Clinical trial NCT02269943
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
Sponsor: Celgene
Start date: 2015-02-13; Completion date: 2017-04-20
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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 documents:
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 


',6&/2685(
5('$&7('67$7,67,&$/$1$/<6,63/$1
&&13&
$3+$6(08/7,&(17(5,17(51$7,21$/6,1*/($50678'<72$66(66
7+(6$)(7<$1'()),&$&<2)6,1*/($*(17&&25$/$=$&,7,',1(
,135(9,286/<75($7('68%-(&76:,7+/2&$//<$'9$1&('25
0(7$67$7,&1$623+$5<1*($/&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,
ILIL
5,(7$5<,1)250$7,21
6
1(
1(
5
5
RWEHVKDUHG
RWEHVKDUHG
FKHUVDQGSD
KHUVDQ
JXO
JXODWLRQVUH
DWLRQVU
DORUF
RUFRQWUDF
RQWUDF
WRFHUWDLQSD
FHUWDLQS
DLQLQIRUPDW
LQLQIRUPDW
&HOJHQH¶VF
&HOJHQH¶V
SULQFLSOHV
SULQFLSOHV
H\ VSDFHPD
VSDFHPD
FDWLRQRIL
FDWLRQRIL
QFRQILGHQ
FRQILG
WLD
WL
DLQLGHQWLILD
LQLGHQWLI
OVRPD\FRQ
OVRPD\FRQ
LVJHQHUDWLQ
VJHQHUDWL
DWWDFKPHQWV
WWDFKPHQ
RIWKHUHSR
RIWKHUH
W&HOJHQHY
&HOJHQHY
KDWLQIRUPDW
KDWLQIRUPD
DERXWRXUY
DERXWRXU
RQDERXW&H
DERXW&H
QGDWKWWSZ
QGDWKWWSZ


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.
&(/*(1(35235,(7$5<,1)250$7,21
half o
alf of
ene Corpor
ne Corpor
86 Morris
86 Morris
Summ
um
mation con
ation con
cept to the e
cept to the 
sclosed to a
sclosed to a
regulati
regulati
infor
nfor
35
35
&(
&(
&(
&(
&(


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
&(/*(1(35235,(7$5<,1)250$7,21
11
11
........11
11
............
............11
1
..............
.............
.............
.........
.............
.....
..............
..........
.............
...........
.............
............
....
... ..........
...
ATIONS
ATIONS
..........
....... ...
..............
.............
.............
..........
..............
...........
Populat
Populatioion
c Populat
 Populatio
ISPOSITI
ISPOSI
COL DEV
OL DEV
MOGRAPH
MOGRAPH
Dem
Demograph
ograp
Can
Cancer
ce
Me
Me
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
2
.......22
2
..........
.... 22
2
..............
...........
..............
............
.............
.............
..............
............
.............
.............
Status
Statu ...
..............
...........
.............
.............
.............
............
.............
..........
.............
..........
atioions
ns.....
ry, Urinaly
, Urinaly
s-DNA me
DNA m
easurement
easurement
Examinat
Examinatio
rocardiogra
rocardiogra
HARMAC
ARMAC
Pl
P asma c
asma 
Phar
Ph
2.3.
2.3.
13.3.


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
&(/*(1(35235,(7$5<,1)250$7,21
..41
4
.............
............41
4
.............
............
..............
.........
..............
........
.............
.............
..............
...........


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


0$7
(1




35,
3523


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
&(/*(1(35235,(7$5<,1)250$7,21
guanine sepa
uanine sep
mography
mography
Terminology
erminology
e control rat
contro
os
ose limiting
e limitin
deoxyrib
eoxyrib
Eps
E
e
F
IP


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
&(/*(1(35235,(7$5<,1)250$7,21
aluation Cri
luation Cri
promoter
promoter
time
im -polym
polym
sererious ad
ious a
Statis
Statis
DEV
EV
TEAE
TEAE
L


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
&(/*(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
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. 
&(/*(1(35235,(7$5<,1)250$7,21
fetyty.
urpose of th
urpose of th
cal approac
al approa
ed prior to 
d prior t
in this SAP
in this SAP


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 
 
 
&(/*(1(35235,(7$5<,1)250$7,21
of CC
of CC-
s.s
)25
1)


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, 
&(/*(1(35235,(7$5<,1)250$7,21
2
erall
eral
on’s 
n’s 
e response
e response
on indepen
on indepen
34 efficacy
34 efficacy
enrollment
nrollment
ge 2 decisio
e 2 decis
will be repl
ll be repl
udy pri
y
or t
r to
re not evalu
re not ev
are not eva
are not eva
will be per
will be per
ompleted w
ompleted w
ity y cri
criteria
teria
i
For all subse
r all subs
re 21 day
re 21 days
less otherw
ess otherw
QD) 
D) on Da
on D
nicit
nic y eval
eva
to14 of 21 
14 of 2
uent subject
uent subjec
of a 21
of a 21-da
d
Assessmen
Assessmen
se assessm
se assessm
e the start 
e the start
C1
C1D1)
D1) fofor t
r t
of
of a new a
ew 
f
spon
spon


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.
&(/*(1(35235,(7$5<,1)250$7,21
cts
cts
to
will be
will be
gning
gnin ICF
ICF
wn to the I
wn to the I
llected.
ected.
eatment fo
atment fo
drawal of c
awal of 
and subseq
and subs
cts wil
cts will l be 
be 
h, or lost
h, or lost-tot
ted at the s
ed at the s
stemic or l
temic or lo
ect’s cance
ct’s cance
by record re
record r
y
family
amily, o
, or th
r
f enrolled su
f enrolled s
ced sites tha
ced sites tha
te in PK
in PK sam
 administer
administe
in the PK s
n the PK 
thnicit
thnicity y w
on.n
K day
K day (i(i
y
e, C
e
uired overn
uired overn
co
comp
mplet
leting
ing
iven at app
iven at app
Bl
Blood sa
ood 
mi


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 
&(/*(1(
ratificatio
atificat
cable for thi
ble for th
Sam
Sam
The sample
The sample
Popul
opulata i
nt
( 35235,(7$5<,1)250$7,21
m
death by
death by an
a
y
e of CR an
of CR
nse are first
nse are first
ment, based
ment, base
ergent 
rgent AEs
AEs
ial interest,
l interes
of Asian
of Asian-Pa
P
23
52
352
( 3
1(


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.
&(/*(1(35235,(7$5<,1)250$7,21
ll be
l be
as s 
ess specif
ess speci ie
f
e of 
of subject
subj
e sam
e sample si
ple si
m
artiles,
artiles, min
m
o one more
one more
ll be forma
l be form
decimal po
ecimal poi
form XX (X
orm XX (X
ables will h
bles will 
e column h
e column
ort
orted for pr
ed for pr
dure or eve
dure or eve
e first dose
e first do
le starts wi
e starts w
cle is the d
cle is the d
mber for ea
mber for e
window set
window set
before
before st
!
For 
For
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. 
&(/*(1(35235,(7$5<,1)250$7,21
duled 
uled
erative
ative
on-treatm
treatmen
e
st dose dat
t dose da
package u
package
es.s.
ere
ere enrolle
enrol
s who 
who rece
rece
ulation
ulation
on n include
include
2 cycles of
cles
sease, OR 
sease, OR
at least 
t least 4 4 cy
cy
reening tum
reening tu
eceiving the
ceiving the
criteria.
criteria. Su
Su
iscret
scretioion o
n o
5.2.4.
5.2.4
e P


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. 
&(/*(1(35235,(7$5<,1)250$7,21
rvival
vival
e subject 
subjec
led
ed under e
under e
didiscont
scontinu
inu
ation
on inclu
inc


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 
&(/*(1(35235,(7$5<,1)250$7,21
ne
ne
ues. 
ues. 
y,y, ECOG
ECOG
at baseline
at baseline
ript
riptive
ive
CR
CR])) 
])) at ba
at b
Informed C
formed
ht in kg)
ht in 
0.42
0.42
e fo
e follo
llowin
wi
vanced
anced, met
me
 I, II
, II, III, IV
III I
nitial diagn
ial diagn
N1, N2, N3
N1, N2, N3
o prior thera
prior the
agnosis to
gnosis to f
summarize
summarize
Medical H
Medical H
mmary
mar of
of
y
rere
ivit
vities
es (Me
(Me
popul
opulatatioion
3


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. 
&(/*(1(35235,(7$5<,1)250$7,21
will be co
will be co
ctioionary
nary an
Chemical co
hemical co
elevant cate
evant ca
ions will b
ns w
pri
prior to the
or to the
ber and per
ber and pe
eneric
eneric drug
drug
medicat
edication
io
ns
ns
ned as
ned as a a m
during the
during th
thin
thin 28
28 day
resen
resented sh
ted s
n
catatioions
ns by 
by 
rcentage of
rcentage of
Concom
Concom
nco
comit
mitant 
ant
bove
bove. A sum
. A sum
concomit
oncomit


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.
&(/*(1(35235,(7$5<,1)250$7,21
ment end da
ent end d
he treatm
treatmen
ded.d. Descrip
escri
received
eceived an
a
tal number 
al numbe
f all
all admin
adm
mg
mg/day
day wil
wi
ys which
ch is
age Daily
age Daily
y dose (m
dose (m
y
g/g
m
Rela
Re
Relative dos
Relative do
x 100.
100. Th
Th
6 at
6 t


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
&(/*(1(35235,(7$5<,1)250$7,21
y
ose basis,
ose basis,
ssigned to a
ssigned to 
requent tha
requent th
ows:
ws:
ose reducti
se reduct
ian, STDEV
ian, STDE
t reduction
t reductio
with at lea
with at lea
errupti
erruption
on
f subjects w
f subjec
ose
ose int
i erru
err
cs (sample
cs (samp
d maxim
d maximu
m


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).
&(/*(1(35235,(7$5<,1)250$7,21
nfirmed no
nfirmed no
radio
radiolology
gy a
y
than
than 14 re
4 r
e ORR will
ORR will
be provide
be provide
adio
diolology
gy a
y
the time fr
the time fr
th (any cau
th (any cau
urs earlier. S
s earlier. 
utut-off date
off date
utut-off date.
off da
ented progr
ented pro
ere the subj
ere the su
ncer
cer th
thera
era
ented disea
nted dise
c assessme
c assessm
radio
adiolologigic
 censored a
censored a
o be progre
be progr
an-Meier (
Meier (
wo
wo-sid
s ed 9
ed 9
pothesis te
othesis te
intnterval
val w
l
sea


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.
&(/*(1(35235,(7$5<,1)250$7,21
ment 
nt will
will
ont
ontinuat
inuatioio
ly. 
y. List
Listings
ing
ce Status
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
&(/*(1(35235,(7$5<,1)250$7,21
All
All
on the CRF
on the CRF
ty of AEs 
AEs
f
AEs not de
AEs not de
1), modera
), mo
xperiencing
xperienci
each of the 
ach of the
h Incidence
Incidence
h
s
r 4
r 4
d d TEAEs
TEAEs G
(1(
by maximu
(1
nt relate
ious TEAE
ous TEAE
All
Al seri
eriou
ou
TEAEs
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
&(/*(1(35235,(7$5<,1)250$7,21
an once wit
n once wit
“by
by maxim
maxi
he sam
same SO
SO
ition, AEs 
on, AEs
itity catego
y categ
T, and SO
and SO
TEAEs, TE
TEAEs, TE
l be listed 
l be listed
cial Inter
ial Inte
st
nterest refe
nterest refe
cal condit
l cond ioi
itioions (sear
ns (sea
cut
cut-off date
off dat
yelelosuppre
osuppre
myelosupp
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.
&(/*(1(35235,(7$5<,1)250$7,21
:
ameters (eg
ameters (e
rotocol
rotocol and
and
uable for s
uable for s
ed including
d includin
elected list
ected listi
atory Eva
atory Ev
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. 
&(/*(1(35235,(7$5<,1)250$7,21
lyly.
on Day
on Day 1 o
1 o
y
afet
afety y popul
pop
and maximu
and maxim
ne will be d
e will b
by normal 
by normal
be used to d
e used t
d.d.
asurement
asuremen
Range
Range (Uni
(Uni
,(
(mmHg)
(mmHg
5,
00, 140 (mm
00, 140 (m
3
60, 100 
60, 100 
2
5
[35,
[3
5
35
3
ical Ex
ical Exam
am
s fro
s from phy
phy
history
tory on t
on t
docum
document
ent
minat
minatio
&
n.n.
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:
&(/*(1(35235,(7$5<,1)250$7,21
c
the
the
m blood 
blood 
ulati
lation of
on of
ta for each
ta for each
mic scales
mic sca
re BLQ or 
re BLQ o
meters
eters. . An
A
clinical
clinical
ue
ue is ≤5%
5% 
5% of
of C
f
descri
descriptpt
i ive
iv
ssigned 
signed a a
file.
file. A BL
B
A
be
be evaluat
eval
ax, BLQ 
BLQ va
en
en calcula
calcula
of
of t
f he
he co
c l
g data.
ata. IfI c
erminal
ermin
po
po
K analysis
analysis
ion
ion-titime
me p
zero in the
ero in th
railing zero
ailing zero
sampling t
sampling t
derived usin
erived usin
.3, or hi
.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]. 
&(/*(1(35235,(7$5<,1)250$7,21
rved 
rved 
ersus t
ersus time
im
 t1/2
1/2 will on
wi
d. 
d. 
f]. 
]
f
s [(CL/F)/
(CL/F)/∃


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.
&(/*(1(35235,(7$5<,1)250$7,21
atio
ation of 
n of ∃z
on from th
from th
e provided.
e provided
number of s
umber of s
coefficient
oefficien
each
ach dose 
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
&(/*(1(35235,(7$5<,1)250$7,21
gn. . If 
If 
icacy
acy
cont
ontinue t
inue t
tudy
udy
included 
included in
d.d.
tage 1 inter
age 1 inter
fo
for r th
the enr
enr
latatioion
diolology
gy asse
asse
y
gator asses
gator asses
ure and do
ure and do
f f TEAEs
TEAEs b
ence of 
nce of TE
TE
ncidence o
ncidence 
! Incide
Incide
po
po


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.
&(/*(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
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.
&(/*(1(35235,(7$5<,1)250$7,21
-
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 
&(/*(1(35235,(7$5<,1)250$7,21
5235,(7$5<,1)250$7
35
l
$5
Positive if 
>14
R/P
otal  o
Me
> 5
5<,1
ag
 in Eff
luable set
Dates 
Dates
numeric va
numeric v
rmat (
mat (eg
eg, th
t
 the categ
the catego
tes.
es.
Procedur
Procedur
perform
perform
scan
sca
a


