endpoints
10.6.2.1.
Overall Survival
Overall survival (OS) will be defined as the time from the date of randomization to the date of 
death (any cause).  Subjects who are alive will be censored at the last time that the subject was 
known to be alive. The OS analysis may also be conducted at the time when 70 deaths occur, in 
addition to when the primary analysis is performed.
Medians of overall survival including two-sided 90% CI for each treatment group will be 
calculated.  The hazard ratio and a two-sided 90% CI will be estimated using Cox proportional 
hazard model with treatment, and all stratification factors in the model.  The Kaplan-Meier curve 
for survival will be presented for each strata and treatment group.
10.6.2.2.
Overall Response Rate (ORR)
Overall response rate is the percentage of subjects that achieve a confirmed complete or partial 
response as assessed by the Investigator using RECIST version 1.1 guideline. This rate will be 
presented for each treatment group and strata.  The 90% CI of the response rates will be 
provided.  A two-sided 90% CI of the Response rate differences between pembrolizumab plus 
placebo and pembrolizumab plus CC-486 arm, with each strata and overall will be provided.
10.6.2.3.
Disease Control Rate (DCR)
The percentage of disease control (i.e., confirmed SD, CR or PR) according to RECIST 1.1 will 
be analyzed in the same manner as ORR.  When SD is believed to be best response, it must meet 
the minimum duration of 18 weeks from randomization.
10.6.2.4.
irPFS, irORR and irDCR per irRECIST
Exploratory endpoints such as irPFS, irORR, and irDCR assessed by Investigator according to 
irRECIST will be analyzed using statistical methods described previously for similar primary or 
secondary endpoints.
10.6.3.
Subgroup Analysis
The effect of treatment on the efficacy variable OS, PFS, and DCR may be investigated within 
subgroups defined by selected baseline prognostic variables and any stratification factors.
The methods described in previous statistical analysis sections will be used for each subgroup 
separately. A forest plot may also be provided.
10.7.
Safety Analysis
Safety analysis will be performed using the safety population. Safety and tolerability will be 
monitored through continuous reporting of all AEs and SAEs, laboratory abnormalities, and 
incidence of subjects experiencing adverse events resulting in dose reductions, dose 
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0.7.

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interruptions, and/or premature discontinuation of study drugs. TEAEs, TEAEs leading to death 
or discontinuation from treatment, events assessed as Grade 3 or Grade 4,  vital signs, weight, 
clinical laboratory information, and concomitant medications/procedures will be tabulated and 
summarized.
Treatment-emergent adverse events will be coded according to MedDRA. All TEAEs will be 
summarized by MedDRA system organ class and preferred term, frequency, severity grade based 
on the CTCAE (Version 4.0) and relationship to treatment. Serious adverse events, events of 
interest, and events leading to discontinuation or death will be listed separately.
10.8.
Pharmacokinetic Analysis
When appropriate, plasma PK samples collected will be analyzed for CC-486 concentration 
determination using a validated high-performance liquid chromatography/tandem mass 
spectrometric method.
10.8.1.
Plasma Concentrations
By-subject listing of pharmacokinetic blood sample collection times as well as derived sampling 
time deviations will be provided.  CC-486 plasma concentrations will be summarized using 
descriptive statistics (N, arithmetic mean, standard deviation, standard error, minimum, median, 
maximum, percent coefficient of variation, geometric mean, and geometric percent coefficient of 
variation) for each cycle, if/when appropriate.  Concentrations that are below the limit of 
quantitation (BLQ) will be treated as zero for the computation of descriptive statistics. Missing 
concentrations and concentrations from blood samples collected more than ± 10% of nominal 
time will be omitted from the calculation of descriptive statistics.
Individual subject concentration-time data and mean concentration-time data for each cycle will 
be graphically presented on linear and semi-logarithmic scales.
Following single dose administration, predose samples that are BLQ or missing will be assigned 
a numerical value of zero for the calculation of AUC.  Any anomalous concentration values 
observed at predose will be identified in the clinical study report (CSR) and used for the 
computation of AUC.  Pharmacokinetic parameters will be computed if the anomalous value is
not greater than 5% of the Cmax.  If the anomalous value is greater than 5% of Cmax, the computed 
pharmacokinetic parameters for the given subject will be dropped from the pharmacokinetic 
analysis.  
Any other BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.  A BLQ value that occurs between quantifiable data 
points, especially prior to Cmax, will be evaluated to determine if an assigned concentration of 
zero makes sense, or if reanalysis or exclusion of the data is warranted.  Following Cmax, BLQ 
values embedded between 2 quantifiable data points will be treated as missing when calculating 
AUC.  BLQ values occurring at the end of the collection interval (after the last quantifiable 
concentration) will be treated as missing data.  If consecutive BLQ concentrations are followed 
by quantifiable concentrations in the terminal portion of the concentration curve, these quantified 
values will be excluded from the pharmacokinetic analysis by assigning them a value of missing, 
unless otherwise warranted by the concentration-time profile.  For the purpose of analysis, these 
trailing BLQ values may be designated as zero in the dataset if the pharmacokinetic program 
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used to do the analysis (such as WinNonlin®) will treat trailing zero values as missing when 
calculating AUC.
Actual sampling times will be used in the calculations of pharmacokinetic parameters that will be 
derived using noncompartmental methods with Phoenix™ WinNonlin® Professional Version 6.3, 
or higher, 
  Graphics may be prepared 
with SAS Version 9.1, or higher; or Excel 2007, or higher; Phoenix™ WinNonlin® Professional 
6.3, or higher; or S-Plus 8.2., or higher 
.
10.8.2.
Pharmacokinetic Parameters
The following PK parameters will be calculated for CC-486:
AUCinf
Area under the plasma concentration-time curve from Time 0 extrapolated 
to infinity, calculated as [AUCt + Ct/∀z].  Ct is the last quantifiable 
concentration. No AUC extrapolation will be performed with unreliable 
∀z.  If AUC %Extrap is ≥25%, AUCinf will not be reported
AUCt
Area under the plasma concentration-time curve from Time 0 to the time 
of the last quantifiable concentration, calculated by linear trapezoidal 
method when concentrations are increasing and the logarithmic 
trapezoidal method when concentrations are decreasing.
Cmax
Maximum observed plasma concentration, obtained directly from the 
observed concentration versus time data.
Tmax
Time to Cmax, obtained directly from the observed concentration versus 
time data.
t1/2
Terminal phase half-life in plasma, calculated as [(ln 2)/ ∀z].  t1/2 will only 
be calculated when a reliable estimate for ∀z can be obtained.  
CL/F
Apparent total clearance, calculated as [Dose/AUCinf]. 
Vz/F
Apparent volume of distribution, calculated as [(CL/F)/∀z ].
The following PK parameters for CC-486 will be calculated for diagnostic purposes and listed, 
but they will not be summarized:
∀z
Apparent terminal rate constant, calculated by linear regression of the 
terminal portion of the log-concentration versus time curve in plasma.  
Visual assessment will be used to identify the terminal linear phase of the 
concentration versus time profile.  A minimum of three data points will be 
used for calculation.  
