Conditions: Nasopharyngeal Neoplasms
Keywords: Metastatic nasopharyngeal carcinoma oral azacitidine oral AZA CC-486 metastatic recurrent nasopharyngeal carcinoma nasal solid tumors locally advanced rare head and neck cancer nasopharynx single chemotherapy agent Epstein-Barr Virus (EBV) + nasopharyngeal carcinoma EBV-DN Celgene Sponsor-study oral chemotherapy phase 2 oral Vidaza EBV promoter methylation hypomethylation tumor infiltrating lymphocytes (TILs) EBV gene expression neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of CC-486 in previously treated patients with locally advanced or metastatic nasopharyngeal carcinoma having failed one to two previous regimens, including platinum-based chemotherapy. Participants 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 participants based on independent radiological assessment), then the study will continue to enroll an additional 34 participants. If 4 or less responses out of 17 are observed, then the study enrollment will be stopped.

Detailed description:

Arms:
arm 1: CC-486 will be administered orally every day on Days 1-14 of a 21 day cycle at a dose of 300 mg. The first 6 participants of Asian-Pacific ethnicity will receive a starting dose of 200 mg. If there are no safety concerns, the 300 mg dose will be administered to all subsequent participants of Asian-Pacific ethnicity.

Interventions: intervention 1: CC-486
Intervention descriptions: intervention 1: None

Protocol document:
SAP_004.pdf: 
 
 
 
 
 
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 
Statistical Analysis Plan Date:  15 May 2017 


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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
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
STUDY DRUG:
CC-486 (Oral Azacitidine)
PROTOCOL NUMBER:
CC-486-NPC-001
DATE FINAL:
15 May 2017
Prepared by:
On behalf of 
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
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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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION..................................................................................................10
3.
STUDY OBJECTIVES...........................................................................................11
3.1.
Primary Objective...................................................................................................11
3.2.
Secondary Objectives .............................................................................................11
3.3.
Exploratory Objectives ...........................................................................................11
4.
INVESTIGATIONAL PLAN .................................................................................12
4.1.
Overall Study Design and Plan ...............................................................................12
4.1.1.
Primary Endpoints..................................................................................................14
4.1.2.
Secondary Endpoints ..............................................................................................14
4.1.3.
Exploratory Endpoints............................................................................................14
4.2.
Stratification, Randomization and Blinding.............................................................14
4.3.
Sample Size Determination.....................................................................................14
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................16
5.1.
Reporting Conventions ...........................................................................................16
5.2.
Analysis Populations ..............................................................................................17
5.2.1.
Enrolled Population ................................................................................................17
5.2.2.
Safety Population....................................................................................................17
5.2.3.
Efficacy Evaluable Population................................................................................17
5.2.4.
Pharmacokinetic Population....................................................................................17
6.
SUBJECT DISPOSITION......................................................................................18
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................19
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................20
8.1.
Demographics and Baseline Characteristics ............................................................20
8.1.1.
Cancer History........................................................................................................20
8.2.
Medical History......................................................................................................20
8.3.
Prior Therapies/Surgeries........................................................................................20
8.4.
Prior and Concomitant Medications........................................................................21
8.4.1.
Prior Medications ...................................................................................................21
8.4.2.
Concomitant Medications .......................................................................................21
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8.3.
.3.
4


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
3
8.5.
Concomitant Procedures/Surgeries .........................................................................21
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................22
9.1.
Treatment Duration.................................................................................................22
9.2.
Dose Exposure........................................................................................................22
9.3.
Cumulative Dose ....................................................................................................22
9.4.
Dose Intensity.........................................................................................................22
9.5.
Average Daily Dose................................................................................................22
9.6.
Relative Dose Intensity...........................................................................................22
9.7.
Dose Reduction, Interruption and Overdose............................................................23
10.
EFFICACY ANALYSIS ........................................................................................24
10.1.
Multiplicity.............................................................................................................24
10.2.
Analysis of the Efficacy Endpoints .........................................................................24
10.3.
Analyses of Other Evidence of Anti-cancer Activities.............................................25
10.4.
Eastern Cooperative Oncology Group Performance Status......................................25
11.
SAFETY ANALYSIS ............................................................................................26
11.1.
Adverse Events.......................................................................................................26
11.2.
Adverse Events of Special Interest..........................................................................27
11.2.1.
AE of Special Interest.............................................................................................27
11.2.2.
Dose Limiting Toxicity...........................................................................................28
11.3.
Clinical Laboratory Evaluations..............................................................................28
11.3.1.
Hematology, Chemistry, Urinalysis, and Coagulation.............................................28
11.3.2.
Epstein-Barr Virus-DNA measurements .................................................................29
11.4.
Vital Sign Measurements........................................................................................29
11.5.
Physical Examination .............................................................................................29
11.6.
Electrocardiograms.................................................................................................29
12.
PHARMACOKINETICS ANALYSIS....................................................................31
12.1.
Plasma concentrations.............................................................................................31
12.2.
Pharmacokinetic Parameters...................................................................................31
12.3.
Pharmacokinetic Analyses......................................................................................33
13.
BIOMARKER AND CORRELATION ANALYSES..............................................34
14.
QUALITY OF LIFE ANALYSIS...........................................................................35
15.
INTERIM ANALYSIS...........................................................................................36
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
4
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................38
17.
REFERENCES.......................................................................................................39
18.
APPENDICES........................................................................................................40
18.1.
Study schematic......................................................................................................40
18.2.
Handling of Dates...................................................................................................40
18.3.
Date Imputation Guideline......................................................................................41
18.3.1.
Impute Missing Adverse Events/ Prior or Concomitant 
Medications/Procedures..........................................................................................41
18.3.2.
Impute Missing Prior Therapy Dates or Cancer Diagnosis Date..............................42
18.3.3.
Adverse Events.......................................................................................................42
18.3.4.
Prior/Concomitant Medications/Procedures ............................................................42
18.3.5.
Medical History......................................................................................................43
18.3.6.
Birth Date...............................................................................................................43
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Normal Ranges of Vital Sign Measurements...........................................................29
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
adverse event
AUC
area under the curve
BE
Biomarker Evaluable 
BLQ
below the limit of quantitation
BSA
body surface area
C1D1
Cycle 1, Day 1
C2D1
Cycle 2, Day 1
CI
confidence interval
Cmax
maximum drug concentration
CpG
C-phosphate-G (cytosine and guanine separated by only one phosphate)
CR
complete response
CRF
case report form
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
EBV
Epstein-Barr virus
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
end of treatment
H-score
measurement of immunoreactivity via IHC
ICF
informed consent form
IP
investigational product
K-M
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory Activities
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
8
MRI
magnetic resonance imaging
NCA
noncompartmental
NCI
National Cancer Institute
NPC
nasopharyngeal carcinoma
ORR
overall response rate
OS
overall survival
PD
pharmacodynamic
PET
positron emission tomography
PFS
Progression free survival
PK
pharmacokinetic
PO
oral(ly)
PR
partial response
PT
preferred term
Q1
first quartile
Q3
third quartile
QD
daily
RECIST
Response Evaluation Criteria in Solid Tumors
Rp
BRLF1 promoter
RT-PCR
real time-polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SI
International System of Units
SMQ
Standardized MedDRA Query
SOC
system organ class
STDEV
standard deviation
TEAE
treatment-emergent adverse event
TIL
tumor infiltrating lymphocyte
Tmax
time to Cmax
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
9
WHO
World Health Organization
Zp
BZLF1 promoter
Zta
EBV lytic protein
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
10
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol CC-486-NPC-001 “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”, which was finalized
on 11 July 2014 and subsequently amended on 1 October 2014 (Amendment 1), 03 April 2015 
(Amendment 2), and 23 September 2016 (Amendment 3). It contains definitions of analysis 
populations, derived variables and statistical methods for the analysis of efficacy and safety.
These analyses include one pre-planned interim analysis, and a final analysis. The purpose of the 
SAP is to ensure the credibility of the study findings by pre-specifying the statistical approaches 
to any data analysis prior to database lock. This SAP will be finalized and signed prior to the 
clinical database lock for the final analysis. All statistical analyses detailed in this SAP will be 
conducted using SAS® Version 9.2 or higher. 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
11
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective is to evaluate the efficacy of CC-486 in subjects with nasopharyngeal 
carcinoma (NPC).
3.2.
Secondary Objectives
The secondary objectives 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.
3.3.
Exploratory Objectives 
 
 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
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 NPC, who have progressed (clinically or radiographically) after having received 1 or 2 
previous regimens, including a platinum-based chemotherapy. The primary endpoints are overall 
response rate (ORR) and progression-free survival (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 [complete response 
(CR)/partial response (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. 
The study will consist of the following visits: 
Screening Assessments: Screening evaluations will be performed for all subjects to determine 
study eligibility. These evaluations must be completed within 21 days of first dosing unless 
otherwise noted.
Treatment: Subjects meeting eligibility criteria 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. Treatment cycles are 21 days in duration. All evaluations should be performed prior 
to dosing on the visit day, unless otherwise specified. CC-486 will be administered at a dose of 
300 mg orally (PO) daily (QD) on Days 1to14 of a 21-day cycle. However, the first 6 subjects of 
Asian-Pacific Island ethnicity evaluable for safety will receive CC-486 at a dose of 200 mg 
orally QD on Days 1to14 of 21 days of Cycle 1; and if well-tolerated, and there are no safety 
concerns, subsequent subjects of Asian-Pacific Island ethnicity will be treated at the 300 mg QD 
on Days 1to14 of a 21-day cycle.
Response Assessment by Response Evaluation Criteria In Solid Tumors (RECIST) v 1.1: 
Response assessments (tumor evaluations) should be performed at screening within 28 days 
before the start of investigational product (IP), and every 6 weeks (± 5 days) from Cycle 1 Day 1 
(C1D1) 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. Evaluation of 
response will be performed using RECIST v1.1. 
An independent radiological assessment of responses will be conducted using RECIST v1.1.
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, 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
13
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. The same mode of imaging for lesion evaluation at screening must be used
consistently throughout the study.
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.
End of Treatment (EOT) Evaluation: An 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. Radiologic response assessment will be 
repeated only if required per the defined study imaging schedule.
Adverse Event (AE) Collection and Follow-up: Any AE that started after signing ICF and up 
to 28 days after the last dose of IP and those serious AEs (SAEs) made known to the Investigator 
at any time thereafter that are suspected of being related to IP will be collected. 
Follow-up for Efficacy Endpoints: 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.
Follow-up for Survival: 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.
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 1to14 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 
given at approximately the same time of day. 
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).
Biomarkers: Biomarkers will be assessed for Stage 1 subjects only.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
14
4.1.1.
Primary Endpoints
The primary endpoints are: 
!
ORR defined as the combined incidence of CR and PR, confirmed no less than 4 
weeks after the criteria for response are first met, based on independent radiology 
assessment using RECIST v1.1, AND 
!
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 (from 
any cause), whichever is earlier. 
4.1.2.
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 the combined incidence of CR and PR, 
confirmed no less than 4 weeks after the criteria for response are first met, and stable 
disease (SD) for ≥ 16 weeks from the date of first treatment, based on independent 
radiology assessment using RECIST v1.1.
!
Safety to include the incidence of treatment-emergent AEs (TEAEs), SAEs, Grade 3-
4 AEs, Grade 3 and higher AEs, AEs of special interest, and laboratory abnormalities 
and other safety parameters.
!
PK of CC-486 in a subset of subjects of Asian-Pacific Island ethnicity at experienced 
selected sites.
4.1.3.
Exploratory Endpoints
 
 
 
 
 