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. 
&(/*(1
t
(1(35235,(7$5<,1)250$7,21
ermine
mine
les if the
les if the
d they
d they i
y nclu
nclu
nd imputat
nd imputat
specific for
pecific
omitant M
omitant 
the first dos
the first do
ed to the m
ed to the m
of first dos
of first do
year of firs
year of firs
th and y
th and year
ing date w
ing date w
her the y
her the ye
years o
years of f th
the
date i
date is s b
assign
sign
!
IfIf


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
&(/*(1(35235,(7$5<,1)250$7,21
ds. 
ds. 
ate or
te or
d to the
to the
st dosing da
dosing d
ng date wil
ng date wi
f the last do
he last do
date are the
ate are t
last dosing
ast dosing
is not equ
not equ
the last dos
he last dos
e m
e month of
onth 
the missing
the mis
or Therap
or Therap
s purposes,
 purpose
h given (ie, 
h given (
ic day or m
c day or m
If the above
If the abov
or after the
or after the
ose date.
se date.
Advers
Adver
ially missin
ally missi
missing AE
missing AE
wi
with
ti
no m
no m
h
low
l


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. 
&(/*(1(35235,(7$5
y
5<,1)250$7,21
le
t fo
for m
r medic
edic
date that ha
ate that h
art date tha
art date tha
et. M
et. Missing
i
and missi
and missi
y

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 


',6&/2685(
5('$&7('35272&2/$0(1'0(17
&&13&
$3+$6(08/7,&(17(5,17(51$7,21$/6,1*/($50678'<72$66(66
7+(6$)(7<$1'()),&$&<2)6,1*/($*(17&&25$/$=$&,7,',1(
,135(9,286/<75($7('68%-(&76:,7+/2&$//<$'9$1&('25
0(7$67$7,&1$623+$5<1*($/&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,
ILIL
5,(7$5<,1)250$7,21
6
1(
1(
5
5
RWEHVKDUHG
RWEHVKDUHG
FKHUVDQGSD
KHUVDQ
JXO
JXODWLRQVUH
DWLRQVU
DORUF
RUFRQWUDF
RQWUDF
WRFHUWDLQSD
FHUWDLQS
DLQLQIRUPDW
LQLQIRUPDW
&HOJHQH¶VF
&HOJHQH¶V
SULQFLSOHV
SULQFLSOHV
H\ VSDFHPD
VSDFHPD
FDWLRQRIL
FDWLRQRIL
QFRQILGHQ
FRQILG
WLD
WL
DLQLGHQWLILD
LQLGHQWLI
OVRPD\FRQ
OVRPD\FRQ
LVJHQHUDWLQ
VJHQHUDWL
DWWDFKPHQWV
WWDFKPHQ
RIWKHUHSR
RIWKHUH
W&HOJHQHY
&HOJHQHY
KDWLQIRUPDW
KDWLQIRUPD
DERXWRXUY
DERXWRXU
RQDERXW&H
DERXW&H
QGDWKWWSZ
QGDWKWWSZ


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.
&(/*(1(3
ocol is provide
col is provide
( 35235,(7$5<,1)250$7,21
S 
S 
cit
citidine)
idine
001
001
14
tober
tobe 2014
01
April
April 201
2
23
23 Septe
Sep
2014
14
your staff, an
our staff, a
ocument is reg
cument is reg
may not 
may no
Persons
Perso
( 3
( 3
(/
(/
(


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: 
&(/*(1(35235,(7$5<,1)250$7,21
0
50
25
)2
er should o
r should
Medical M
Medic
enter:
enter:
$5
7$5


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.  
,1
,1)250$7,21
0$
0$
50
content to 
content to
,1


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.
&(/*(1(35235,(7$5<,1)250$7,21
0$
0$
50
s study
s study at m
at
y
, informed 
nformed
ocedures, i
edures, i
Good Clin
Good C
ct of clinica
of clinic
$5
$5


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.
&(/*(1(35235,(7$5<
5<
5<,1)
wi
wi
1)250$7,21
0$
0$
50
th
th
i
ICH G
ICH 
h
ghout the st
out the st
5<


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.
&(/*(1(35235,(
r, internat
r, interna io
ated
ated subjec
sub
 previous
previous
bjects will b
jects will
t (
t (> 4 respo
4 res
subjects
subjects ba
n addi
addititi
i on
on
t w
t willill be st
be st
dent Data M
dent Data M
s with expe
ith expe
who
whom are n
are n
MC will rev
MC will rev
be detailed
e detailed
tudy 
tudy
7$5<,1)250$7,21
inically or 
inically o
py
py.
CC
CC-486 in
4
(7$
,(7


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 
&(/*(1(35235,(7$5<,1)250$7,21
the
he
the
the
udy
udy have be
have
y
study
study and 
nd
y
ministered 
inistered 
wever, f
wever, for
f
dose of 200
ose of 200
verse even
verse ev
ministered t
ministered 
ogigic didisease
seas
l of
of
l
consen
consen
f
r tumor res
r tumor res
um
umors (RE
ors (RE
e tum
tumor ev
or ev
w ant
w anticance
anc
nts 
nts will
will inc
inc
f the head 
the head
f
vis, neurol
is, neurolo
or all subjec
all subjec
bone metas
bone metas
he fo
he follo
llow-
w-
urvival wil
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, 
&(/*(1(35235,(7$5<,1)250$7,21
h lolocally
cally
ous 
ous 
who recei
who recei
sed on the
sed on the
igibilit
ibility cri
y cr
nd discont
d discon
any
any dose in
dose 
y
ficient samp
ficient samp
20% or me
20% or m
first stage,
first stage
jects, enrol
jects, enrol
a total of 5
total of 5
responders
esponder
rejected.
rejected. T
when the tr
when the 
PFS is > 5 
PFS is > 
es will be p
es will be p
esis testing 
esis testing
and t
d two
wo-sisid
g for the PF
g for the PF
ed 90
90% CI
% CI
Safety An
Safety An
fet
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
&(/*(1(35235,(7$5<,1)250$7,21
7
....... 18
18
...........
.......... 19
1
.............
............
..............
............
.............
............
.............
.............
..............
.............
.............
.........
..............
...
..............
..........
.............
.............
..............
.............
.............
.......
.............
.........
..............
.............
..............
.........
EVENTS
VENT
URES
RES......
ment Perio
ment Perio
nd of Trea
nd of Trea
Fo
Follo
llow
.
Effi
Eff
.2.2.
.2.2
.3.
.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
&(/*(1(35235,(7$5<,1)250$7,21
7
.......38
3
..........
.... 40
4
..............
...........
..............
............
.............
.............
..............
............
.............
.............
.............
.....
Hepatit
epatitis B
is B
.............
.............
.............
............
ilitity y and D
and D
liance
liance.......
CATI
ATIONS 
ONS 
t Medicati
Medicati
mit
mitant Med
ant Me
comi
mitant M
tant M
i
ICAL ANA
CAL A
view
iew.......
.......
tudy
tudy Popul
Popu
y
Sam
Sample 
ple 
m
Bac
Ba
0.5.
0.5.
10.6.
0.6.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
12
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
10.10.
Other Topics...........................................................................................................50
10.10.1.
Independent Data Monitoring Committee (iDMC)..................................................51
11.
ADVERSE EVENTS..............................................................................................52
11.1.
Monitoring, Recording and Reporting of Adverse Events .......................................52
11.2.
Evaluation of Adverse Events.................................................................................52
11.2.1.
Seriousness.............................................................................................................52
11.2.2.
Severity / Intensity..................................................................................................54
11.2.3.
Causality ................................................................................................................54
11.2.4.
Duration .................................................................................................................55
11.2.5.
Action Taken..........................................................................................................55
11.2.6.
Outcome.................................................................................................................55
11.3.
Abnormal Laboratory Values..................................................................................55
11.4.
Pregnancy...............................................................................................................55
11.4.1.
Females of Childbearing Potential: .........................................................................55
11.4.2.
Male Subjects.........................................................................................................56
11.5.
Reporting of Serious Adverse Events......................................................................56
11.5.1.
Safety Queries ........................................................................................................57
11.6.
Expedited Reporting of Adverse Events..................................................................57
12.
DISCONTINUATIONS .........................................................................................59
12.1.
Treatment Discontinuation......................................................................................59
12.2.
Study Discontinuation ............................................................................................59
13.
EMERGENCY PROCEDURES.............................................................................60
13.1.
Emergency Contact.................................................................................................60
13.2.
Emergency Identification of Investigational Products .............................................60
14.
REGULATORY CONSIDERATIONS...................................................................61
14.1.
Good Clinical Practice............................................................................................61
14.2.
Investigator Responsibilities ...................................................................................61
14.3.
Subject Information and Informed Consent.............................................................61
14.4.
Confidentiality........................................................................................................62
14.5.
Protocol Amendments.............................................................................................62
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................62
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................63
&(/*(1(35235,(7$5<,1)250$7,21
2
.......54
5
..........
.... 54
5
..............
...........
..............
............
.............
.............
..............
............
.............
.............
.............
.....
..............
...........
.............
.............
.............
............
vents
vents......
......
.............
..........
n.............
....
.............
.........
ROCEDUR
ROCEDU
ontact
tact.....
cy
cy Identific
Identif
y
ULATORY
ULATORY
ood Clinic
od Clinic
Invest
Investig
Subj
Su
4.4.
4.4.
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
6
..........
.... 66
6
..............
...........
..............
............
.............
.............
ance Status
ance Stat


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


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


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
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.
asal
sal
the lungs.
the lungs.
upper surfa
upper surf
sa of 
sa of 
harynx abu
harynx abu
the m
the muscle
uscle
m
e pharyngea
haryng
an irre
n irregular
gula
system des
system d
mo
mon subt
n subty
in so
in some
me are
ar
ca are diag
a are dia
zing ty
zing type
pe
y
(A
btype.
btype.
heast Chin
heast Chin
Asia, North
sia, North
g immigran
g immigra
ot exactly u
ot exactly u
lude
ude th
the pr
e p
et ri
et rich in s
ch in s
PC cells
PC cells an
an
have high 
have high
tigens. The
igens. Th
severa
everal y
nes
nes


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 
&(/*(1(35235,(7$5<,1)250$7,21
ecludes ear
ecludes ea
disease
disease
, 1993
, 1993; Sha
Sh
lvement at
lvement at
s is to bone
is to bo
d rate in ax
d rate in a
herapy
herapy alal
y
on
ry f
y or resi
or resi
f
d
diatatioion the
n th
r the primar
r the primar
e retreated w
e retreated 
d radiation 
radiation
e site of re
e site of
e or local re
 or local r
py shoul
py should b
d
py
py remains 
remains
y
especially 
specially
stages (IIB
stages (IIB
ith local an
th local a
survival an
survival an
hs and 4
and 4 toto
%.
%. Isolated
Isolated
ar survival 
r survival 
plplatatinum
inum-b
ecomm
ecomm


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
es
es
c
the
he
l studies,
studies, 
can have
can have
and capeci
and capeci
months 
months (F
ang, 2008
ang, 2008)
008 and rep
008 and r
val o
val of f 12.8
12
ies, m
es
ostly
ostly
ucleoside cy
cleoside
sis and met
sis and m
d by the US
by the US
ish
sh (FAB) 
(FAB
proved by
proved b t
y
mia (A
mia (AML)
r hematopo
hematopo
 (IV
IV) or 
or su
ioav
oavailable
ailab
rati
ration into 
on into 
cts wi
ts with
ti  DN
 D
h
nance of DN
ance of DN
tic changes
change
ate the stab
ate the sta
st recogni
st recogniz
group to c
group to c
nd is a
nd is a


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 
&(/*(1(35235
n Solid
olid Tu
n combinat
n combinat
psed or ref
ed or ref
of this two
of this tw
ys 1 to 14 o
 1 to 14 o
AZA
ZA-ST
ST-0
-0
subjects re
ubjects re
300 mg w
300 mg w
itaxel was a
itaxel was 
ncountered
ncountered
nab-
na
pacli
pacli
com
com
5,(7$5<,1)250$7,21
ring 
ng 
aily
ily and tw
and tw
y
fashio
fashion. 
n. C
mulat
mulative ex
ive e
tely
ely 40%
40% an
espect
espectively
ivel
day
ay sc
sc
y
hed
h
being the m
being the m
n lelevelsls ini b
hypo
hypomet
methy
hy
ally act
ally active,
ve
.
5,(
35,


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).
&(/*(1(35235,(7$5<,1)250$7,21
aluable
uable
hers had 
hers had
in subjects
n subject
ovocative, 
ovocativ
ZA
Z -ST
ST-00
-0
The ongoin
he ongoin
PC subjects
PC subject
able diseas
able diseas
or NPC sub
or NPC sub
format
formation n
clinical stu
clinical stu
own promi
own promi
nefit
nefit. . CC
CC
out of 
t of 21-
2
d
ifying agen
ifying ag
n subjects w
n subjects w
orted
orted in the 
in the
Frequent w
Frequent w
!
Genet
Genetici
!
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.
&(/*(1(35235,(7$5<,1)250$7,21
e settings
settings.
21 day
21 days of 
s of
enia.
ia. Alt
A ho
edule may 
edule may 
al is
l 
design
desig
g daily for 
daily
g the dose t
g the dose 
owed for a
wed for a
who receive
who receive
couraging y
couraging 
single age
single ag


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
 
&(/*(1(35235,(7$5<,1)250$7,21
netetics
i
lected 
ected 
)25
1)


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
 
&(/*(1(35235,(7$5<,1)250$7,21
eri
eria a
dy
dy treatm
treatm
y
e
nse using
se using
eatment to 
tment to
isease (SD)
isease (SD
ntnt-emergen
emergen
-4 AEs,
4 AEs, Gr
G
atory abnorm
tory abno
86
86 inin a sub
su
ted si
ted sites
tes
i
oints
oint
352
35
( 3
(1(
*(1


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.
&(/*(1(35235,(7
d d 
(7$5<,1)250$7,21
nts s
n’s 
n s
ut of the fi
ut of the f
en
en th
the stud
e stud
es out of 17
es out of 17
will be
will be base
bas
bjects who 
ects wh
or. Subjects
Subject
y reason oth
reason ot
jects who p
ects w
ioion, or as d
n, or as
ST v1
ST v .1 init
i it
disease p
disease p
w-up
up. All su
. All 


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.
&(/*(1(35235,(7$5<,1)250$7,21
5,(7$5<,1)250$7
  
PFS
months  
1)
tm
tment is ex
ent is e
population
population
itori
tori
i
ng of 
ng o
ssio
ss
n (if ap
n (if 
r analysis, o
r analysi
nd of 
d of Stu
Stu
of Study
Study is
or the date
or the date
mary
mary, secon
, secon
Stati
Statistical
ical A
subjects
ubject


