A Phase 2, Multicenter, International, Single Arm Study To Assess The Safety And Efficacy Of Single Agent Cc-486 (Oral Azacitidine) In Previously Treated Subjects With Locally Advanced Or Metastatic Nasopharyngeal Carcinoma
Phase: PHASE2
Conditions: Nasopharyngeal Neoplasms
Sponsor: Celgene

 
 
 
 
 
Protocol Title: A Phase 2, Multicenter, International, 
Single Arm Study to Assess The Safety And Efficacy Of 
Single Agent CC-486 (Oral Azacitidine) In Previously 
Treated Subjects With Locally Advanced Or Metastatic 
Nasopharyngeal Carcinoma 
 
NCT Number:  NCT02269943 
Protocol Amendment 3 Date:  23 September 2016 

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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
TITLE PAGE
A PHASE 2, MULTICENTER, INTERNATIONAL, 
SINGLE ARM STUDY TO ASSESS THE SAFETY AND 
EFFICACY OF SINGLE AGENT CC-486 (ORAL 
AZACITIDINE) IN PREVIOUSLY TREATED SUBJECTS 
WITH LOCALLY ADVANCED OR METASTATIC 
NASOPHARYNGEAL CARCINOMA
INVESTIGATIONAL PRODUCT (IP):
CC-486 (Oral Azacitidine)
PROTOCOL NUMBER:
CC-486-NPC-001
ORIGINAL DATE FINAL:
11 July 2014
AMENDMENT 1 DATE FINAL:
01 October 2014
AMENDMENT 2 DATE FINAL:
03 April 2015
AMENDMENT 3 DATE FINAL:
23 September 2016
EudraCT NUMBER:
2014-001745-25
IND NUMBER:
122556
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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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
2
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
3
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
4
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
PROTOCOL SUMMARY
Study Title
A Phase 2, Multicenter, International, Single Arm Study to Assess the Safety and Efficacy of 
Single Agent CC-486 (Oral Azacitidine) in Previously Treated Subjects With Locally Advanced 
or Metastatic Nasopharyngeal Carcinoma
Indication
Subjects with locally advanced or metastatic nasopharyngeal carcinoma (NPC) with an 
undifferentiated or poorly differentiated carcinoma, who have previously progressed clinically or 
radiographically on 1 to 2 previous regimens including platinum-based chemotherapy.
Objectives
Primary Objectives:
To evaluate the efficacy of CC-486 in subjects with NPC
Secondary Objectives:
To evaluate safety in all subjects and pharmacokinetics (PK) of CC-486 in a subset of subjects of 
Asian-Pacific Island ethnicity at experienced selected sites
Exploratory Objective:
 
Study Design
This is a Phase 2, single arm, multicenter, international study to assess the safety and efficacy of 
single agent CC-486 in previously treated subjects with locally advanced or metastatic NPC, 
having previously failed one to two previous regimens, including a platinum-based 
chemotherapy.
Approximately 51 to 55 subjects will be enrolled according to a Simon two-stage design; if the 
predefined activity is met (> 4 responses [complete response/partial response {CR/PR}] out of 
the first 17 evaluable subjects based on independent radiological assessment), then the study will 
continue to enroll an additional 34 subjects. If ≤ 4 responses out of 17 are observed, then the 
study enrollment will be stopped.
An independent Data Monitoring Committee (iDMC) will be convened that will include 
clinicians with experience in treating subjects with nasopharyngeal carcinoma and a statistician, 
all of whom are not otherwise involved in the study conduct. During the course of the study, the 
iDMC will review the safety and efficacy data regularly. Operational details for the iDMC will 
be detailed in the iDMC charter.
Study Population
The study will be conducted in subjects with locally advanced or metastatic undifferentiated or 
poorly differentiated nasopharyngeal carcinoma who have failed at least one, but not more than 
two prior regimens, including a platinum-based chemotherapy.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Length of Study
The median duration of study treatment is expected to be 6 months with an estimated median 
survival for the entire enrolled population of approximately 8 to 10 months.
All subjects will be followed for safety and monitoring of adverse events (AEs) for 28 days after 
the last dose of investigational product (IP), for response until progression (if applicable), and for 
new anticancer therapies and for survival until the study is mature for analysis, or the End of 
Study, whichever occurs earlier.
The End of Study is defined as either the date of the last visit of the last subject to complete the 
study, 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 prespecified in the protocol and/or the 
Statistical Analysis Plan, whichever is the later date.
The Sponsor may end the study when all key endpoints and objectives of the study have been 
analyzed. Any subjects that remain on study may be consented to a roll-over study and continue 
to receive treatment with CC-486.  
Study Treatments
Subjects will receive the investigational product (IP) CC-486, administered orally every day 
(QD) on Days 1-14 of a 21-day cycle at a dose of 300 mg. However, for the first 6 evaluable for 
safety subjects of Asian-Pacific Island ethnicity, a starting dose of 200 mg will be tested. If there 
are no safety concerns, eg, unexpected AEs or serious adverse events (SAEs), AEs leading to 
discontinuation, or death, the 300 mg dose will be administered to all subsequent subjects of 
Asian-Pacific ethnicity.
Subjects may remain on treatment until radiologic disease progression, unacceptable toxicity, a 
new anticancer therapy is begun, withdrawal of consent, subject refusal, physician decision, or 
death.
Overview of Efficacy Assessments
All subjects will be evaluated for tumor response and progression according to Response 
Evaluation Criteria In Solid Tumors (RECIST) v1.1 guidelines at screening and every 6 weeks 
(± 5 days) for the first three tumor evaluations and then every 9 weeks until documented disease 
progression, start of new anticancer therapy, or withdrawal of consent.
Response assessments will include computed tomography (CT) scan or magnetic resonance 
imaging (MRI) of the head and neck with supraclavicular node imaging, the chest and
abdomen/pelvis, neurological examination with facial nerve evaluation, and bone scans at 
baseline for all subjects. Bone scans will be repeated only if the subject is symptomatic or with 
known bone metastasis.
In the follow-up phase, anticancer treatment administered following the last dose of IP and 
survival will be followed every 8 weeks (± 5 days) until death, withdrawal of consent, or lost-to-
follow up, whichever occurs first.
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 28 days after the last dose of IP. A thorough evaluation of 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
medical conditions will be conducted during screening for eligibility. Documented physical 
examination, vital signs, laboratory assessments, (eg, serum chemistry, hematology, including 
Epstein-Barr virus [EBV] – deoxyribonucleic acid [DNA]), and Eastern Cooperative Oncology 
Group (ECOG) performance status will be monitored regularly (Oken, 1982) see Appendix A.
Preventative measure 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 1 and Section 6.
Overview of Statistical Methods
This Phase 2 multicenter, single-arm study is designed to evaluate the overall response rate 
(ORR) and progression-free survival (PFS) of CC-486 in previously treated subjects with locally 
advanced or metastatic nasopharyngeal carcinoma, having received one to two previous 
regimens. A Simon’s optimal two-stage design will be used (Simon, 1989).
Analysis Population
All safety analyses will be based on the population of all enrolled subjects who received at least 
one dose of IP. All primary and secondary efficacy analyses will be based on the Efficacy 
Evaluable population, which consists of all subjects who meet all eligibility criteria, and
EITHER received at least two cycles of IP at any dose intensity and discontinued treatment for 
progressive disease; OR received at least four cycles of IP at any dose intensity and have 
baseline and at least two post-screening tumor assessments.
Sample Size
The sample size estimation is based on having sufficient sample in the Efficacy Evaluable 
population to show that the ORR is higher than 20% or median PFS is > 5 months. Simon’s 
optimal two-stage design will be used. In the first stage, 17 subjects will be accrued. If there are 
4 or fewer responders within these 17 subjects, enrollment will be stopped. Otherwise 34 
additional subjects will be accrued for a total of 51 subjects. This Phase 2 study will be 
considered positive if more than 14 responders are observed in 51 subjects or the hypothesis of 
median PFS equal to 5 months is rejected. This design yields a marginal one-sided type I error 
rate of 5% and power of 85% when the true ORR is 40%. After the second stage (n = 51), the 
power for showing median PFS is > 5 months is 80% (60%) when the true median PFS is about 
8 (7) months.
Efficacy Analysis
Efficacy analyses will be performed on the efficacy evaluable population.
The hypothesis testing for the ORR will be based on the exact binomial distribution. Point 
estimate and two-sided 90% confidence interval (CI) of ORR will be provided. The hypothesis 
testing for the PFS will be based on the exponential distribution. Median PFS, OS, and their two-
sided 90% CIs will be provided.
Safety Analysis
Safety and tolerability will be monitored through continuous reporting of AEs and serious 
adverse events (SAEs), laboratory abnormalities, and incidence of subjects experiencing dose 
modifications, dose interruptions, and/or premature discontinuation of IP. Data from all subjects 
who receive one or more doses of IP will be included in the safety analyses. Adverse events, 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
physical examinations (including vital sign measurements), clinical laboratory information, and 
concomitant medications/procedures will be tabulated.
All adverse events will be summarized by frequency, severity grade based on the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) 
and relationship to treatment. Adverse events will be coded according to the Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized by system organ class and 
preferred term. Serious adverse events, events of interest, and events leading to discontinuation 
or death will be listed separately.
&(/*(1(35235,(7$5<,1)250$7,21