∀z will not be estimated if the terminal phase of the log-concentration 
versus time profile does not exhibit a linear decline phase, or if the 
regression coefficient < 0.8.  
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('06'RF1XPEHU
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∀z lower
Lower limit of time (h) included in the calculation of ∀z. 
∀z N
Number of data points used in the calculation of ∀z.
∀z upper
Upper limit of time (h) included in the calculation of ∀z.
Rsq
Regression coefficient for calculation of ∀z.  
AUC % Extrap
Percentage of AUCinf due to extrapolation from the last quantifiable time 
point to infinity.
10.8.3.
PK Analyses
By-subject listing of pharmacokinetic parameters will be provided.  The pharmacokinetic 
parameters will also be summarized using descriptive statistics (N, arithmetic mean, standard 
deviation, standard error, minimum, median, maximum, percent coefficient of variation, 
geometric mean, and geometric percent coefficient of variation) for each cycle.  Also, when 
appropriate, graphical representations (i.e., scatter plots, box plots, etc) may be used to visualize
the results.
The effect of pembrolizumab on the PK of CC-486 will be assessed using graphic comparison 
and descriptive stats.
Exploratory analysis may be conducted to investigate the relationship between PK parameters 
and efficacy endpoints.
10.9.
Interim Analysis
No interim analysis of efficacy is planned for this study.
10.10.
Other Topics
10.10.1.
Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will be established and will include 
medical oncologists and a statistician, all of whom are not otherwise involved in the study 
conduct.  During the course of the study, the DMC will review the safety data regularly. The first 
DMC meeting will occur when 10 subjects in each arm have safety data from at least one cycle 
of treatment, with subsequent meetings approximately every 6 months or more often if requested 
by the DMC Chairman. The DMC will offer recommendations to continue, modify or stop the 
study based only on periodic evaluations of comparative safety data, in accordance with criteria 
outlined in the DMC Charter. An independent statistician will prepare the reports to the DMC 
members for each scheduled meeting. Operational details for the DMC will be detailed in the 
DMC charter.
10.10.2.
Steering Committee
The conduct of this trial will be overseen by a Steering Committee (SC), presided over by the 
coordinating principal Investigator and if possible the representative regional Investigators from 
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countries participating in this study.  The SC will serve in an advisory capacity to the Sponsor.  
Operational details for the SC will be detailed in a separate SC charter.
Note: The SC is separate from the DMC.
&(/*(1(35235,(7$5<,1)250$7,21

('06'RF1XPEHU
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CC-486-NSCL-001 Final: 15 May 2015
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 11.3), regardless of etiology. Any 
worsening (i.e., any clinically significant adverse change in the frequency or intensity of a pre-
existing condition) should be considered an AE.  A diagnosis or syndrome should be recorded on 
the AE page of the CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 8.2.2 for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE CRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should not be reported 
as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for CC-486 and 
pembrolizumab overdose. Actual treatment should depend on the severity of the clinical situation 
and the judgment and experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the Investigator from the time the subject signs informed consent 
until 30 days after the last dose of either study drug and those SAEs made known to the 
Investigator at any time thereafter that are suspected of being related to IP. Adverse events and 
SAEs will be recorded on the AE page of the CRF and in the subject’s source documents.  All 
SAEs must be reported to Celgene Drug Safety within 24 hours of the Investigator’s knowledge 
of the event by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form.
In addition, adverse events known as pembrolizumab Events of Clinical Interest (ECI) must also 
be recorded on the Adverse Event CRFs and reported within 5 days of the Investigator’s 
knowledge of the event, regardless of whether or not the Investigator considers the event related 
to the IP. If the event meets serious criteria (SAE), the event must also reported to Celgene Drug 
Safety within 24 hours by facsimile, or other appropriate method, using the SAE Report Form, or 
approved equivalent form as outlined in Section 11.5. This includes the reporting of  any 
pembrolizumab ECIs that become known to the investigator > 30 days to ≤90 days after the last 
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('06'RF1XPEHU
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dose of pembrolizumab, or 30 days after the last dose of pembrolizumab if the subject initiates a 
new anticancer therapy, whichever is earlier, whether or not related to pembrolizumab. 
See Section 11.5.1 (or Section 11.7) as well as Appendix C for detailed guidance on the 
reporting of pembrolizumab ECIs.  
11.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
11.2.1.
Seriousness 
A serious adverse event (SAE) is any AE occurring at any dose that:
!
Results in death;
!
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
!
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
!
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);
!
Is a congenital anomaly/birth defect;
!
Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:
!
A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
!
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.
!
The administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.
!
A procedure for protocol/disease-related investigations (eg, surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE.
!
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.
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('06'RF1XPEHU
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!
A procedure that is planned (i.e., planned prior to starting of treatment on study); 
must be documented in the source document and the CRF.  Hospitalization or 
prolonged hospitalization for a complication remains a reportable SAE.
!
An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication, that has not worsened from baseline. 
!
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the CRF and the SAE Report Form 
must be completed.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event. 
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
Adverse events that are not defined in the CTCAE should be evaluated for severity / intensity 
according to the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
11.2.3.
Causality 
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
rm
ates,
ates,
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ty
i
of
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t
f
t’s symptom
s sympto
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er
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or A
f
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ld be evalu
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mfort; n
rt; n
moderate 
moderate 
dical interv
dical interv
arked limita
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/therapy r
threatening
hreatening
gnificant me
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e 5 = Death
e 5 = Deat
Causality 
Causality
vestigator m
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urrence of a
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No
No

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Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
11.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE). 
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.  
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
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possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies, suspected pregnancies and lactation occurring in either a female subject of 
childbearing potential or partner of a male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential
Pregnancies, suspected pregnancies (including elevated β-hCG or a positive pregnancy test in a 
female of childbearing potential regardless of age or disease state) and lactation of a female 
subject that occur during the trial or within 120 days of completing the trial (or longer if required 
by local requirements), or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, are considered immediately reportable events.  
Investigational product is to be discontinued immediately.  The pregnancy, suspected pregnancy, 
or positive pregnancy test, or lactation must be reported to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form.  
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
The female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 30 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 30 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking investigational product becomes pregnant while the 
subject is receiving investigational product or within 3 months of the last dose of IP, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. The female partner should be referred to an 
obstetrician-gynecologist, preferably one experienced in reproductive toxicity for further 
evaluation and counseling.  Male subjects should avoid fathering a child until 3 months after the 
last dose of IP (or longer if required by local requirements). The ICF will address any country-
specific requirements, as needed.
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11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  Any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression of 
the cancer under study that occurs to any subject from the time the consent is signed through 90 
days following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, whether or not related to the Sponsor's 
product  must be reported to Celgene Drug Safety within 24 hours of the Investigator’s 
knowledge of the event by facsimile, or other appropriate method, using the SAE Report Form, 
or approved equivalent form.  This instruction pertains to initial SAE reports as well as any 
follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to study drugs) that occur during 
the study (from the time the subject signs informed consent until 90 days after the last dose of 
either IP) or any SAE made known to the Investigator at anytime thereafter that are suspected of 
being related to IP.  SAEs occurring prior to treatment (after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the Investigator is responsible for informing the IRB/Ethics 
Committee (EC) of the SAE and providing them with all relevant initial and follow-up 
information about the event. The Investigator must keep copies of all SAE information on file 
including correspondence with Celgene and the IRB/EC.