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
---
&(/
pri
prietet
(/*(1(35235,(7$5<,1)250$7,21
e Cor
e Corpora
pora
r
21
0$
quent 
uen
ycles
ycles
25
25
25
25
1
)2
1
----
< ,
< ,
< ,
< ,
---
---
5<
$ <
---
$5
7$
---
---
7$
7$
7$
7$
---
---
(7
5,
5,
5,
5,(
23
52
rom 
rom 
ning)
ing)
52
52
52
52
X
3
(
Con
C
(1
*(
patitis
patitis
tsts
*(
*(
*(
(/*(


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
---
&(/*(1
pri
prietet
1(35235,(7$5<,1)250$7,21
e Cor
e Corpora
pora
r
21
Fo
Fo
7,2
$7
0$
5
EO
50
25
X
25
25
25
2
---
---
)2
X
1
< ,
X
< ,
< ,
< ,
< ,
X
5<
X
$5
7$
---
--
(7
, 7
--
,(
5,
---
---
5
---
---
3
2
rs)
rs)
X
2
52
EFFI
EF
52
52
52
28d to
28d to -1)
-1
3
X (
X (≤2
1
(
*(
*


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.
&(/
pri
prietet
/*(1(35235,(7$5<,1)250$7,21
e Cor
e Corpora
pora
r
21
Fo
7,2
$7
0$
5
E
50
25
S
25
25
25
Every other
Every oth
cycle
cycl
star
sta
Cyc
)2
7$ < ,
----
7$
7$
7$
7$
X3
(7
5,
ATIONAL P
ATIONAL 
5,
5,
5,
Daily on D
Daily on D
35
52
52
52
52
52
35
---
3
-
1(
*(
*(
*(
*(
ubunit of 
ubunit of hu
Group; 
Group; EOT
EOT
atitis C virus
atitis C viru
R =
R = real time
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.
&(/*(1(3523
pri
prietet
35,(7$5<,1)250$7,21
e Cor
e Corpora
pora
r
21
le 3 day 1 on
e 3 day 1 o
ne.  
ne.  Hepatitis
Hepatitis
and Man
nd Manage
ge
signature.
ignature.
documents at
documents at
ort form (CR
t form (
blood cell (R
blood cell (
asured with a
red with 
n (BUN), cre
n (BUN),
etic transamin
tic transamin
, and 
and internat
interna
mal at baseli
mal at bas
may be serum
may be serum
and prior to d
and prior to
performed.  T
performed.  T
being done i
being don
ose Cycle 1 D
ose Cycle 1 D


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)
&(/*(1(35235,(7$5<,1)250$7,21
tory
ry
ndow if 
dow if 
(Table
Table 1),)
nosis, stagi
osis, stagin
nicit
ic y-y-if all
if al
ct number r
number r
radi
adiatation, s
n
vant medic
vant medic
ded)
ded). . 
ust be taken
ust be ta
CV, intraven
, intrave
d any
d any past 
past 
y
ls, ri
s, right up
ght up
Manageme
anageme
identify
dentify su
hepat
hepatititis C
is C
ogi
ogical mar
cal mar
±
Al
All
±
S
±
!


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.
&(/*(1(35235,(7$5<,1)250$7,21
e subject is
subject is
mited to red
mited to re
BC) count, a
BC) count,
measured w
easure
potassium,
potassium
umin, total
umin, t
e aminotran
e aminotran
ne aminotra
e aminotra
olymerase c
lymeras
ected durin
ected durin
rothrombin
rothrombin
ized rati
zed ra o 
sts ick 
ick may y b
e)
is required 
required
nancy test w
nancy test
e performe
e perform
stration of 
stration of 
osing
osing (n
(neg
e
Ad
Adver
verse ev
se e
evaluat
valuatioion
rs of Cy
rs of Cycle
cle
&
6.1.
6.1


EDMS Doc. Number:
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Treatment cycles are 21 days in duration, and will occur as described in Section 8.2.
The following evaluations will be performed at the frequency specified in Table 1, Table of 
Events. The evaluations should be performed prior to dosing on the visit day, unless otherwise 
specified:
!
Concomitant medications evaluation
!
Concomitant procedures evaluation
!
Physical examination (source documented only)
!
Vital signs: on-treatment vital sign measurements will be source documented only.  
However, if an abnormal (out of range) value is reported at any given visit, that 
parameter should be collected in the case report form (CRF) at every subsequent 
scheduled visit until it returns to normal, and as an AE if appropriate.
!
Weight
!
Complete blood count with differential
!
Chemistry panel
!
Subjects identified as having hepatitis B at baseline will be tested for HBV- DNA and 
serological markers at every other cycle starting Cycle 3 Day 1 (eg Cycle 3, 5, 7, … 
etc.) Also, subjects identified as having chronic hepatitis C at baseline will be tested 
for HC viral load by quantitative RNA-PCR [by polymerase chain reaction]
!
Epstein-Barr Virus-DNA [by real time polymerase chain reaction (RT-PCR)] in all 
subjects
!
PK sample (only being done in 6 subjects of Asian-Pacific ethnicity at 200 mg dose 
initially; then in an additional 6 if dose is escalated to 300 mg dose) (see Section 6.4)
!
Tumor biopsy [STRONGLY encouraged/recommended] (Only being done in Stage 1 
subjects) (see Section 6.5)
!
ECOG Performance status (Oken, 1982) see Appendix A
!
IRT for IP accountability
!
Adverse event evaluation (continuously)
!
Response assessment/tumor evaluation (see Section 6.3)
!
Bone scans (only if the subject is symptomatic or with known bone metastasis, per 
standard of care)
!
Urine (or serum) β-hCG pregnancy test (prior to dosing on Day 1)
!
Urinalysis (at screening and D1 of each cycle if abnormal at baseline)
6.1.1.
End of Treatment
An end of treatment (EOT) evaluation should be performed for subjects who are withdrawn from 
treatment for any reason as soon as possible after the decision to permanently discontinue 
treatment has been made. Subjects should also be discontinued through the IRT system.
&(/*(1(35235,(7$5<,1)250$7,21
only
nly.  
that
that
bsequent
bsequent
will be test
will b
Cycle 3
ycle Da
Da
c hepatit
c hepatitis 
i
R 
R [by polym
[by polym
polymeras
polymeras
6 subjects o
subjects 
l 6 if dose 
6 if dos
l
GLY encou
LY enco
6.5
6.5)
nce status
ce statu (
countabilit
countabi
event evalu
vent eval
ponse asses
ponse asses
Bone scans
Bone scans
standard
standar
!
Urin
Uri
!
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.
&(/*(1(35235,(7$5<,1)250$7,21
e of IP)
e of IP)
e tested for
e tested for
nic hepatit
ic hepatiti
R [by
R [by polym
y
ales of child
es of ch
be cont
be continu
in
o be perform
o be perfo
od
od
ow
ow-up
cont
ontinue tre
inue t
y, or wi
, or with
th
i dr
dr
sments
ments and
an
Survival
Survival
the EOT v
the EOT 
thdrawal
drawal o
l
therapi
erapies s
es s
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 
&(/*(1(35235,(7$5<,1)250$7,21
.1.1.
ment
ent. . Resp
Resp
imaging (
imaging (M
en/pelvis,
n/pelvis,
t ba
baseline f
selin
atic or with 
ic or with
must be use
must be u
chedule is c
hedule is
dically cont
ically con
mm or les
m or less in
s i
struction al
struction a
mor respon
mor respon
he next sch
e next sch
curred 
curred ≥ 6 
≥ 
nts
nts
tomat
oma ic fo
for
All subjects
ll subject
armacoki
armaco
f enro
enrolled s
lled s
nced 
c
sisites th
tes t
i
cipate in PK
cipate in P
dministered
dministered
PK sampl
PK sampl
ill pa
ill pa


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
35
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
given at approximately the same time of day.  The exact date and time of dosing will be recorded 
in the source documents and appropriate CRF.
Blood samples for oral azacitidine PK assessment will be collected prior to each dose 
administration (pre-dose) and over the 8-hour period following each dose administration (0.25, 
0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose or similar schedule) (see Table 2).
Table 2:
Schedule of Pharmacokinetic Blood Sample Collection in the 
Pharmacokinetics Phase
Nominal Times
Acceptable Deviation Window
Pre-dose
≤ 60 min
0.25 hr
± 3 min
0.5 hr
± 3 min
1 hr
± 3 min
1.5 hr
± 3 min
2 hr
± 3 min
2.5 hr
± 3 min
3 hr
± 3 min
3.5 hr
± 3 min
4 hr
± 3 min
6 hr
± 20 min
8 hr
± 20 min
6.4.1.
Dietary Restrictions in the Pharmacokinetics Phase
Fasted Condition
After an overnight fast of at least 8 hours, all required pre-dose assessments and procedures 
(including obtaining the pre-dose PK sample) should be performed.  Then, if applicable, subjects 
should ingest antiemetic premedication (eg, odansetron) with 240 mL of water and wait 30 
minutes before administration of IP.  Subjects will then ingest CC-486 with 240 mL of room 
temperature water.  No food will be allowed for at least 2 hours post-dose.  Water can be allowed 
as desired except for 1 hour before and after CC-486 administration.  The only water permitted 
in the 1-hour period before CC-486 administration is the 240 mL of water for antiemetic and IP
ingestion.
6.5.
Biomarkers
 
 
Biomarkers will 
7
$7
$7
$7
$7
0$
50
n
25
min
min
)2
± 3 min
± 3 min
1)
± 3 mi
3 m
,1
± ±
<
5<
$5
7$
(7
5,
5,
5,
5,(
Pharmaco
Pharmac
st 8 hours
st 8 hours
dose PK sa
dose PK sa
remedicati
medicati
tration of I
tration of 
No o fo
food wi
od w
for 1 hour 
for 1 hour 
peri
eriod befo
od bef
Biom
iom
&(/
&(
&


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.
 
 
7
$7
0$
0$
0$
50
250


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.
&(/*(1(35235,(7$5<,1)250$7,21
ment.
nt.
poorly
poorly
etastati
astatic.c *
y afafter
ter
f
1 toto
, 1982
, 1982) see
)
ble disease,
e disease
ed
ed by the fo
by the fo
per limit of
per limit of
nge, or cor
ge, or cor
marrow fun
arrow fun
l count 
l count ≥ 1
≥ 
10
109 cells/L
cells
≥ 9 g/dL
≥ 9 g/dL
hildbearing
ildbearin
der
dergone a 
gone a 
ectomy
ectomy (th
(t
y
menopausa
enopausa
he precedin
precedi
a.a
Hav
Hav
st


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
38
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
the 72-hour timeframe). She must agree to ongoing pregnancy testing during the 
course of the study, and after end of study therapy. This applies even if the subject 
practices true abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be reviewed 
on a monthly basis) or commit to use, and be able to comply with effective 
contraception (oral, injectable, or implantable hormonal contraceptive; tubal ligation;
intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner)
without interruption, 28 days prior to starting IP, during the study therapy (including 
dose interruptions), and for 3 months after discontinuation of CC-486.
10. Male subjects with a female partner of childbearing potential must commit to true 
abstinence* from heterosexual contact or commit to the use of an effective contraceptive 
method throughout the course of the study, and avoid fathering a child during the course 
of the study (including dose interruptions) and for 3 months following the last dose of 
CC-486. The ICF will address any country-specific requirements, as needed.
11. Subject understands and voluntarily signs an ICF prior to any study-related 
assessments/procedures are conducted.
12. Subject is able to adhere to the study visit schedule and other protocol requirements.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a history of, or current brain metastasis. In subjects who are symptomatic, a 
brain scan is required to exclude metastasis.  Primary NPC tumors that are 
touching/penetrating the skull are not considered brain metastasis.
2. Subject has any other malignancy within 5 years prior to randomization, with the 
exception of adequately treated in situ carcinoma of the cervix, uteri, or non-
melanomatous skin cancer (all treatment of which should have been completed 6 months 
prior to enrollment), in situ squamous cell carcinoma of the breast, or incidental prostate 
cancer T1a, Gleason < 7, PSA <10 ng/ml.
3. Subject has been previously treated with azacitidine (any formulation), decitabine, or any 
other hypomethylating agent.
4. Subject has a history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative 
colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other 
gastrointestinal disorder or defect that would interfere with the absorption, distribution, 
metabolism, or excretion of the IP and/or predispose the subject to an increased risk of 
gastrointestinal toxicity.
5. Subject has an impaired ability to swallow oral medication.
                                               
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception).
&(/*(1(35235,(7$5<,1)250$7,21
g
e
ntracepti
ntraceptive
ve
i
ing the cou
ng the co
he l
he last dose
ast do
needed.
neede
udy-related
rela
her protoco
er protoco
bject
bject fro
from
etastasis. In
etastasis. In
asis.  Prima
sis.  Prima
considered
considered
y wit
within 5 y
hin 5 y
d in
d in sisitu car
tu car
i
(all treatme
ll treatm
tu 
tu squamo
squamo
< 7, PSA <
< 7, PSA <
previously
previou
hylat
ylating ag
ing ag
s a h
s a history
istory
celiac dise
celiac di
rointestinal 
ointestinal
etabo
ab lism
lism
gastrointe
gastrointe
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
er 
virus
irus
ndit
nditioion that
n t
ation in the
ation in th
those subje
those subje
agemen
gement of
t o
n
ubject previ
bject previ
riries a high
es a high
eudoaneury
eudoaneury
ays prior to 
ays prior to
gat
gatioional the
nal th
ever is sh
ever is s o
m th
the acut
e ac
y/significan
/significa
y
herapy
erapy ≤ 4
≤4
and/or from
nd/or fro
nant or bre
nant or bre
s any 
ny signi
signi
hat 
hat wo
would p
ul
bject has a
ect has an
plp aces the s
es the 
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;
&(/*(1(35235,(7$5<,1)250$7,21
vent 
en
ntained
tained.
ay
ays of
s of a 21
2
f
ble
ble fo
for safe
r safe
ycle 1
ycle 1; and
; an
equent
uent subj
ubj
dose f
e or 14
1
f
(8
(8 ounces) 
ounces) 
od (a light b
od (a light 
g days.
g days.
vent occurs
vent occu
at the subje
at the subje
Section
Section 9.9
tion in Asia
ion in A
ubjects of A
ubjects of 
y y and dete
and dete
1 subject of
subject o
ial 200 mg 
al 200 mg
cts of Asia
ts of Asi
mg
mg daily
daily, a
, a
ned as 
ed as an I
an 
ay 1) that l
1) that l
y
!
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
&(/*
eutropenia or
eutropenia or
delay to the
delay to th
C < 0.5 
< 0.5 x 10
x 109
latatelet
l s < 25
s < 25
or ANC 
or ANC
*(1(3
ombocytopen
ombocytop
nned start of 
d start of 
L
( 35235,(7$5<,1)250$7,21
of the nex
of the nex
begin.
begin.
ing a dose 
ng a dose 
unacceptab
unaccepta
will
will b
l e def
e def
poses a med
oses a m
Grade 3 or
Grade 3 o
ed after th
ed after th
t Gui
Guideline
delin
se Delays
e Delays f
Recomm
Recomm
35
2
to 
1.5 x
5 x
Hold 
Hold
D
23
2
09/L
/L
( 3
*