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................16
1.1.
Nasopharyngeal Carcinoma ....................................................................................16
1.2.
Diagnosis and Treatment ........................................................................................17
1.3.
CC-486...................................................................................................................18
1.3.1.
CC-486 Experience in Solid Tumors.......................................................................19
1.3.2.
CC-486 in Nasopharyngeal Carcinoma (NPC)........................................................20
1.4.
Rationale ................................................................................................................20
2.
STUDY OBJECTIVES...........................................................................................22
2.1.
Primary Objectives .................................................................................................22
2.2.
Secondary Objectives .............................................................................................22
2.3.
Exploratory Objectives ...........................................................................................22
3.
STUDY ENDPOINTS............................................................................................23
3.1.
Primary Endpoints..................................................................................................23
3.2.
Secondary Endpoints ..............................................................................................23
3.3.
Exploratory Endpoints............................................................................................23
4.
OVERALL STUDY DESIGN ................................................................................24
4.1.
Study Design ..........................................................................................................24
4.2.
Study Duration .......................................................................................................25
4.3.
End of Study...........................................................................................................25
5.
TABLE OF EVENTS.............................................................................................26
6.
PROCEDURES......................................................................................................30
6.1.
Treatment Period ....................................................................................................31
6.1.1.
End of Treatment....................................................................................................32
6.2.
Follow-up Period....................................................................................................33
6.2.1.
Efficacy Follow-up.................................................................................................33
6.2.2.
Survival Follow-up.................................................................................................33
6.3.
Response Assessments............................................................................................34
6.3.1.
Assessment of Response According to RECIST Version 1.1...................................34
6.3.1.1.
Other Assessments..................................................................................................34
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
11
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
6.4.
Pharmacokinetics....................................................................................................34
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase ................................................35
6.5.
Biomarkers .............................................................................................................35
7.
STUDY POPULATION.........................................................................................37
7.1.
Number of Subjects and Sites .................................................................................37
7.2.
Inclusion Criteria....................................................................................................37
7.3.
Exclusion Criteria...................................................................................................38
8.
DESCRIPTION OF STUDY TREATMENTS........................................................40
8.1.
Description of Investigational Product(s)................................................................40
8.2.
Treatment Administration and Schedule .................................................................40
8.2.1.
Tolerability Determination in Asian-Pacific Island Ethnicity ..................................40
8.2.2.
Dose Adjustment Guidelines...................................................................................41
8.2.3.
Missing Doses ........................................................................................................42
8.2.4.
Overdose ................................................................................................................42
8.2.5.
Guidelines for Screening and Management of Hepatitis B and C ............................42
8.3.
Method of Treatment Assignment...........................................................................46
8.4.
Packaging and Labeling..........................................................................................46
8.5.
Investigational Product Accountability and Disposal ..............................................46
8.6.
Investigational Product Compliance........................................................................46
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................47
9.1.
Permitted Concomitant Medications and Procedures...............................................47
9.2.
Prohibited Concomitant Medications and Procedures..............................................47
9.3.
Required Concomitant Medications and Procedures................................................47
10.
STATISTICAL ANALYSES..................................................................................48
10.1.
Overview................................................................................................................48
10.2.
Study Population Definitions ..................................................................................48
10.3.
Sample Size and Power Considerations...................................................................48
10.4.
Background and Demographic Characteristics........................................................49
10.5.
Subject Disposition.................................................................................................49
10.6.
Efficacy Analysis....................................................................................................49
10.7.
Safety Analysis.......................................................................................................49
10.8.
Interim Analysis .....................................................................................................50
10.9.
Assessment of Pharmacokinetics ............................................................................50
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.......38
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0.5.
0.5.
10.6.
0.6.

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
10.10.
Other Topics...........................................................................................................50
10.10.1.
Independent Data Monitoring Committee (iDMC)..................................................51
11.
ADVERSE EVENTS..............................................................................................52
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................52
11.2.
Evaluation of Adverse Events.................................................................................52
11.2.1.
Seriousness.............................................................................................................52
11.2.2.
Severity / Intensity..................................................................................................54
11.2.3.
Causality ................................................................................................................54
11.2.4.
Duration .................................................................................................................55
11.2.5.
Action Taken..........................................................................................................55
11.2.6.
Outcome.................................................................................................................55
11.3.
Abnormal Laboratory Values..................................................................................55
11.4.
Pregnancy...............................................................................................................55
11.4.1.
Females of Childbearing Potential: .........................................................................55
11.4.2.
Male Subjects.........................................................................................................56
11.5.
Reporting of Serious Adverse Events......................................................................56
11.5.1.
Safety Queries ........................................................................................................57
11.6.
Expedited Reporting of Adverse Events..................................................................57
12.
DISCONTINUATIONS .........................................................................................59
12.1.
Treatment Discontinuation......................................................................................59
12.2.
Study Discontinuation ............................................................................................59
13.
EMERGENCY PROCEDURES.............................................................................60
13.1.
Emergency Contact.................................................................................................60
13.2.
Emergency Identification of Investigational Products .............................................60
14.
REGULATORY CONSIDERATIONS...................................................................61
14.1.
Good Clinical Practice............................................................................................61
14.2.
Investigator Responsibilities ...................................................................................61
14.3.
Subject Information and Informed Consent.............................................................61
14.4.
Confidentiality........................................................................................................62
14.5.
Protocol Amendments.............................................................................................62
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................62
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................63
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4.4.
14.5.
4.5.

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
14.8.
Closure of the Study ...............................................................................................63
15.
DATA HANDLING AND RECORDKEEPING.....................................................64
15.1.
Data/Documents.....................................................................................................64
15.2.
Data Management...................................................................................................64
15.3.
Record Retention....................................................................................................64
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................66
16.1.
Study Monitoring and Source Data Verification......................................................66
16.2.
Audits and Inspections............................................................................................66
17.
PUBLICATIONS ...................................................................................................67
18.
REFERENCES.......................................................................................................68
19.
APPENDICES........................................................................................................71
Appendix A.
Eastern Cooperative Oncology Group (ECOG) Performance Status...................71
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6
.......66
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..........
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..............
...........
..............
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.............
.............
ance Status
ance Stat

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
14
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
LIST OF TABLES
Table 1:
Table of Events.......................................................................................................26
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase..........................................................................................35
Table 4:
Dose Adjustments and Dose Delays for Toxicity ....................................................41
Table 5:
Action to be taken based on Screening Hepatitis B Results .....................................44
Table 6:
Guidelines for the management of Hepatitis B reactivation.....................................44
Table 7:
Guidelines for the management of exacerbation of Hepatitis C ...............................45
&(/*(1(35235,(7$5<,1)250$7,21
1
......44
..........
.... 44
4
..............
.............