4.2.
Stratification, Randomization and Blinding
Not applicable for this study. 
4.3.
Sample Size Determination
The sample size estimation is based on having sufficient sample in the Efficacy Evaluable 
Population (see Section 5.2.3) 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 ≤20% or median PFS is ≤5 months will be tested against a one-sided 
alternative. In the first stage, 17 subjects will be accrued. If there are ≤4 responders among these 
17 subjects, enrollment will be stopped. Otherwise, if there are > 4 responders, 34 additional 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
15
subjects will be accrued for a total of 51 subjects. Subjects who progress by 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 
≤ 5 months (alternatively, the PFS rate at 5 months is ≤50%) 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 subjects), the power for showing a median PFS of > 5 months is 80% 
(60%) when the true median PFS is about 8 (7) months.
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
16
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
!
All tables will be presented by ‘AP 200 mg’, ‘300 mg’, and ‘Total’, unless otherwise 
specified.
!
Data from all study centers will be combined for analysis.
!
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as 
‘> 0.9999’.
!
Confidence intervals (CIs) will be presented as 2-sided 90% CIs unless specified 
differently in specific analyses.
!
Summary statistics will consist of the number and percentage of subjects (or cycles, if 
appropriate) in each category for discrete variables, and the sample size, mean, 
median, standard deviation (STDEV), first and third quartiles, minimum and 
maximum for continuous variables.
!
All mean and quartile values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to 2 more decimal places 
than the measured value.
!
All percentages will be rounded to 1 decimal point. The number and percentage of 
responses will be presented in the form XX (XX.X), where the percentage is in the 
parentheses.
!
All analysis and summary tables will have the analysis population sample size (ie, 
number of subjects) in the column heading.
!
All listings will be sorted for presentation in order of study site, subject identification
and date of procedure or event.
!
The day of the first dose of study drug will be defined as Day 1.
!
Each cycle starts with the date of the first dose date of the cycle, and the last day of 
the cycle is the day before the first dose date of the subsequent cycle; The cycle 
number for each date of interest, eg, AE, will be calculated based on the cycle 
window set by its start and end dates. If a date is on or after start date of cycle i and 
before start date of cycle (i+1), the corresponding cycle number will be “i".
!
For the last cycle, the last day of the cycle is the treatment discontinuation date on the 
case report form (CRF) EOT page or the Day 1 of the last cycle + 20, whichever is 
earlier. 
!
In by-cycle analyses, assessments taken pre-dose on Day 1 of a given cycle (eg,
laboratory measures) will be grouped with the previous cycle.
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For 
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c


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
17
!
Baseline value will be defined as the last non-missing value before the first dose of 
study drug is administered; for subjects who were not treated, the baseline will be the 
assessment value taken on the Screening visit.
!
Partial dates will be imputed based on the rules specified in Section 18.3.
!
All laboratory data will be reported using International System of Units (SI).
!
Summaries of the most severe toxicity grade in clinical laboratory in each treatment 
cycle and most severe grade post-baseline overall and shifts from baseline to most 
severe toxicity grade post-baseline overall will include all scheduled and unscheduled 
assessments. A similar approach will be used for summaries of Eastern Cooperative 
Oncology Group (ECOG) performance status.
!
For safety parameters, the Final Evaluation will be defined as the last on-treatment 
value, which is the last non-missing assessment on or prior to the last dose date + 28 
days or the treatment discontinuation date, whichever is later.
!
SAS∀Version 9.2 (or higher) will be the statistical software package used to produce 
all data summaries, listings, graphs, and statistical analyses.
5.2.
Analysis Populations
5.2.1.
Enrolled Population
The Enrolled Population includes all subjects who were enrolled to the study. 
5.2.2.
Safety Population
The Safety Population includes all subjects who received at least 1 dose of IP.
5.2.3.
Efficacy Evaluable Population
The Efficacy Evaluable Population includes all subjects who meet all eligibility criteria, and 
EITHER 
1. Received at least 2 cycles of IP at any dose intensity and discontinued treatment for 
progressive disease, OR 
2. Received at least 4 cycles of IP at any dose intensity and have baseline and at least two 
post-screening tumor assessments. 
Subjects receiving the 200 mg dose will be efficacy evaluable for response if they meet the 
defined criteria. Subjects not eligible for the Efficacy Evaluable Population will be replaced at 
the discretion of the sponsor.
5.2.4.
Pharmacokinetic Population 
The PK Population includes a subset of enrolled subjects of Asian-Pacific Island ethnicity at 
experienced selected sites who have evaluable pharmacokinetic data from at least 1 dose of IP. 
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5.2.4.
5.2.4
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
18
6.
SUBJECT DISPOSITION
Analysis population allocation will be summarized. The number and percentage of subjects who 
are treated and discontinued the treatment and the number and percentage of subjects who 
discontinued the study will be presented for the enrolled population. Each reason for treatment 
discontinuation and each reason for study discontinuation collected on the CRF will be 
summarized in the subject disposition table.
The number and percentage of subjects who died, and the number of subjects who are in survival 
follow-up or lost to survival follow-up at the time of analysis will also be presented in the subject 
disposition table. 
The number and percentage of subjects eligible or not eligible for the study, enrolled under each 
protocol amendment, and treated by site will be summarized. 
Listings will be provided for screen failures with reason for screen failure, discontinued subjects 
with reason for treatment discontinuation or reason for study discontinuation included. 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
19
7.
PROTOCOL DEVIATIONS/VIOLATIONS
Protocol deviations and violations will be identified and assessed periodically by the clinical 
research physician or designee following institution standard operational procedures. Prior to 
database lock, a final review and categorization of protocol violations or deviations will be 
performed by the study team. The protocol violations will be summarized using frequency 
tabulations for the enrolled population. 
A listing of subjects with protocol deviations or violations will also be provided. 
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
20
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographics and baseline characteristics will be summarized for the Enrolled Population, 
unless otherwise specified. Individual subject listings will be provided to support the summary 
tables.
8.1.
Demographics and Baseline Characteristics
Age (years), height (cm), weight (kg), body surface area (BSA) (m2), and vital signs at baseline 
will be summarized by sample size, mean, median, STDEV, minimum, and maximum values. 
Age category (< 65 years, > 65 years and < 75 years, and ≥ 75 years), sex, race, ethnicity, ECOG
performance status at baseline, and electrocardiogram (ECG) overall interpretation at baseline 
will be summarized by number and percentage of subjects in each category. Descriptive 
summary statistics for EBV-DNA (by real time-polymerase chain reaction [RT-PCR])) at baseline 
will be provided.
Age will be calculated as follows: Age = Maximum Integer # ([Date of Informed Consent – Date 
of Birth +1] / 365.25). 
BSA will be calculated as follows: BSA m2 = 0.007184 × (weight in kg)0.425 × (height in cm)0.725
(Du Bois, 1917).
8.1.1.
Cancer History
The number and percentage of subjects in each of the following categories will be presented:
!
Cancer diagnosis
!
Current cancer type (locally advanced, metastatic)
!
Stage at initial diagnosis (0, I, II, III, IVA, IVB, IVC)
!
TNM Classification at initial diagnosis: T category (TX, T0, Tis, T1, T2, T3, T4), N 
category (NX, N0, N1, N2, N3, N3a, N3b), M category (M0, M1)
!
Best response to prior therapy (CR, PR, SD, progressive disease, unknown, not 
applicable)
Time from initial diagnosis to first dose and time from most recent recurrence/ progression to 
first dose will be summarized descriptively.
8.2.
Medical History
A summary of relevant medical history will be presented by Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class (SOC) and preferred term (PT) for the safety 
population.
8.3.
Prior Therapies/Surgeries
Any prior therapy will be collected at screening. Prior systemic anticancer therapies or other 
anticancer therapies will be coded to therapeutic drug classes and generic drug names using the 
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ECOG
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
21
World Health Organization (WHO) drug dictionary. Prior cancer surgeries will be coded by 
MedDRA.
The number and percentage of subjects who had any prior radiation therapies, prior cancer 
surgeries, and prior systemic or other anticancer therapies will be presented for the safety
population. Descriptive statistics (eg, the time from end of prior therapy/surgery to first dose date 
in months) may also be provided, if needed. The therapies/surgeries with the same 
sequence/regimen number will be counted as one prior therapy/surgery. For subjects who had 
prior systemic anticancer therapies or other anticancer therapies, the incidence by coded 
therapeutic drug class and generic drug name will be provided in the summary table. The 
summary table of incidence of prior cancer surgeries will also be provided.
8.4.
Prior and Concomitant Medications
Medications reported on the Prior and Concomitant Medications CRF page will be coded to 
therapeutic drug classes and generic drug names using the WHO drug dictionary and will be 
summarized for the safety population. The Anatomical Therapeutic Chemical coding scheme of 
the WHO drug dictionary will be used to group medications into relevant categories for these 
tabulations. Individual listing of prior and concomitant medications will be provided to support 
the tables.
8.4.1.
Prior Medications
A prior medication will be any medication started prior to the date of the first dose of study drug. 
A summary will be presented showing the number and percentage of subjects who took prior 
medications by therapeutic drug class and generic drug name, as well as the number and 
percentage of subjects that took any prior medication.
8.4.2.
Concomitant Medications
Concomitant medication is defined as a medication that was either initiated before the first dose 
of study drug and continued during the study treatment, or initiated on/after the date of the first 
dose of study drug and within 28 days of the last dose of study drug. 
A summary will be presented showing the number and percentage of subjects who took 
concomitant medications by WHO therapeutic drug class and generic drug name, as well as the 
number and percentage of subjects who took any concomitant medications.
8.5.
Concomitant Procedures/Surgeries
A concomitant procedure/surgery is defined in a manner similar to the concomitant medication 
above. A summary will be presented showing the number and percentage of subjects who had 
concomitant procedures/surgeries by SOC and PT. 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
22
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the safety 
population. Treatment duration, dose exposure, number of cycles, number of doses, cumulative 
dose, dose intensity, average daily dose, relative dose intensity, dose reduction, and dose 
interruption, number of subjects dosed at each cycle and maximum number of cycles received 
per subject will be summarized. Individual subject listings of exposure to study drug will be 
provided. Column headers will be displayed as follows: ‘AP 200 mg’, ‘300 mg’, and ‘Total’.
9.1.
Treatment Duration
The treatment start date is the date of the first dose of study drug and the treatment end date is 
the date of the last non-missing dose of study drug. 
Treatment duration (in days) is calculated as (the treatment end date – the treatment start date + 
1). Summary statistics for treatment duration (in days) will be provided. Descriptive statistics 
will be provided for the total number of treatment cycles subjects received and for the number of 
doses received.
9.2.
Dose Exposure
Dose exposure (days) for overall is defined as the total number of actual days on CC-486 (dose >
0 mg) during treatment phase. 
9.3.
Cumulative Dose
Cumulative dose is defined as the sum of all administered doses in mg during the treatment 
period across all cycles. 
9.4.
Dose Intensity
Dose intensity reported in mg/day will be calculated as the cumulative dose divided by the 
treatment duration in days which is defined in Section 9.1 above.
9.5.
Average Daily Dose
Average daily dose (mg/day) is defined as the cumulative dose of study drug divided by the dose 
exposure.  
9.6.
Relative Dose Intensity
Relative dose intensity will be calculated as the dose intensity divided by the protocol daily dose 
x 100. The protocol daily dose is defined as 300*14/21 mg/day for subjects who received CC-
486 at a starting dose of 300 mg daily. For the first 6 Asian-Pacific Island ethnicity subjects 
evaluable for safety who received CC-486 at a starting dose of 200 mg, the protocol daily dose is 
defined as 200*14/21 mg/day.
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6 at
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
23
Descriptive statistics for the cumulative dose (mg), dose intensity (mg/day), relative dose 
intensity, as well as a frequency summary of subjects within each relative dose intensity
categories (≥ 90%, < 90% to 80%, < 80% to 70%, and < 70%) will be provided.
9.7.
Dose Reduction, Interruption and Overdose
Dose reduction is defined as a non-zero dose administered after the Cycle 1 Day 1 (C1D1) dose 
which is at a lower dose level than the dose the subject received at the previous dosing day.
Dose interruption occurs if the record of actual administered dose is zero except as required by 
the protocol. Consecutive zeros are counted as one interruption.
Overdose, as defined for this protocol, refers to the treatment 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 AEs or sequelae. 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.
Dose reduction, interruption and overdose will be summarized as follows:
!
Number and percentage of subjects with at least one dose reduction, reasons for each 
reduction, and frequency of reductions
!
Summary statistics (sample size, mean, median, STDEV, first and third quartiles,
minimum, and maximum) for time to first reduction
!
Number and percentage of subjects with at least 1 dose interruption, reasons for each 
interruption and frequency of interruption
!
Number and percentage of subjects who had > 5 days of dose interruption due to AE, 
and had ≥ 14 days of dose interruption due to AE
!
Summary statistics (sample size, mean, median, STDEV, first and third quartiles, 
minimum, and maximum) for time to first interruption and total days of interruption
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
24
10.
EFFICACY ANALYSIS
All efficacy results will be summarized for the efficacy evaluable population. If Stage 2 is 
conducted, analyses will be performed for PFS and OS in addition to ORR. Column headers will 
be displayed as follows: ‘AP 200 mg’, ‘300 mg’, and ‘Total’.
10.1.
Multiplicity
There is no multiplicity adjustment for the efficacy endpoints. 
10.2.
Analysis of the Efficacy Endpoints
The primary efficacy endpoints are ORR and PFS. 
Overall response rate is defined as the combined incidence of CR and PR, confirmed no less than 
4 weeks after the criteria for response are first met, based on independent radiology assessment 
using RECIST version 1.1. After the enrollment of 51 patients, if more than 14 responders are 
observed, the null hypothesis (ORR ≤ 20%) will be rejected, the true ORR will be concluded to 
be > 20%, The point estimate and two-sided 90% CI of ORR will be provided using the Clopper-
Pearson method (Clopper, 1934).
Progression-free survival will be based on independent radiology assessed response using 
RECIST v1.1. Progression-free survival is defined as the time from the date of start of the study 
treatment to the date of disease progression or death (any cause) on or prior to the data cut-off 
date for the statistical analysis, whichever occurs earlier. Subjects who do not have disease 
progression or have not died as of the data cut-off date will be censored at the time of the last 
radiologic assessment prior to the data cut-off date. In the event that a new anticancer therapy is 
initiated for a subject prior to documented progression, the subject will be censored at the time of 
the last radiologic assessment where the subject was documented to be progression-free prior to
the initiation of the new anticancer therapy. Subjects with a single missing radiologic assessment 
prior to a visit with documented disease progression (or death) will be analyzed as a PFS event at 
the time of the radiologic assessment that shows progression (or death). Subjects with ≥2 
consecutive missing radiologic assessments prior to a visit with documented disease progression 
(or death) will be censored at the time of the last radiologic assessment where the subject was 
documented to be progression-free prior to the first of the ≥2 consecutive missing visits.
The Kaplan-Meier (K-M) method will be used to estimate PFS distribution, and the medians 
with two-sided 90% CIs will be reported. Since the study did not enter the second stage, no 
hypothesis testing will be conducted for PFS. The K-M estimates of PFS rates at each 2-month 
interval will be provided. Kaplan-Meier curves for PFS will be presented.
Disease control rate, a secondary efficacy endpoint, is defined as CR and PR, confirmed ≥ 4 
weeks after the criteria for response are first met, and SD ≥16 weeks from the first treatment, 
based on independent radiology assessment using RECIST v1.1. The point estimate and two-
sided 90% CI of DCR will be provided using the Clopper-Pearson method (Clopper, 1934).
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
25
Overall survival, another secondary efficacy endpoint, is defined as the time from first treatment 
to death of any cause. Subjects who did not die by the end of study or the clinical data cut-off 
date will be censored on the last-known-to-be-alive date or the clinical cut-off date, whichever is 
earlier. 
The survival distribution of OS will be estimated using K-M method. The median including two-
sided 90% CI will be provided. The survival rates will be provided at each 2-month interval.
Kaplan-Meier curves for OS will also be presented.
10.3.
Analyses of Other Evidence of Anti-cancer Activities
The number and percentage of subjects who received any anticancer therapy post-treatment will 
be summarized overall and by therapy categories. The time from study treatment discontinuation 
to the earliest date of anticancer therapy initiation will be summarized descriptively. Listings will 
be provided for each posttreatment anticancer therapy category.
10.4.
Eastern Cooperative Oncology Group Performance Status
A by-subject ECOG listing will be provided.
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e Status