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 
&(/*(1(35235,(7$5<,1)250$7,21
$
,
486.
486.
$
)2 0$
opean Society
opean Society
ce to ASCO o
ce to ASCO
nia with clinic
nia with
oxicity should 
xicity should
d be managed
be manage
the continuati
he continu
n all of the
n all of the
od should n
d should n
by the subj
the sub
y
protocol, re
protocol, r
verdose is d
verdose 
given subje
given subje
al) ) - any am
any am
or frequen
or freque
qui
quired sche
red sche
i
ete data abo
te data abo
dose was a
dose was a
8.2.5.
8.2
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.
d 
B or C, as 
B or C, as
the subjects
he subject
and for at 
and for at 
study
tudy accor
accor
y
(HCV) (HC
HCV) (HC
anti
nti-HCV 
HCV 
(eg Cy
(eg C cle 3
cle
known to 
known to 
reening (inc
reening (in
subjects pos
ubjects po
provides d
provides d
s of
s of viral
viral
f
ll
r at l
at least 4 
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.
&(/*(1(352
----------
--
ined as:
ined as:
og in HBV
og in HBV-D
V-DNA valu
DNA valu
able HBV
HBV-D
5235,(7$5<,1)250$7,21
HBV 
BV 
cination
ination
$7
-
0$
No spe
No spe
acti
acti
50
2
DNA every
DNA ever
ing from C3
ng from C3
s or more fre
s or more fr
cally indicat
cally indica
$5
Reactivatio
Reactivatio
of hepatit
of hepatiti
nagement o
agement 
ical signs an
ical signs an
23
T elevation 
elevation 
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.
&(/
subjects with
ubjects with
Knowledge o
Knowledge o
detectable
etectab
acer
(/*(1(35235,(7$5<,1)250$7,21
the
the
subject 
subject 
ral
dose of study
ose of study
uld discontin
uld discontin
at least 4 wee
least 4 we
)2
$7
festations
estations – H
athy, coma); i
athy, coma)
or a subject wh
r a subject w
reactivation i
reactivation i
onitored fo
onitored fo
HCV ant
HCV a
ibo
ib
of
of HCV inf
HCV in
f
at were trea
t were trea
reatment fo
reatment fo
or exacerb
exacer
vation and 
vation and
ines for th
nes for th
1(
baseline resu
baseline re
HCV (HCV
HCV (HCV
n is defined 
is defined
vation > 5 U
vation > 5 U
(1
(/


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.
&(/*(1(35235,(7$5<,1)250$7,21
ner, lot 
r, lot 
tatem
tatements 
ents 
er local
er local
osal
osal
nt site perso
t site per
ncluding res
ncluding re
ade in the a
ade in the
The
The Invest
Inve igi
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.
&(/*(1(35235,(7$5<,1)250$7,21
se 
F] and 
and 
per 
er Investi
Invest
) and E
and Euro
uro
t of neutrop
of neu
veststigator
tor’s’
es pri
es prior to e
or 
ribe
ibed at the 
at the
nt doses of 
nt doses of
the subjec
the subjec
g and for a
g and for a
e study
study acco
acco
y
mitant
mita
M
medicat
medicatioi ns 
ns
apeuti
peutic, targ
dine
ine), deci
), de i
Require
Requir
applicable.
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
P.
ibilit
bility y cri
criter
ti
tensit
ensity and d
dose intens
ose inte
ments.
ments.
opulat
opula ion w
n
subjects wh
subjects wh
e will be eff
will be ef
and Pow
nd Pow
5 efficacy 
efficacy 
e est
e estimat
imatio
o show tha
o show tha
wo-sts age d
age d
0% o
0% r med
med
stage,
tage, 17
17
nro
nrollment 
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.
&(/*(1(35235,(7$5<,1)250$7,21
h primary
primary
oth treatme
th treatm
d. Protocol
. Protoco
pulu ation.n.
t bino
binomial d
mia
RR will be p
will be
be used to e
be used to
S will be ba
S will be
eath, will b
eath, will b
dy will
will
y
b
l e c
e 
at the time
at the tim
to fo
to follo
llow-
of last con
f last con
will be used
will be use
90% 
% CI
C wil
w
two
two-sided 
ed
fety Anal
fety Ana
y popul
populatatioio
y and tol
and tolera
era
ous advers
ous advers
mo
modificati
dificati
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.
&(/*(1(35235,(7$5<,1)250$7,21
anner.
anner.
n the popul
n the popu
the extent 
the exten
samples f
ples f
m
of
K paramete
K parame
versus time
rsus tim
curve (AUC
curve (AUC
n (C
n (Cmax
m ););
ncentration 
ncentration
F); and,
F); and,
n (apparen
n (apparen
an, 
an, standar
standar
median, min
median, m
d graphic f
d graphic f
kikits and de
ts and de
i
andling wil
andling wil
cititi
i dine wil
dine wil
(LC-MS/M
MS/
.10.
10.
Ot
O
There i
There is n
s n
onduc
onduc


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);
&(/*(1(35235,(7$5<,1)250$7,21
ome
me
mptoms of 
mptoms of 
be reporte
be reporte
th an AE sh
h an AE sh
overdose.)
erdose
should be 
should be
n the sequel
the seque
lting 
ing in the
and CRF bu
nd CRF b
dy
dy.  Assess
.  Assess
ect’s clinic
ect’s clinic
physical ex
hysical e
gator
ator from t
from
and those S
and tho
ng related t
ng related 
the CRF an
he CRF an
Safet
Safety y wi
w ti
ropriate me
ropriate
uation of
uation of
nvest
nvestigator
igator
Seriou
Seriou
erious
erious adv
adv
!


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.
&(/*(1(35235,(7$5<,1)250$7,21
or 
ve. 
ve. 
E should be
E should be
wever, hos
wever, ho
administrat
dministra
ati
ation 
on not a
fusio
fusion as ro
n as r
rolonged h
rolonged
e SAE.
e SAE.
elelated inve
ated inve
tory
ory tests, b
tests, 
y
hospitaliza
hospitaliz
olongat
olongatioion o
n 
e of an AE.
e of an AE
hat is plann
hat is pl
nted in the 
nted in the 
zati
ation f
on for 
or 
f
lect
lective tre
ive tre
nrelated to
nrelated to
Emerge
Emerg
unles
unl
f an AE i
f an AE is c
s
must be c
must be c


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
54
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
11.2.2.
Severity / Intensity
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of the CTCAE, Version 4.0;
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity / intensity according to 
the following scale:
!
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
!
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required
!
Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible
!
Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable
!
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning.
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality
The Investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the adverse event to IP
administration is unlikely or remote, or other medications, 
therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event.
Suspected:
Means there is a reasonable possibility that the administration 
of IP caused the adverse event.  ‘Reasonable possibility’ means 
there is evidence to suggest a causal relationship between the IP 
and the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
calal
stance may
tance may
e usually re
 usually r
ble
ble
y, significan
significan
red, hospi
red, hospiti
y of a speci
y of a spec
wever, may
wever, m
erio
erion is no
no
ria associ
a associa
uide f
de for def
or de
f
ne the rela
ne the rela
as Not Susp
s Not Sus
Mean
Mea
adm
adm
Suspected:
Suspected:


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
55
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
11.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The Investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation, interruption, or reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event.
11.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered or death (due to the 
SAE).
11.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:
!
results in discontinuation from the study;
!
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or
!
is judged to be of significant clinical importance.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the CRF.  If the abnormality was not a 
part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE. If 
possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject or partner of a 
male subject are immediately reportable events.
11.4.1.
Females of Childbearing Potential:
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 3 months of the 
subject’s last dose of CC-486, are considered immediately reportable events.  IP is to be 
&(/*(1(35235,(7$5<,1)250$7,21
icable
able
comit
mitant
ant
AEs.
AEs.
parti
particicipat
pa
covered or d
overed or
AE
AE if th
the a
udy
dy;
interruption
interruptio
ant clinical 
ant clini
y l
y aboratory
aborato
rious adver
ous adve
y i
y s one co
s one
recorded o
recorded o
r syndrom
syndrom
ratory
ratory abno
abno
y
ratory
atory resu
res
y
Pregna
Pregn
pregnancies
pregnancie
male subject
male subject
1.4.1.
1.4.1.


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
56
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
discontinued immediately and the subject instructed to return any unused portion of CC-486 to 
the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Celgene Drug Safety immediately by facsimile, or other appropriate method, using 
the Pregnancy Initial Report Form, or approved equivalent form.
The female subject should be referred to an obstetrician-gynecologist, or another appropriate 
healthcare professional for further evaluation.
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator
should report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the Investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
11.4.2.
Male Subjects
If a female partner of a male subject taking CC-486 becomes pregnant, the male subject taking 
CC-486 should notify the Investigator, and the pregnant female partner should be advised to call 
their healthcare provider immediately. The female partner may be referred to an obstetrician-
gynecologist or another appropriate healthcare professional for further evaluation.  Male subjects 
should avoid fathering a child during the course of the study and for 3 months following the last 
dose of CC-486. The ICF will address any country-specific requirements, as needed.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the CRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the Investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The Investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to CC-486) that occur during the 
study (from the time the subject signs informed consent until 28 days after the last dose of 
investigational product (IP), and any SAE made known to the Investigator at anytime thereafter 
that are suspected of being related to IP.  SAEs occurring prior to treatment (after signing the 
ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
&(/*(1(35235,(7$5<,1)250$7,21
r 
form
form.
gator
ator
of f th
the seri
e seri
ther approp
ther approp
e SAE Rep
e SAE Rep
ed, without
d, withou
he Invest
Inves igi
to Celgene 
Celgene
Investigat
Investig
form
orm.
86 beco
bec me
me
pregnant f
pregnant f
female par
female par
hcare prof
hcare prof
the course 
the course 
ress any cou
ss any co
Serious A
Serious A
criterion for
riterion 
rded on the
rded on t
ty y wi
with
th
i in 2
in 2
riate metho
iate metho
ertains to in
ertains to in
stigator
gator is r
is r
equi
equiremen
remen
i
dy (f(f
y
rom
rom
f
thth
m
investigat
nvestigatioio
that are 
at are
F)


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).
&(/*(1(35235,(7$5<,1)250$7,21
business 
siness 
e the expec
e the expe
vest
estigator
igat
’s
ons (SUSA
ns (SUSA
32.2.
elgene or it
elgene or 
atory
atory Auth
Auth
y
irect
irective 20
ive 20
n of advers
n of adve
man use (E
man use (E
ase under st
se under st
sidered to b
idered to
pedited saf
pedited s
entative
entative sha
sha
ed of being
ed of bein
rious and u
rious an
ng fro
ng from tet
subject
subjects in
s in
,
uired by
ired by l
y oc
o
ew serious a
w serious 
Investi
Investigat
gat
corresponde
orresponde
inform
nformat


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
58
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
Celgene Drug Safety Contact Information:
!
For Celgene Drug Safety contact information, please refer to the Serious Adverse 
Event Report Form Completion Guidelines or to the Pregnancy Report Form 
Completion Guidelines.
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
59
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
12.
DISCONTINUATIONS
12.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the 
investigational product and/or from the study:
!
Adverse Event
!
Progressive Disease
!
Symptomatic deterioration (global deterioration of health status)
!
Physician decision
!
Withdrawal by subject
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other (to be specified on CRF)
The reason for discontinuation should be recorded in the CRF and in the source documents.
The decision to discontinue a subject remains the responsibility of the treating physician, which 
will not be delayed or refused by the Sponsor. However, prior to discontinuing a subject, the 
Investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
12.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the study 
follow-up periods:
!
Withdrawal of consent
!
Death
!
Lost to follow-up
!
Protocol violation
!
Other
The reason for discontinuation should be recorded in the CRF and in the source documents.
&(/*(1(35235,(7$5<,1)250$7,21
CRF and i
CRF and
sponsibilit
sponsibili y
owever, prio
wever, pr
and forwar
and forwar
n
red sufficie
red suffici
consent
onsen
follow
follow-up
-up
otocol
ocol vivi
l
ol
ol
Other
Other
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.
&(/*(1(35235,(7$5<,1)250$7,21
ot be
ot 
ed on
d on
ntatives are
ntatives are
Celgene/C
Celgene/Co
nly
nly b
y e used
e used
or or design
r or desig
nal Produ
nal Pro
d on the pa
d on the pa


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.
&(/*(1(35235,(7$5<,1)250$7,21
in 
authori
authorititi
i es
es
ical Practic
ical Practic
evaluate an
valuate
study
ud are a
re
study
study-relate
rel
and o
and oth
ther 
e
dy-
dy-rel
related d
ated
of all subje
of all sub
dy.  Su
y.  Subject
bjec
u
uments.
uments.
of the
of the Inve
Inve
ve queries a
queries 
ital charts, 
al charts
st ensure t
st ensure 
rmation a
mation 
obtain infor
obtain info
lated proce
ated proc
that inform
hat inform
ormed 
ormed con
con
the date.  T
he date.  T
and by the
and by the
y, m
, must be 
ust be
m
n addit
n additioion, 
n,
inform
nformed
ed
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.
&(/*(1(35235,(7$5<,1)250$7,21
ain
earch
arch
or written a
or written a
versio
version oc
n oc
the Investi
Inves
able.
ble. Amen
Ame
be submitt
be submit
dent Ethic
ent Ethi
nform
nformed co
d c
e IRB/EC w
IRB/EC w
nd the site 
nd the site 
. If applicab
 If appli
alal ll egal
egal req
l
ststigator
igator by
b
nd legal req
nd legal re
presentativ
presentat
and their o
and their
ns and quali
ns and qu
ming that th
ming that th
B General 
B General 
oval by the 
oval by the 
ble), study
le), study
nts review
nts review
cially signe
cially signe
hihical and l
cal and 
The IRB
The IR
en