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-486 based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance 
with Directive 2001/20/EC and the Detailed Guidance on collection, verification and 
presentation of adverse reaction reports arising from clinical trials on investigational products for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.
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For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP, pembrolizumab based on the 
Pembrolizumab Investigators Brochure for the product.
Events of  disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as expected adverse 
events and will not be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the Investigator of the following 
information:
!
Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (i.e., SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where required by local legislation, the Investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with Sponsor and the IRB/EC.  (See Section 15.3 for record retention 
information).
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
11.7.
Pembrolizumab Events of Clinical Interest
Selected adverse events are also known as Events of Clinical Interest (ECI) and must be recorded 
as such on the Adverse Event CRFs and reported within 5 days of the Investigator’s knowledge 
of the event, regardless of whether or not the Investigator considers the event related to the IP. If
the event meets serious criteria (SAE), the event must also reported to Celgene Drug Safety 
within 24 hours by facsimile, or other appropriate method, using the SAE Report Form, or 
approved equivalent form as outlined in Section 11.5.  
Events of clinical interest for this trial include, but are not limited to :
1. an overdose of pembrolizumab, as defined in Section 8.2.2 - Overdose, that is not 
associated with clinical symptoms or abnormal laboratory results. See Section 11.1 for a 
description of how overdoses of pembrolizumab are to be documented (with or without 
associated adverse events).
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
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*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology.  
There are additional ECIs identified in the Appendix C guidance document which also need to be 
reported to the Sponsor within 5 days of the Investigator’s knowledge of the event by data entry 
into the Adverse Event eCRF, regardless of whether or not the Investigator considers the event 
related to the IP, and if deemed serious (SAE), also reported to Celgene Drug Safety within 24 
hours by facsimile, or other appropriate method, using the SAE Report Form, or approved 
equivalent form as outlined in Section 11.5.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-related 
event.  Subjects who develop an ECI thought to be immune-related should have additional 
testing to rule out other etiologic causes.  If lab results or symptoms indicated a possible 
immune-related ECI then additional testing should be performed to rule out other etiologic 
causes.  If no other cause was found, then it is assumed to be immune-related.
In addition, any pembrolizumab ECIs that become known to the investigator >30 days to ≤90 
days after the last dose of pembrolizumab, or 30 days after the last dose of pembrolizumab if the 
subject initiates a new anticancer therapy, whichever is earlier, whether or not related to 
pembrolizumab, must be reported to the sponsor within 5 days of the Investigator’s knowledge 
of the event by data entry into the Adverse Event eCRF. If the event is deemed serious (SAE), it 
must also be reported to Celgene Drug Safety within 24 hours by facsimile, or other appropriate 
method, using the SAE Report Form, or approved equivalent form as outlined in Section 11.5.
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12.
DISCONTINUATIONS
12.1.
Treatment Discontinuations
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product :
!
Adverse Event
!
Progressive Disease
!
Symptomatic deterioration (global deterioration of health status)
!
Physician decision
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other (to be specified on CRF)
The reason for discontinuation of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
12.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
study:
!
Adverse Event
!
Progressive disease
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other
The reason for study discontinuation should be recorded in the CRF and in the source 
documents.
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13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page).This global Emergency 
Call Center is available 24 hours a day and 7 days a week. The representatives are responsible 
for obtaining your call-back information and contacting the on call Celgene/contract research 
organization (CRO) Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
13.2.
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unless in the opinion of the 
Investigator, it is absolutely necessary to safely treat the subject. IF it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the Investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor. However, the Investigator may 
contact the Medical Monitor prior to breaking the blind to discuss unblinding, mainly in the 
interest of the subject.
The Investigator should ensure that the code is broken only in accordance with the protocol.  The 
Investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the Investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the Investigator through the IRT by using an 
emergency unblinding personal identification number (PIN), and the Investigator should call IRT 
for unblended dose information.
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14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and Investigator abide by Good Clinical Practice (GCP), as described in International 
Conference on Harmonisation (ICH) Guideline E6 and in accordance with the general ethical 
principles outlined in the Declaration of Helsinki. The study will receive approval from an 
IRB/EC prior to commencement. The Investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations.  Celgene staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The Investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
document and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
Investigators with a summary of the results that is written for the lay person.  The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
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14.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents 
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the Investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the Investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an Investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
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Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the Investigator must submit to the IRB/EC:
!
Information on serious or unexpected adverse events as soon as possible; 
!
Periodic reports on the progress of the study;
!
Deviations from the protocol or anything that may involve added risk to subjects.
14.8.
Termination of the Study
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation  will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:
!
Unsatisfactory enrollment;
!
GCP noncompliance;
!
Inaccurate or incomplete data collection;
!
Falsification of records;
!
Failure to adhere to the study protocol.
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15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; X-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of CRFs or CD-ROM.
15.2.
Data Management
Data will be collected via CRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
!
Signed informed consent documents for all subjects;
!
Subject identification code list, screening log (if applicable), and enrollment log;
!
Record of all communications between the Investigator and the IRB/EC;
!
Composition of the IRB/EC;
!
Record of all communications between the Investigator, Celgene, and their authorized 
representative(s);
!
List of Sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;
!
Copies of CRFs (if paper) and of documentation of corrections for all subjects;
!
IP accountability records;
!
Record of any body fluids or tissue samples retained;
!
All other source documents (subject records, hospital records, laboratory records, 
etc.); 
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!
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The Investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The Investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. 
Investigator/Institution should take measures to prevent accidental or premature destruction of 
these documents.
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the Investigator and the staff at a study
initiation visit and/or at an Investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, CRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the Investigator.  Monitoring will 
include on-site visits with the Investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the CRFs against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the Investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the CRFs or via queries by the Investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs  to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The Investigator is required to permit direct access to the facilities where the study took place, 
source documents, CRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, EMA, Health Canada) and 
company authorized representatives.  The Investigator should make every effort to be available 
for the audits and/or inspections.  If the Investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
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17.
PUBLICATIONS
As described in Section 14.2 all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.  
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
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18.
REFERENCES
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BSC in inoperable non-small cell lung cancer – a randomized trial with quality of life as the 
primary outcome. Br J Cancer. 2000;83(4):447-453.
Bang YJ. The potential for crizotinib in non-small cell lung cancer: a perspective review. Ther 
Adv Med Oncol. 2011;3(6):279-291.
Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a reality for 
the treatment of lung cancer. Cancer Immunol Res. 2013;1(2):85-91.
Brahmer JR, Horn L, Antonia SJ, et al. Survival and long-term follow-up of the phase I trial of 
nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated 
advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;(suppl; abstr 8030).
Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med. 2012;366(26):2455-2465.
Bria E, Cuppone F, Ciccarese M, et al. Weekly docetaxel as second line chemotherapy for 
advanced non-small-cell lung cancer: meta-analysis of randomized trials. Cancer Treat Rev. 
2006;32(8):583-587.