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
26
11.
SAFETY ANALYSIS
All safety analyses will be conducted based on the safety population. Descriptive statistics will 
be provided by treatment dose and for total safety population.
11.1.
Adverse Events
Adverse events will be analyzed in terms of TEAEs which are defined as any AE that begins or 
worsens on or after the start of study drug through 28 days after the last dose of study drug. All 
AEs will be coded using MedDRA version 19 or higher. 
A treatment-related TEAE is defined as a TEAE which was reported as “Suspected” on the CRF.
Adverse events with a missing relationship will be treated as “treatment-related.”
The incidence of TEAE will be summarized by MedDRA SOC and PT. Severity of AEs will be 
graded 1 to 5 according to the CTCAE Version 4.0 or higher. For all other AEs not described in 
the CTCAE, severity will be assessed by the investigator as mild (Grade 1), moderate (Grade 2), 
severe (Grade 3), life-threatening (Grade 4) or death (Grade 5). 
Tables summarizing the number and percentage of subjects experiencing TEAEs by treatment 
dose and for total safety population will be generated for each of the following:
!
All TEAEs by SOC and PT
!
All TEAEs by SOC
!
All TEAEs by PT
!
All TEAEs by Preferred term with Incidence of >5%
!
All TEAEs by onset cycle
!
Treatment-related TEAEs
!
TEAEs of Grade 3 or 4
!
Treatment-related TEAEs Grade 3 or 4
!
All TEAEs by maximum CTCAE grade
!
Treatment-related TEAEs by maximum CTCAE grade
!
Serious TEAEs
!
All serious TEAEs by Preferred term with Incidence of >5%Treatment-related serious 
TEAEs
!
All treatment-related serious TEAEs by Preferred term with Incidence of >5% 
!
TEAEs with action of study drug withdrawn
!
Treatment-related TEAEs with action of study drug withdrawn
!
TEAEs with action of study drug dose reduced
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All
All
on the CRF
on the CRF
ty of AEs 
AEs
f
AEs not de
AEs not de
1), modera
), mo
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s
r 4
r 4
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TEAEs G
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TEAE
!
Al
Al
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
27
!
Treatment-related TEAEs with action of study drug dose reduced
!
TEAEs with action of study drug dose interrupted
!
Treatment-related TEAEs with action of study drug dose interrupted
!
TEAEs with outcome of death
!
Treatment-related TEAEs with outcome of death
!
All deaths within 28 days of last dose with cause of death
!
TEAEs for the following baseline subgroups (provided the number of subjects is 
       sufficient): 
!
Age (< 65 years, 65 years to < 75 years, ≥75 years)
!
Sex 
For summaries by severity, if a subject experiences the same AE more than once with different 
toxicity grades, the event with the maximum grade will be tabulated in “by maximum grade” 
tables. If a subject experiences multiple occurrences of AEs under the same SOC and/or PT, the 
subject will be counted only once for that SOC and/or PT. In addition, AEs with a missing 
intensity will be presented in the summary table with an intensity category of “Missing.” 
Listings will be prepared that include the verbatim term, PT, and SOC as well as full details of 
all AEs for subjects in the safety population. 
Separate listings will also be prepared for serious TEAEs, TEAEs leading to death, and TEAEs 
resulting in discontinuation of IP. All deaths will be listed with the cause of death collected on 
the Death CRF page.
11.2.
Adverse Events of Special Interest
11.2.1.
AE of Special Interest
The selected AEs of special interest refers to a group of terms/PTs from one or more SOCs
relating to a defined medical condition or area of interest. The following AEs of Special Interest 
are based on risk definitions (search criteria) as outlined in the Vidaza RMP currently approved 
at the time of data cut-off date:
!
Myelosuppression (neutropenia, thrombocytopenia, anemia, general 
myelosuppression)
!
Haemorrhagic events
!
Infections
!
Renal failure
!
Hepatic failure
!
Ischemic colitis
!
Interstitial lung disease
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an once wit
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and SO
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cut-off date
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myelosupp
!
Haem
aem
!
In
In
!


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
28
!
Tumor lysis syndrome
!
Cardiac disorders (cardiac failure, cardiac arrhythmias and myocardial infarction)
!
Anxiety, confusion, insomnia
!
Other psychiatric disorders
After review of the data, there may be other AEs of special interest identified. The following 
summaries will be provided for TEAEs included in the above-mentioned AEs of special interest: 
!
All TEAEs 
!
TEAEs of Grade 3 or 4
!
Serious TEAEs 
!
TEAEs leading to study drug withdrawal
!
TEAEs leading to study drug dose reduction
!
TEAEs leading to study drug dose interruption
!
TEAEs leading to death 
Additional safety analyses may be performed by specific parameters (eg, time to occurrence), if 
warranted.  
11.2.2.
Dose Limiting Toxicity 
Dose limiting toxicity (DLT) is defined in the protocol and will be evaluated only for the first 6 
subjects of Asian-Pacific Island ethnicity evaluable for safety (receiving 200 mg QD of CC-486). 
A summary table of DLTs will be presented including number and percentage of subjects having 
DLT.  
A flag for DLTs may be added to selected listings of AEs as appropriate.
11.3.
Clinical Laboratory Evaluations
Clinical laboratory values will be graded according to CTCAE version 4.0 for applicable tests. 
Normal ranges will be used to determine the categories high, low, and normal for laboratory
tests. Listings will be provided for all clinical lab evaluations with normal ranges included. 
11.3.1.
Hematology, Chemistry, Urinalysis, and Coagulation
The laboratory values will be graded using CTCAE v4.0 for applicable tests as follows:
!
Hematology: red blood cell count, hemoglobin, hematocrit, white blood cell count, 
absolute neutrophil count, absolute lymphocytes, absolute monocytes, absolute 
eosinophils, absolute basophils, and platelets.
!
Chemistry: sodium, potassium, calcium, magnesium, phosphorus, blood urea 
nitrogen, creatinine, uric acid, glucose, lactate dehydrogenase, total protein, albumin, 
alkaline phosphatase, bilirubin (total and direct), aspartate aminotransferase/serum 
glutamic oxaloacetic transaminase, alanine aminotransferase.
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:
ameters (eg
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and
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s will be gr
s will be
used to
used 
de
d
be provided
provided
ematology,
matology
atory
or  value
value
y
!
Hem
em
ab
ab


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
29
For laboratory values that fall outside the grade criteria of CTCAE v4.0 for laboratory tests listed 
above, a Grade of 0 will be assigned. 
For hematology and chemistry, the number and percentage of subjects that have each CTCAE 
grade will be summarized using the most severe grade overall during the treatment for each of 
the applicable tests. A shift table representing the shift from the baseline grade to the most severe 
grade during treatment will be provided for all applicable laboratory tests listed above. For 
coagulation, a listing will be provided. The onset day of nadir across all cycles, the analyte value 
at nadir, and the change from baseline to analyte value at nadir will be summarized descriptively.
11.3.2.
Epstein-Barr Virus-DNA measurements
Epstein-Barr Virus DNA (by RT-PCR) in serum will be measured at baseline and on Day 1 of all 
cycles. Results and change from baseline will be summarized by cycle for the safety population 
using descriptive statistics (sample size, mean, median, STDEV, minimum, and maximum 
values). A by-subject listing will be provided.
11.4.
Vital Sign Measurements
For vital signs, a shift table from baseline to worst post-baseline will be displayed for 
temperature, systolic and diastolic blood pressure and pulse by normal range categories 
(low/normal/high). Normal ranges given in Table 2 will be used to determine the categories low, 
normal and high. A by-subject listing will be provided. 
Table 2:
Normal Ranges of Vital Sign Measurements
Test 
Normal Range (Unit)
Diastolic Blood Pressure 
60, 90 (mmHg)
Systolic Blood Pressure 
100, 140 (mmHg)
Pulse 
60, 100 (beats per minute)
Temperature 
[35, 38] (°C)
11.5.
Physical Examination
Any findings from physical examination before the start of study drug will be documented as 
medical history on the medical history CRF page and any findings after the start of study drug 
will be documented as AEs on CRF. Therefore, there will be no separate analysis for physical 
examination. 
11.6.
Electrocardiograms
The 12-lead ECG overall investigator interpretation will be documented at screening and EOT
visits. 
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60, 100 
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11.6.
11.6.