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.
&(/*(1(35235,(7$5<,1)250$7,21
e;e;
ed risk to su
ed risk to su
reasonable
asonable
e appropria
e appropr
uthori
horititi
i es, e
es,
o discont
o discontinu
inu
ns such as
ns such a
ta collect
a collectioi
;
protocol
protocol.
r closing th
osing th
analyzed. I
analyzed. 
duct, and it 
ct, and it 
ve benefit f
ve benefit f
y under a se
under a s
y


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;
&(/*(1(35235,(7$5<,1)250$7,21
on as 
n as 
macy, and 
acy, and
elgene
elgene stan
stan
hrough use 
ugh us
es in the da
s in the d
nnel, if nece
nel, if nec
witithin the s
hin 
stigator
stigator fo
for
region a
egion and 
nd
CH region,
CH region,
pment of th
pment of th
ed above or
d above o
ments incl
ents inc
nsent docum
nsent docum
catatioion code
n cod
ll co
ll commu
mmun
osisititi
i on of
on of thth
f
cord of all 
ord of all
representat
representat
!
List of
List of
Inv
Inv
t


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
ities.
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.
&(/*(1(35235,(7$5<,1)250$7,21
fter 
ter 
udy
dy
udy
dy, a
, a
formed 
formed 
itoring will
itoring wil
ropriate
ropriate
ts, the facil
s, the facil
and
nd all oth
all 
tive in acco
ive in acc
on that i
n that s a
rce docume
ce docum
d/or his/her 
d/or his/he
queries by t
queries by t
d consents, 
d consents, 
roper recor
oper reco
udy
udy-specifi
specifi
s
ng procedu
ng procedu
presentative
resentative
Celgene S
Celgene
s.
quired to p
quired to
 CRFs and
CRFs and
ect
ectioions by I
ns by I
thorized rep
thorized rep
dits and/or 
ts and/or 
i
ing an inspe
ng an inspe


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.
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 
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 
metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 
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 
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.
&(
th
&(/*(1(35235,(7$5<,1)250$7,21
atat-
753 pati
753 patien
en
haryngeal
haryngeal
HNS
NS-ESMO
ESMO
. Ann Onco
. Ann On
demethylat
demethylat
1.
otherapy
therapy f
y o
f
:244
244-249.
-249.
of
of capeci
capeci
f
tata
i
eated wit
ated with
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.
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


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 
external beam radiotherapy with or without brachytherapy. Int J. Radiat Oncol Biol Phys 
2010;76:130-137.
Lo KW, Chung GTY, To KF, et al. Acquired genetic and epigenetic alterations in 
nasopharyngeal carcinoma. In: Busson P, ed. Nasopharyngeal Carcinoma. New York, 
NY:Springer New York;2013:61-81.
Loomba R, Rowley A, Wesley R, et al. Systematic Review: the effect of preventive lamivudine 
on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-528
Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of 
advanced nasopharyngeal carcinoma. Cancer 2005;103:22-31.
Mendenhall WM, Werning JW, Pfister DG. Treatment of head and neck cancer. In: DeVita VT 
Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. 
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 
disseminated nasopharyngeal carcinoma. Ann Oncol 2011;22:718-722.
Okada T, Nakamura M, Nishikawa J, et al. Identification of genes specifically methylated in 
Epstein-Barr virus-associated gastric carcinomas. Cancer Sci 2013;104:1309-1314.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic 
nasopharyngeal carcinoma. Eur J Cancer 2003;39:1535-1541.
Paulson EJ, Speck SH. Differential methylation of Epstein-Barr virus latency promoters 
facilitates viral persistence in healthy seropositive individuals.  J Virol 1999;73:9959-9968.
Robertson KD, Ambinder RF. Methylation of the Epstein-Barr virus genome in normal 
lymphocytes.  Blood 1997;90:4480-4484.
Salamon D, Takacs M, Ujvari D, et al. Protein-DNA binding and CpG methylation at nucleotide 
resolution of latency-associated promoters Qp, Cp, and LMP1p of Epstein-Barr virus. J Virol 
2001;75:2584-2596.
Sham JS, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases 
from nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1993;26:787-792.
Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma; orderly neck node spread. Int J Radiat 
Oncol Biol Phys 1990;19:929-933.
Shiu WCT, Tsao SY. Efficacy of 4'-epidoxorubicin in advanced nasopharyngeal carcinoma. Clin 
Trials J 1989;26:419.
Simon R. Optimal two-Stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-
10.
&(/*(1(35235,(7$5<,1)250$7,21
: DeVita V
: DeVita 
9 h ed.
ed.
ion.n. J Cell 
J C
vily pretrea
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,
y-associ
assoc ate
ate
96.
96.
eung YK, C
eung YK, 
opharyngea
haryngea
JS, Cho
JS, Choy y D
col Bi
Biol
ol Ph
Ph
l
Shiu WC
Shiu WC
ririals
als


EDMS Doc. Number: 
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
70
CC-486-NPC-001 Amendment 3 Final: 23 Sep 2016
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.
Tierney R, Kirby H, Nagra J, et al. The Epstein-Barr virus promoter initiating B-cell 
transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5.  
J Virol 2000;74:10458-10467.
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.
Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of 
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 
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.
&(/*(1(35235,(7$5<,1)250$7,21
7
$7
$7
$7
$7
work of a 
ork of a 
0$
activities. U
activities
5
han 50% of w
an 50%
)2
onfined to b
nfined to 
1)
,1
5<


EDMS Doc. Number: 
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.
8VHU1DPH
7LWOH
'DWH0RQGD\6HSWHPEHU$0(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
&(/*(1(35235,(7$5<,1)250$7,21

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 


',6&/2685(
5('$&7('35272&2/$0(1'0(17
&&13&
$3+$6(08/7,&(17(5,17(51$7,21$/6,1*/($50678'<72$66(66
7+(6$)(7<$1'()),&$&<2)6,1*/($*(17&&25$/$=$&,7,',1(
,135(9,286/<75($7('68%-(&76:,7+/2&$//<$'9$1&('25
0(7$67$7,&1$623+$5<1*($/&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,
ILIL
5,(7$5<,1)250$7,21
6
1(
1(
5
5
RWEHVKDUHG
RWEHVKDUHG
FKHUVDQGSD
KHUVDQ
JXO
JXODWLRQVUH
DWLRQVU
DORUF
RUFRQWUDF
RQWUDF
WRFHUWDLQSD
FHUWDLQS
DLQLQIRUPDW
LQLQIRUPDW
&HOJHQH¶VF
&HOJHQH¶V
SULQFLSOHV
SULQFLSOHV
H\ VSDFHPD
VSDFHPD
FDWLRQRIL
FDWLRQRIL
QFRQILGHQ
FRQILG
WLD
WL
DLQLGHQWLILD
LQLGHQWLI
OVRPD\FRQ
OVRPD\FRQ
LVJHQHUDWLQ
VJHQHUDWL
DWWDFKPHQWV
WWDFKPHQ
RIWKHUHSR
RIWKHUH
W&HOJHQHY
&HOJHQHY
KDWLQIRUPDW
KDWLQIRUPD
DERXWRXUY
DERXWRXU
RQDERXW&H
DERXW&H
QGDWKWWSZ
QGDWKWWSZ


('06'RF1XPEHU
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.
&(/*(1(35
 provided to y
provided to
staff, and ethi
taff, and ethi
35235,(7$5<,1)250$7,21
S 
S 
cit
citidine)
idine
001
001
14
tober
tobe 2014
01
April
April 201
2
2014-00
2014-
1225
25
ent is regarded
ent is regarde
may not be dis
may not be di
Persons to w
ersons to w
35
35
(/
(/
(/
(/
(/
(/
(/


('06'RF1XPEHU
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: 
&(/*(1(35235,(7$5<,1)250$7,21
0
50
25
)2
er should o
r should
Medical M
Medic
enter:
enter:
$5
7$5


('06'RF1XPEHU
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.  
&(/*(1(35235,(7$5<,1
,1
,1)250$7,21
0$
0$
50
content to 
content to
,1


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5
$5
$5<,1)250$7,21
0$
0$
50
s study
s study at m
at
y
, inform
nformed d
ocedures, in
edures, i
Good Clin
Good C
ct of cl
of clinica
inic
$5


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<
5<
5<,1)
wi
wi
1)250$7,21
0$
0$
50
th
th
i
ICH G
ICH 
h
ghout the st
out the st
5<


('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.
&(/*(1(35235,(
r, internat
r, interna io
ated
ated subjec
sub
 previous
previous
bjects will b
jects will
t (
t (> 4 respo
4 res
subjects
subjects ba
n addi
addititi
i on
on
t will be st
t will be st
dent Data M
dent Data M
s with expe
ith expe
who
whom are n
are n
MC will rev
MC will rev
be detailed
e detailed
tudy 
tudy
7$5<,1)250$7,21
inically or 
inically o
py
py.
CC
CC-486 in
4
(7$
,(7


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<,1)250$7,21
he
he
the
the
orally
orally eve
eve
the fi
e first 6 
rs
i
0 mg will b
0 mg will b
nts 
nt (SAEs
SAEs)
toto all
al subs
e progress
progre
nt, subj
nt, subject t
sponse and
sponse and
ECIST)
ECIST) v1
valaluat
uat
l
ioions
n
er therapy
er therapy
clude
clude com
and neck w
and neck 
ogi
ogical exam
exa
l
cts. Bone s
ts. Bone 
stasis
tasis.
up phase,
up phase,
ll be
be fo
follo
llo
up, whi
up, whichev
che
erview of S
rview of S
All
All subjec
subjec
nform
nform
d


('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
ed at least 
d at least
Efficacy
fficacy
eri
eria,a, and
and
nued treatm
nued trea
ensit
nsity y and h
and h
le in the
le in the Ef
dian PFS is
ian PFS is
17 subjects
7 subjec
ment will b
ment will b
subjects. T
subjects. T
are observe
are observ
his design y
his design y
ue ORR is 4
ue ORR is 
months
onths is 8
is
erformed on
rformed 
for the ORR
for the OR
ed d 90%
90% co
co
S will be ba
S will be ba
will
will be pro
be p
alysis
lysis
and tol
and tolerab
erab
erse events
erse events
mo
modificati
dificatio
who rece
who re
ysi


('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
&(/*(1(35235,(7$5<,1)250$7,21
7
....... 18
18
...........
.......... 19
1
.............
............
..............
............
.............
............
................
..........
..............
.............
.............
.........
..............
...
..............
..........
......
...............
..............
.............
.............
.......
.............
.........
..............
.............
..............
.........
EVENTS
VENT
URES
URES......
ment Per
ment Perioi
nd of Trea
nd of Trea
Fo
Follo
llow
.
Eff
Effif
.2.2.
.2.2
.3.
.3.


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
11
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
&(/*(1(35235,(7$5<,1)250$7,21
8
.......39
3
..........
.... 41
4
..............
...........
..............
............
.............
.............
..............
............
... ...........
......
.............
.....
Hepatit
epatitis B
is B
.............
.............
.........
..
....
...
ilitity y and D
and D
liance
liance.......
CATI
ATIONS 
ONS 
t Medicati
Medicati
mit
mitant Med
ant Me
comi
mitant M
tant M
i
ICAL 
CAL ANA
A
view
iew.......
.......
tudy
tudy Popul
Popu
y
Sam
Sample 
ple 
m
Bac
Ba
0.5.
0.5.
10.6.
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
3
.......55
5
..........
.... 55
5
..............
...........
..............
............
.............
.............
..............
............
.............
.............
.......
..........
.
..............
...........
.............
.............
.............
............
vents
vents......
......
.............
..........
n.............
....
.............
.........
ROCEDUR
ROCEDU
ontact
ontact.....
cy
cy Identific
Identif
y
ULATORY
ULATORY
ood Clinic
od Clinic
Invest
Investig
Subj
Su
4.4.
4.4.
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
6
..........
.... 67
6
..............
...........
..............
............
.............
.............
ance Status
ance Stat


('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
......45
..........
.... 45
4
..............
.............


('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.
&(/*(1(35235,(7$5<,1)250$7,21
sal
sal
the lungs.
the lungs.
upper surfa
upper surf
sa of 
sa of 
harynx abu
harynx abu
the m
the muscle
uscle
m
e pharyngea
haryng
an irregular
n irregula
system
ystem des
d
m
mo
mon subt
n subty
in so
in some
me are
ar
ca are diag
a are dia
zing ty
zing type
pe
y
(A
bty
btype.
pe.
y
heast Chin
heast Chin
Asia, North
sia, North
g immigran
g immigra
ot exactly u
ot exactly u
lude
ude th
the pr
e p
et ri
et rich in s
ch in s
PC cells 
PC cells an
an
have high 
have high
tigens. The
igens. Th
several ye
everal ye
nes
nes


('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 
&(/*(1(35235,(7$5<,1)250$7,21
ecludes ear
ecludes ea
disease
disease
, 1993
, 1993; Sha
Sh
lvement at
lvement at
s is to bone
is to bo
d rate in ax
d rate in a
herapy
herapy alal
y
on
ry f
y or resi
or resi
f
d
diatatioion the
n th
r the primar
r the primar
e retreated w
e retreated 
d radiation 
radiation
e site of re
e site of
e or local re
 or local r
py shoul
py should b
d
py
py remains 
remains
y
especially 
specially
sta
stages (IIB
ges (IIB
ith local an
th local a
survival an
survival an
hs and 4
and 4 toto
%.
%. Isolated
Isolated
ar survival 
r survival 
plplatatinum
inum-b
ecomm
ecomm


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
18
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 
&(/*(1(35235,(7$5<,1)250$7,21
es
es
c
the
he
l studies,
studies, 
ecan have
ecan have
and capeci
and capeci
months 
months (F
ang, 2008
ang, 2008)
008 and rep
008 and r
val o
val of f 12.8
12
ies, m
es
ostly
ostly
ucleoside cy
cleoside
sis and met
sis and m
d by th
by the US
e US
ish
sh (FAB) 
(FAB
proved by
proved b t
y
ia (A
(AML)
r hematopo
hematopo
 (IV
IV) or 
or su
ioioavailable
availab
rati
ration into 
on into 
cts wi
ts with
ti  DN
 D
h
nance of DN
ance of DN
tic changes
change
ate the stab
ate the sta
st recogni
st recogniz
group to c
group to c
nd is a
nd is a


('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 
&(/*(1(35235
n Solid
olid Tu
n combinat
n combinat
psed or ref
ed or ref
of this two
of this tw
ys 1 to 14 o
 1 to 14 o
AZA
ZA-ST
ST-0
-0
subjects re
ubjects re
300 mg w
300 mg w
itaxel was a
itaxel was 
ncountered
ncountered
nab-
na
pacli
pacli
com
com
5,(7$5<,1)250$7,21
ring 
ng 
aily
ily and tw
and tw
y
fashio
fashion. 
n. C
mulat
mulative ex
ive e
tely
ely 40%
40% an
espect
espectively
ivel
day
ay sc
sc
y
hed
h
being the m
being the m
n lelevelsls ini b
hypo
hypomet
methy
hy
ally act
ally active,
ve
.
5,(
35,