Crino L, Mosconi AM, Scagliotti G, et al. Gemcitabine as second-line treatment for advanced 
non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1999;17(7):2081-2085.
Edge SB, Byrd DR, Compton CC, et al. AJCC cancer Staging Manual. 7th Ed. Springer, 2009.
Eisenhauer E, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 45(2):228-247.
ESMO Clinical Practice Guidelines: Metastatic Non-Small-Cell Lung Cancer. Available at: 
www.esmo.org/Guidelines/Lung-Cancer/Metastatic-Non-Small-Cell-Lung-Cancer. Accessed 
11Feb2015.
Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus 
vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated 
with platinum-containing chemotherapy regimens. J Clin Oncol. 2000;18(12):2354-2362.
Garcia-Manero G, Gore SD, Cogle C, et al. Phase I study of oral azacitidine in myelodysplastic 
syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J Clin Oncol. 
2011;29(18):2521-2527.
Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of pembrolizumab in 
previously treated patients (pts) with non-small cell lung cancer (NSCLC) [abstract]. In: 
Proceedings of the 2014 ASCO Annual Meeting; 2014 May 30-Jun 3; Chicago, IL. J Clin Oncol.
32:5s, 2014 (suppl; abstr 8020).
Gilotrif [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. 
Revised April 2014.
Globocan 2012: Estimated Cancer Incidence, Mortality and Prevalance Worldwide in 2012. 
Available at: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed 11Feb2015
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sly treated 
str 8030).
r 8030).
L1 antibod
L1 antibod
.
d line chem
d line che
ed tri
tr als. C
s second
second-li
ol.l. 1999;17
1999;1
ncer Stagin
ncer Stagi
ew respons
ew respons
ur J Cancer
r J Cance
etastati
tastat c N
ancer/Meta
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2
r RN, et al.
r RN, et al
in pat
in patieients
ng chemot
ng chemot
Gore SD, C
Gore SD, 
onic myelo
onic myelo
:2521
:2521-2527
2527
B, Leighl N
Leighl 
ously treate
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oceedings o
ceedings o
32:5s, 201
2:5s, 201
ilotri
ilotri

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Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol. 2004;22(15):1589-1597.
Harvey RD. Immunologic and clinical effects of targeting PD-1 in lung cancer. Clin Pharmacol 
Ther. 2014;96(2):214-223.
Juergens RA, Wrangle J, Vendetti FP, et al. Combination epigenetic therapy has efficacy in 
patients with refractory advanced non small cell lung cancer. Cancer Discov. 2011;1(7):598-607.
Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell 
lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372(9652):1809-1818.
Lang-Lazdunski L. Surgery for nonsmall cell lung cancer. Eur Respir Rev. 2013;22(129):382-
404.
Miranda RB, Jones PA. DNA methylation: the nuts and volts of repression. J Cell Physiol. 
2007;213(2):384-390.
NCCN Practice Guidelines in Oncology: Non-Small Cell Lung Cancer v.4.2014.  Available at: 
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 11Feb2015.
Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-898.
Perol M, Ciuleanu TE, Arrieta O. REVEL: A randomized, double-blind, phase III study of 
docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the 
second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease 
progression after one prior platinum-based therapy. J Clin Oncol. 2014; 32 (5s): suppl; abstr 
LBA8006.
Peterson P, Park K, Fossella FV, et al. Is pemetrexed more effective in adenocarcinoma and 
large cell lung cancer than in squamous cell carcinoma? A retrospective analysis of a phase III 
trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung 
cancer (NSCLC): P2-328 [abstract]. In: 12th World Conference on Lung Cancer. J of Thoracic 
Oncol 2007;2(8 suppl 4):S851.
Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus 
placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 
3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2): 143-155.
Sculier JP, Lafitte JJ, Berghmans T, et al. A phase II trial testing gemcitabine as second-line 
chemotherapy for non small cell lung cancer. Lung Cancer. 2000;29(1):67-73.
Shaw AT, Kimm D-W, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-
positive lung cancer. N Engl J Med. 2013;368(25):2385-2394.
Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best 
supportive care in patients with non-small-cell lung cancer previously treated with platinum-
based chemotherapy. J Clin Oncol. 2000;18(10):2095-2103.
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-
cell lung cancer. N Engl J Med. 2005;353(2):123-132.
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000;191(5
d, double-
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ng cancer (
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apy. J Clin O
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pemetrexe
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us cell carci
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previously 
reviously
act]. In: 12t
act]. In: 12
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mgaard A, 
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itte JJ, Berg
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Speicher MR, Petersen S, Uhrig S, et al. Analysis of chromosomal alterations in non-small cell 
lung cancer by multiplex-FISH, comparative genomic hybridization, and multicolor bar coding. 
Lab Invest. 2000;80(7):1031-1041.
Tarceva [package insert]. OSI Pharmaceuticals, LLC, Northbrook, IL, USA an affiliate of 
Astellas Pharma US, Inc., 2012.
Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated 
patients with refractory advanced non-small-cell lung cancer: results from a randomised, 
placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 
2005;366(9496):1527-1537.
Topalian SL. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J 
Med. 2012;366(26):2443-2454.
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multiple genes in the tumor and bronchoalveolar lavage of patients with lung cancer. Clin Cancer 
Res. 2004;10(7):2284–2288.
Xalkori [package insert]. Pfizer Labs, New York, NY, USA, revised Aug, 2011.
Zeng L, Jarrett C, Brown K, et al. Insulin-like growth factor binding protein-3 (IGFBP-3) plays a 
role in the anti-tumorigenic effects of 5-Aza-2’-deoxycytidine (AZA) in breast cancer cells. Exp 
Cell Res. 2013;319(14):2282-2295.
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N Engl J 
thylat
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2011.
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19.
APPENDICES
19.1.
Appendix A: RECIST 1.1
The following information is extracted/summarized from Eisenhauer, 2009, New response
evaluation criteria in solid tumors:  Revised RECIST guideline (version 1.1). Please refer to the 
primary reference for further information.
19.1.1.
Definitions
At screening, tumor lesions/lymph nodes will be categorized as measurable or non-measurable.
19.1.1.1.
Measurable Disease
Tumor Lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
!
10 mm by CT scan (CT scan slice thickness no greater than 5 mm)
!
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable)
!
20 mm by chest X-ray
Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.
19.1.2.
Tumor Response Evaluation
19.1.2.1.
Target Lesions
When more than one measurable tumor lesion is present at baseline all lesions up to a maximum 
of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. Target
lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. Note that pathological nodes must meet the measurable 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will 
contribute to the baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed. At baseline, the sum of the 
target lesions (longest diameter of tumor lesions plus short axis of lymph nodes:  overall 
maximum of 5) is to be recorded.
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used.
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19.1.2.2.
Non-target Lesions
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as “present,” “absent,” or 
“unequivocal progression.”
19.1.2.3.
Response Criteria
Target and non-target lesions are evaluated for response separately, and then the tumor burden as 
a whole is evaluated as the overall response.
19.1.2.3.1. Target Lesion Response
Target lesions will be assessed as follows:
!
Complete Response (CR).  Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to < 10 
mm.