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
15
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
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Confidential and Proprietary
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CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
1.
INTRODUCTION
1.1.
Nasopharyngeal Carcinoma
Nasopharyngeal carcinoma, or NPC, is a rare type of head and neck cancer, but it is the most 
common cancer originating in the nasopharynx, which is composed of the upper part of the 
throat (pharynx) behind the nose. The pharynx is composed of three sections: the hypopharynx, 
the oropharynx, and the nasopharynx.
The nasopharynx lies just above the soft palate of the mouth and just in the back of the nasal 
passages, serving as a passageway for air from the nose to the throat and eventually to the lungs. 
Anatomically, it has a cuboidal shape that extends from the base of the skull to the upper surface 
of the soft palate. The lateral walls are formed by the Eustachian tube and the fossa of 
Rosenmuller (a deep recess, aka the pharyngeal recess). Anteriorly, the nasopharynx abuts the 
posterior choana and nasal cavity, and the posterior boundary is formed by the muscles of the 
posterior pharyngeal wall and the mass of lymphoid tissue known as the pharyngeal tonsil. 
Above the pharyngeal tonsil, in the midline is the pharyngeal bursa, an irregular flask-shaped 
depression of the mucus membrane.
World Health Organization (WHO) histopathological grading system describes three subtypes of 
nasopharyngeal carcinoma:
1. Keratinizing squamous cell carcinoma
2. Non-keratinizing differentiated carcinoma
3. Undifferentiated carcinoma (most common subtype)
Each of these subtypes appear more often in some areas of the world than in others. Only about 1 
in seven million people in North America are diagnosed with NPC, and of those diagnosed, 
about 1 in 4 cases are of the keratinizing type (American Cancer Society, 2013). In China, it is 
mostly of the undifferentiated subtype.
NPC is most common in southeast China (American Cancer Society, 2013), and is much more 
common in other parts of Asia, North Africa, the Inuit populations of Alaska and Canada, and 
the Chinese and Hmong immigrant groups in the United States (US), than in the general 
population.
Although it is not exactly understood what causes NPC, factors thought to predispose patients to 
this tumor include the presence of the Epstein-Barr virus (EBV), heavy alcohol and tobacco 
intake, a diet rich in salt-cured meats and fish, and a family history of NPC. The EBV appears in 
most NPC cells and is thought to be linked although not completely elucidated. Patients with 
NPC have high levels of antibodies to EBV viral capsid antigen (VCA) and viral nuclear 
antigens. The presence of these antibodies is thought to precede the development of NPC by 
several years. The EBV infection has been shown to decrease expression of tumor suppressor 
genes, which may help understand the carcinogenesis of NPC. In the clinical setting, EBV 
antibody or circulating viral deoxyribonucleic acid (DNA) titers may be useful as a prognostic 
tool at diagnosis, and as a measure of tumor burden during treatment.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
17
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Heavy alcohol and tobacco intake are mostly associated with the keratinizing squamous cell 
carcinoma subtype. NPC also appears to be more common in males than in females, and in 
patients younger than 55 years of age (American Cancer Society, 2013).
Thus, the multifactorial etiology implicates genetic, viral, and environmental factors.
However, studies have shown that all subtypes derive from the epithelial cells that line the 
surface of the nasopharynx, and many NPCs also contain a high concentration of lymphocytes 
among the cancer cells. The presence of keratin has been associated with reduced local control 
and survival.
1.2.
Diagnosis and Treatment
Nasopharyngeal carcinoma can be asymptomatic for long periods of time, which precludes early 
diagnosis. In most cases, the diagnosis is made based on locoregional advanced disease 
symptoms, with cranial nerve involvement or cervical node metastases (Sham, 1993; Sham,
1990). Most patients present with stages III and IV with cervical node involvement at first 
clinical presentation. The most frequently reported location of metastasis is to bone (70% to
80%), followed by viscera (liver, 30%; lung, 18%) and, at a decreased rate in axillary, 
mediastinal, pelvic, and inguinal nodes (Ahmad, 1986).
Standard treatments for patients with NPC include radiation therapy alone, concurrent 
chemoradiation followed by adjuvant chemotherapy, surgery for residual nodal disease, and 
chemotherapy alone for metastatic disease. High-dose radiation therapy with chemotherapy is the 
primary treatment of nasopharyngeal cancer, both for the primary tumor site and the neck (Sham, 
1993).
Selected patients with local recurrence may be retreated with moderate-dose external-beam 
radiation therapy using intensity-modulated radiation therapy, stereotactic radiation therapy, or 
intracavitary or interstitial radiation to the site of recurrence (Baujat, 2006; Mendenhall, 2011; 
Vikram, 1985).
If a patient has metastatic disease or local recurrence that is no longer amenable to surgery or 
radiation therapy, chemotherapy should be considered (Koutcher, 2010; Al-Sarraf, 1988; Jacobs, 
1992).
Therefore, chemotherapy remains an important treatment modality for palliative treatment and 
for metastatic NPC, especially those with a good performance status. Prognosis, especially for 
locally advanced stages (IIB – IVB) and metastatic NPC remains poor: more than a third of cases 
will present with local and/or metastatic recurrence. In the recurrent metastatic disease setting, 
the median survival and progression-free survival (PFS) are even shorter, at approximately 8 to 
14 months and 4 to 6 months, respectively. Response rates (RR) range from approximately 14% 
to 38%. Isolated bone metastasis may be associated with long survival (Ong, 2003). Overall, 5-
year survival for all NPC stages ranges from 50% to 70%. In first-line treatment of metastasis, 
platinum-based doublets, especially that of 5-fluorouracil (5-FU) and cisplatin, is generally 
recommended. In second line treatment of metastasis, the choice of chemotherapy depends on 
the previous treatment. In patients pretreated with platins, there is no established standard; 
reintroduction of platins depending on toxicity and the interval to recurrence: for an interval 
greater than 6 to 12 months, a second platin-based doublet associating taxanes or gemcitabine 
seems to be the most effective, with Overall Response (OR) 22% to 75%, but with associated 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Grade 3 to 4 hematologic toxicity, which may limit its use. Second line capecitabine, 
gemcitabine or docetaxel monochemotherapy is recommended in cases of platin resistance (early 
[<6 months] recurrence) or in fragile subjects in whom toxicity could be threatening (Foo, 2002).
However, a review of the literature on clinical trials for the treatment of metastatic NPC show 
that there is no consensus in second-line therapy or beyond and after progression with platins. 
Monotherapy with gemcitabine, capecitabine or taxanes has been the most widely tested, with 
acceptable results (Chan, 2010). In older studies, the most often used chemotherapy agents for 
monotherapy were methotrexate, bleomycin, 5-FU, cisplatin and carboplatin, with response rates 
of 15% to 31% (Bensouda, 2011).  There were two Phase 2 studies that focused on metastatic 
NPC with two other drugs:  4-epidoxorubicine (an anthracycline) and mitoxantrone, and the 
observed OR rates were about 20% (Shiu, 1989; Dugan, 1993). In more recent clinical studies, 
other molecules such as gemcitabine, capecitabine, paclitaxel, docetaxel and irinotecan have 
been studies in patients pretreated with cisplatin (Bensouda, 2011); gemcitabine and capecitabine 
had OR rates in the range of 23-48% and median survival between 7.2 and 14 months (Foo, 
2002; Shiu, 1989; Ma, 2005; Chua, 2003; Chua, 2008; Ciuleanu, 2008; Zhang, 2008). The first 
study of weekly docetaxel in monotherapy for NPC was conducted in 2008 and reported similar 
results with an overall response rate (ORR) of 37% and median survival of 12.8 months (Ngeow, 
2011). All of the above-mentioned studies have been Phase 2 studies, mostly for pretreated 
patients, and for metastatic and recurrent NPC.
1.3.
CC-486
5-Azacitidine (AZA), an analog of the pyrimidine nucleoside cytidine, has effects on cell 
differentiation, gene expression, and DNA synthesis and metabolism, and causes cytotoxicity
(Azacitidine Investigator’s Brochure [IB]).
Vidaza® (azacitidine injection) is approved by the US Food and Drug Administration (FDA) for 
5 subtypes of the French-American British (FAB) classification system of myelodysplastic 
syndrome (MDS).  Vidaza is also approved by the European Commission for the treatment of 
adult MDS, acute myeloid leukemia (AML) and chronic myeolomonocytic leukemia (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.
CC-486 is an orally bioavailable formulation of AZA.
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 repression of genes with high density of CpGs (CpG 
islands) in the vicinity of their promoters (Miranda, 2007). Genomic methylation patterns are 
precisely regulated during normal embryonic development and 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 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
19
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 
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 maximal tolerated 
dose (MTD) of 480 mg daily for 7 days was defined based on dose-limiting diarrhea at 600 mg
(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 went on to explore both daily and twice
daily extended dosing schedules of 14 and 21 out of 28 days in a non-crossover fashion.  CC-486 
administered 300 mg QD for 14 and 21 days of a 28-day cycle produces cumulative exposures 
(area under the concentration 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.
1.3.1.
CC-486 Experience in Solid Tumors
A Phase 1 study of CC-486 in combination with carboplatin and 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 200 
mg and 300 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 give 
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 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 on Arm B. Of 8 evaluable 
subjects with relapsed pancreatic carcinoma, one had a partial response (PR) and 3 others had 
stable disease (SD) > 16 weeks. Dramatic objective responses were also observed in subjects 
with relapsed cervical and endometrial cancer. These observations, although provocative, do not 
provide conclusive evidence of an epigenetic modifying effect by CC-486.
1.3.2.
CC-486 in Nasopharyngeal Carcinoma (NPC)
Limited data exists with CC-486 in NPC. In Part 1 Arm C of the AZA-ST-001 study, 2 subjects 
with NPC were enrolled and received CC-486 as monotherapy. The ongoing Part 2 of the study
included an NPC expansion cohort of 6 subjects. Of the 8 NPC subjects enrolled in Part 1 and 
Part 2, three subjects had a partial response (PR), 4 had stable disease (SD), and 1 subject 
progressed . The median duration on study treatment for NPC subjects was 252 days (8.3 
months).
Please refer to the Azacitidine IB for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) profile of 
azacitidine/CC-486.
1.4.
Rationale
CC-486 as a single agent has shown promising activity in NPC subjects in a Phase 1 clinical 
study with durable clinical benefit. CC-486 was tolerated in subjects when used at the dose of 
300 mg daily for 14 days out of 21-day cycle with a manageable safety profile.
As an epigenetic modifying agent, it is hypothesized that CC-486 will lead to immune-mediated 
antitumor effects in subjects with NPC. The use of epigenetic modifying therapy in the treatment 
of NPC is supported in the scientific literature:
!
Frequent wide-spread methylation of cancer-related genes in NPC (Lo, 2013).
!
Genetic abnormalities and EBV play major role in pathogenesis of NPC.
!
NPC is strongly associated with EBV infection (Thompson, 2007), with DNA 
methylation playing an important role in the maintenance of specific EBV latency 
programmers and regulating EBV lifecycle and latency in NPC cells (Paulson, 1999; 
Tierney, 2000; Salamon, 2001; Zhang, 2012a).
!
Promoter hypermethylation is a major mechanism for inactivation of critical tumor 
suppressor genes (p16,RASSF1A) (Lo, 2013).
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NP
NP