('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).
&(/*(1(35235,(7$5<,1)250$7,21
aluable
uable
hers had 
hers had
in subjects
n subject
ovocative,
ovocative
ZA
Z -ST
ST-00
-0
The ongoin
he ongoin
PC subjects
PC subject
able diseas
able diseas
or NPC sub
or NPC sub
format
formation n
clinical stu
clinical stu
own promi
own promi
CC
CC-486 w
486 w
-day
day cycle
cycle
ifying agen
ifying ag
n subjects w
n subjects w
orte
orted in the 
in the
Frequent w
Frequent w
!
Genet
Genetici
!
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.
&(/*(1(35235,(7$5<,1)250$7,21
e settings
settings.
21 day
21 days of 
s of
enia.
ia. Alt
A ho
edule may 
edule may 
al is
l 
design
desig
g daily for 
daily
g the dose t
g the dose 
owed for a
wed for a
who receive
who receive
couraging y
couraging 
single age
single ag


('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
i
lected 
ected 
)25
1)


('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
 
&(/*(1(35235,(7$5<,1)250$7,21
eri
eria a
dy
dy treatm
treatm
y
e
nse using
se using
eatment to 
tment to
isease (SD)
isease (SD
ntnt-emergen
emergen
-4 AEs, 
4 AEs, Gr
G
atory abnorm
tory abno
86
86 inin a sub
su
ted si
ted sites
tes
i
oints
oint
352
35
( 3
(1(
*(1


('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.
&(/*(1(35235,(7
d d 
(7$5<,1)250$7,21
nts s
n’s 
n s
ut of the fi
ut of the f
en
en th
the stud
e stud
es out of 17
es out of 17
will be base
will be bas
bjects who 
ects wh
r. . Subjects
Subject
y reason oth
reason ot
jects who p
ects w
ioion, or as d
n, or as
ST
ST v1
v .1 init
i it
disease p
disease p
w-up
up. All su
. All 


('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.
&(/*(1(35235,(7$5<,1)250$7,21
5,(7$5<,1)250$7
  
PFS
months  
1)
tm
tment is ex
ent is e
population
population
itori
tori
i
ng of 
ng o
ssio
ss
n (if ap
n (if 
r analysis, o
r analysi
nd of Tri
d of Tri
of Trial is 
Trial i
or the date
or the date
mary
mary, secon
, seco
Stati
Statistical
ical A
subjects
ubject


('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
&(/*
pri
prietet
/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
0$
quent 
en
es
es
25
25
25
25
1
)2
< ,
<
---
5<
$
---
--
$5
7$
----
7$
7$
7$
7$
---
---
(7
5,
----
5,
5,
5,
5,
As needed
s neede
35
52
Conti
Conti
52
52
52
52
8d from 
m
eening)
eening)
3
X
1(
(1
C
*(
*(
*(
/*(


('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
---
pri
prietet
1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
X
1)
< ,
X
<
---
---
5<
$
X
$5
7$
X
X
X
(7$
7$
7$
, 7$
---
--
,(
5,
-
5,
5,
5,
5,
---
---
23
52
X
52
52
52
52
35
( 3
X(w/in72 h
(w/in72 h
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
---
---
&(/
pri
prietet
(/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
$
E
50
25
1)2
Cycle 1 Day 
ycle 1 Da
disease prog
disease prog
f consent
consent
1
mptomatic or
mptomatic o
5<
X
$5
7$
AND PK A
AND PK A
7$
7$
7$
---
---
(7
52 5,
3
(
1(
(1
*(
/*
(/


('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.
&(/*
pri
prietet
*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
1)
---
---
,1
< ,
----
5<
$ <
mputed tomo
mputed to
childbearing 
childbearing
teractive
eractiv re
hin
hin.
e the measure
the measur
eks only if th
eks only if
Section
ction 6. Pr
1 which mus
1 which m
ng evaluation
evaluation
ys before firs
ys before fi
days before 
days befor
in the databa
n the databa
d at a given v
d at a given v
od count (CB
od count (CB
te neutrophil
neutrophil


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
30
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.
&(/*(1(35235,(7$5<,1)2
pri
prietet
250$7,21
e Corpora
e Corpora
21
l protein, alk
protein, a
aminotransf
aminotransf
discretion. P
discretion. P
. I
. If the serum
f the seru
until the
ntil the Inv
Inv
ONGLY enco
ONGLY en


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
31
CC-486-NPC-001 Amendment 2 Final: 03 April 2015
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)
&(/*(1(35235,(7$5<,1)250$7,21
tory
ry
ndow if 
dow if 
(Table
Table 1),)
nosis, stagin
osis, stagin
nicit
ni
y-y-if all
if al
ct number r
number r
radi
radiatation, s
n
vant medic
vant medic
ded)
ded). . 
ust be taken
ust be ta
CV, intraven
, intrave
d any
d any past 
past 
y
ls, ri
s, right up
ght up
Manageme
anageme
identify
dentify su
hepat
hepatititis C
is C
ogi
ogical mar
cal mar
±
Al
All
±
S
±
!


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
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.
&(/*(1(35235,(7$5<,1)250$7,21
e subject is
subject is
mited to red
mited to re
BC) count, a
BC) count,
measured w
easure
potassium,
potassium
umin, total
umin, t
e aminotran
e aminotran
ne aminotra
e aminotra
olymerase c
lymeras
ected durin
ected durin
rothrombin
rothrombin
ized rati
zed ra o 
sts ick 
ick may y b
e)
is required 
required
nancy test w
nancy test
e performe
e perform
stration of 
stration of 
osing
osing (n
(neg
e
Ad
Adverse e
verse e
evaluat
valuatioion
&
rs of Cy
rs of Cycle
cle
6.1.
6.1


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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.
&(/*(1(35235,(7$5<,1)250$7,21
only
nly.  
that
that
bsequent
bsequent
will be test
will b
Cycle 3
ycle Da
Da
c hepatit
c hepatitis 
i
R 
R [by polym
[by polym
polymeras
polymeras
6 subjects o
subjects 
l 6 if dose 
6 if dos
l
GLY encou
LY enco
6.5
6.5)
nce status
ce statu (
countabilit
countabi
event evalu
vent eval
ponse asses
ponse asses
Bone scans
Bone scans
standard
standar
!
Urin
Uri
!
1


('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.
&(/*(1(35235,(7$5<,1)250$7,21
e of IP)
e of IP)
e tested for
e tested for
nic hepatit
ic hepatiti
R [by
R [by polym
y
ales of child
es of ch
be cont
be continu
in
o be perform
o be perfo
od
od
ow
ow-up
cont
ontinue tre
inue t
y, or wi
, or with
th
i dr
dr
sments
ments and
an
Survival
Survival
the EOT v
the EOT 
thdrawal
drawal o
l
there api
apies s
es s
imited 
mited


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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 
&(/*(1(35235,(7$5<,1)250$7,21
.1.1.
ment
ent. . Resp
Resp
imaging (
imaging (M
en/pelvis,
n/pelvis,
t baseline f
baselin
atic or with 
ic or with
must be use
must be u
hedule is c
hedule is
dically cont
ically con
mm or less in
m or less i
struction al
struction a
mor respon
mor respon
he next sch
e next sch
curred 
curred ≥ 6 
≥ 
nts
nts
tomat
oma ic fo
for
ll s
ll subjects
ubject
armacoki
armaco
f enro
enrolled s
lled s
nced 
c
sisites th
tes t
i
cipate in PK
cipate in P
dministered
dministered
PK sampl
PK sampl
ill pa
ill pa


('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 
(/*(1(35235,(7$5<,1)250$7,21
7
$7
$7
$7
$7
0$
50
n
25
min
min
)2
± 3 min
± 3 min
1)
± 3 mi
3 m
,1
± ±
<
5<
$5
7$
(7
5,
5,
5,
5,(
Pharmaco
Pharmac
st 8 hours
st 8 hours
dose PK sa
dose PK sa
remedicati
medicati
tration of I
tration of 
No o fo
food wi
od w
for 1 hour 
for 1 hour 
peri
eriod befo
od bef
Biom
iom
&(/
&(
&


('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.
 
 
7
$7
0$
0$
0$
50
250


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ment.
ment.
poorly
poorly
etastati
astatic.c *
y afafter
ter
f
1 1 toto
, 1982
, 1982) see
)
ble disease,
e disease
ed by
ed by the f
the f
y
f
per limit of
per limit of
nge, or cor
ge, or cor
marrow fun
arrow fun
l count 
l count ≥ 1
≥ 
10
109 cells/L
cells
≥ 9 g/dL
≥ 9 g/dL
hildbearing
ildbearin
ndergone a h
dergone a 
ectomy
ectomy (th
(t
y
menopausa
enopausa
he pre
precedin
cedi
a.a
Hav
Hav
st


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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).
&(/*(1(35235,(7$5<,1)250$7,21
g
e
ntracepti
ntraceptive
ve
i
ing the cou
ng the co
he l
he last dose
ast do
needed.
neede
udy-related
rela
her 
er protoco
otoco
bject
bject fro
from
etastasis. In
etastasis. In
sis.  
sis.  Prima
Prima
considered
considered
y wit
within 5 y
hin 5 y
d in
d in sisitu car
tu car
i
(all treatme
ll treatm
tu 
tu squamo
squamo
< 7, PSA <
< 7, PSA <
previously
previou
hylat
ylating ag
ing ag
s a h
s a history
istory
celiac dise
celiac di
rointestinal 
ointestinal
etabo
ab lism
lism
gastrointe
gastrointe
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.
&(/*(1(35235,(7$5<,1)250$7,21
er 
virus
irus
ndit
nditioion that
n t
ation in the
ation in th
those subje
those subje
agement of
gement o
ubject previ
bject previ
riries a high
es a high
eudoaneury
eudoaneury
ays prior to 
ays prior to
gat
gatioional the
nal th
ever is sh
ever is s o
m th
the acut
e ac
y/significan
/significa
y
herapy
erapy ≤ 4
≤4
and/or from
nd/or fro
nant or bre
nant or bre
s any 
ny signi
signi
hat would p
hat woul
bject has a
ect has an
plp aces the s
es the 
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;
&(/*(1(35235,(7$5<,1)250$7,21
vent 
en
ntained
tained.
ay
ays of
s of a 21
2
f
ble
ble fo
for safe
r safe
ycle 1
ycle 1; and
; an
equent
uent subj
ubj
dose for 14
se for 1
(8
(8 ounces) 
ounces) 
od (a light b
od (a light 
g days.
g days.
vent occurs
vent occu
at the subje
at the subje
Section
Section 9.9
tion in Asia
ion in A
ubjects of A
ubjects of 
y y and dete
and dete
1 subject of
subject o
ial 200 mg 
al 200 mg
cts of Asia
ts of Asi
mg
mg daily
daily, a
, a
ned as 
ed as an I
an 
ay 1) that l
1) that l
y
!
Gra
Gr


('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
&(/*(1(3
ombocytopen
ombocytop
nned start of 
d start of 
L
0
( 35235,(7$5<,1)250$7,21
of the nex
of the nex
begin.
begin.
ring a dose 
ing a dose 
unacceptab
unaccepta
will
will b
l e def
e def
poses a med
oses a m
Grade 3 or
Grade 3 o
ed after th
ed after th
t Gui
Guideline
delin
se Delays
e Delays f
Recomm
Recomm
35
2
to
1.5 x
5 x
Hold 
Hold
D
23
2
9/L
/L
( 3
eutropenia or
eutropenia or
delay to the
delay to th
C < 0.5 
< 0.5 x 10
x 109
latatelet
l s < 25
s < 25
or ANC 
or ANC
*


('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 
$
,
486.
486.
$
)2 0$
opean Society
opean Society
ce to ASCO o
ce to ASCO
nia with clinic
nia with
oxicity should 
xicity should
d be managed
be manage
the continuati
he continu
n all of the
n all of the
od should n
d should n
by the subj
the sub
y
protocol, re
protocol, r
verdose is d
verdose 
given subje
given subje
al) ) - any am
any am
or frequen
or freque
qui
quired sche
red sche
i
ete data abo
te data abo
dose was a
dose was a
8.2.5.
8.2
G
pa


('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.
&(/*(1(35235,(7$5<,1)250$7,21
d 
B or C, as 
B or C, as
the subjects
he subject
and for at 
and for at 
study
tudy accor
accor
y
(HCV) (HC
HCV) (HC
anti
nti-HCV 
HCV 
(eg Cy
(eg C cle 3
cle
known to 
known to 
reening (inc
reening (in
subjects pos
ubjects po
provides d
provides d
s of
s of viral
viral
f
ll
r at l
at least 4 
ast 4 


('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.
&(/*(1(35
lts:
ts:
-------------
---------
defined as:
defined as:
1 log in HBV
log in HBV
HBV
H
-DNA v
DNA v
surable HBV
surable HB
ND
&(
ALT elevati
ALT elevat
35235,(7$5<,1)250$7,21
HBV 
BV 
cination
ination
$7
-
0$
V-DNA ever
DNA ever
rting from C
rting from
ds or more f
s or more f
nically indic
cally ind
No spe
No spe
acti
acti
50
7$
2
B Reactiva
Reactiv
on of hepa
n of hep
manageme
anagem
clinical sign
linical sign
52
35


('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.
&(/
subjects with
ubjects with
(/*(1(35235,(7$5<,1)250$7,21
the
the
subject 
subject 
ral
dose of study
ose of study
uld discontin
uld discontin
at least 4 wee
least 4 we
)2
$7
festations
estations – H
athy, coma); i
athy, coma)
or a subject wh
r a subject w
reactivation i
reactivation i
onitored fo
onitored fo
HCV ant
HCV a
ibo
ib
of
of HCV inf
HCV in
f
at were trea
t were trea
reatment fo
reatment fo
or exacerb
or exacer
vation and 
vation and
ines for th
nes for th
1(
baseline resu
baseline re
HCV (HCV
HCV (HCV
n is defined 
is defined
vation > 5 U
vation > 5 U
(1
Knowledge o
Knowledge o
detectable
etectab
acer
(/


('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.
&(/*(1(35235,(7$5<,1)250$7,21
mber,
mber,
umber,
mber,
ons, storage
ns, storag
ble.
ble.
lations
lations.
alal
ite personn
te personn
uding respo
uding resp
e in the app
e in the app
Invest
Investigato
iga
ministered 
ministered 