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
30
The shift of overall interpretation (‘normal’, ‘abnormal, not clinically significant’ and ‘abnormal, 
clinically significant’) from baseline to the final evaluation on treatment will be displayed in 
cross–tabulations.
A by-subject listing of ECG data will be provided. 
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
31
12.
PHARMACOKINETICS ANALYSIS
12.1.
Plasma concentrations
A by-subject listing of PK blood sample collection times, derived sampling time deviations, and 
azacitidine concentrations will be provided. Azacitidine plasma concentrations will be 
summarized using descriptive statistics (number of subjects, arithmetic mean, STDEV, 
minimum, median, maximum, percent coefficient of variation, geometric mean, and geometric 
percent coefficient of variation) for each dose level/cycle/day, if/when appropriate. 
Concentrations that are below the limit of quantitation (BLQ) will be treated as zero for the 
computation of descriptive statistics. Missing concentrations and concentrations from blood 
samples collected more than ± 10% of nominal time will be omitted from the calculation of 
descriptive statistics.
Individual subject concentration-time data and mean concentration-time data for each dose 
level/cycle/day will be graphically presented on linear and semi-logarithmic scales.
12.2.
Pharmacokinetic Parameters
Following single dose administration, predose samples that are BLQ or missing will be assigned 
a numerical value of zero for the calculation of PK parameters. Any anomalous concentration 
values observed at predose will be identified in the clinical study report. Pharmacokinetic 
parameters will be computed if the anomalous value is ≤ 5% of the maximum drug plasma 
concentration (Cmax). If the anomalous value is > 5% of Cmax, the computed PK parameters for 
the given subject will be excluded from the PK descriptive statistics.  
Any other BLQ concentrations will be assigned a value of zero if they precede quantifiable 
samples in the initial portion of the profile.  A BLQ value that occurs between quantifiable data 
points, especially prior to Cmax, will be evaluated to determine if reanalysis or exclusion of the 
data is warranted.  Following Cmax, BLQ values embedded between 2 quantifiable data points 
will be treated as missing when calculating PK parameters. Below the limit of quantitation
values occurring at the end of the collection interval (after the last quantifiable concentration) 
will be treated as missing data. If consecutive BLQ concentrations are followed by quantifiable 
concentrations in the terminal portion of the concentration curve, these quantified values will be 
excluded from the PK analysis by assigning them a value of missing, unless otherwise warranted 
by the concentration-time profile. For the purpose of analysis, these trailing BLQ values may be 
designated as zero in the dataset if the PK program used to do the analysis (such as WinNonlin®) 
will treat trailing zero values as missing when calculating PK parameters.
Actual sampling times will be used in the calculations of pharmacokinetic parameters, which will 
be derived using noncompartmental methods with Phoenix™ WinNonlin® Professional Version 
6.3, or higher, 
. Graphics may be 
prepared with SAS Version 9.2, or higher; or Excel 2007, or higher; Phoenix™ WinNonlin®
Professional 6.3, or higher; or S-Plus 8.2., or higher 
The following PK parameters will be calculated for azacitidine:
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the
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5% 
5% of
of C
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descriptpt
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signed a a
file.
file. A BL
B
A
be
be evaluat
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BLQ va
en
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calcula
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ata. IfI c
erminal
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.3, or high
gh
prepared
prepared
ofes
f


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
AUC0-∞
Area under the plasma concentration-time curve from Time 0 extrapolated to 
infinity, calculated as [AUCt + Ct/∃z]. Ct is the last quantifiable concentration. No 
AUC extrapolation will be performed with unreliable ∃z.  If AUC %Extrap is 
≥25%, AUCinf will not be reported
AUC0-t
Area under the plasma concentration-time curve from Time 0 to the time of the 
last quantifiable concentration, calculated by linear trapezoidal method when 
concentrations are increasing and the logarithmic trapezoidal method when 
concentrations are decreasing.
Cmax
Maximum observed plasma concentration, obtained directly from the observed 
concentration vs. time data.
Tmax
Time to Cmax, obtained directly from the observed concentration versus time data.
t1/2
Terminal phase half-life in plasma, calculated as [(ln 2)/∃z].  t1/2 will only be 
calculated when a reliable estimate for ∃z can be obtained.  
CL/F
Apparent total clearance, calculated as [dose/AUCinf]. 
Vz/F
Apparent volume of distribution, calculated as [(CL/F)/∃z]. 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
33
The following PK parameters for azacitidine will be calculated for diagnostic purposes and 
listed, but they will not be summarized:
∃z
Apparent terminal rate constant, calculated by linear regression of the 
terminal portion of the log-concentration versus time curve in plasma.  
Visual assessment will be used to identify the terminal linear phase of the 
concentration versus time profile.  A minimum of 3 data points will be 
used for calculation.  
∃z will not be estimated if the terminal phase of the log-concentration 
versus time profile does not exhibit a linear decline phase, or if the 
regression coefficient < 0.8.  
∃z lower
Lower limit of time (hours) included in the calculation of ∃z. 
∃z N
Number of data points used in the calculation of ∃z.
∃z upper
Upper limit of time (hours) included in the calculation of ∃z.
Rsq
Regression coefficient for calculation of ∃z.  
%AUC Extrap
Percentage of AUC∞due to extrapolation from the last quantifiable time 
point to infinity.
12.3.
Pharmacokinetic Analyses
A by-subject listing of PK parameters will be provided.  The PK parameters will also be 
summarized using descriptive statistics (number of subjects, arithmetic mean, STDEV,  
minimum, median, maximum, percent coefficient of variation, geometric mean, and geometric 
percent coefficient of variation) for each dose level/cycle/day. Also, when appropriate, graphical 
representations (egscatter plots, box plots) may be used to visualized the results.
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dose
box pl
box plots)
ots)


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
34
13.
BIOMARKER AND CORRELATION ANALYSES
No biomarker and correlation analysis will be done due to limited tumor biopsy data collected.
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
35
14.
QUALITY OF LIFE ANALYSIS
Not applicable for this study. 
&(/*(1(35235,(7$5<,1)250$7,21


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
36
15.
INTERIM ANALYSIS
One interim analysis will be performed for Stage 1 according to Simon's optimal two-stage 
design based on efficacy evaluable population.
The ORR will be monitored by Celgene study team according to Simon’s optimal two-stage 
design based on the efficacy evaluable population. The interim analysis will be performed using
the data collected by the cutoff date for the interim analysis. The cutoff date is defined as the 
date when there are more than 4 responders observed in Stage 1 of Simon’s two-stage design. If 
at Stage 1 the predefined activity is met (> 4 responses [CR or PR] out of the first 17 efficacy 
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. All subjects enrolled prior to the cutoff date will be included in the 
interim analysis and all data up to the cutoff date will be summarized or listed.
The following summary tables and listings will be provided for the Stage 1 interim analysis:
! Analysis populations
!
Demographic and baseline characteristics for the enrolled population
!
Cancer history for the enrolled population
!
ORR based on independent radiology assessment for the efficacy evaluable 
population
! ORR based on investigator assessment for the efficacy evaluable population
!
Treatment exposure and dose modification for the safety population
! Incidence of TEAEs by MedDRA SOC and PT for the safety population
!
Incidence of TEAEs leading to dose discontinuation for the safety population
! Incidence of TEAEs with outcome of death for the safety population
!
Incidence of Grade 3 or 4 TEAEs by MedDRA SOC and PT for the safety 
population
! Incidence of serious TEAEs by MedDRA SOC and PT for the safety 
population
! Incidence of TEAEs of Special Interest by MedDRA SOC and PT for the 
safety population
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gator asses
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ure and do
ure and do
f f TEAEs
TEAEs b
ence of 
nce of TE
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ncidence o
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! Incide
Incide
po
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
37
!
Listing of subject eligibility
!
Listing of demographics and baseline characteristics
!
Listing of cancer history
!
Listing of dosing
!
Listing of tumor assessment
!
Listing of tumor response
!
Listing of adverse events
!
Listing of deaths
!
PK and biomarker analysis provided there are sufficient data
The above related data for the Stage 1 interim analysis will be cleaned and the detailed 
data cleaning plan will be documented in the data management plan.
a
be cleaned
be cle
gement
ement plpla


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
16.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
‘Enrolled Population’ is defined in SAP.
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
39
17.
REFERENCES
Eisenhauer EA, Therasse P, Boqaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45:228-47.
Du Bois D, Du Bois E. A formula to estimate the approximate surface area if height and weight 
be known. Arch Int Med. 1917, 17(6), 863-71.
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10:1-
10.
Clopper C, Pearson E S. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26:404–413.
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-
of the
of the


CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
40
18.
APPENDICES 
18.1.
Study schematic
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
18.2.
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (eg, the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.
!
Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, tumor 
scans, etc. They should be present whenever data for a protocol-specified procedure 
are present and should only be missing when a procedure are marked as NOT DONE
(ND) in the database. Procedure dates will not be imputed.
!
Log Dates are dates recorded in the CRF data logs. Specifically, they are the start and 
end dates for AEs and concomitant medications/procedures. They should not be 
missing unless an event or medication is marked as ongoing in the database.  
Otherwise, incomplete log dates will be imputed according to the rules in Appendix 
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5235,(7$5<,1)250$7
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
41
17.2 (eg, for duration or cycle assignment). However, in listings log dates will be 
shown as recorded without imputation.
!
Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.
!
Outcome Dates are dates corresponding to study endpoints such as survival and 
disease progression. In most cases they are derived either from a milestone (e.g., the 
survival date is derived from the death date), or a procedure date (e.g., the disease 
progression date is derived from the date of the tumor scan that was used to determine 
disease progression). They may be subject to endpoint-specific censoring rules if the 
outcome did not occur, but are not otherwise subject to imputation.
!
Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
18.3.
Date Imputation Guideline
18.3.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications/Procedures 
Incomplete Start Date:
Missing day and month
!
If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields.
!
If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.
!
If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 
!
If the month and year are the same as the year and month of first dosing date, then the 
first dosing date will be assigned to the missing day.
!
If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.
!
If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.
!
If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
42
Missing day, month, and year
!
No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month
!
If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 
!
If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 
!
If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only 
!
If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 
!
If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
18.3.2.
Impute Missing Prior Therapy Dates or Cancer Diagnosis Date
When necessary for analysis purposes, the diagnosis dates or prior therapy dates without a 
specific day of the month given (ie, JAN2008) will be assigned the 15th day of the month and 
dates without a specific day or month (ie, 2008) will be assigned the 30th day of June to 
complete the date. If the above imputation inappropriately results in a diagnosis date or prior 
therapy date on or after the first dose date, then the incomplete date will be assigned to the day 
prior to first dose date. 
18.3.3.
Adverse Events
Partially missing AE start dates will be imputed in the derived dataset for AEs, but partially 
missing AE end dates will not be imputed in the same dataset. If the AE end date is complete 
with no missing year, month, or day, and the partially missing start date imputed by the rules 
below is after the AE end date, then the start date will be imputed by the AE end date.
18.3.4.
Prior/Concomitant Medications/Procedures
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CC-486 (Oral Azacitidine)
Statistical Analysis Plan. Protocol CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
43
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the derived dataset for 
prior/concomitant medications/procedures. For prior/concomitant medications, if the stop date is 
complete with no missing year, month, or day, and the partially missing start date imputed by the 
rule below is after the stop date, then the start date will be imputed by the stop date.
Partially missing prior/concomitant medication/procedure start dates will be imputed by the 
earliest possible date given the non-missing field(s) of the date.
Partially missing prior/concomitant medication stop dates will be imputed by the latest possible 
date given the non-missing field(s) of the date.
18.3.5.
Medical History
Partially missing medical history start dates will be imputed in the derived dataset for medical 
history. The 15th of the month will be used to impute a partially missing start date that has only 
the day missing, and June 30th will be used to impute a partially missing start date that has both 
the month and day missing.
18.3.6.
Birth Date
Partially missing birth date will be imputed in the derived dataset. Missing day will be imputed 
by 15th of the month, missing month will be imputed by July and missing year will result in
missing age. 
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Prot_003.pdf: 
 
 
 
 
 
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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urvival wi
follo
ll w u
w 


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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f


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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.3.


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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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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14.5.
4.5.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
13
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
&(/*(1(35235,(7$5<,1)250$7,21
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
..........
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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
Celgene Corporation
Confidential and Proprietary
16
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
18
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 
&(/*(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
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
20
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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real time


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


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


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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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.
&(/*(1(35235,(7$5<,1)250$7,21
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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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Gra
Gr


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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G
pa


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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east 4 


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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administere
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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wo-sts age d
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llment 
subjects.
ubject
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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who rec
who re
ysi


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


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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y, significan
significan
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as Not Susp
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Mean
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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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recorded o
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syndrom
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abno
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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.
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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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mend
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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Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic nasopharyngeal carcinoma of the 
undifferentiated type. Ann Oncol 2002;13:150-156.Garcia-Manero G, Gore SD, Cogle C, et al.  
Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic 
leukemia, and acute myeloid leukemia. J Clin Oncol 2011;29:2521-2527.
Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin 
and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of 
the head and neck. J Clin Oncol 1992;10:257-263.
Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer 
Biol 2014;26:60-68. Available at: http://dx.doi.org/10.1016/j.semcancer.2014.01.002.
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753 pati
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haryngeal
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HNS
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ESMO
. Ann Onco
. Ann On
demethylat
demethylat
1.
otherapy
therapy f
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:244
244-249.
-249.
of
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eated wit
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et al.
et al. Cape
Cap
ase II study
ase II study
et al.
et al. Mul
M ti
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carcino
carcinom
dy
dy. J Clin O
. J Clin 
Leong SS, 
Leong SS, 
d ty
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Ann
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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
Koutcher L, Lee N, Zelefsky M, et al. Reirradiation of locally recurrent nasopharynx cancer with 
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Philadelphia, PA. Lippincott Williams & Wilkins;2011:729-780.
Miranda MB, Jones PA. DNA methylation: the nuts and bolts of repression. J Cell Physiol
2007;213:384-390.
Ngeow J, Lim WT, Leong SS, et al. Docetaxel is effective in heavily pretreated patients with 
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10.
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: DeVita V
: DeVita 
9 h ed.
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J C
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718
718-722.
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of genes sp
of genes sp
er Sci 2013
er Sci 201
y and respon
y and respo
1982;5:64
1982;5:64
of a progn
of a progn
2003;39:1
2003;39:1
methylat
methylation
thy seropos
hy serop
Methylat
Methylati
90:4480
0:4480-44
-4
, Ujvari D, 
Ujvari D,
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96.
eung YK, C
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opharyngea
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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
Sorrell M, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development 
Conference Statement: Management of Hepatitis B. Ann Int Med 2009;150:104-10.
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patients with advanced nasopharyngeal carcinoma after the failure of platinum-based 
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microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma 
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Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma. 
Intech Open; ISBN:978-953-307-867-0;2012a:1-27.
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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Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
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Prot_002.pdf: 
 
 
 
 
 
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 2 Date:  03 April 2015 


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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
2
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
Title:
 
Address:
Route de Perreux 1,
Boudry, Switzerland  2017
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls
Back-up 24 Hour Global Emergency Contact Call Center: 
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
3
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
4
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 
Trial, whichever occurs earlier.
The End of Trial 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.
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 
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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, 
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) 
&(/*(1(35235,(7$5<,1)250$7,21
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 Trial ............................................................................................................25
5.
TABLE OF EVENTS.............................................................................................26
6.
PROCEDURES......................................................................................................31
6.1.
Treatment Period ....................................................................................................32
6.1.1.
End of Treatment....................................................................................................33
6.2.
Follow-up Period....................................................................................................34
6.2.1.
Efficacy Follow-up.................................................................................................34
6.2.2.
Survival Follow-up.................................................................................................34
6.3.
Response Assessments............................................................................................35
6.3.1.
Assessment of Response According to RECIST Version 1.1...................................35
6.3.1.1.
Other Assessments..................................................................................................35
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7
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CC-486-NPC-001 Amendment 2 Final: 03 April 2015
6.4.
Pharmacokinetics....................................................................................................35
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase ................................................36
6.5.
Biomarkers .............................................................................................................36
7.
STUDY POPULATION.........................................................................................38
7.1.
Number of Subjects and Sites .................................................................................38
7.2.
Inclusion Criteria....................................................................................................38
7.3.
Exclusion Criteria...................................................................................................39
8.
DESCRIPTION OF STUDY TREATMENTS........................................................41
8.1.
Description of Investigational Product(s)................................................................41
8.2.
Treatment Administration and Schedule .................................................................41
8.2.1.
Tolerability Determination in Asian-Pacific Island Ethnicity ..................................41
8.2.2.
Dose Adjustment Guidelines...................................................................................42
8.2.3.
Missing Doses ........................................................................................................43
8.2.4.
Overdose ................................................................................................................43
8.2.5.
Guidelines for Screening and Management of Hepatitis B and C ............................43
8.3.
Method of Treatment Assignment...........................................................................47
8.4.
Packaging and Labeling..........................................................................................47
8.5.
Investigational Product Accountability and Disposal ..............................................47
8.6.
Investigational Product Compliance........................................................................47
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................48
9.1.
Permitted Concomitant Medications and Procedures...............................................48
9.2.
Prohibited Concomitant Medications and Procedures..............................................48
9.3.
Required Concomitant Medications and Procedures................................................48
10.
STATISTICAL ANALYSES..................................................................................49
10.1.
Overview................................................................................................................49
10.2.
Study Population Definitions ..................................................................................49
10.3.
Sample Size and Power Considerations...................................................................49
10.4.
Background and Demographic Characteristics........................................................50
10.5.
Subject Disposition.................................................................................................50
10.6.
Efficacy Analysis....................................................................................................50
10.7.
Safety Analysis.......................................................................................................50
10.8.
Interim Analysis .....................................................................................................51
10.9.
Assessment of Pharmacokinetics ............................................................................51
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0.6.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
10.10.
Other Topics...........................................................................................................51
10.10.1.
Independent Data Monitoring Committee (iDMC)..................................................52
11.
ADVERSE EVENTS..............................................................................................53
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................53
11.2.
Evaluation of Adverse Events.................................................................................53
11.2.1.
Seriousness.............................................................................................................53
11.2.2.
Severity / Intensity..................................................................................................55
11.2.3.
Causality ................................................................................................................55
11.2.4.
Duration .................................................................................................................56
11.2.5.
Action Taken..........................................................................................................56
11.2.6.
Outcome.................................................................................................................56
11.3.
Abnormal Laboratory Values..................................................................................56
11.4.
Pregnancy...............................................................................................................56
11.4.1.
Females of Childbearing Potential: .........................................................................56
11.4.2.
Male Subjects.........................................................................................................57
11.5.
Reporting of Serious Adverse Events......................................................................57
11.5.1.
Safety Queries ........................................................................................................58
11.6.
Expedited Reporting of Adverse Events..................................................................58
12.
DISCONTINUATIONS .........................................................................................60
12.1.
Treatment Discontinuation......................................................................................60
12.2.
Study Discontinuation ............................................................................................60
13.
EMERGENCY PROCEDURES.............................................................................61
13.1.
Emergency Contact.................................................................................................61
13.2.
Emergency Identification of Investigational Products .............................................61
14.
REGULATORY CONSIDERATIONS...................................................................62
14.1.
Good Clinical Practice............................................................................................62
14.2.
Investigator Responsibilities ...................................................................................62
14.3.
Subject Information and Informed Consent.............................................................62
14.4.
Confidentiality........................................................................................................63
14.5.
Protocol Amendments.............................................................................................63
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................63
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................64
&(/*(1(35235,(7$5<,1)250$7,21
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14.5.
4.5.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
13
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
14.8.
Closure of the Study ...............................................................................................64
15.
DATA HANDLING AND RECORDKEEPING.....................................................65
15.1.
Data/Documents .....................................................................................................65
15.2.
Data Management...................................................................................................65
15.3.
Record Retention....................................................................................................65
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................67
16.1.
Study Monitoring and Source Data Verification......................................................67
16.2.
Audits and Inspections............................................................................................67
17.
PUBLICATIONS ...................................................................................................68
18.
REFERENCES.......................................................................................................69
19.
APPENDICES........................................................................................................72
Appendix A.
Eastern Cooperative Oncology Group (ECOG) Performance Status...................72
&(/*(1(35235,(7$5<,1)250$7,21
7
.......67
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
14
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
LIST OF TABLES
Table 1:
Table of Events.......................................................................................................26
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase..........................................................................................36
Table 4:
Dose Adjustments and Dose Delays for Toxicity ....................................................42
Table 5:
Action to be taken based on Screening Hepatitis B Results .....................................45
Table 6:
Guidelines for the management of Hepatitis B reactivation.....................................45
Table 7:
Guidelines for the management of exacerbation of Hepatitis C ...............................46
&(/*(1(35235,(7$5<,1)250$7,21
2
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..........
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
15
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
16
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
17
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
19
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
20
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 trial
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 trial
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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PC subjects
PC subject
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able diseas
or NPC sub
or NPC sub
format
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clinical stu
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NP
NP


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
21
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
!
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
22
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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
 
&(/*(1(35235,(7$5<,1)250$7,21
netetics
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
23
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
24
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
25
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 Trial (as defined in Section 4.3), whichever occurs 
earlier.
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
26
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
5.
TABLE OF EVENTS
Table 1:
Table of Events
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
27
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
Physical examination (source 
documented only) Detailed hepatitis 
medical history for all subjects
X
X
---
X
X
X
---
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
---
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1(
(1


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
28
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
---
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
---
---
&(/
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ycle 1 Da
disease prog
disease prog
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5<
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$5
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AND PK A
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
29
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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.
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.
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('06'RF1XPEHU
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CC-486-NPC-001
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CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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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 trial, 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
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CC-486-NPC-001 Amendment 2 Final: 03 April 2015
!
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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33
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
34
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
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35
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
36
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
37
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
be assessed for Stage 1 subjects only.
 