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
21
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
!
DNA CpG methylation is associated with silencing of EBV immunodominant 
antigens and tumor suppressor genes (Robertson, 1997; Okada, 2013).
∀
May inhibit the tumorgenicity of EBV-infected cells
In addition, epigenetic therapy may reactivate the host immune response through demethylation 
of silenced genes (Kenney, 2014).
!
Viral lytic reactivation via demethylation may provide a path to targeting EBV-
associated tumors.
!
Azacitidine induces demethylation of the EBV genome in tumors (Chan, 2004).
!
DNA methylation inhibitors can reverse chemoresistance and prevent the 
development of acquired drug resistance (Zhang, 2012b).
No standard of care options exist for patients with NPC in second and third line settings.
In a Phase 1 study of Japanese subjects treated at a dose of 300 mg QD for 21 days of 28-day 
cycle, all evaluable subjects (4 out of 5) experienced Grade 3-4 neutropenia. Although the 
numbers were small, the 300 mg starting dose and 21 of a 28-day schedule may be difficult to 
tolerate in Asian-Pacific Island ethnicity. Thus, the current proposal is designed to allow the first 
6 subjects of this ethnicity to begin at a reduced dose of 200 mg daily for 14 days of a 21-day 
schedule to preserve safety and tolerability, before increasing the dose to 300 mg daily for 14 
days of a 21-day schedule. Careful monitoring will be followed for all subjects.
The high unmet medical need in patients with NPC who received one or two prior chemotherapy 
treatments, the lack of standard of care, and the encouraging yet immature data in the Phase 1 
study warrant further evaluation of CC-486 as a single agent to confirm the activity of the drug 
in subjects with NPC.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
22
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
2.
STUDY OBJECTIVES
2.1.
Primary Objectives
The primary objective of this study is to evaluate the efficacy of CC-486 in subjects with NPC.
2.2.
Secondary Objectives
The secondary objectives of this study are to evaluate safety in all subjects and pharmacokinetics
(PK) of CC-486 in a subset of subjects of Asian-Pacific Island ethnicity at experienced selected 
sites.
2.3.
Exploratory Objectives
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
23
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
3.
STUDY ENDPOINTS
3.1.
Primary Endpoints
The primary endpoints are:
!
Overall response rate (ORR) defined as the combined incidence of complete response 
(CR) and PR, confirmed no less than 4 weeks after the criteria for response are first 
met, based on independent radiology assessment using Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1, AND
!
Progression-free survival (PFS) measured as time from the start of the study treatment 
to progression based on an independent radiology assessment of response using 
RECIST v1.1, or death, whichever is earlier.
3.2.
Secondary Endpoints
The secondary endpoints include:
!
Overall survival (OS) defined as the time from first treatment to death by any cause
!
Disease Control Rate (DCR) defined as Stable Disease (SD) for ≥ 16 weeks from the 
date of the first treatment, or CR or PR
!
Safety to include the incidence of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), Grade 3-4 AEs, Grade 3 and higher AEs, adverse 
events of special interest, and laboratory abnormalities and other safety parameters
!
Pharmacokinetics (PK) of CC-486 in a subset of subjects of Asian-Pacific Island 
ethnicity at experienced selected sites
3.3.
Exploratory Endpoints
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
24
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 2, single arm, multicenter, international study to assess the safety and efficacy of
single agent CC-486 (oral azacitidine) in previously treated subjects with locally advanced or 
metastatic nasopharyngeal carcinoma, who have progressed (clinically or radiographically) after 
having received 1 to 2 previous regimens, including a platinum agent. The co-primary endpoints 
are ORR and PFS.
Approximately 51 to 55 efficacy evaluable subjects will be enrolled according to Simon’s 
optimal two-stage design; if the predefined activity is met (> 4 responses [CR/PR] out of the first 
17 efficacy evaluable subjects based on independent radiological assessment), then the study will 
continue to enroll an additional 34 efficacy evaluable subjects. If ≤ 4 responses out of 17 are 
observed, then the study enrollment will be stopped. The Stage 1 decision will be based on ORR 
only, and the Stage 2 decision will be based on both ORR and PFS.  Subjects who are not 
evaluable for efficacy will be replaced at the discretion of the Sponsor. Subjects who are 
discontinued from study prior to the first tumor assessment for any reason other than for 
progressive disease are not evaluable and will be replaced. Subjects who progress prior to the 
end of Cycle 1 are not evaluable and will be replaced.
Subjects will be treated until radiologic disease progression, or as described in Section 6.3. 
Tumor response will be assessed according to RECIST v1.1 initially every 6 weeks (± 5 days) 
and then according to Section 6.2 until documented disease progression, start of new anticancer 
therapy, withdrawal of consent, or lost to follow-up. All subjects will also be followed for 
survival and subsequent anticancer therapies.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
25
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Figure 1:
Study Design
Screening
Subjects ≥ 18 years old with metastatic 
nasopharyngeal carcinoma, 
previously treated with 1 - 2 lines of treatment
Post treatment follow-up
28 day safety follow-up
Tumor evaluation according to protocol until 
progression or new cancer therapy
Survival follow-up until death
If  > 4 
subjects with 
CR/PR, 
continue.
Eligibility check
Positive if 
>14 CR/PR 
total  or     
Median PFS 
> 5 months  
Treatment
CC-486 300 mg daily
(CC-486 200 mg daily in 1st 6 Asian-Pacific  
Island  Ethnicity Subjects for safety) 
for Days 1-14, of 21 day cycle
Treatment until radiologic disease progression, 
unacceptable toxicity, a new anticancer therapy 
is begun, withdrawal of consent, subject 
refusal, physician decision, or death
Simon Stage 1
17 subjects in Efficacy 
Evaluable set
Simon Stage 2
34 subjects in Efficacy 
evaluable set
4.2.
Study Duration
The median duration of study treatment is expected to be 6 months with an estimated median 
survival for the entire enrolled population of approximately 8 to 10 months. All subjects will be 
followed for safety and monitoring of adverse events (AEs) for 28 days after the last dose of IP, 
for response until progression (if applicable), and for new anticancer therapies and survival until 
the study is mature for analysis, or the End of Study (as defined in Section 4.3), whichever 
occurs earlier.
4.3.
End of Study
The End of Study is defined as either the date of the last visit of the last subject to complete the 
study, 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 and/or the 
Statistical Analysis Plan, whichever is the later date. If ≤ 4 responses out of 17 efficacy evaluable 
subjects are observed in Stage 1, then the study enrollment will be stopped.
The Sponsor may end the study when all key endpoints and objectives of the study have been 
analyzed. Any subjects that remain on study may be consented to a roll-over study and continue 
to receive treatment with CC-486.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
26
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
5.
TABLE OF EVENTS
Table 1:
Table of Events
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Disease 
Progression/ 
Survival
Day
-21 to -1
1b
14
1
1
EOT
STUDY ENTRY
Informed consent
X
---
---
---
---
---
---
Prior cancer history
X
---
---
---
---
---
---
Prior cancer therapies
X
---
---
---
---
---
---
Complete medical history
X
---
---
---
---
---
---
Demographics
X
---
---
---
---
---
---
IRT [registration/IP accountability 
only]
X
As needed
Prior/ concomitant medication 
evaluationc
X (≤28d from 
screening)
Continuous, until 28 days after treatment discontinuation
Prior/ concomitant procedures 
evaluationd
X (≤28d from 
screening)
Continuous, until 28 days after treatment discontinuation
Inclusion/exclusion criteria
X
---
---
---
---
---
---
SAFETY ASSESSMENTS
Adverse event evaluation
Continuous starting after informed consent signature, until 28 days after treatment discontinuation
Physical examination (source 
documented only) Detailed hepatitis 
medical history for all subjects
X
X
---
X
X
X
---
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
27
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Disease 
Progression/ 
Survival
Day
-21 to -1
1b
14
1
1
EOT
Weight
X
X
---
X
X
X
---
Height
X
---
---
---
---
---
---
Vital signse
X
X
---
X
X
X
---
Hematology laboratoryf
X
X
X
X
X
X
---
Chemistry laboratoryg
X
X
---
X
X
X
---
Epstein-Barr Virus-DNA [by RT-PCR] 
in All Subjects
X
X
---
X
X
---
---
Coagulation (Baseline only)h
X
---
---
---
---
---
---
Urinalysisi
X
X
---
X
X
X
---
12-lead electrocardiogram
X
---
---
---
---
X
---
Serum β-hCG (for all FCBP)j
X
---
---
---
---
X
---
Urine β-hCG (for all FCBP)j
X (w/in72 hours)
X
---
X
X
X
---
EFFICACY ASSESSMENTS
Tumor evaluation (CT/MRI)
X (≤28d to -1)
Every 6 weeks (± 5 days) from Cycle 1 Day 1, for the first three tumor evaluations 
and then every 9 weeks until disease progression or start of a new anticancer 
treatment, or withdrawal of consent
Bone scans [All subjects]
X (≤28d to -1)
Repeated ONLY if symptomatic or with known bone metastasis, per standard of care.
ECOG performance status
X
X
---
X
X
X
---
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
28
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1
Cycle 2
Subsequent 
cycles
Disease 
Progression/ 
Survival
Day
-21 to -1
1b
14
1
1
EOT
HEPATITIS, BIOMARKER, AND PK ASSESSMENTS
HBV-DNA & serology, HCV serology 
& RNA-PCR (for all subjects 
considered at high risk of having HBV 
or HCV)1
X
---
---
---
Every other 
cycle 
starting 
Cycle 3 Day 
1.  Repeated 
every 6 
weeks as 
indicated.1
X
---
Tumor biopsy2 (for Biomarkers) 
Xk,l
Xk,l
---
X
---
---
PK blood draws sampling
---
X3
X3
---
---
---
---
INVESTIGATIONAL PRODUCT (IP)
Administer CC-486
Daily on Days 1-14
Daily on 
Days 1-14
Daily on 
Days 1-14
IP accountability
---
X
---
---
X
---
---
FOLLOW-UP
Survival follow-up
---
---
---
---
---
---
Every 8 weeks 
(+/- 5 days)
Anticancer therapy since IP 
discontinuation
---
---
---
---
---
---
At every survival 
follow-up visit
A-P = Asia-Pacific; β-hCG = beta subunit of human chorionic gonadotropin; CT = computed tomography; d = day; DNA = deoxyribonucleic acid; ECOG =
Eastern Cooperative Oncology Group; EOT = end of treatment; FCBP = female of childbearing potential; FFPE = formalin-fixed, paraffin-embedded; HBV =
hepatitis B virus; HCV = hepatitis C virus; IP = investigational product; IRT = interactive response technology; MRI = magnetic resonance imaging; PK =
pharmacokinetics; RT-PCR = real time polymerase chain reaction; w/in = within.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
29
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
1 Monitoring for HBV reactivation, according to Table 6, will only require the measurement of HBV-DNA every 6 weeks, that is, from Cycle 3 day 1 onwards.
Follow-up testing for HCV RNA-PCR will be performed every 6 weeks only if the subject has a history of HCV or is positive at baseline.  Hepatitis testing 
may be repeated more frequently as clinically indicated. Refer to Section 6. Procedures, and Section 8.2.5. Guidelines for Screening and Management of 
Hepatitis B and C
2 Refer to Section 6.5., Table 3.
3 Refer to Section 6.4., Table 2 for detailed schedule.
a All visits have a ± 2-day window, except Cycle 1 Day 1 which must occur within 21 days from Informed Consent Form signature.
b Cycle 1 Day 1 evaluations can be omitted if screening evaluations are performed within 72 hours of Cycle 1 Day 1.
c Prior/concomitant medication evaluation ≤ 28 days before first treatment through 28 days after last dose.
d Prior/concomitant procedures evaluation ≤ 28 days before first treatment through 28 days after last dose.
e Vital sign measurements must be recorded in the database at screening and EOT only, and kept in the source documents at all other visits.  However, if an 
abnormal (out of range) value is reported at a given visit, that parameter should be collected in the case report form (CRF) at every subsequent scheduled visit 
until it returns to normal.
f 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, absolute neutrophil count (ANC), and platelet count. ANC should be measured with automated count where available.
g Chemistry includes, but not limited to sodium, potassium, calcium, chloride, blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), and alanine aminotransferase 
(ALT/SGPT).
h Coagulation tests, including prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ration (INR)
i Urinalysis (a urine dipstick may be used) at screening and D1 of each cycle if abnormal at baseline.
j 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 urine pregnancy test should be performed.  The subject may not receive IP until the Investigator has verified that 
the result of the pregnancy test is negative.
k Sample can be collected during screening or pre-dose Cycle 1 Day 1; being done in Stage 1 subjects only. [STRONGLY encouraged/recommended]
l Archival FFPE sample can be submitted for the screening or pre-dose Cycle 1 Day 1 timepoint.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
30
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
6.
PROCEDURES
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.
Any questions regarding subject eligibility should be directed to the Celgene medical monitor or 
designee. Waivers to the protocol will not be granted during the conduct of this study, under any 
circumstances.
Safety laboratory analyses and all assessments will be performed locally. 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 1), after 
informed consent has been obtained:
!
Cancer history (including specific information regarding diagnosis, staging, 
histology)
!
Demographics (initials, date of birth, sex, race, and ethnicity-if allowed by local 
regulations)
!
Interactive response technology (IRT) for subject number registration and IP 
accountability only
!
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 also be included). 
!
Careful medical history must be taken for all subjects to look for risk factors (family 
history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, blood 
transfusions, etc), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light-colored stools, right upper quadrant pain). See Section 8.2.5. Guidelines for 
Screening and Management of Hepatitis B and C 
!
In order to identify subjects with hepatitis B (whether carriers or in chronic state) and 
chronic hepatitis C, the following subjects must be tested for HBV- DNA and 
serological markers, and HCV viral load by quantitative RNA-PCR:
±
All subjects of Asian-Pacific ethnicity
±
Subjects known to have history of hepatitis B or hepatitis C
±
Any other subject considered to be at high risk of having hepatitis B or C, as 
per the investigator’s discretion based on medical history.
!
Prior and concomitant procedures (including all procedures occurring ≤ 28 days 
before screening)
!
Prior and concomitant medication evaluation (including those taken ≤ 28 days before 
screening, except for those taken for cancer)
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!