('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.
&(/*(1(35235,(7$5<,1)250$7,21
se
F] and 
and 
per 
er Investi
Invest
) and E
and Euro
uro
t of neutrop
of neu
veststigator
tor’s’
es pri
es prior to e
or 
ribe
ibed at the 
at the
nt doses of 
nt doses of
the subjec
the subjec
g and for a
g and for a
e study
study acco
acco
y
mitant
mita
M
medicat
medicatioi ns 
ns
apeuti
peutic, targ
dine
ine), deci
), de i
Require
Requir
applicable.
applicable


('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
P.
ibilit
bility y cri
criter
ti
tensit
ensity and d
dose intens
ose inte
ments.
ments.
opulat
opula ion w
n
subjects wh
subjects wh
e will be eff
will be ef
and Pow
nd Pow
5 efficacy 
efficacy 
e est
e estimat
imatio
o show tha
o show tha
wo-sts age d
age d
0% o
0% r med
med
stage,
tage, 17
17
nro
nrollment 
llment 
subjects.
ubject
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.
&(/*(1(35235,(7$5<,1)250$7,21
h primary
primary
oth treatme
th treatm
d. Protocol
. Protoco
pulu ation.n.
t bino
binomial d
mia
RR will be p
will be
be used to e
be used to
S will be ba
S will be
eath, will b
eath, will b
dy will
will
y
 b b
l e c
e 
at the time
at the tim
to fo
to follo
llow-
of last con
f last con
will be used
will be use
90% 
% CI
C wil
w
tw
two-sided 
ed
fety Anal
fety Ana
y popul
populatatioio
y and tol
and tolera
era
ous advers
ous advers
mo
modificati
dificati
who rec
who re
ysi


('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.
&(/*(1(35235,(7$5<,1)250$7,21
nner.
nner.
n the popul
n the popu
the extent 
e exten
samples f
ples f
m
of
K paramete
K parame
versus time
rsus tim
curve (AUC
curve (AUC
n (C
n (Cmax
m ););
ncentration 
ncentration
F); and,
F); and,
n (apparen
n (apparen
an, 
an, standar
standar
median, min
median, m
d graphic f
d graphic f
kikits and de
ts and de
i
andling wil
andling wil
cititididine wil
ine wil
(LC-MS/M
MS/
.10.
10.
Ot
O
There i
There is n
s n
onduc
onduc


('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);
&(/*(1(35235,(7$5<,1)250$7,21
ome
me
mptoms of 
mptoms of 
be reporte
be reporte
h an AE sh
an AE sh
h
overdose.)
erdose
should be 
should be
n the sequel
the seque
lting 
ing in the
and CRF bu
nd CRF b
dy
dy.  Assess
.  Assess
ect’s clinic
ect’s clinic
physical ex
hysical e
gator
ator from t
from
and those S
and tho
ng related t
ng related 
the CRF an
he CRF an
Safet
Safety y wi
w ti
ropriate me
ropriate
uation of
uation of
nvest
nvestigator
igator
Seriou
Seriou
serious adv
erious adv
!


('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.
&(/*(1(35235,(7$5<,1)250$7,21
or 
ve. 
ve. 
E should be
E should be
wever, hos
wever, ho
administrat
dministra
ati
ation 
on not a
fusio
fusion as ro
n as r
rolonged h
rolonged
e SAE.
e SAE.
elelated inve
ated inve
tory
ory tests, b
tests, 
y
hospitaliza
hospitaliz
olongat
olongatioion o
n 
 of an AE.
of an AE
hat is plann
hat is pl
nted in the 
nted in the 
zati
ation f
on for 
or 
f
lect
lective tre
ive tre
nrelated to
nrelated to
Emerge
Emerg
unles
unl
f an AE i
f an AE is
must be c
must be c


('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.
&(/*(1(35235,(7$5<,1)250$7,21
calal
stance may
tance may
e usually re
 usually r
ble
ble
y, significan
significan
red, hospi
red, hospiti
y of a speci
y of a spec
wever, may
wever, m
erio
erion is no
no
ria associ
a associa
uide f
de for def
or de
f
ne the rela
ne the rela
as Not Susp
s Not Sus
Mean
Mea
adm
adm
Suspected:
Suspected:


('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
icable
able
comit
mitant
ant
AEs.
AEs.
parti
participat
cipat
covered or d
overed or
AE
AE if th
the a
udy
dy;
interruption
interruptio
ant clinical 
ant clini
y l
y aboratory
aborato
rious adver
ous adve
y i
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
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 
&(/*(1(35235,(7$5<,1)250$7,21
r 
form
form.
gator
ator
of f th
the seri
e seri
ther approp
ther approp
e SAE Rep
e SAE Rep
ed, without
d, withou
he Invest
Inves igi
to Celgene 
Celgene
Investigato
Investig
form
orm.
86 beco
bec me
me
pregnant f
pregnant f
female par
female par
hcare prof
hcare prof
the course 
the course 
ress any
s any co
co
Serious A
Serious A
criterion for
riterion 
rded on the
rded on t
ty y wi
with
th
i in 2
in 2
riate metho
iate metho
ertains to in
ertains to in
stigator
gator is r
is r
equi
equiremen
remen
i
dy (f(f
y
rom
rom
f
thth
m
investigat
nvestigatioio
that are 
at are
F)


('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).
&(/*(1(35235,(7$5<,1)250$7,21
business
siness
e the expec
e the expe
vest
estigator
igat
’s
ons (SUSA
ns (SUSA
32.2.
elgene or it
elgene or 
latory
atory Auth
Auth
y
irect
irective 20
ive 20
n of adverse
of adve
an use (EN
an use (EN
ase under st
se under st
sidered to b
idered to
pedited saf
pedited s
entative
entative sha
sha
ed of being
ed of bein
rious and u
rious an
ng fro
ng from tet
subject
subjects in
s in
,
uired by
ired by l
y oc
o
ew serious a
w serious 
Investi
Investigat
gat
corresponde
orresponde
inform
nformat


('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.
&(/*(1(35235,(7$5<,1)250$7,21
CRF and i
CRF and
sponsibilit
sponsibili y
wever, prio
wever, pri
and forwar
and forwar
n
red sufficie
red suffici
consent
onsen
follow
follow-up
-up
otocol
ocol vivi
l
ol
ol
Other
Other
eason for d
eason for


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
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.
&(/*(1(35235,(7$5<,1)250$7,21
ot be
ot 
ed on
d on
ntatives are
ntatives are
Celgene/C
Celgene/Co
nly
nly b
y e used
e used
or or design
r or desig
nal Produ
nal Pro
d on the pa
d on the pa


('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.
in 
authori
authorititi
i es
es
ical Practic
cal Practic
evaluate an
valuate
study
ud are a
re
study
study-relate
rel
s and other 
and othe
dy-
dy-rel
related d
ated
of all subje
of all sub
dy.  Subject
y.  Subjec
uments.
uments.
of the
of the Inve
Inve
ve queries a
queries 
talal charts, 
charts
l
st ensure t
st ensure 
rmation a
mation 
obtain infor
obtain info
lated proce
ated proc
that inform
hat inform
formed con
formed con
the date.  T
he date.  T
and by the
and by the
y, m
, must be 
ust be
m
n addit
n additioion, 
n,
inform
nformed
ed
mend
end


('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.
ain
arch
arch
or written a
or written a
versio
version oc
n oc
the Investi
Inves
able.
ble. Amen
Ame
be
be submi
bmittti
dent Ethic
ent Ethi
nform
nformed co
d c
e IRB/EC w
IRB/EC w
nd the site 
nd the site 
. If applicab
 If appli
alal ll egal
egal req
l
ststigator
igator by
b
nd legal req
nd legal re
presentativ
presentat
and their o
and their
ns and quali
ns and qu
ming that th
ming that th
B General 
B General 
oval by the 
oval by the 
ble), study
le), study
nts review
nts review
cially signe
cially signe
hihical and l
cal and 
The IRB
The IR
en


('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.
&(/*(1(35235,(7$5<,1)250$7,21
e;e;
ed risk to su
ed risk to su
reasonable
asonable
e appropria
e appropr
uthori
horititi
i es, e
es,
o discont
o discontinu
inu
ns such as
ns such a
ta collect
a collectioi
;
protocol
protocol.


('06'RF1XPEHU
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;
&(/*(1(35235,(7$5<,1)250$7,21
on as 
n as 
macy
acy, and
, and
elgene
elgene stan
stan
hrough use 
ugh us
es in the da
s in the d
nnel, if nece
nel, if nec
witithin the s
hin 
stigator
stigator fo
for
region and 
egion and
CH region,
CH region,
pment of th
pment of th
ed above or
d above o
ments incl
ents inc
nsent docum
nsent docum
catatioion code
n cod
ll co
ll commu
mmun
osisititi
i on of
on of thth
f
cord of all 
ord of all
representat
representat
!
List of
List of
Inv
Inv
t


('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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
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.
&(/*(1(35235,(7$5<,1)250$7,21
fter 
ter 
udy
dy
udy
dy, a
, a
formed 
formed 
itoring will
itoring wil
ropriate
ropriate
ts, the facil
s, the facil
and all oth
nd all 
tive in acco
ive in acc
on that i
n that s a
rce docume
ce docum
d/or his/her 
d/or his/he
querie
quer s by
s b t
y
d consents, 
d consents, 
roper recor
oper reco
udy
udy-specifi
specifi
s
ng procedu
ng procedu
presentative
resentative
Celgene S
Celgene
s.
quired to p
quired to
 CRFs and
CRFs and
ect
ectioions by I
ns by I
thorized rep
thorized rep
ditsts
i
and/or 
nd/or 
ing an inspe
ng an inspe


('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 
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 
metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 
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 
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.
&(/*(1(35235,(7$5<,1)250$7,21
atat-
753 patient
753 patien
haryngeal
aryngeal
HNS
NS-ESMO
ESMO
. Ann Onco
. Ann On
demethylat
demethylat
1.
otherapy
therapy f
y or
f
:244
244-249.
-249.
of
of capeci
capeci
f
tata
i
eated wit
ated with
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.
pe.
y
Ann
Ann
y of
of
y
oral
ora
f
 az
 az
l
and acute 
nd acute 
s C, Ly
s C, Lyman
ma
d fluoroura
fluoroura
the head an
e head an
enne
enne


('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 
external beam radiotherapy with or without brachytherapy. Int J. Radiat Oncol Biol Phys 
2010;76:130-137.
Lo KW, Chung GTY, To KF, et al. Acquired genetic and epigenetic alterations in 
nasopharyngeal carcinoma. In: Busson P, ed. Nasopharyngeal Carcinoma. New York, 
NY:Springer New York;2013:61-81.
Loomba R, Rowley A, Wesley R, et al. Systematic Review: the effect of preventive lamivudine 
on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-528
Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of 
advanced nasopharyngeal carcinoma. Cancer 2005;103:22-31.
Mendenhall WM, Werning JW, Pfister DG. Treatment of head and neck cancer. In: DeVita VT 
Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. 
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 
disseminated nasopharyngeal carcinoma. Ann Oncol 2011;22:718-722.
Okada T, Nakamura M, Nishikawa J, et al. Identification of genes specifically methylated in 
Epstein-Barr virus-associated gastric carcinomas. Cancer Sci 2013;104:1309-1314.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic 
nasopharyngeal carcinoma. Eur J Cancer 2003;39:1535-1541.
Paulson EJ, Speck SH. Differential methylation of Epstein-Barr virus latency promoters 
facilitates viral persistence in healthy seropositive individuals.  J Virol 1999;73:9959-9968.
Robertson KD, Ambinder RF. Methylation of the Epstein-Barr virus genome in normal 
lymphocytes.  Blood 1997;90:4480-4484.
Salamon D, Takacs M, Ujvari D, et al. Protein-DNA binding and CpG methylation at nucleotide 
resolution of latency-associated promoters Qp, Cp, and LMP1p of Epstein-Barr virus. J Virol 
2001;75:2584-2596.
Sham JS, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases 
from nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1993;26:787-792.
Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma; orderly neck node spread. Int J Radiat 
Oncol Biol Phys 1990;19:929-933.
Shiu WCT, Tsao SY. Efficacy of 4'-epidoxorubicin in advanced nasopharyngeal carcinoma. Clin 
Trials J 1989;26:419.
Simon R. Optimal two-Stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-
10.
&(/*(1(35235,(7$5<,1)250$7,21
: DeVita V
: DeVita 
9 h ed.
ed.
ion.n. J Cell 
J C
vily pretrea
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,
y-associ
assoc ate
ate
96.
96.
eung YK, C
eung YK, 
opharyngea
haryngea
JS, Cho
JS, Choy y D
col Bi
Biol
ol Ph
Ph
l
Shiu WC
Shiu WC
ririals 
als


('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.
Tierney R, Kirby H, Nagra J, et al. The Epstein-Barr virus promoter initiating B-cell 
transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5.  
J Virol 2000;74:10458-10467.
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.
Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of 
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 
ent of
nt of
ne expressio
e express
aryngeal ca
aryngeal c
rcino
inoma.
ma In
In
r Nasophar
Nasophar


('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.
&(/*(1(35235,(7$5<,1)250$7,21
7
$7
$7
$7
$7
work of a 
ork of a 
0$
activities. U
activities
5
han 50% of w
an 50%
)2
onfined to b
nfined to 
1)
,1
5<


('06'RF1XPEHU
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.
8VHU1DPH

7LWOH

'DWH)ULGD\$SULO30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
&(/*(1(35235,(7$5<,1)250$7,21
  

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 


',6&/2685(
5('$&7('35272&2/$0(1'0(17
&&13&
$3+$6(08/7,&(17(5,17(51$7,21$/6,1*/($50678'<72$66(66
7+(6$)(7<$1'()),&$&<2)6,1*/($*(17&&25$/$=$&,7,',1(
,135(9,286/<75($7('68%-(&76:,7+/2&$//<$'9$1&('25
0(7$67$7,&1$623+$5<1*($/&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,
ILIL
5,(7$5<,1)250$7,21
6
1(
1(
5
5
RWEHVKDUHG
RWEHVKDUHG
FKHUVDQGSD
KHUVDQ
JXO
JXODWLRQVUH
DWLRQVU
DORUF
RUFRQWUDF
RQWUDF
WRFHUWDLQSD
FHUWDLQS
DLQLQIRUPDW
LQLQIRUPDW
&HOJHQH¶VF
&HOJHQH¶V
SULQFLSOHV
SULQFLSOHV
H\ VSDFHPD
VSDFHPD
FDWLRQRIL
FDWLRQRIL
QFRQILGHQ
FRQILG
WLD
WL
DLQLGHQWLILD
LQLGHQWLI
OVRPD\FRQ
OVRPD\FRQ
LVJHQHUDWLQ
VJHQHUDWL
DWWDFKPHQWV
WWDFKPHQ
RIWKHUHSR
RIWKHUH
W&HOJHQHY
&HOJHQHY
KDWLQIRUPDW
KDWLQIRUPD
DERXWRXUY
DERXWRXU
RQDERXW&H
DERXW&H
QGDWKWWSZ
QGDWKWWSZ