!
Partial Response (PR).  At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.
!
Progressive Disease (PD).  At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm. (Note:  the appearance 
of one or more new lesions is also considered progression).
!
Stable Disease (SD).  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of diameters while on 
study.
19.1.2.3.2. Non-target Lesion Response
Non-target lesions will be assessed as follows:
!
Complete Response (CR).  Disappearance of all non-target lesions and normalisation 
of tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm 
short axis).
!
Non-CR/Non-PD.  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
!
Progressive Disease (PD).  Unequivocal progression (see comments below) of 
existing non-target lesions. (Note: the appearance of one or more new lesions is also 
considered progression).
When the Subject Also Has Measurable Disease:  In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of one or more non-target lesions is usually not sufficient to quality for 
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unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely
rare.
When the Subject Has Only Non-measurable Disease:  This circumstance arises in some 
Phase 3 trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above; however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition:  if all 
lesions are truly non-measurable) a useful test that can be applied when assessing subjects for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: ie, an increase in tumor burden representing an 
additional 73% increase in “volume” (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large,” 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If “unequivocal progression” is seen, the 
subject should be considered to have had overall PD at that point. While it would be ideal to 
have objective criteria to apply to non-measurable disease, the very nature of that disease makes 
it impossible to do so: therefore, the increase must be substantial.
19.1.2.3.3. Overall Response
Overall response should be assessed according to Table 8 for subjects with target lesions, and
Table 9 for subjects with only non-target lesions.
Table 8:
Time Point Response: Subjects With Target (± Non-target) Disease
Target Lesions 
Response
Non-target Lesion Response
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/ non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD1
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, NE = inevaluable, PD = progressive disease, PR = partial response, SD = stable disease
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Table 9:
Time Point Response: Subjects With Non-target Disease Only
Non-target Lesion Response
New Lesions
Overall Response
CR
No
CR
Non-CR/ non-PD
No
Non-CR/non-PD1)
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No
NE
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PD
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Yes
PD
CR = complete response, PD = progressive disease, NE =  inevaluable
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
19.1.2.4.
Symptomatic Deterioration
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease.
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19.2.
Appendix B: irRECIST
Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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Table 10:
Imaging Guidance for Standard RECIST 1.1 and Immune-related (ir) RECIST (Continued)
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19.3.
Appendix C: Events of Clinical Interest (ECI) Guidance Document
19.3.1.
Overview
The purpose of this appendix is to provide study sites with guidance on the identification and 
management of ECIs associated with pembrolizumab.
Based on the literature review, and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are the primary Event of ECI. Immune-related 
AEs are adverse events associated with the treatment of patients with immunotherapy treatments 
that appear to be associated with the immune therapy’s mechanism of action. Based on these 
potential irAEs, the Sponsor has defined a list of specific adverse event terms (ECIs) that are 
selected adverse experiences that must be reported to Sponsor within 5 days from the time the 
Investigator/physician is aware of such an occurrence, regardless of whether or not the 
Investigator/physician considers the event to be related to IP. ECIs may be identified through 
spontaneous patient report and/or upon review of subject data. Table 11 provides the list of terms 
and reporting requirements for AEs that must be reported as ECIs.  
Given that the current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab. Therefore any Grade 3 or higher event that the 
Investigator/physician considers to be immune-related should be reported as an ECI regardless of 
whether the specific event term is in Table 11 and reported to Sponsor within 5 days from the 
time the Investigator/physician is aware of such an occurrence. Adverse events that are both an 
SAE and an ECI should be reported on both the eCRF and also reported to Celgene Drug Safety 
within 24 hours by facsimile, or other appropriate method, using the SAE Report Form, or 
approved equivalent form as outlined in Section 11.5.
Table 11:
Events of Clinical Interest
Pneumonitis (reported as ECI if  ≥ Grade 2)
Acute interstitial pneumonitis
Interstitial lung disease
Pneumonitis
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to 
treat the AE)
Intestinal Obstruction
Colitis
Colitis microscopic
Enterocolitis
Enterocolitis hemorrhagic
Gastrointestinal perforation
Necrotizing colitis
Diarrhea
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic 
steroids to treat the AE)
Adrenal Insufficiency
Hyperthyroidism
Hypophysitis
Hypopituitarism
Hypothyroidism
Thyroid disorder
Thyroiditis
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA)
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Table 11:
Events of Clinical Interest (Continued)
Endocrine (reported as ECI)
Type 1 diabetes mellitus (if new onset)
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE)
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic 
Purpura (TTP)
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP)
Disseminated Intravascular 
Coagulation (DIC)
Haemolytic Uraemic Syndrome 
(HUS)
Any Grade 4 anemia regardless of underlying mechanism
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids 
to treat the AE)
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT 
and/or AST)
Infusion Reactions (reported as ECI for any grade)
Allergic reaction
Anaphylaxis
Cytokine release syndrome
Serum sickness
Infusion reactions
Infusion-like reactions
Neurologic (reported as ECI for any grade)
Autoimmune neuropathy
Guillain-Barre syndrome
Demyelinating polyneuropathy
Myasthenic syndrome
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to 
treat the AE)
Uveitis
Iritis
Renal (reported as ECI if  ≥ Grade 2)
Nephritis
Nephritis autoimmune
Renal Failure
Renal failure acute
Creatinine elevations (report as ECI if ≥Grade 3 or any grade 
resulting in dose modification or use of systemic steroids to treat the 
AE)
Skin (reported as ECI for any grade)
Dermatitis exfoliative
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Skin (reported as ECI if ≥ Grade 3)
Pruritus
Rash
Rash generalized
Rash maculo-papular
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade)
Myocarditis
Pancreatitis
Pericarditis
Any other Grade 3 event which is considered immune-related by the physician
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Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor.  In addition, the guidelines include 
recommendations on the management of these ECIs. These guidelines are intended to be applied 
when the Investigator determines the events to be related to pembrolizumab. Note: if after the 
evaluation the event is determined not to be related, the Investigator is instructed to follow the 
ECI reporting guidance but does not need to follow the treatment guidance (below). Therefore, 
these recommendations should be seen as guidelines and the treating physician should exercise 
individual clinical judgment based on the patient.  For any question of dose modification or other 
treatment options, the specific language in the protocol should be followed.  Any questions 
pertaining to the collection of this information or management of ECIs should be directed to your 
local Sponsor contact. 
19.3.1.1.
Dose Modification/Discontinuation
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune-related adverse event.  Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of treatment 
may be considered assuming the patient meets the criteria for resumption of treatment.
19.3.2.
ECI Reporting Guidelines
Events of clinical interest are selected non-serious and serious adverse experiences that must be 
reported to Sponsor within 5 days for NON-SERIOUS events regardless of attribution to study 
treatment.  The AEs listed in this document and any event that meets the ECI criteria (as noted) 
in Table 11 or in the respective protocol (event term and Grade) must be reported regardless of 
physician-determined causality with IP and whether or not considered immune-related by the 
physician (unless otherwise specified).   Physicians/study coordinators/designated site personnel 
are required to record these experiences as ECIs on the Adverse Event CRF and to provide 
supplemental information (such as medical history, concomitant medications, investigations, 
etc.) about the event.  