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
31
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
!
Physical examination (source documented only), height, weight
!
Vital signs (including blood pressure, temperature, and heart rate)
!
Eastern Cooperative Oncology Group (ECOG) Performance status (Oken, 1982) see 
Appendix A
!
12-lead electrocardiogram (ECG)
!
Response assessment/ tumor evaluation (see Section 6.3). Subjects with historical 
tumor scans evaluable per RECIST v1.1 performed ≤ 28 days before the first dose 
need not repeat scans for the purposes of screening
!
Bone scans (All subjects) baseline only (≤28d to -1); repeated ONLY if the subject is 
symptomatic or with known bone metastasis, per standard of care. 
!
Complete blood count (CBC) with differential, including but not limited to red blood 
cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, absolute 
neutrophil count (ANC), and platelet count. ANC should be measured with automated 
count where available
!
Chemistry panel including, but not limited to, sodium, potassium, calcium, chloride, 
blood urea nitrogen (BUN), creatinine, glucose, albumin, total protein, alkaline 
phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum glutamic 
oxaloacetic transaminase (AST/SGOT), alanine aminotransferase (ALT/SGPT)
!
Epstein-Barr Virus-DNA [by real time-polymerase chain reaction (RT-PCR)] in all 
subjects
!
Tumor biopsy: Sample can be collected during screening or pre-dose Cycle 1 Day 1
!
Coagulation tests including, prothrombin time (PT), partial thromboplastin time 
(PTT), international normalized ratio (INR)
!
Urinalysis (a urine dipstick may be used) at screening (and D1 of each cycle if 
abnormal at baseline)
!
Pregnancy test is required for all female subjects of childbearing potential.  Serum 
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 with 72 hours 
of dosing (negative results required for IP administration)
!
Adverse event assessment begins after the subject signs the informed consent form
Day 1 evaluations for Cycle 1 may be omitted if Screening evaluations are performed within 72 
hours of Cycle 1 Day 1.
6.1.
Treatment Period
The subject will begin treatment upon confirmation of eligibility. The subject must start 
treatment within 21 days of signing the informed consent form (ICF). For all subsequent visits, 
an administrative window of ± 2 days is permitted.
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6.1.
6.1

EDMS Doc. Number:
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 1, Table of 
Events. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Physical examination (source documented only)
!
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.
!
Weight
!
Complete blood count with differential
!
Chemistry panel
!
Subjects identified as having hepatitis B at baseline will be tested for HBV- DNA and 
serological markers at every other cycle starting Cycle 3 Day 1 (eg Cycle 3, 5, 7, … 
etc.) Also, subjects identified as having chronic hepatitis C at baseline will be tested 
for HC viral load by quantitative RNA-PCR [by polymerase chain reaction]
!
Epstein-Barr Virus-DNA [by real time polymerase chain reaction (RT-PCR)] in all 
subjects
!
PK sample (only being done in 6 subjects of Asian-Pacific ethnicity at 200 mg dose 
initially; then in an additional 6 if dose is escalated to 300 mg dose) (see Section 6.4)
!
Tumor biopsy [STRONGLY encouraged/recommended] (Only being done in Stage 1 
subjects) (see Section 6.5)
!
ECOG Performance status (Oken, 1982) see Appendix A
!
IRT for IP accountability
!
Adverse event evaluation (continuously)
!
Response assessment/tumor evaluation (see Section 6.3)
!
Bone scans (only if the subject is symptomatic or with known bone metastasis, per 
standard of care)
!
Urine (or serum) β-hCG pregnancy test (prior to dosing on Day 1)
!
Urinalysis (at screening and D1 of each cycle if abnormal at baseline)
6.1.1.
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 should also be discontinued through the IRT system.
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1

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
33
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
The following evaluations will be performed as specified in the Table of Events (Table 1):
!
Physical examination (including weight)
!
Vital signs
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
ECOG performance status (Oken, 1982) see Appendix A
!
IRT for IP accountability
!
Adverse event evaluation (monitored through 28 days after the last dose of IP)
!
Complete blood count (with differential)
!
Chemistry panel
!
Subjects identified as having hepatitis B at baseline will be tested for HBV-DNA and 
serological markers; subjects identified as having chronic hepatitis C at baseline will 
be tested for HC viral load by quantitative RNA-PCR [by polymerase chain reaction]
!
Urine (or serum) β-hCG pregnancy test for females of childbearing potential
!
Response assessment/ tumor evaluation will be continued at the schedule defined in 
the Table of Events, and does not need to be performed specifically for the EOT visit 
except as specified in Section 6.3.
!
12-lead ECG
!
Weight
!
Urinalysis
6.2.
Follow-up Period
6.2.1.
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 6.3.
6.2.2.
Survival Follow-up
After the 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. 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.
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imited 
mited

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
34
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
6.3.
Response Assessments
Response assessments (tumor evaluations) should be performed at screening within 28 days 
before the start of IP, and every 6 weeks (± 5 days) from Cycle 1 Day 1 for the first 3 tumor 
evaluations and then every 9 weeks until disease progression, start of a new anticancer therapy, 
or withdrawal of consent from the entire study. Subjects with historical tumor scans evaluable 
per RECIST v1.1 performed ≤ 28 days before the first dose need not repeat scans for the 
purposes of screening. Evaluation of response should be performed using RECIST v1.1 
guidelines, by Investigator assessment.
An independent radiological assessment of responses will be conducted using RECIST v1.1.
6.3.1.
Assessment of Response According to RECIST Version 1.1
Response will be assessed using RECIST v1.1, according to Investigator assessment.  Response 
assessments include computed tomography (CT) scan or magnetic resonance imaging (MRI) of 
the head and neck with supraclavicular node imaging, the chest and abdomen/pelvis, 
neurological examination with facial nerve evaluation, and bone scans at baseline for all 
subjects. Bone scans will be repeated only if the subject is symptomatic or with known bone 
metastasis, per standard of care.
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.
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.  
Response assessments must have occurred ≥ 6 weeks from Cycle 1 Day 1 to be considered as SD 
for a best response.
6.3.1.1.
Other Assessments
Subjects who are symptomatic for brain metastasis at screening must undergo a brain scan to 
confirm eligibility. All subjects must undergo bone scans at baseline.
6.4.
Pharmacokinetics
A subset of enrolled subjects (Asian-Pacific island ethnicity only) at a selected number of 
experienced sites that have the ability to collect, process, and ship CC-486 PK samples will 
participate in PK sample collection. Six subjects of Asian-Pacific island ethnicity initially being 
administered 200 mg CC-486 on Days 1-14 of a 21-day cycle will be asked to participate in the 
PK sample collection at these selected sites. An additional 6 subjects of Asian-Pacific ethnicity
will participate in the PK sampling if the dose is escalated to 300 mg in this population.
On each PK day (ie, Cycle 1 Days 1 and 14), subjects will ingest IP in the clinic after performing 
the required overnight fasting, if applicable taking antiemetic premedication (eg, odansetron), 
and completing the required pre-dose assessments (where applicable), with each dose being 
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ill pa
ill pa

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
35
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
given at approximately the same time of day.  The exact date and time of dosing will be recorded 
in the source documents and appropriate CRF.
Blood samples for oral azacitidine PK assessment will be collected prior to each dose 
administration (pre-dose) and over the 8-hour period following each dose administration (0.25, 
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose or similar schedule) (see Table 2).
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase
Nominal Times
Acceptable Deviation Window
Pre-dose
≤ 60 min
0.25 hr
± 3 min
0.5 hr
± 3 min
1 hr
± 3 min
1.5 hr
± 3 min
2 hr
± 3 min
2.5 hr
± 3 min
3 hr
± 3 min
3.5 hr
± 3 min
4 hr
± 3 min
6 hr
± 20 min
8 hr
± 20 min
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase
Fasted Condition
After an overnight fast of at least 8 hours, all required pre-dose assessments and procedures 
(including obtaining the pre-dose PK sample) should be performed.  Then, if applicable, subjects 
should ingest antiemetic premedication (eg, odansetron) with 240 mL of water and wait 30 
minutes before administration of IP.  Subjects will then ingest CC-486 with 240 mL of room 
temperature water.  No food will be allowed for at least 2 hours post-dose.  Water can be allowed 
as desired except for 1 hour before and after CC-486 administration.  The only water permitted 
in the 1-hour period before CC-486 administration is the 240 mL of water for antiemetic and IP
ingestion.
6.5.
Biomarkers
 
 
Biomarkers will 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
36
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
be assessed for Stage 1 subjects only.
 