 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
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39
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
40
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
∀
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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*


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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.
Monitor HBV-DNA every 6 
weeks starting from C3D1 
onwards or more frequently if 
clinically indicated
No prophylaxis
Monitor HBV-DNA every 6 
weeks starting from C3D1 
onwards or more frequently if  
clinically indicated
No specific 
action
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
49
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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plac


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
50
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
51
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
52
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
53
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
54
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
!
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
55
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
56
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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male subject
male subject
1.4.1.
1.4.1.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
57
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
58
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
59
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
60
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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.
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('06'RF1XPEHU
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CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
61
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
62
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
63
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
64
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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.
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protocol
protocol.


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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
65
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
66
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
!
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.
e
ities.
ties.
destruction
destruction


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CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
67
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
68
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
69
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
18.
REFERENCES
Ahmad A, Stefani S. Distant metastases of nasopharyngeal carcinoma: a study of 256 male 
patients. J Surg Oncol 1986;33:194-197.
Al-Sarraf M. Head and neck cancer: chemotherapy concepts. Semin Oncol 1988;15:70-85.
American Cancer Society: Nasopharyngeal Cancer. September 23, 2013. Available at : 
http://www.cancer.org/cancer/nasopharyngealcancer/detailedguide/nasopharyngeal-cancer-what-
is-nasopharyngeal-cancer. Accessed February 26, 2014.
Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced nasopharyngeal 
carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. 
Int J Radiat Oncol Biol Phys 2006;64:47-56.
Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastatic nasopharyngeal 
carcinoma. Eur Ann Otorhinolaryngol Head Neck Dis 2011;128:79-85.
Chan AT, Gregoire V, Lefebvre JL, et al. Nasopharyngeal cancer: EHNS-ESMO-ESTRO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;(21 Suppl 
5):v187-189.
Chan AT, Tao Q, Robertson KD, et al. Azacitidine induces demethylation of the Epstein-Barr 
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&(/*(1(35235,(7$5<,1)250$7,21
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aryngeal
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ESMO
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. Ann On
demethylat
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:244
244-249.
-249.
of
of capeci
capeci
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i
eated wit
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et al
et al. Cape
Cap
ase II study
ase II study
et al.
et al. Mul
M ti
l
carcino
carcinom
dy
dy. J Clin O
. J Clin 
Leong SS, 
Leong SS, 
d ty
d type.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
70
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
Koutcher L, Lee N, Zelefsky M, et al. Reirradiation of locally recurrent nasopharynx cancer with 
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: DeVita V
: DeVita 
9 h ed.
ed.
ion.n. J Cell 
J C
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ly pretrea
718
718-722.
-722
of genes sp
of genes sp
er Sci 2013
er Sci 201
y and respon
y and respo
1982;5:64
1982;5:64
of a progn
of a progn
2003;39:1
2003;39:1
methylat
methylation
thy seropos
hy serop
Methylat
Methylati
90:4480
0:4480-44
-4
, Ujvari D, 
Ujvari D,
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
71
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
Sorrell M, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development 
Conference Statement: Management of Hepatitis B. Ann Int Med 2009;150:104-10.
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transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5.  
J Virol 2000;74:10458-10467.
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and neck cancer. Am J Surg 1985;150:485-487.
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patients with advanced nasopharyngeal carcinoma after the failure of platinum-based 
chemotherapy. Cancer Chemother Pharmacol 2008;61:33-38.
Zhang X, Li W, Li H, et al. Genomic methylation profiling combined with gene expression 
microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma 
taxol resistance.  Anticancer Drugs 2012b;23:856-864.
Zhang Z, Chen F, Kuang H, et al. Epigenetics of nasopharyngeal carcinoma. In: Chen SS, ed. 
Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma. 
Intech Open; ISBN:978-953-307-867-0;2012a:1-27.
d d 
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aryngeal c
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
72
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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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This is a representation of an electronic record that was signed electronically in Livelink.
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the organizations electronic signature policies and procedures.
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Prot_001.pdf: 
 
 
 
 
 
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 1 Date:  01 October 2014 


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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
2
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
Title:
 
Address:
Route de Perreux 1,
Boudry, Switzerland  2017
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls
Back-up 24 Hour Global Emergency Contact Call Center: 
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
3
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
4
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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.
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 
Trial, whichever occurs earlier.
The End of Trial 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.
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 
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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, 
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 
&(/*(1(35235,(7$5<,1)250$7,21
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
preferred term. Serious adverse events, events of interest, and events leading to discontinuation 
or death will be listed separately.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 Trial ............................................................................................................25
5.
TABLE OF EVENTS.............................................................................................26
6.
PROCEDURES......................................................................................................31
6.1.
Treatment Period ....................................................................................................32
6.1.1.
End of Treatment....................................................................................................33
6.2.
Follow-up Period....................................................................................................34
6.2.1.
Efficacy Follow-up.................................................................................................34
6.2.2.
Survival Follow-up.................................................................................................34
6.3.
Response Assessments............................................................................................34
6.3.1.
Assessment of Response According to RECIST Version 1.1...................................34
6.3.1.1.
Other Assessments..................................................................................................35
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.3.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
11
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
6.4.
Pharmacokinetics....................................................................................................35
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase ................................................36
6.5.
Biomarkers .............................................................................................................36
7.
STUDY POPULATION.........................................................................................38
7.1.
Number of Subjects and Sites .................................................................................38
7.2.
Inclusion Criteria....................................................................................................38
7.3.
Exclusion Criteria...................................................................................................39
8.
DESCRIPTION OF STUDY TREATMENTS........................................................41
8.1.
Description of Investigational Product(s)................................................................41
8.2.
Treatment Administration and Schedule .................................................................41
8.2.1.
Tolerability Determination in Asian-Pacific Island Ethnicity ..................................41
8.2.2.
Dose Adjustment Guidelines...................................................................................42
8.2.3.
Missing Doses ........................................................................................................43
8.2.4.
Overdose ................................................................................................................43
8.3.
Method of Treatment Assignment...........................................................................43
8.4.
Packaging and Labeling..........................................................................................44
8.5.
Investigational Product Accountability and Disposal ..............................................44
8.6.
Investigational Product Compliance........................................................................44
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................45
9.1.
Permitted Concomitant Medications and Procedures...............................................45
9.2.
Prohibited Concomitant Medications and Procedures..............................................45
9.3.
Required Concomitant Medications and Procedures................................................45
10.
STATISTICAL ANALYSES..................................................................................46
10.1.
Overview................................................................................................................46
10.2.
Study Population Definitions ..................................................................................46
10.3.
Sample Size and Power Considerations...................................................................46
10.4.
Background and Demographic Characteristics........................................................47
10.5.
Subject Disposition.................................................................................................47
10.6.
Efficacy Analysis....................................................................................................47
10.7.
Safety Analysis.......................................................................................................47
10.8.
Interim Analysis .....................................................................................................48
10.9.
Assessment of Pharmacokinetics ............................................................................48
10.10.
Other Topics...........................................................................................................48
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0.6.
10.7.
0.7.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
11.
ADVERSE EVENTS..............................................................................................49
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................49
11.2.
Evaluation of Adverse Events.................................................................................49
11.2.1.
Seriousness.............................................................................................................49
11.2.2.
Severity / Intensity..................................................................................................51
11.2.3.
Causality ................................................................................................................51
11.2.4.
Duration .................................................................................................................52
11.2.5.
Action Taken..........................................................................................................52
11.2.6.
Outcome.................................................................................................................52
11.3.
Abnormal Laboratory Values..................................................................................52
11.4.
Pregnancy...............................................................................................................52
11.4.1.
Females of Childbearing Potential: .........................................................................52
11.4.2.
Male Subjects.........................................................................................................53
11.5.
Reporting of Serious Adverse Events......................................................................53
11.5.1.
Safety Queries ........................................................................................................54
11.6.
Expedited Reporting of Adverse Events..................................................................54
12.
DISCONTINUATIONS .........................................................................................56
12.1.
Treatment Discontinuation......................................................................................56
12.2.
Study Discontinuation ............................................................................................56
13.
EMERGENCY PROCEDURES.............................................................................57
13.1.
Emergency Contact.................................................................................................57
13.2.
Emergency Identification of Investigational Products .............................................57
14.
REGULATORY CONSIDERATIONS...................................................................58
14.1.
Good Clinical Practice............................................................................................58
14.2.
Investigator Responsibilities ...................................................................................58
14.3.
Subject Information and Informed Consent.............................................................58
14.4.
Confidentiality........................................................................................................59
14.5.
Protocol Amendments.............................................................................................59
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................59
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................60
14.8.
Closure of the Study ...............................................................................................60
15.
DATA HANDLING AND RECORDKEEPING.....................................................61
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7


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
13
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
15.1.
Data/Documents .....................................................................................................61
15.2.
Data Management...................................................................................................61
15.3.
Record Retention....................................................................................................61
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................63
16.1.
Study Monitoring and Source Data Verification......................................................63
16.2.
Audits and Inspections............................................................................................63
17.
PUBLICATIONS ...................................................................................................64
18.
REFERENCES.......................................................................................................65
19.
APPENDICES........................................................................................................68
Appendix A.
Eastern Cooperative Oncology Group (ECOG) Performance Status...................68
&(/*(1(35235,(7$5<,1)250$7,21
3
.......64
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
14
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 ....................................................42
Table 5:
Eastern Cooperative Oncology Group (ECOG) Performance Status........................68
&(/*(1(35235,(7$5<,1)250$7,21
2
......68


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
15
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25
&(/*(1(35235,(7$5<,1)250$7,21


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
16
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
17
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
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CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
19
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
20
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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, subjects 
with NPC were enrolled and received CC-486 as monotherapy. The ongoing Part 2 of the trial
included an NPC expansion cohort of up to 11 subjects, of which 5 are enrolled. Two subjects 
have shown a partial response (PR) [1 not yet confirmed], and 3 subjects are ongoing and too 
early to be evaluated for tumor response. Although the subject reportedly progressed quickly 
after showing the initial confirmed PR, the results are encouraging as the subject had received 2 
prior anticancer regimens and remained on CC-486 treatment for 370 days.
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 trial
with durable responses. 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).
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
21
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
!
Promoter hypermethylation is a major mechanism for inactivation of critical tumor 
suppressor genes (p16,RASSF1A) (Lo, 2013).
!
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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86 as
86 as a a sin
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
22
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
23
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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
!
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
24
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
25
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 Trial (as defined in Section 4.3), whichever occurs 
earlier.
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
26
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
5.
TABLE OF EVENTS
Table 1:
Table of Events
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
27
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
Physical examination (source 
documented only)
X
X
---
X
X
X
---
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
---
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
28
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
---
BIOMARKER AND PK ASSESSMENTS
HBV and HCV titers (for subjects of 
A-P ethnicity only)
X
---
---
---
---
X
---
Tumor biopsy* (for Biomarkers) 
Xk,l
Xk,l
---
X
---
---
PK blood draws sampling
---
X**
X**
---
---
---
---
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
---
---
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Cycle 1 Da
disease prog
disease pro
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f consent
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5<
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7$
PK ASSES
PK ASSES
(7$
7$
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INVESTIG
52
52
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
29
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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.
*
Refer to Section 6.5, Table 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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
30
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
31
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 trial, 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)
!
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)
!
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. 
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Appendix A
Appendix A
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12-
2-lead
lead
!
Re
Re


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
!
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
!
HBV and HCV titers (Asian-Pacific ethnicity subjects only)
!
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.
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
33
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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
!
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.
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
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as possibl
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ects shoul
will be per
will be pe
xaminat
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igns
igns
ncomitant
comitant
Concomi
Concom
!
ECO
EC
!