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be 
reported to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate 
method, using the SAE Report Form, or approved equivalent form as outlined in Section 
11.5.
!
Please refer to the CRF Completion Guidelines. 
!
Please refer to protocol for details on reporting timelines and reporting of overdose 
19.3.3.
ECI Categories and Terms
This section describes the ECI categories and outlines subject management guidelines when an 
ECI is reported.
19.3.3.1.
Pneumonitis
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to 
the Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
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!
Pneumonitis
!
Interstitial lung disease
!
Acute interstitial pneumonitis 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered. 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral 
infection.  It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded.  
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted.  Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics.  If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should be 
reported regardless of etiology.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
Course of Action
Grade 2 events:
!
Report as ECI
!
Hold pembrolizumab
!
Consider pulmonary consultation with bronchoscopy and biopsy/bronchoalveolar 
lavage (BAL)
!
Consider infectious disease (ID) consult
!
Conduct an in person evaluation approximately twice per week
!
Consider frequent chest X-ray as part of monitoring
!
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or 
equivalent.  When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.   
!
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or higher pneumonitis.
Grade 3 and 4 events:
!
Report as ECI
!
Discontinue pembrolizumab
!
Hospitalize patient
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!
Bronchoscopy with biopsy and/or BAL is recommended.
!
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 
mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks.
!
If IV steroids followed by high dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue 
additional anti-inflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate 
a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more 
prolonged taper and administer additional anti-inflammatory measures, as needed.
!
Add prophylactic antibiotics for opportunistic infections.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.3.2.
Diarrhea/Colitis
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor on 
the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Colitis 
!
Colitis microscopic
!
Enterocolitis
!
Enterocolitis hemorrhagic 
!
Gastrointestinal perforation
!
Intestinal obstruction 
!
Necrotizing colitis
!
Diarrhea
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy.   However the AE should be reported regardless of etiology.
Course of Action
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal pain, mucus or blood in stool):  
!
Report as ECI
!
Hold pembrolizumab
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!
Symptomatic Treatment
!
For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood 
and/or mucus, 
o
Consider GI consultation and endoscopy to confirm or rule out colitis 
o
Administer oral corticosteroids (prednisone 1-2 mg/kg once daily or 
equivalent)
!
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.   
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
!
If symptoms worsen or persist > 3 days treat as Grade 3
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week):
!
Report as ECI
!
Hold pembrolizumab
!
Rule out bowel perforation.  Imaging with plain films or CT can be useful
!
Recommend consultation with gastroenterologist and confirmation biopsy with 
endoscopy
!
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high-dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 
hours).  When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  Taper over 6 to 8 weeks in patients with 
diffuse and severe ulceration and/or bleeding.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
!
If IV steroids followed by high-dose oral steroids does not reduce initial symptoms 
within 48 to 72 hours, consider treatment with additional anti-inflammatory measures 
as described in the literature (Topalian, 2012). Discontinue additional anti-
inflammatory measures upon symptom relief and initiate a prolonged steroid taper 
over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering 
of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged 
taper and administer additional anti-inflammatory measures as needed. 
Grade 4 events: 
!
Report as ECI
!
Permanently discontinue pembrolizumab
!
Manage as per Grade 3
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Celgene Corporation
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NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.  
19.3.3.3.
Endocrine
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and should 
be reported to the Sponsor on the Adverse Event CRF within 5 days if determined to be a non-
serious event:
!
Adrenal insufficiency
!
Hyperthyroidism
!
Hypophysitis
!
Hypopituitarism 
!
Hypothyroidism
!
Thyroid disorder 
!
Thyroiditis 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection.  However the AE should be reported regardless of etiology.
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism
Grade 2-4 events:
!
Report as ECI if appropriate
!
Hold pembrolizumab
!
Rule out infection and sepsis with appropriate cultures and imaging.
!
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values.
!
Pituitary gland imaging should be considered (MRIs with gadolinium and selective 
cuts of the pituitary can show enlargement or heterogeneity and confirm the 
diagnosis).
!
Treat with prednisone 40 mg orally or equivalent per day.  When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.  Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
!
Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis.
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('06'RF1XPEHU
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105
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!
Consultation with an endocrinologist may be considered.
Hyperthyroidism and Hypothyroidism
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events:
!
Report as ECI if appropriate (see Table 11)
!
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values.
!
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency.
!
Therapy with pembrolizumab can be continued while treatment for the thyroid 
disorder is instituted. 
!
In hyperthyroidism, non-selective beta-blockers (eg, propranolol) are suggested as 
initial therapy. 
!
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
!
Consultation with an endocrinologist may be considered.
Grade 3 hyperthyroidism events:
!
Report as ECI
!
Hold pembrolizumab
!
Rule out infection and sepsis with appropriate cultures and imaging.
!
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed 
by oral prednisone 1 to 2 mg/kg per day.  When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 hyperthyroidism events:
!
Report as ECI
!
Discontinue pembrolizumab
!
Manage as per Grade 3
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.  
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('06'RF1XPEHU
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Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia
The following AE terms are considered ECIs and should be reported to the Sponsor on the 
Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Type 1 diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis 
(DKA) 
!
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA).
Immune-mediated diabetes may present as new onset of type 1 diabetes or an abrupt worsening 
of pre-existing diabetes associated with laboratorial evidence of beta cell failure. All attempts 
should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM 
decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly 
controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above criteria 
should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia 
(abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or 
laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic 
acidosis, or low or undetected c-peptide.
Course of Action
T1DM should be immediately treated with insulin.
Type 1 diabetes mellitus or Grade 3-4 hyperglycemia events:
!
Report as ECI if appropriate (see Table 11)
!
Hold pembrolizumab for new onset type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of beta cell failure, and resume 
pembrolizumab when patients are clinically and metabolically stable. 
!
Insulin replacement therapy is recommended for type 1 diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
!
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
!
Consultation with an endocrinologist is recommended.
!
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, 
and insulin may be obtained.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.  
19.3.4.
Hematologic
The following AE term, if considered Grade ≥3 or requiring dose modification or use of 
systemic steroids to treat the AE, are considered an ECI and should be reported to the Sponsor on 
the Adverse Event CRF within 5 days if determined to be a non-serious event:
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atory
to
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!
Autoimmune hemolytic anemia
!
Aplastic anemia
!
Disseminated Intravascular Coagulation (DIC)
!
Haemolytic Uraemic Syndrome (HUS)
!
Idiopathic (or immune) Thrombocytopenia Purpura (ITP)
!
Thrombotic Thrombocytopenic Purpura (TTP)
!
Any Grade 4 anemia regardless of underlying mechanism
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.   
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, 
haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to confirm the 
diagnosis. However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
!
Report as ECI
!
Hold pembrolizumab
!
Prednisone 1-2 mg/kg daily may be indicated
!
Consider hematology consultation.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3 events:
!
Report as ECI
!
Hematology consultation. 
!
Hold pembrolizumab   Discontinuation should be considered as per specific protocol 
guidance.
!
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg orally (or 
equivalent) as appropriate
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
!