 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
37
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
Approximately 51 to 55 subjects with advanced or metastatic NPC will be enrolled. 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 document.
2. Subject has a histological or cytological diagnosis of undifferentiated or poorly 
differentiated nasopharyngeal carcinoma that is locally advanced or metastatic.*
3. Subject has disease progression either clinically or radiographically after 1 to 2 previous 
regimens.
4. Subject has received a platinum-containing regimen.
5. Subject has an ECOG performance status 0 to 2. (Oken, 1982) see Appendix A
6. Subject has radiographically-documented measurable disease, as per RECIST v1.1.
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.
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
9. Females 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) 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: negative serum pregnancy test, sensitivity of at least 25 mIU/mL at 
screening AND have a negative serum or urine pregnancy test within 72 hours prior 
to starting study therapy (note that the screening serum pregnancy test can be used as 
the test prior to starting study therapy in the treatment phase if it is performed within 
                                               
* Patients who received definitive chemoradiation treatment and had disease progression within 6 months may be 
eligible at the investigator's discretion.
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st

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
the 72-hour timeframe). She must agree to ongoing pregnancy testing during the 
course of the study, and after end of study therapy. 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 commit to use, and be able to comply with effective 
contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation;
intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner)
without interruption, 28 days prior to starting IP, during the study therapy (including 
dose interruptions), and for 3 months after discontinuation of CC-486.
10. Male subjects with a female partner of childbearing potential must commit to true 
abstinence* from heterosexual contact or commit to the use of an effective contraceptive 
method throughout the course of the study, and avoid fathering a child during the course 
of the study (including dose interruptions) and for 3 months following the last dose of 
CC-486. The ICF will address any country-specific requirements, as needed.
11. Subject understands and voluntarily signs an ICF prior to any study-related 
assessments/procedures are conducted.
12. Subject is able to adhere to the study visit schedule and other protocol requirements.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a history of, or current brain metastasis. In subjects who are symptomatic, a 
brain scan is required to exclude metastasis.  Primary NPC tumors that are 
touching/penetrating the skull are not considered brain metastasis.
2. Subject has any other malignancy within 5 years prior to randomization, with the 
exception of adequately treated in situ carcinoma of the cervix, uteri, or non-
melanomatous skin cancer (all treatment of which should have been completed 6 months 
prior to enrollment), in situ squamous cell carcinoma of the breast, or incidental prostate 
cancer T1a, Gleason < 7, PSA <10 ng/ml.
3. Subject has been previously treated with azacitidine (any formulation), decitabine, or any 
other hypomethylating agent.
4. 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, 
metabolism, or excretion of the IP and/or predispose the subject to an increased risk of 
gastrointestinal toxicity.
5. Subject has an impaired ability to swallow oral medication.
                                               
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception).
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5.5. Subje
Subje

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
39
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
6. Subject has persistent diarrhea or malabsorption ≥ National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2, despite medical 
management.
7. 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.
8. 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).
9. Subject has a known history or current diagnosis of human immunodeficiency virus 
(HIV) infection, regardless of treatment status.
10. Subject has any other concurrent severe and/or uncontrolled medical condition that 
would, in the Investigator’s judgment, contraindicate subject participation in the clinical 
study (eg, chronic pancreatitis, chronic active hepatitis, etc.). (For those subjects with 
hepatitis, See Section 8.2.5. Guidelines for Screening and Management of Hepatitis B 
and C)
11. Subject has active bleeding (eg, profuse epistaxis in a subject previously treated with 
radiotherapy), or has a pathological condition that carries a high risk of bleeding (eg, 
tumors involving major vessels), or is at risk of pseudoaneurysm of the internal carotid 
artery and carotid blowout syndrome.
12. Subject has had major surgery within 14 days prior to starting IP or has not recovered 
from major side effects.
13. Subject has received another investigational therapy within 28 days or 5 half lives of 
randomization/enrollment, whichever is shorter.
14. Subject has not recovered from the acute toxic effects of prior anticancer therapy, 
radiation, or major surgery/significant trauma.
15. 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.
16. Subject is pregnant or breast feeding.
17. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
18. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study.
19. Subject has any condition that confounds the ability to interpret data from the study.
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19.9. Subject
Subject

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
40
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Product(s)
Celgene Corporation will supply CC-486 100-, 150-, and/or 200-mg tablets for oral 
administration.  All tablets will be packaged in blister packs. Each tablet is formulated using 
excipients that are generally regarded as safe and are used in marketed drug products.  A list of 
excipients included in the formulations is provided in the Azacitidine IB.
All IP 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.
8.2.
Treatment Administration and Schedule
CC-486 will be administered at a dose of 300 mg orally daily (QD) for 14 days of a 21-day 
cycle.  However, the first 6 Asian-Pacific Island ethnicity subjects evaluable for safety will 
receive CC-486 at a dose of 200 mg orally daily for 14 of 21 days of Cycle 1; and if well-
tolerated, and there are no safety concerns, (see Section 8.2.1) subsequent subjects of Asian-
Pacific Island ethnicity will be administered at the 300 mg daily dose for 14 days of a 21-day 
cycle.
Subjects will ingest CC-486 with approximately 240 mL (8 ounces) of room temperature water.  
CC-486 may be taken on an empty stomach or with food (a light breakfast or meal of up to 
approximately 600 calories), except on PK sampling days.
If following CC-486 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 (see Section 9.1).
8.2.1.
Tolerability Determination in Asian-Pacific Island Ethnicity
The first 6 evaluable for safety subjects of Asian-Pacific island ethnicity receiving 200 mg daily 
will be assessed for tolerability and determination if dose can be increased to 300 mg daily in 
subsequent subjects.  If ≤ 1 subject of Asian-Pacific Island ethnicity experiences a dose-limiting 
toxicity (DLT), the initial 200 mg dose will be increased to the 300 mg dose in subsequent 
subjects. If ≥2 subjects of Asian-Pacific Island ethnicity experience a DLT, the dose may be 
decreased to 100 mg daily, at the discretion of the Sponsor.
A DLT is defined as an IP-related AE(s) occurring in Cycle 1 (including predose assessments on 
Cycle 2 Day 1) that leads to permanent treatment discontinuation or meets one of the following 
criteria:
!
Grade 4 neutropenia lasting > 10 days or accompanied by fever (defined as > 38.5°C 
requiring hospitalization);
!
Grade 3 thrombocytopenia with clinically significant bleeding; and,
!
Any Grade ≥ 3 non-hematologic toxicity with the following exceptions:
∀
Grade 3 emesis that responds to optimal antiemetic therapy within 72 hours;
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EDMS Doc. Number:
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
∀
Grade 3 diarrhea that responds to optimal medical management within 72 hours;
∀
Grade 3 fatigue in a subject who had Grade 2 fatigue at study entry and that 
recovers to baseline grade or less within 72 hours;
∀
Grade 3 or 4 laboratory abnormalities that are not accompanied by clinical signs 
or symptoms and are not believed by the Investigator to be medically significant.
An event that starts in Cycle 1 (including Cycle 2 Day 1 predose assessments) that becomes a 
DLT due to its duration will be considered a DLT.
8.2.2.
Dose Adjustment Guidelines
A maximum of 1 dose reduction will be allowed from the original dose.
CC-486 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 the study is 14 days.
For the purposes of dose adjustments, unacceptable toxicity will be defined as any AE that is 
deemed by the Investigator to be related to CC-486 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.
Please refer to Table 4 for the Dose Adjustment Guidelines due to unacceptable toxicity.
Table 4:
Dose Adjustments 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 until ANC & Platelets ≤ Grade 1
Delay ≤ 7 days, resume CC-486 at same dose
Delay 8 – 14 days, reduce CC-486 by 100 mg
Delay > 14 days, permanently discontinue CC-486
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 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 at same dose
Recovery in 8–14 days, reduce CC-486 by 100 mg
No recovery by 14 days, permanently discontinue CC-486
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 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 by 100 mg
No recovery by 7 days, permanently discontinue CC-486
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Table 4:
Dose Adjustments and Dose Delays for Toxicity (Continued)
Toxicity
Recommendation
Grade 3 or 4 Nausea or Vomiting
Grade 3 or 4 Diarrhea
Grade 3 of 4 Fatigue/Asthenia
Hold until resolution to ≤ Grade 1 and provide optimal 
medical management
If response ≤ 72 hours (3 days), and recovery ≤ 7 days, 
reduce CC-486 by 100 mg.
If event recurs after re-challenge at reduced dose, 
discontinue CC-486.
If no recovery by 7 days, discontinue CC-486.
Grade 3 or 4 any other non-hematologic 
toxicity
Hold until resolution to ≤ Grade 1 and provide optimal 
medical management.
If recovery ≤ 7 days, reduce CC-486 by 100 mg.
If event recurs after re-challenge at reduced dose, 
discontinue CC-486.
If no recovery by 7 days, discontinue CC-486.
ANC = absolute neutrophil count; ASCO = American Society of Clinical Oncology; 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.
8.2.3.
Missing Doses
All efforts should be made to administer IP on all of the scheduled days of each 21-day treatment 
cycle. Any missed doses during that period should not be added after the last scheduled day of 
administration, but should be returned by the subject for IP accountability.
8.2.4.
Overdose
Overdose, as defined for this protocol, refers to CC-486 only.
On a per dose basis, an overdose is defined as any amount over the protocol-specified dose of 
CC-486 assigned to a given subject, regardless of any associated adverse events or sequelae.
!
PO (oral) - any amount over the protocol-specified dose
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 (CRF).
8.2.5.
Guidelines for Screening and Management of Hepatitis B and C
Hepatitis B and C Screening
In cancer subjects with hepatitis B, whether carriers or in chronic state (subjects with active 
disease are excluded from the study), use of antivirals during anticancer therapy has been shown 
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
to reduce the risk of HBV reactivation and associated HBV morbidity and mortality (Loomba, 
2008; Sorrell, 2009). 
Careful medical history must be taken for all subjects to look for risk factors (family history of 
HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, blood transfusions, etc), and 
any past or present HBV symptoms (e.g., jaundice, dark urine, light-colored stools, right upper 
quadrant pain). 
In order to identify subjects with hepatitis B (whether carriers or in chronic state) and chronic 
hepatitis C, the following subjects must be tested for HBV- DNA and serological markers, and 
HCV viral load by quantitative RNA-PCR:
!
All subjects of Asian-Pacific ethnicity
!
Subjects known to have history of hepatitis B or hepatitis C
!
Any other subject considered to be at high risk of having hepatitis B or C, as per the 
investigator’s discretion based on medical history.
HBV testing
!
Hepatitis B surface antigen (HBsAg)
!
Hepatitis B core antibody (HBcAb) (Total)
!
Hepatitis B surface antibody (HBsAb)
!
HBV-DNA levels
Based on the results of the screening HBV tests, the subjects may be given prophylactic antiviral 
treatment 1 week prior to receiving study drug and for at least 4 weeks after last dose of study 
drug and will be monitored throughout the study according to the Table of Events.
HCV testing
!
Anti-Hepatitis C Virus (HCV) (HCV antibody)
!
HCV-RNA by PCR
Subjects will be tested for anti-HCV (HCV antibody) at the screening visit and every other cycle 
starting Cycle 3 Day 1 (eg Cycle 3, 5, 7, … etc.) Monitoring for HCV is required for:
!
subjects known to have a history of HCV infection, despite a negative viral load test 
at screening (including those that were treated and are considered ‘cured’)
!
subjects positive for viral load on HCV test at screening.
Table 5 provides details of monitoring and prophylactic therapy according to the screening 
results of viral load and serologic markers testing. Antiviral prophylaxis therapy should continue 
for at least 4 weeks after last dose of study drug.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Table 5:
Action to be taken based on Screening Hepatitis B Results
Test
Result
Result
Result
Result
Result
HBV-DNA 
+
+ or -
-
-
-
HBsAg
+ or -
+
-
-
-
HBsAb 
+ or -
+ or -
+
and no prior 
HBV 
vaccination
+ or -
-
or + with 
prior HBV 
vaccination
HBcAb
+ or -
+ or -
+ or -
+
-
Recommendation
Prophylactic antiviral 
treatment should be started 1 
week prior to first dose of 
study drug.
No prophylaxis
No specific 
action
Monitor HBV-DNA every 6 
weeks starting from C3D1 
onwards or more frequently if 
clinically indicated
Monitor HBV-DNA every 6 
weeks starting from C3D1 
onwards or more frequently if  
clinically indicated
Guidelines for The Treatment for Hepatitis B Reactivation
Table 6 provides the definition of reactivation of hepatitis B as well as the recommended 
management.
Table 6:
Guidelines for the management of Hepatitis B reactivation
HBV reactivation (with or without clinical signs and symptoms)*
For subjects with baseline results: 
Positive HBV-DNA
OR
positive HBsAg
--------------------------------------
reactivation is defined as:  
[Increase of 1 log in HBV-DNA relative to 
baseline HBV-DNA value OR new appearance 
of measurable HBV-DNA]
AND
ALT elevation > 5 ULN
Treat: Start a second antiviral 
AND
Interrupt study drug administration until resolution: 
!
≤  grade 1 ALT (or baseline ALT, if > grade 1) and
!
≤  baseline HBV-DNA levels
If resolution occurs within ≤ 14 days, study drug should be re-
started at one dose lower, if available (see Table 4 of protocol 
for dose levels available). If the subject is already receiving the 
lowest dose of study drug according to the protocol, the subject 
should restart at the same dose after resolution. Both antiviral 
therapies should continue at least 4 weeks after last dose of 
study drug. 
If resolution occurs > 14 days, subjects should discontinue 
study drug but continue both antiviral therapies at least 4 weeks 
after last dose of study drug.
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52