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
34
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
!
HBV and HCV titers (Asian-Pacific ethnicity subjects only)
!
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.
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
35
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 
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
e
nse 
nse
weeks.  
weeks.  
sidered as S
sidered as
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.
y y only)
only) at 
at
s, and ship 
and ship
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Asian-Pacif
Pac
1-day
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n addit
additioiona
na
ose is escala
se is escala
d 14), subje
14), sub
licable
licable taki
ta
dose assessm
dose asses
me time of d
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d appropria
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dose) and o
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3, 3.5, 4, 6
3, 3.5, 4, 6
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
36
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase (Continued)
Nominal Times
Acceptable Deviation Window
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 
be assessed for Stage 1 subjects only.
 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
37
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
 
 
 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 
the 72-hour timeframe). She must agree to ongoing pregnancy testing during the 
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poorly
poorly
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range, or co
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hil count 
hil count ≥ ≥
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109 cells
cells
≥ 9 g/dL
≥ 9 g/dL
childbearin
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
39
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
6. Subject has persistent diarrhea or malabsorption ≥ National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2, despite medical 
management.
                                               
* 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
40
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.).
11. Subject has had major surgery within 14 days prior to starting IP or has not recovered 
from major side effects.
12. Subject has received another investigational therapy within 28 days or 5 half lives of 
randomization/enrollment, whichever is shorter.
13. Subject has not recovered from the acute toxic effects of prior anticancer therapy, 
radiation, or major surgery/significant trauma.
14. 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.
15. Subject is pregnant or breast feeding.
16. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
17. 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.
18. Subject has any condition that confounds the ability to interpret data from the study.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
∀
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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, 
reintroduce CC-486 at 200 mg.
If event recurs after re-challenge at 200 mg, 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, reintroduce CC-486 at 200 mg.
If event recurs after re-challenge at 200 mg, 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).
8.3.
Method of Treatment Assignment
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will receive CC-486.
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3


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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.
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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Concomita
Concom


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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 
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.
1.1.1
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51
51 s


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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.
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
49
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
50
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
!
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
51
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
52
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 
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pregnancie
male subject
male subject
1.4.1.
1.4.1.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
53
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
54
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
55
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
56
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
57
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
58
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
59
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
60
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
61
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
62
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
!
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
63
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
64
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
65
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
18.
REFERENCES
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patients. J Surg Oncol 1986;33:194-197.
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American Cancer Society: Nasopharyngeal Cancer. September 23, 2013. Available at : 
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is-nasopharyngeal-cancer. Accessed February 26, 2014.
Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced nasopharyngeal 
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Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastatic nasopharyngeal 
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Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic 
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Jacobs C, Lyman G, Velez-Garcia E, et al. A phase III randomized study comparing cisplatin 
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Kenney SC, Mertz JE. Regulation of the latent-lytic switch in Epstein-Barr virus. Semin Cancer 
Biol 2014;26:60-68. Available at: http://dx.doi.org/10.1016/j.semcancer.2014.01.002.
&(
th
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atat-
753 patient
753 patien
haryngeal
haryngeal
HNS
NS-ESMO
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. Ann Onco
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demethylat
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et al. Mul
M ti
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carcino
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dy. J Clin 
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Leong SS, 
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pe.
y
Ann
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
66
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Koutcher L, Lee N, Zelefsky M, et al. Reirradiation of locally recurrent nasopharynx cancer with 
external beam radiotherapy with or without brachytherapy. Int J. Radiat Oncol Biol Phys 
2010;76:130-137.
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Sham JS, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases 
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Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma; orderly neck node spread. Int J Radiat 
Oncol Biol Phys 1990;19:929-933.
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Tierney R, Kirby H, Nagra J, et al. The Epstein-Barr virus promoter initiating B-cell 
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ta VT
a VT
Cell Physio
ell Phys
l
etreated pat
reated 
2.2.
s specifical
specifical
2013;104:1
013;104
sponse crit
sponse cri
:649
:649-655.
-655.
ognostic in
ognostic in
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9:1535-15
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n of Eps
oposit
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ylat
ylatioion of th
n o
0-4484.
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 D, et al.
D, et al. P
ated prom
ated prom
YK, Cho
K, Choy y D
geal carcin
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D, Wei
Wei
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WCT, Tsao
WCT, Tsao
als J 1989;
ls J 1989;
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Simo
m n R.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
67
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
Thompson LD. Update on nasopharyngeal carcinoma. Head Neck Pathol 2007;1:81-86.
Vikram B, Strong EW, Shah JP, et al. Intraoperative radiotherapy in patients with recurrent head 
and neck cancer. Am J Surg 1985;150:485-487.
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patients with advanced nasopharyngeal carcinoma after the failure of platinum-based 
chemotherapy. Cancer Chemother Pharmacol 2008;61:33-38.
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microarray reveals the aberrant methylation mechanism involved in nasopharyngeal carcinoma 
taxol resistance.  Anticancer Drugs 2012b;23:856-864.
Zhang Z, Chen F, Kuang H, et al. Epigenetics of nasopharyngeal carcinoma. In: Chen SS, ed. 
Carcinogenesis, Diagnosis, and Molecular Targeted Treatment for Nasopharyngeal Carcinoma. 
Intech Open; ISBN:978-953-307-867-0;2012a:1-27.
&(/*(1(35235,(7$5<,1)250$7,21
ma 
ma
n SS, ed. 
n SS, ed. 
l Carcino
Carcinom


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
68
CC-486-NPC-001 Amendment 1 Final: 01 October 2014
19.
APPENDICES
Appendix A. Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Table 5:
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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Prot_000.pdf: 
 
 
 
 
 
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 
Original Protocol Date:  11 July 2014 


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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
1
CC-486-NPC-001 Final: 11 July 2014
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
DATE FINAL:
11 July 2014
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.
ided to you as
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
2
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
3
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
4
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
5
CC-486-NPC-001 Final: 11 July 2014
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
6
CC-486-NPC-001 Final: 11 July 2014
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.
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.
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
7
CC-486-NPC-001 Final: 11 July 2014
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 
Trial, whichever occurs earlier.
The End of Trial 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.
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 
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
8
CC-486-NPC-001 Final: 11 July 2014
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, 
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
9
CC-486-NPC-001 Final: 11 July 2014
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
10
CC-486-NPC-001 Final: 11 July 2014
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 Trial ............................................................................................................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............................................................................................33
6.3.1.
Assessment of Response According to RECIST Version 1.1...................................33
6.3.1.1.
Other Assessments..................................................................................................34
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
11
CC-486-NPC-001 Final: 11 July 2014
6.4.
Pharmacokinetics....................................................................................................34
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase ................................................35
6.5.
Biomarkers .............................................................................................................35
7.
STUDY POPULATION.........................................................................................36
7.1.
Number of Subjects and Sites .................................................................................36
7.2.
Inclusion Criteria....................................................................................................36
7.3.
Exclusion Criteria...................................................................................................37
8.
DESCRIPTION OF STUDY TREATMENTS........................................................39
8.1.
Description of Investigational Product(s)................................................................39
8.2.
Treatment Administration and Schedule .................................................................39
8.2.1.
Tolerability Determination in Asian-Pacific Island Ethnicity ..................................39
8.2.2.
Dose Adjustment Guidelines...................................................................................40
8.2.3.
Missing Doses ........................................................................................................41
8.2.4.
Overdose ................................................................................................................41
8.3.
Method of Treatment Assignment...........................................................................41
8.4.
Packaging and Labeling..........................................................................................41
8.5.
Investigational Product Accountability and Disposal ..............................................42
8.6.
Investigational Product Compliance........................................................................42
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................43
9.1.
Permitted Concomitant Medications and Procedures...............................................43
9.2.
Prohibited Concomitant Medications and Procedures..............................................43
9.3.
Required Concomitant Medications and Procedures................................................43
10.
STATISTICAL ANALYSES..................................................................................44
10.1.
Overview................................................................................................................44
10.2.
Study Population Definitions ..................................................................................44
10.3.
Sample Size and Power Considerations...................................................................44
10.4.
Background and Demographic Characteristics........................................................45
10.5.
Subject Disposition.................................................................................................45
10.6.
Efficacy Analysis....................................................................................................45
10.7.
Safety Analysis.......................................................................................................45
10.8.
Interim Analysis .....................................................................................................46
10.9.
Assessment of Pharmacokinetics ............................................................................46
10.10.
Other Topics...........................................................................................................46
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-NPC-001 Final: 11 July 2014
11.
ADVERSE EVENTS..............................................................................................47
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................47
11.2.
Evaluation of Adverse Events.................................................................................47
11.2.1.
Seriousness.............................................................................................................47
11.2.2.
Severity / Intensity..................................................................................................49
11.2.3.
Causality ................................................................................................................49
11.2.4.
Duration .................................................................................................................50
11.2.5.
Action Taken..........................................................................................................50
11.2.6.
Outcome.................................................................................................................50
11.3.
Abnormal Laboratory Values..................................................................................50
11.4.
Pregnancy...............................................................................................................50
11.4.1.
Females of Childbearing Potential: .........................................................................50
11.4.2.
Male Subjects.........................................................................................................51
11.5.
Reporting of Serious Adverse Events......................................................................51
11.5.1.
Safety Queries ........................................................................................................52
11.6.
Expedited Reporting of Adverse Events..................................................................52
12.
DISCONTINUATIONS .........................................................................................54
12.1.
Treatment Discontinuation......................................................................................54
12.2.
Study Discontinuation ............................................................................................54
13.
EMERGENCY PROCEDURES.............................................................................55
13.1.
Emergency Contact.................................................................................................55
13.2.
Emergency Identification of Investigational Products .............................................55
14.
REGULATORY CONSIDERATIONS...................................................................56
14.1.
Good Clinical Practice............................................................................................56
14.2.
Investigator Responsibilities ...................................................................................56
14.3.
Subject Information and Informed Consent.............................................................56
14.4.
Confidentiality........................................................................................................57
14.5.
Protocol Amendments.............................................................................................57
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................57
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................58
14.8.
Closure of the Study ...............................................................................................58
15.
DATA HANDLING AND RECORDKEEPING.....................................................59
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7


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CC-486-NPC-001 Final: 11 July 2014
15.1.
Data/Documents .....................................................................................................59
15.2.
Data Management...................................................................................................59
15.3.
Record Retention....................................................................................................59
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................61
16.1.
Study Monitoring and Source Data Verification......................................................61
16.2.
Audits and Inspections............................................................................................61
17.
PUBLICATIONS ...................................................................................................62
18.
REFERENCES.......................................................................................................63
19.
APPENDICES........................................................................................................66
Appendix A.
Eastern Cooperative Oncology Group (ECOG) Performance Status...................66
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
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14
CC-486-NPC-001 Final: 11 July 2014
LIST OF TABLES
Table 1:
Table of Events.......................................................................................................26
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase..........................................................................................34
Table 4:
Dose Adjustments and Dose Delays for Toxicity ....................................................40
Table 5:
Eastern Cooperative Oncology Group (ECOG) Performance Status........................66
&(/*(1(35235,(7$5<,1)250$7,21
0
......66


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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CC-486-NPC-001 Final: 11 July 2014
LIST OF FIGURES
Figure 1:
Study Design ..........................................................................................................25
&(/*(1(35235,(7$5<,1)250$7,21