Report as ECI
!
Hematology consultation
!
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies.
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!
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg orally (or 
equivalent) as appropriate
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.5.
Hepatic
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification 
or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the 
Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Autoimmune hepatitis 
!
Hepatitis 
!
Transaminase elevations
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other hepatic diseases. However the AE should be reported regardless of etiology.
Drug-induced Liver Injury (DILI)
In addition, the event must be reported as a drug-induced liver injury (DILI) ECI, if the patient 
meets the laboratory criteria for potential DILI defined as: 
!
An ALT or AST lab value that is greater than or equal to three times (3X) the upper 
limit of normal (ULN) and 
!
An elevated total bilirubin lab value that is greater than or equal to two times (2X) 
ULN and
!
At the same time, an alkaline phosphatase lab value that is less than 2X ULN,
!
As a result of within-protocol-specific testing or unscheduled testing.
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI 
event.  
Course of Action
Grade 2 events:
!
Report as ECI
!
Hold pembrolizumab when AST or ALT > 3.0 to 5.0 times ULN and/or total bilirubin 
> 1.5 to 3.0 times ULN.
!
Monitor liver function tests (LFTs) more frequently until returned to baseline values 
(consider weekly).
o
Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when 
LFT returns to Grade 1 or baseline, taper steroids over at least 1 month, 
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('06'RF1XPEHU
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consider prophylactic antibiotics for opportunistic infections, and resume 
pembrolizumab per protocol.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
!
Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% 
relative to baseline and lasts ≥1 week.
Grade 3 events:
!
Report as ECI
!
Discontinue pembrolizumab when AST or ALT > 5.0 times ULN and/or total 
bilirubin > 3.0 times ULN.  
!
Consider appropriate consultation and liver biopsy to establish etiology of hepatic 
injury, if necessary
!
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours.  When 
symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 
4 hours or prednisone at 1 to 2 mg/kg should be started and continued over no less 
than 4 weeks. 
!
If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab 
is not recommended due to its potential for hepatotoxicity.
!
Several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events: 
!
Report as ECI
!
Permanently discontinue pembrolizumab
!
Manage patient as per Grade 3 above
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.6.
Neurologic
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Autoimmune neuropathy
!
Demyelinating polyneuropathy
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!
Guillain-Barre syndrome
!
Myasthenic syndrome
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
!
Report as ECI
!
Moderate (Grade 2) – consider withholding pembrolizumab. 
!
Consider treatment with prednisone 1-2 mg/kg orally daily as appropriate
!
Consider neurology consultation. Consider biopsy for confirmation of diagnosis.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3 and 4 events:
!
Report as ECI
!
Discontinue pembrolizumab
!
Obtain neurology consultation.  Consider biopsy for confirmation of diagnosis.
!
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens consider intravenous immunoglobulin (IVIG) or 
other immunosuppressive therapies as per local guidelines
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.7.
Ocular
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor on 
the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Uveitis
!
Iritis 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (eg, glaucoma or cataracts). However the AE should be reported regardless 
of etiology.
Course of Action
Grade 2 events: 
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('06'RF1XPEHU
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!
Evaluation by an ophthalmologist is strongly recommended.
!
Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics.
!
Discontinue pembrolizumab as per protocol if symptoms persist despite treatment 
with topical immunosuppressive therapy.
Grade 3 events:
!
Evaluation by an ophthalmologist is strongly recommended 
!
Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance.
!
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day.  When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events: 
!
Evaluation by an ophthalmologist is strongly recommended 
!
Permanently discontinue pembrolizumab
!
Treat with corticosteroids as per Grade 3 above
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.8.
Renal
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor on 
the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Nephritis
!
Nephritis autoimmune
!
Renal failure
!
Renal failure acute
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids 
to treat the AE.
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 
disease, or injury due to other chemotherapy agents.  A renal consultation is recommended. 
However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
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are conside
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Celgene Corporation
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!
Hold pembrolizumab
!
Treatment with prednisone 1-2 mg/kg orally daily.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 3-4 events: 
!
Discontinue pembrolizumab
!
Renal consultation with consideration of ultrasound and/or biopsy as appropriate
!
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or 
equivalent once per day.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.9.
Skin
Rash and Pruritus
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Pruritus
!
Rash
!
Rash generalized
!
Rash maculo-papular
!
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, 
in the physician's judgment, should be treated as an ECI. Clinical significance is left 
to the physician to determine, and could possibly include rashes such as the 
following: 
o
rash with a duration > 2 weeks; OR 
o
rash that is > 10% body surface area; OR 
o
rash that causes significant discomfort not relieved by topical medication or 
temporary cessation of IP.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
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Other Skin ECIs
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the Sponsor on the Adverse Event CRF within 5 days if determined to be a non-
serious event:
!
Dermatitis exfoliative
!
Erythema multiforme
!
Stevens-Johnson syndrome
!
Toxic epidermal necrolysis
Please note, the AE should be reported regardless of etiology.
Course of Action
Grade 2 events:
!
Symptomatic treatment should be given such as topical glucocorticosteroids (eg, 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral anti-pruritics (eg, diphenhydramine hydrochloride [HCl] or 
hydroxyzine HCl). 
!
Treatment with oral steroids is at physician’s discretion for Grade 2 events.
Grade 3 events:
!
Hold pembrolizumab.
!
Consider dermatology consultation and biopsy for confirmation of diagnosis.
!
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.
Grade 4 events:
!
Permanently discontinue pembrolizumab.
!
Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph.
!
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.
19.3.9.1.
Immediate Evaluation for Potential Skin ECIs
A. Photographs:
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Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon 
as possible. 
!
Take digital photographs of: 
o
the head (to assess mucosal or eye involvement), 
o
the trunk and extremities, and 
o
a close-up of the skin lesion/rash.
!
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
!
The time/date stamp should be set in the 'ON' position for documentation purposes. 
!
Photographs should be stored with the subject’s study records. 
!
The Sponsor may request copies of photographs. The local study contact (eg, clinical 
research associate [CRA]) will provide guidance to the site, if needed. 
B. Past Medical History:
Collect past medical history relevant to the event. Any pre-existing conditions not previously 
reported (eg, drug allergy) should be entered into the Medical History electronic case report form 
(eCRF). 
C. Vitals Signs and Standard Laboratory Tests:
Measure vital signs and record on the Vital Signs CRF.  Perform standard laboratory tests (CBC 
with differential and serum chemistry panel, including LFTs). 
D. Dermatology Consult
Refer the subject to a dermatologist as soon as possible. 
!
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
!
For clinically significant rash, the subject should be seen within 3-5 days. 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or 
to a pathologist experienced in reviewing skin specimens. 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results.
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.10.
Other
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Myocarditis
!
Pericarditis
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.3.10.
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!
Pancreatitis
!
Any additional Grade 3 or higher event which the physician considers to be immune 
related
All attempts should be made to rule out other causes.  Therapeutic specialists should be 
consulted as appropriate. However the AE should be reported regardless of etiology.
Course of Action
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment:
!
Withhold pembrolizumab.  
!
Systemic corticosteroids may be indicated. 
!
Consider biopsy for confirmation of diagnosis.