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Table 6:
Guidelines for the management of Hepatitis B reactivation (Continued)
HBV reactivation (with or without clinical signs and symptoms)*
For subjects with baseline results: 
Negative HBV-DNA and HBsAg 
AND
[Positive HBsAb (with no prior history of 
vaccination against HBV), OR positive HBcAb]
-------------------------------------
reactivation is defined as:
New appearance of measurable HBV-DNA
Treat: Start first antiviral medication 
AND
Interrupt study drug administration until resolution:
≤ baseline HBV-DNA levels
If resolution occurs within ≤ 14 days, study drug should be re-
started at one dose lower, if available (see Table 4 of protocol 
for dose levels available). If the subject is already receiving the 
lowest dose of study drug according to the protocol, the subject 
should restart at the same dose after resolution. Antiviral 
therapy should continue at least 4 weeks after last dose of study 
drug.
If resolution occurs > 14 days Subjects should discontinue 
study drug but continue antiviral therapy at least 4 weeks after 
last dose of study drug.
* All reactivations of HBV are to be recorded as grade 3 (CTCAE Version 4.0 – Infection and Infestations – Hepatitis Viral), 
unless associated with decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma); in which case they 
should be recorded as grade 4. 
Date of viral reactivation is the date on which DNA (and ALT) criteria were met (e.g.. for a subject who was HBV-DNA positive 
on 01-JAN-14 and whose ALT reached > 5 × ULN on 01-APR-14, the date of viral reactivation is 01-APR-14)
Monitoring for exacerbation of Hepatitis C
The following two categories of subjects should be monitored for HCV reactivation:
!
Subjects with detectable  anti-HCV (HCV antibody) test at baseline
!
Subjects known to have a history of HCV infection, despite a negative viral load test 
at baseline (including those that were treated and are considered ‘cured’) 
Subjects should be retested at end of treatment for anti-HCV.
Guidelines for The Treatment for exacerbation of Hepatitis C
For definitions of HCV reactivation and actions to be taken in the event of reactivation, please 
refer to Table 7.
Table 7:
Guidelines for the management of exacerbation of Hepatitis C
HCV exacerbation*
For subjects with baseline results: 
Detectable anti-HCV (HCV antibody)
Exacerbation is defined as:
ALT elevation > 5 ULN
Discontinue study drug 
For subjects with baseline results:
Knowledge of past hepatitis C infection with no 
detectable anti-HCV
Exacerbation is defined as:
New appearance of detectable anti-HCV 
Discontinue study drug
* All Exacerbations of HCV are to be recorded as grade 3 (CTCAE Version 4.03 – Infection and Infestations – Hepatitis Viral), 
unless associated with decompensated liver function (e.g., ascites, coagulopathy, encephalopathy, coma); in which case they 
should be recorded as grade 4.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
8.3.
Method of Treatment Assignment
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will receive CC-486.
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 IP will include 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 vs. Celgene (or designee).
8.6.
Investigational Product Compliance
Accurate recording of all IP 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 IP either administered or in their custody during the course 
of the study.
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administer

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
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.
9.1.
Permitted Concomitant Medications and Procedures
Subjects may be administered supportive and palliative care (eg, pain control) as clinically 
indicated throughout the study. However, palliative radiotherapy in the absence of disease 
progression will not be allowed while receiving IP.
The use of myeloid growth factors (granulocyte colony stimulating factor [G-CSF] and 
granulocyte macrophage colony-stimulating factor [GM-CSF]) may be given per Investigator’s 
discretion and 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; however, at the Investigator’s discretion, subjects 
may receive prophylactic antiemetics 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.
Based on the results of the screening HBV tests, the subjects may be given prophylactic antiviral 
treatment 1 week prior to receiving study drug and for at least 4 weeks after last dose of study 
drug and will be monitored throughout the study according to the Table of Events. See Section 
8.2.5.
9.2.
Prohibited Concomitant Medications and Procedures
The following concomitant medications are specifically prohibited during the course of the 
study:
Cytotoxic, chemotherapeutic, targeted, or investigational agents/therapies or any other anticancer 
treatment.
Vidaza (azacitidine), decitabine, or other demethylating agents.
9.3.
Required Concomitant Medications and Procedures
Not applicable.
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applicable

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
10.
STATISTICAL ANALYSES
10.1.
Overview
This is a Phase 2, single arm, multicenter, international study to assess the safety and efficacy of 
single agent CC-486 in previously treated subjects with locally advanced or metastatic NPC, 
having failed one to two previous regimens, including a platinum agent. The primary efficacy 
endpoints are ORR and PFS, based on an independent radiology assessment using RECIST v1.1.
An independent DMC (iDMC) will monitor the safety and efficacy of the study.
10.2.
Study Population Definitions
The following study population will be used for this study:
!
Safety Population – All subjects who received at least one dose of IP.
!
Efficacy Evaluable Population – All subjects who meet all eligibility criteria, and 
EITHER
1. Received at least two cycles of IP at any dose intensity and discontinued 
treatment for progressive disease, OR
2. Received at least four cycles of IP at any dose intensity and have baseline and at 
least two post-screening tumor assessments.
Subjects not eligible for the Efficacy Evaluable population will be replaced at the discretion of 
the Sponsor.
!
Pharmacokinetic Population – All subjects who have evaluable pharmacokinetic data 
from at least one dose of IP.
Subjects receiving the 200 mg dose will be efficacy evaluable for response if they meet the 
defined criteria.
10.3.
Sample Size and Power Considerations
Approximately 51 to 55 efficacy evaluable subjects will be enrolled and administered CC-486 
orally.
The sample size estimation is based on having sufficient sample in the Efficacy Evaluable
population to show that the ORR is higher than 20% or median PFS is > 5 months. Simon’s 
optimal two-stage design will be used (Simon, 1989). The null hypothesis that the true ORR is at
least 20% or median PFS is at least 5 months will be tested against a one-sided alternative. In the 
first stage, 17 subjects will be accrued. If there are 4 or fewer responders in these 17 subjects, 
enrollment will be stopped. Otherwise, 34 additional subjects will be accrued for a total of 51
subjects. Subjects who progress to the end of Cycle 1 are not evaluable for efficacy and will be 
replaced. This Phase 2 study will be considered positive if more than 14 responders are observed 
in 51 subjects or the hypothesis of median PFS equal to 5 months is rejected. This design yields a 
marginal one-sided type I error rate of 5% and power of 85% when the true ORR is 40%. After 
1.1.1
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0% o
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subjects.
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plac