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CC-486-NPC-001
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CC-486-NPC-001 Final: 11 July 2014
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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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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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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CC-486-NPC-001 Final: 11 July 2014
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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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, subjects 
with NPC were enrolled and received CC-486 as monotherapy. The ongoing Part 2 of the trial
included an NPC expansion cohort of up to 11 subjects, of which 5 are enrolled. Two subjects 
have shown a partial response (PR) [1 not yet confirmed], and 3 subjects are ongoing and too 
early to be evaluated for tumor response. Although the subject reportedly progressed quickly 
after showing the initial confirmed PR, the results are encouraging as the subject had received 2 
prior anticancer regimens and remained on CC-486 treatment for 370 days.
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 trial
with durable responses. 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).
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!
Promoter hypermethylation is a major mechanism for inactivation of critical tumor 
suppressor genes (p16,RASSF1A) (Lo, 2013).
!
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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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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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.
3.2.
Secondary Endpoints
The secondary endpoints include:
!
Overall survival (OS) defined as the time from first treatment to death by any cause
!
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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CC-486-NPC-001 Final: 11 July 2014
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.
ioio
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CC-486-NPC-001 Final: 11 July 2014
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 Trial (as defined in Section 4.3), whichever occurs 
earlier.
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
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.
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5.
TABLE OF EVENTS
Table 1:
Table of Events
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
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27
CC-486-NPC-001 Final: 11 July 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
Physical examination (source 
documented only)
X
X
---
X
X
X
---
Weight
X
X
---
X
X
X
---
Height
X
---
---
---
---
---
---
Vital signse
X
X
---
X
X
X
---
Hematology laboratory
X
X
X
X
X
X
---
Chemistry laboratory
X
X
---
X
X
X
---
Epstein-Barr Virus-DNA [by RT-PCR] 
in All Subjects
X
X
---
X
X
---
---
Coagulation (Baseline only)
X
---
---
---
---
---
---
Urinalysisf
X
X
---
X
X
X
---
12-lead electrocardiogram
X
---
---
---
---
X
---
Serum β-hCG (for all FCBP)g
X
---
---
---
---
X
---
Urine β-hCG (for all FCBP)g
X(w/in72 hours)
X
---
X
X
X
---
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28
CC-486-NPC-001 Final: 11 July 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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
ECOG performance status
X
X
---
X
X
X
---
BIOMARKER AND PK ASSESSMENTS
Plasma for Epstein-Barr Virus-DNA 
Xh
Xh
---
X
(Xi), C3, 5, 
and 7 only
---
HBV and HCV titers (for subjects of 
A-P ethnicity only)
X
---
---
---
---
X
---
Tumor biopsy* (for Biomarkers) 
Xh,j
Xh,j
---
X
---
---
PK blood draws sampling
---
X**
X**
---
---
---
---
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
---
---
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X**
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CC-486-NPC-001 Final: 11 July 2014
Table 1:
Table of Events (Continued)
Screening 
Period
Treatment Perioda
Follow-up Period
Events
Screening
Cycle 1 
Cycle 2
Subsequent 
cycles
Day
-21 to -1
1b
14
1
1
EOT
Disease 
Progression/ 
Survival
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.
*
Refer to Section 6.5, Table 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 Urinalysis (a urine dipstick may be used) at screening and D1 of each cycle if abnormal at baseline.
g 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.
h Sample can be collected during screening or pre-dose Cycle 1 Day 1; being done in Stage 1 subjects only. [STRONGLY encouraged/recommended]
i Sample is collected at Cycle 3 Day 1, Cycle 5 Day 1, and Cycle 7 Day 1; being done in Stage 1 subjects only. [STRONGLY encouraged/recommended]
j Archival FFPE sample can be submitted for the screening or pre-dose Cycle 1 Day 1 timepoint.
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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 trial, 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)
!
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)
!
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 1.1 performed ≤ 28 days before the first dose 
need not repeat scans for the purposes of screening
!
Complete blood count (CBC) with differential, including but not limited to red blood 
cell (RBC) count, hemoglobin, hematocrit, white blood cell (WBC) count, absolute 
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Appendix A
Appendix A
!
12-
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Re
Re


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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
!
HBV and HCV titers (Asian-Pacific ethnicity subjects only)
!
Plasma for Epstein-Barr Virus-DNA (Stage 1 subjects only; refer to Section 6.5): 
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.
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 
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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
!
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)
!
Plasma for Epstein-Barr Virus-DNA (Stage 1 subjects only)
!
ECOG Performance status (Oken, 1982) see Appendix A
!
IRT for IP accountability
!
Adverse event evaluation (continuously)
!
Response assessment/tumor evaluation (see Section 6.3)
!
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.
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
!
HBV and HCV titers (Asian-Pacific ethnicity subjects only)
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!


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!
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.
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
34
CC-486-NPC-001 Final: 11 July 2014
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 
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
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
35
CC-486-NPC-001 Final: 11 July 2014
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase (Continued)
Nominal Times
Acceptable Deviation Window
3 hr
± 3 min
3.5 hr
± 3 min
4 hr
± 3 min
6 hr
± 20 min
8 hr
± 20 min
6.4.1.
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 
be assessed for Stage 1 subjects only.
 
 
 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
36
CC-486-NPC-001 Final: 11 July 2014
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 1.1.
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 
the 72-hour timeframe). She must agree to ongoing pregnancy testing during the 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
37
CC-486-NPC-001 Final: 11 July 2014
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.
6. Subject has persistent diarrhea or malabsorption ≥ National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Grade 2, despite medical 
management.
                                               
* 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-NPC-001 Final: 11 July 2014
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.).
11. Subject has had major surgery within 14 days prior to starting IP or has not recovered 
from major side effects.
12. Subject has received another investigational therapy within 28 days or 5 half lives of 
randomization/enrollment, whichever is shorter.
13. Subject has not recovered from the acute toxic effects of prior anticancer therapy, 
radiation, or major surgery/significant trauma.
14. 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.
15. Subject is pregnant or breast feeding.
16. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study.
17. 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.
18. Subject has any condition that confounds the ability to interpret data from the study.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
39
CC-486-NPC-001 Final: 11 July 2014
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 IP with approximately 240 mL (8 ounces) of room temperature water.  
Investigational product 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.
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 150 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;
∀
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;
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
40
CC-486-NPC-001 Final: 11 July 2014
∀
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 2 dose reductions will be allowed from the original dose. Except for those 
subjects starting at 200 mg, wherein only one dose reduction is permitted after Cycle 1.
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 50 mg
Delay > 14 days, permanently discontinue from study
Grade 3* neutropenia or thrombocytopenia 
causing delay to the planned start of a Cycle 
ANC 0.5-0.99 x 109/L
Platelets 25-49 x 109/L
Hold CC-486 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 50 mg
No recovery by 14 days, permanently discontinue from 
study
Grade 4* neutropenia or thrombocytopenia 
causing delay to the planned start of a Cycle
ANC < 0.5 x 109/L
Platelets < 25 x 109/L
For ANC < 0.5 x 109/L
The initiation of G-CSF is left at the 
Investigator’s discretion. If initiated administer 
G-CSF per institutional practice or package 
insert and continue until ANC recovers to ≥ 2.0 
x 109/L
Hold CC-486 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 50 mg
No recovery by 7 days, permanently discontinue from study
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
41
CC-486-NPC-001 Final: 11 July 2014
Table 4:
Dose Adjustments and Dose Delays for Toxicity (Continued)
Toxicity
Recommendation
Grade 3 or 4 non-hematologic toxicity or other 
Investigator defined unacceptable toxicity
Hold CC-486 until recovery to baseline
Recovery in ≤ 7 days, resume CC-486 at same dose
Recovery in 8-14 days, reduce CC-486 by 50 mg
No recovery by 14 days, withdraw from study
In case of recurrence of the Grade 3 or 4 toxicity, hold CC-
486 until recovery to baseline. Recovery in ≤ 7 days, reduce 
CC-486 by 50 mg. No recovery by 7 days, withdraw from 
study
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).
8.3.
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, 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
42
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
43
CC-486-NPC-001 Final: 11 July 2014
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.
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.
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
44
CC-486-NPC-001 Final: 11 July 2014
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.
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 
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.
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51 s


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
45
CC-486-NPC-001 Final: 11 July 2014
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.
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.
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 
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
46
CC-486-NPC-001 Final: 11 July 2014
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
47
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
48
CC-486-NPC-001 Final: 11 July 2014
!
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
49
CC-486-NPC-001 Final: 11 July 2014
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.
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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
50
CC-486-NPC-001 Final: 11 July 2014
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 
icable
able
comit
mitant
ant
AEs.
AEs.
parti
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covered or d
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AE
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ant clini
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aborato
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y s one co
s one
recorded o
recorded o
r syndro
syndrome
m
ratory
ratory abno
abno
y
ratory
atory resu
res
y
Pregna
Pregn
pregnancies
pregnancie
male subject
male subject
1.4.1.
1.4.1.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
51
CC-486-NPC-001 Final: 11 July 2014
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 
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CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
52
CC-486-NPC-001 Final: 11 July 2014
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 trials 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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
53
CC-486-NPC-001 Final: 11 July 2014
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
54
CC-486-NPC-001 Final: 11 July 2014
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.
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CRF and i
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CC-486-NPC-001
Celgene Corporation
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55
CC-486-NPC-001 Final: 11 July 2014
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
56
CC-486-NPC-001 Final: 11 July 2014
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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
57
CC-486-NPC-001 Final: 11 July 2014
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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('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
58
CC-486-NPC-001 Final: 11 July 2014
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.
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ta collect
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protocol
protocol.


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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
59
CC-486-NPC-001 Final: 11 July 2014
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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List of
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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
60
CC-486-NPC-001 Final: 11 July 2014
!
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.
e
ities.
ties.
destr
destruction
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Celgene Corporation
Confidential and Proprietary
61
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16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative
for compliance with applicable government regulations with respect to current GCP and 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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CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
62
CC-486-NPC-001 Final: 11 July 2014
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


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Celgene Corporation
Confidential and Proprietary
63
CC-486-NPC-001 Final: 11 July 2014
18.
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is-nasopharyngeal-cancer. Accessed February 26, 2014.
Baujat B, Audry H, Bourhis J, et al. Chemotherapy in locally advanced nasopharyngeal 
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Bensouda Y, Kaikani W, Ahbeddou N, et al. Treatment for metastatic nasopharyngeal 
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Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;(21 Suppl 
5):v187-189.
Chan AT, Tao Q, Robertson KD, et al. Azacitidine induces demethylation of the Epstein-Barr 
virus genome in tumors. J Clin Oncol 2004;22:1373-1381.
Chua D, Wei WI, Sham JS, et al. Capecitabine monotherapy for recurrent and metastatic 
nasopharyngeal cancer. Jpn J Clin Oncol 2008;38:244-249.
Chua DT, Sham JS, Au GK. A phase II study of capecitabine in patients with recurrent and 
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2003;39:361-366.
Ciuleanu E, Irimie A, Ciuleanu TE, et al. Capecitabine as salvage treatment in relapsed 
nasopharyngeal carcinoma: a phase II study. J BUON 2008;13:37-42.
Dugan M, Choy D, Ngai A, et al. Multicenter phase II trial of mitoxantrone in patients with 
advanced nasopharyngeal carcinoma in Southeast Asia: an Asian-Oceanian Clinical Oncology 
Association Group Study. J Clin Oncol 1993;11:70-76.
Foo KF, Tan EH, Leong SS, et al. Gemcitabine in metastatic nasopharyngeal carcinoma of the 
undifferentiated type. Ann Oncol 2002;13:150-156.Garcia-Manero G, Gore SD, Cogle C, et al.  
Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic 
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19.
APPENDICES
Appendix A. Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Table 5:
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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