!
If pembrolizumab held and corticosteroid required, manage as per Grade 3 below.
Grade 3 events:
!
Hold pembrolizumab
!
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.  
!
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
!
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab 
treatment may be restarted and the dose modified as specified in the protocol
Grade 4 events:
!
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.  
!
Discontinue pembrolizumab
NOTE:  Any event that meets the criteria for SERIOUS adverse event (SAE), must be reported 
to the Celgene Drug Safety within 24 hours by facsimile, or other appropriate method, using the 
SAE Report Form, or approved equivalent form as outlined in Section 11.5.
19.3.11.
Infusion Reactions
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor on the Adverse Event CRF within 5 days if determined to be a non-serious event:
!
Allergic reaction
!
Anaphylaxis
!
Cytokine release syndrome
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!
Serum sickness
!
Infusion reactions
!
Infusion-like reactions
Please note, the AE should be reported regardless of etiology.
Course of Action
Table 12 shows treatment guidelines for subjects who experience an infusion reaction associated 
with the administration of pembrolizumab.
Table 12:
Infusion Reactions
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator.
None
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
! IV fluids
! Antihistamines
! NSAIDS
! Acetaminophen
! Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and 
the subject should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further trial 
treatment administration.
Subject may be 
premedicated 1.5 hrs.
(± 30 minutes) prior to 
infusion of 
pembrolizumab with:
Diphenhydramine 50 mg 
p.o. (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg p.o. (or equivalent 
dose of antipyretic).
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Table 12:
Infusion Reactions (Continued)
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
•
IV fluids
•
Antihistamines
•
NSAIDS
•
Acetaminophen
•
Narcotics
•
Oxygen
•
Pressors
•
Corticosteroids
•
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the Investigator.
Hospitalization may be indicated. Subject is 
permanently discontinued from further trial 
treatment administration.
No subsequent dosing
CTCAE = Common Terminology Criteria for Adverse Events;  hr = hour; IV = intravenous(ly); NCI = National 
Cancer Institute; NSAID = non-steroidal anti-inflammatory drug;  p.o. = oral(ly)
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
For Further information, please refer to CTCAE v4.0 at http://ctep.cancer.gov
19.3.12.
Follow-up to Resolution
Subjects should be followed to resolution. The Adverse Event CRF should be updated with 
information regarding duration and clinical course of the event. Information obtained from the 
consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. 
Any treatments administered for the event should also be entered in the Concomitant Medication 
eCRF.
19.3.13.
References
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer.  N Engl J Med 2012; 366:2455-2465.
Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse 
reactions—YERVOY Risk Evaluation and Mitigation Strategy (REMS). 
http://www.yervoy.com/hcp/rems.aspx
Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf
y y
all
a y 
bject is
bject is
further tri
urther tr
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vents; 
vents; hr = h
hr = 
matory drug
matory drug
ilable in the r
able in the r
AE v4.0
E v4.0 at ht
tion
tion
to resol
to resolut
l io
ration and c
ration an
ncluding di
ncluding d
ministered 
ministered 
Referenc
Referenc
mer JR, Ty
mer JR, Tyk
ibody
ibody i
y n P
n P
Bri
Br stolol-M
eacti
eactio

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Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010.
Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the 
Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature Reviews 
Cancer 2012; 12:252-264.
Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal Antibodies in 
Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–
3021.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 
366:2443-2454.
Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase 
II study comparing the tolerability and efficacy of ipilimumab administered with or without 
prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 
15:5591-5598, 2009.
Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint 
Protein Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-
9118/10/1-10.
Weber JS, Kahler KC, and Hauschild A. Management of Immune-Related Adverse Events and 
Kinetics of Response With Ipilimumab. J Clin Oncol 30. 2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750.
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19.4.
Appendix D: Table of Abbreviations
Table 13:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
AIM
Azacitidine-induced immune
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase (SGPT)
ALK 
Anaplastic lymphoma kinase
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the concentration-time curve
AZA
Azacitidine
β-hCG
Beta-subunit of human chorionic gonadotropin
BCG
Bacillus Calmette-Guerin
BLQ
Below the limit of quantitation
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CI
Confidence interval
CL/F
Apparent total body clearance
Cmax
Maximum plasma concentration of drug
CMMoL
Chronic myelomonocytic leukemia
CNS
Central nervous system
CR
Complete response
CRA
Clinical research associate
CRO
Contract research organization
CRF
Case report form
CSR
Clinical Study Report
CT
Computed tomography
F
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease control rate
DIC
Disseminated Intravascular Coagulation
DILI
Drug-induced liver injury
DKA
Diabetic ketoacidosis
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DNMT1
DNA methyltransferase-1
DNMTi
DNA methyltransferase inhibitor
DMC
Data Monitoring Committee
EBUS
Endobronchial ultrasound
EC
Ethics Committee
ECI
Events of clinical interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
EGFR
Endothelial growth factor receptor
ESMO
European Society for Medical Oncology
EOT
End of treatment
EU
European Union
FFPE
Formalin fixed paraffin embedded
FAB
French American British
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte macrophage colony-stimulating factor
GI
Gastrointestinal
GITR
Glucocorticoid-induced tumor necrosis factor receptor
HBV
Hepatitis B virus
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
HBcAb
Hepatitis B core antibody
HBeAb
Hepatitis B e antibody
HBeAg
Hepatitis B e antigen
HBsAg
Hepatitis B surface antigen
HBsAb
Hepatitis B surface antibody
HCl
Hydrochloride
HCV
Hepatitis C virus
HCVAb
Hepatitis C virus antibody
HDAC
Histone deacetylase
HIV
Human immunodeficiency virus
HR
Hazard ratio
HUS
Haemolytic Uraemic Syndrome
ICF
Informed consent form
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
iDMC
Independent Data Monitoring Committee
IDO
Indoleamine 2,3-dioxygenase
ILD
Interstitial lung disease
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
irAEs
Immune-related adverse events
irDCR
Immune-related disease control rate
irPFS
Immune-related progression-free survival
irRC
Immune-related response criteria
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
irORR
Immune-related overall response rate
IRT
Interactive response technology
ITT
Intent-to-treat
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ITP
Idiopathic (or immune) Thrombocytopenia Purpura
IV
Intravenous
LDH
Lactate dehydrogenase
LFT
Liver function test
mAb
Monoclonal antibody
MDS
Myelodysplastic syndrome
MM
Multiple myeloma
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PD
Pharmacodynamics
PD
Progressive disease
PD-1
Programmed cell death protein-1
PD-L1
Programmed death-ligand 1
PE
Physical examination
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response
PT
Prothrombin time
PTT
Partial thromboplastin time
QD
Once daily
RBC
Red blood cell count
RCC
Renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Steering Committee
SC
Subcutaneous
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
TKI
Tyrosine kinase inhibitor
TIL
Tumor-infiltrating lymphocyte
Tmax
Time to maximum concentration
TTP
Thrombotic Thrombocytopenic Purpura
t1/2
Terminal half-life
ULN
Upper limit of normal
US
United States 
Vz/F
Apparent volume of distribution
WBC
White blood cell count
WHO
World Health Organization
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