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
49
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
the second stage (n = 51), the power for showing median PFS is > 5 months is 80% (60%) when 
the true median PFS is about 8(7) months.
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
Efficacy analyses will be performed on the Efficacy Evaluable population.
The hypothesis testing for the ORR will be based on the exact binomial distribution. The point 
estimate and two-sided 90% confidence interval (CI) of ORR will be provided. In addition, if 
Stage 2 is conducted, the Kaplan-Meier procedure will be used to estimate the median PFS and 
two-sided 90% CI. The hypothesis testing for the PFS will be based on the exponential 
distribution.
Subjects who die, regardless of the cause of death, will be considered to have had an event.  
Subjects who withdraw consent for the study will be considered censored at the time of 
withdrawal.  Subjects who are still alive at the time of the clinical data cut-off date will be 
censored.  All subjects who were lost to follow-up prior to the clinical data cut-off date will also 
be considered censored at the time of last contact.
The Kaplan-Meier procedure will be used to estimate proportions of event-free intervals for OS.  
Median OS and two-sided 90% CI will be provided.
The point estimate and two-sided 90% confidence interval (CI) of Disease Control Rate (DCR) 
will be provided.
10.7.
Safety Analysis
The safety population will be included in the safety analyses.
Safety and tolerability will be monitored through continuous reporting of adverse events and 
serious adverse events, laboratory abnormalities, and incidence of subjects experiencing dose 
modifications, dose interruptions, and/or premature discontinuation of IP. Data from all subjects
who receive one or more doses of IP will be included in the safety analyses. Adverse events, 
physical examinations (including vital sign measurements), clinical laboratory information, and 
concomitant medications/procedures will be tabulated and summarized.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
50
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Adverse events will be analyzed in terms of TEAE defined to be any event that begins or 
worsens in grade after the start of IP through 28 days after the last dose of IP. Adverse events 
will be summarized by severity/grade based on the CTCAE v4.0 and relationship to study 
treatment. If a subject experiences the same AE multiple times during the treatment, the event 
will be counted only once and by the greatest severity. All AEs, as well as TEAEs, will be 
summarized by system organ class and preferred term. Adverse events leading to death or to 
discontinuation from treatment, events classified as CTCAE Grade 3 or Grade 4, IP related 
events, and serious adverse events will be summarized separately. Adverse events will be coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events of 
special interest of CC-486 identified in previous studies will be summarized in a similar manner.
10.8.
Interim Analysis
Interim analysis will be performed according to Simon’s optimal design based on the population 
evaluable for efficacy as described in Section 10.2.
10.9.
Assessment of Pharmacokinetics
Pharmacokinetic measures are incorporated into the study to assess the extent of exposure, and to
explore the relationship between CC-486 and PD effects. Blood samples for PK will be collected 
from a subset of subjects at selected visits. As appropriate, PK parameters, but not limited to the 
following, will be determined from plasma concentration versus time profile data:
!
Area under the plasma concentration time-curve (AUC);
!
Peak (maximum) plasma concentration (Cmax);
!
Terminal half-life (t1/2);
!
Time to maximum plasma concentration (Tmax);
!
Clearance (apparent, CL/F); and,
!
Volume of distribution (apparent, Vz/F).
Descriptive statistics (N, mean, standard deviation, coefficient of variation [CV%], geometric 
mean, geometric CV%, median, min, and max) will be provided for all data. Results will be 
presented in tabular and graphic forms as appropriate.
Sample collection kits and detailed instructions for PK sample collection, processing, storage, 
shipping, and handling will be provided to the Investigator sites upon study initiation.
Plasma azacitidine will be measured using validated liquid chromatography-mass spectrometry 
methods (LC-MS/MS).
10.10.
Other Topics
There is no formal Steering Committee for this Phase 2 study. Safety findings and updates, study 
conduct and Interim Efficacy results will be discussed with the regional Principal Investigators 
(PIs) regularly. The interval of these reviews will be defined with the PIs at the Kick-off 
Meeting.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
51
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
10.10.1.
Independent Data Monitoring Committee (iDMC)
An iDMC will be convened that will include clinicians with experience in treating subjects with 
nasopharyngeal carcinoma and a statistician, all of whom are not otherwise involved in the study 
conduct. During the course of the study, the iDMC will review the safety and efficacy data 
regularly. Operational details for the iDMC will be detailed in the iDMC charter.
&(/*(1(35235,(7$5<,1)250$7,21

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
52
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording and Reporting of Adverse Events
An adverse event (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 (ie, 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 8.2.4 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.
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 28 days after the last dose of IP and those SAEs made known to the Investigator at any time 
thereafter that are suspected of being related to IP. AEs and serious adverse events (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.
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 (ie, in the opinion of the Investigator, the subject is at immediate 
risk of death from the AE);
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!

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
53
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
!
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.
!
A procedure that is planned (ie, 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.
!
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.
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must be c
must be c

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
54
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 CTCAE, Version 4.0;
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs 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
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
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:
Means 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.
Suspected:
Means 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.
calal
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as Not Susp
s Not Sus
Mean
Mea
adm
adm
Suspected:
Suspected:

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
55
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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, recovered with sequelae, not recovered 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.
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 
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 or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 3 months of the 
subject’s last dose of CC-486, are considered immediately reportable events.  IP is to be 
&(/*(1(35235,(7$5<,1)250$7,21
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aborato
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recorded o
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syndrom
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abno
y
ratory
atory resu
res
y
Pregna
Pregn
pregnancies
pregnancie
male subject
male subject
1.4.1.
1.4.1.

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
56
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
discontinued immediately and the subject instructed to return any unused portion of CC-486 to 
the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy test 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 female subject should be referred to an obstetrician-gynecologist, or another appropriate 
healthcare professional for further evaluation.
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.
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 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 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 CC-486 becomes pregnant, the male subject taking 
CC-486 should notify the Investigator, and the pregnant female partner should be advised to call 
their healthcare provider immediately. The female partner may be referred to an obstetrician-
gynecologist or another appropriate healthcare professional for further evaluation.  Male subjects 
should avoid fathering a child during the course of the study and for 3 months following the last 
dose of CC-486. The ICF will address any country-specific requirements, as needed.
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.  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.  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 CC-486) that occur during the 
study (from the time the subject signs informed consent until 28 days after the last dose of 
investigational product (IP), and 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 
&(/*(1(35235,(7$5<,1)250$7,21
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
57
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 Institutional 
Review Board/Ethics Committee (IRB/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 Azacitidine Investigator’s 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, SUSARs in accordance with Directive 2001/20/EC and the Detailed 
Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical studies on investigational products for human use (ENTR/CT3) and also in accordance 
with country-specific requirements.
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 (ie, SUSAR);
!
Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity; 
and,
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 Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information).
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
58
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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.
&(/*(1(35235,(7$5<,1)250$7,21

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
59
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
12.
DISCONTINUATIONS
12.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
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 should be recorded in the CRF and in the source documents.
The decision to discontinue a subject 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 
follow-up periods:
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other
The reason for discontinuation should be recorded in the CRF and in the source documents.
&(/*(1(35235,(7$5<,1)250$7,21
CRF and i
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eason for d
eason for

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
60
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 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
This is an open-label study; therefore, IP will be identified on the package labeling.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
61
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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. 
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.
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 informed consent document 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 
informed consent document 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 informed 
consent document.  The revised informed consent document 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.
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end

EDMS Doc. Number:
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
62
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 informed consent document, 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, informed consent document, 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 
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 informed consent document 
should also be revised.
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
63
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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.
Closure of the Study
Celgene reserves the right to terminate this study 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.
The Sponsor may consider closing this study when data supporting key endpoints and objectives 
of the study have been analyzed. In the case where there are subjects still being administered the
Investigational Product, and it is the opinion of the investigator(s) that these subjects would
continue to receive benefit from treatment, the Sponsor may choose to initiate an open-label, 
roll-over study under a separate protocol to allow those subjects to continue receiving CC-486.
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under a s
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
64
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. 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;
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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
65
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
!
All other source documents (subject records, hospital records, laboratory records, 
etc.);
!
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.
&(/*(1(35235,(7$5<,1)250$7,21
e
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ties.
destruction
destruction

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
66
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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 standard 
operating procedures.
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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EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
67
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
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.  Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.
&(/*(1(35235,(7$5<,1)250$7,21

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
68
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
18.
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th
&(/*(1(35235,(7$5<,1)250$7,21
atat-
753 pati
753 patien
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haryngeal
haryngeal
HNS
NS-ESMO
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Ann
y of
of
y
oral
ora
f
az
az
l
and acute 
nd acute 
s C, Lyman
s C, Lyma
d fluoroura
fluoroura
e head an
e head an
enne
enne

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
69
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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: DeVita V
: DeVita 
9 h ed.
ed.
ion.n. J Cell 
J C
vily pretrea
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of genes sp
er Sci 2013
er Sci 201
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2003;39:1
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thy seropos
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Methylat
Methylati
90:4480
0:4480-44
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Ujvari D,
y-associ
assoc ate
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96.
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eung YK, 
opharyngea
haryngea
JS, Cho
JS, Choy y D
col Bi
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ol Ph
Ph
l
Shiu WC
Shiu WC
ririals
als

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
70
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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d d 
ent of
nt of
ne expressio
e express
aryngeal ca
aryngeal c
rcino
inoma.
ma In
In
r Nasophar
Nasophar

EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
71
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
19.
APPENDICES
Appendix A. Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Table 8:
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.
5
Dead.
Source: Oken, 1982.
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EDMS Doc. Number: 
Celgene Signing Page
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