('06'RF1XPEHU
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.
&(/*(1(35
ovided to you 
ovided to yo
f, and
f, and ethics c
ethics
5235,(7$5<,1)250$7,21
S 
S 
cit
citidine)
idine
001
001
14
tober
tobe 2014
01
14-001745
14-0017
122556
12255
Cel
Ce
8
is regarded as
s regarded as
not be disclo
not be dis
rsons to whom
rsons to whom
52
52
/*
/*


('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: 
&(/*(1(35235,(7$5<,1)250$7,21
0
50
25
)2
er should o
r should
Medical M
Medic
enter:
enter:
$5
7$5


('06'RF1XPEHU
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.  
&(/*(1(35235,(7$5<,1
,1
,1)250$7,21
0$
0$
50
s content to
conten
,1


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<,1)250$7,21
0$
0$
50
s study
s study at m
at
y
, informed 
nformed
ocedures, in
edures, i
Good Clin
Good C
ct of clinica
of clinic
$5
$5


('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.
&(/*(1(35235,(7$5<
5<
5<,1)
wi
wi
1)250$7,21
0$
0$
50
th
th
i
ICH G
ICH 
h
ghout the st
out the st
5<


('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.
&(/*(1(35235,(
r, internat
r, interna io
ated
ated subjec
sub
 previous
previous
bjects will b
jects will
t (
t (> 4 respo
4 res
subjects
subjects ba
n addi
addititi
i on
on
t will be st
t will be st
ulation
ulation
dy
dy will
will
y
be c
be 
l
lyly different
differen
y
wo o pri
prior 
o reg
reg
Length 
Length
7$5<,1)250$7,21
inically or 
inically o
py
py.
CC
CC-486 in
4
(7$
,(7


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ry day
y day
valuable
valuable fof
e tested. If 
e tested. If
AEs l
AEs leadin
eadi
equent subj
quent subj
on, unacce
n, unacce
refusal, phy
fusal, ph
progressio
progressio
1 gui
1 gu deline
deline
and then ev
nd then e
or wi
or with
th
i draw
draw
puted
uted tom
omog
wit
with suprac
h sup
minat
na ion wi
n w
cans will b
cans will b
ntnticancer
nce t
wed every
wed every 8
y
er occurs f
occurs f
Safety Asse
afety As
ts will be m
will be m
d Consent 
d Consent
cal condit
cal conditi
aminat
aminatioion
Epstein
Epstein-B
Group 
roup


('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
ment for 
ment for 
have
have
fficacy Eva
ficacy 
f
s > 5 month
s > 5 month
ts will be ac
s will be a
be stopped
be stopped
This
This Phase
as
ed in 51 su
ed in 51 su
yields a ma
yields a m
40%. Afte
40%. Aft
80%
80% (60%)
(60%
on the
on the effica
ef
RR will be b
R will be
onfidence in
nfidence i
based on the
ased on t
ovi
ov ded.
ed.
bilit
bility will
y will
s (SAEs)
(SAEs) l
ons, dose in
ns, dose in
eive one or
eive one o
ical examin
ical exami
ncomitant 
ncomitant 
All
All adve
dv
nc


('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
&(/*(1(35235,(7$5<,1)250$7,21
7
....... 18
18
...........
.......... 19
1
.............
............
..............
............
.............
............
................
..........
..............
.............
.............
.........
..............
...
..............
..........
......
...............
..............
.............
.............
.......
.............
.........
..............
.............
..............
.........
EVENTS
VENT
URES
URES......
ment Perio
ment Perio
nd
nd of
of Trea
Trea
f
Fo
Follo
llow
.
Effi
Eff
.2.2.
.2.2
.3.
.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
&(/*(1(35235,(7$5<,1)250$7,21
8
.......39
3
..........
.... 41
4
..............
...........
..............
............
.............
.............
..............
............
... ...........
......
.............
.....
............
.............
..... ..........
.......
y and Dispo
and Dispo
ce............
..........
IONS AND
ONS AND
edications 
ications 
nt Medi
M
cat
c
itant Medi
tant Med
i
L ANALY
ANALY
..............
..........
y Popul
Popul
y
atatioio
ample Si
ple Si
m
ze
ze
Backgro
Backgro
Subj
Su
0.6.
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
&(/*(1(35235,(7$5<,1)250$7,21
1
.......52
5
..........
.... 52
5
..............
...........
..............
............
.............
.............
..............
............
.............
......
..........
..... ...
..............
...........
.............
.............
..........
...............
..............
..........
.............
..........
URES
RES....
..............
.........
ficati
fication of
on of
RY CONSI
Y CONS
nical
cal Pract
Pra i
igator Res
igator Res
ubject Info
ubject Info
Confide
Confide
Prot
Pro
4.6.
4.6.
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
6
..........
.... 65
6
..............
...........
tus
us..........
.......


('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.
&(
t
(/*(1(35235,(7$5<,1)250$7,21
asal
sal
the lungs.
the lungs.
upper surfa
upper surf
sa of 
sa of 
harynx abu
harynx abu
the m
the muscle
uscle
m
e pharyngea
haryng
an irregular
n irregula
system des
system d
mo
mon subt
n subty
in so
in some
me are
ar
ca are diag
a are dia
zing ty
zing type
pe
y
(A
btype.
btype.
heast Chin
heast Chin
Asia, North
sia, North
g immigran
g immigra
ot exactly u
ot exactly u
lude
ude th
the pr
e p
et ri
et rich in s
ch in s
PC cells
PC cells an
an
have high 
have high
igens. The
igens. Th
several ye
everal ye
nes
nes


('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 
&(/*(1(35235,(7$5<,1)250$7,21
ecludes ear
ecludes ea
disease
disease
, 1993
, 1993; Sha
Sh
lvement at
lvement at
s is to bone
is to bo
d rate in ax
d rate in a
herapy
herapy alal
y
on
ry f
y or resi
or resi
f
d
diatatioion the
n th
r the primar
r the primar
e retreated w
e retreated 
radiation
radiation
e site of re
e site of
e or local re
or local r
py shoul
py should b
d
py
py remains 
remains
y
especially 
specially
stages (IIB
stages (IIB
ith local an
th local a
survival an
survival an
hs and 4
and 4 toto
%.
%. Isolated
Isolated
ar survival 
r survival 
plplatatinum
inum-b
ecomm
ecomm


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
18
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 
es
es
c
the
he
l studies,
studies, 
ecan have
ecan have
and capeci
and capeci
months 
months (F
ang, 2008
ang, 2008)
008 and rep
008 and r
val o
val of f 12.8
12
ies, m
es
ostly
ostly
ucleoside cy
cleoside
sis and met
sis and m
d by the US
by the US
ish
sh (FAB) 
(FAB
proved by
proved b t
y
mia (A
mia (AML)
r hematopo
hematopo
 (IV
IV) or 
or su
ioioavailable
availab
rati
ration into 
on into 
cts wi
ts with
ti  DN
 D
h
nance of DN
ance of DN
tic changes
change
ate the stab
ate the sta
st recogniz
ecogniz
group to c
group to c
nd is a
nd is a


('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 
&(/*(1(35235
n Solid
olid Tu
n combinat
n combinat
psed or ref
ed or ref
of this two
of this tw
ys 1 to 14 o
 1 to 14 o
AZA
ZA-ST
ST-0
-0
subjects re
ubjects re
300 mg w
300 mg w
itaxel was a
itaxel was 
ncountered
ncountered
nab-
na
pacli
pacli
com
com
5,(7$5<,1)250$7,21
ring 
ng 
aily
ily and tw
and tw
y
fashio
fashion. 
n. C
mulat
mulative ex
ive e
tely
ely 40%
40% an
espect
espectively
ivel
day
ay sc
sc
y
hed
h
being the m
being the m
n lelevelsls ini b
hypo
hypomet
methy
hy
ally act
ally active,
ve
.
5,(
35,


('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).
&(/*(1(
o
1(35235,(7$5<,1)250$7,21
aluable
uable
hers had 
hers had
in subjects
n subject
ovocative, 
ovocativ
ZA
Z -ST
ST-00
-0
The ongoin
he ongoin
hich
hich 5 are 
are
and 3 subj
and 3 subj
subject
subject rep
rep
re encourag
re encoura
86 treatmen
86 treatme
informat
informatioio
m, clinical
, clinical
shown pro
shown pro
C-486 w
486 was 
ay
ay cycle wi
cycle w
difying ag
difying a
s in subject
in subjec
pported
pported in t
in t
Frequent
Freque
!
Gen
Gen
!


('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.
&(/*(1(35235,(7$5<,1)250$7,21
, 2004
, 2004).).
nt the
nt the
ird d
i
line set
line 
QD for 21 
D for 21 
neutrop
utr
enia
ni
day
day schedu
sche
proposal is
roposal 
200 mg da
200 mg d
creasing th
creasing th
l be fo
be follo
llow
NPC who 
NPC who 
d the encou
the encou
86 as
86 as a a sin
s


('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
 
&(/*(1(35235,(7$5<,1)250$7,21
netetics
i
lected 
ected 
)25
1)


('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
 
&(/*(1(35235,(7$5<,1)250$7,21
eri
eria a
dy
dy treatm
treatm
y
e
nse using
se using
eatment to 
tment to
rgent adver
rgent adve
, , Grade
Grade 3 a
3
normalities
normalities
subset of 
subset of
s
235
523
352
( 35
1(3


('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.
&(/*(1(35235,(7
d d 
(7$5<,1)250$7,21
nts s
n’s 
n s
ut of the fi
ut of the f
en
en th
the stud
e stud
es out of 17
es out of 17
will be base
will be bas
bjects who 
ects wh
r. . Subjects 
Subject
y reason oth
reason ot
jects who p
ects w
ioion, or as d
n, or as
ST
ST v1.1 1 init
i it
disease p
disease p
w-up
up. All su
. All 


('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.
&(/*(1(35235,(7$5<,1)250$7,21
5,(7$5<,1)250$7
   
FS
month
1)
atm
tment is ex
ent is e
population
populatio
nitori
tori
i
ng of 
ng o
ssio
ss
n (if ap
n (if 
r analysis, 
r analysi
nd of Tri
nd of Tri
of Trial is 
Trial i
 or the date
or the date
mary
mary, seco
, seco
Stati
Statistical
ical A
subjects
ubject


('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
&(/*
pri
prietet
/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
0$
quent 
en
es
es
25
25
25
25
1
)2
< ,
<
---
5<
$
---
--
$5
7$
----
7$
7$
7$
7$
---
---
(7
5,
----
5,
5,
5,
5,
As needed
s neede
35
52
Conti
Conti
52
52
52
52
8d from 
m
eening)
eening)
3
X
1(
(1
C
*(
*(
*(
/*(


('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
---
&(/*(1(
pri
prietet
1(
(w/in72 hou
w/in72 ho
( 35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
X
1)
< ,
X
< ,
< ,
< ,
< ,
----
5<
X
$5
7$
X
7$
7$
7$
7$
-----
(7
5, 7
---
5,
5,
5,(
5,
----
35
X
2
52
--
52
52
52
52
35
(
1(


('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
---
---
e Corpora
e Corpora
21
pri
prietet
Fo
Follo
7,2
$7
0$
5
E
50
25
1)
Cycle 1 Day
Cycle 1 Da
disease prog
disease pro
f consent
f consent
,1
mptomatic o
mptomat
5<
X
$
7$
PK ASSES
PK ASSES
(7$
7$
7$
---
---
,(
5,
l
35
X**
X**
23
52
INVESTIG
INVESTIG
52
52
52
35
-
(
1


('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.
&(/*
pri
prietet
*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
1)
---
---
,1
< ,
----
5<
$ <
mputed tomo
mputed to
childbearing 
childbearing
teractive
eractiv re
hin
hin.
ust occur wit
ust occur
ons are perfo
s are perfo
irst treatment
rst treatmen
e first treatm
e first treatm
base at screen
ase at scre
visit, that pa
visit, tha
CBC) with di
BC) with d
hil count (AN
hil count (AN
dium, potass
dium, potass
ct), aspartate
), aspartate
rothrombin ti
rombin 
may be
may b used)
used)


('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.
&(/*(1(35235,(7$5<,1)250$
pri
prietet
0$7,21
e Corpora
e Corpora
21
gnancy testin
nancy test
screening pre
screening pre
stigator
gator has
h
v
uraged/recom
aged/recom


('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. 
&(/*(1(35235,(7$5<,1)250$7,21
tory
ry
ndow if 
dow if 
(Table
Table 1),)
nosis, stagin
osis, stagin
nicit
ic y-y-if all
if al
ct number r
number r
radi
radiatation, s
n
vant medic
vant medic
ded)
ded)
cedures (in
cedures
ant m
nt medica
edic
pt for those
t for thos
aminat
amina ion (
n
gns (includ
gns (includ
stern Coope
tern Coop
Appendix A
Appendix A
!
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 
&(/*(1(35235,(7$5<,1)250$7,21
n all
n all
ycle 1 Day
cle 1 Day
omboplast
mboplastinin
and D1 of e
and D1 of
of childbe
of childbe
reening. Ur
eening. Ur
gibilit
gibility y wi
withth
i
ancy test di
ancy test d
or IP admin
r IP admin
afafter
ter
f
th
the s
e s
mi
mitted if Sc
tted if 
i
od
tment upon
ment upo
s of signing
s of signin
ndow of ± 2
dow of ±
are 21
are 21 day
day
ng evaluatio
ng evaluatio
he evaluat
evaluati
ed:
ed:
!
Co
Co
!


('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
&(/*(1(35235,(7$5<,1)250$7,21
g dose
dose
ection
ction 6.4
6.4)
done in Sta
one in Sta
n 6.3
6.3)
c or with kn
or with kn
t (pri
t (prior t
r to d
o d
each cycle
each cycle
n shoul
n should b
d
as possible 
as possibl
ects should
ects shoul
will be per
will be pe
xaminat
amination
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 
&(/*(1(35235,(7$5<,1)250$7,21
gression, st
gression, st
be fo
be follo
llowe
w
ed in Secti
d in Secti
weeks 
eks (± 5 
(± 5
chever occu
chever occ
New antica
New anti
ery
ery, radiati
, radiat
ecord revie
ecord revie
ily, or the
, or the
ments
ments
r evaluat
r evaluatioio
every
ery 6
y
wee
we
ery
ery 9 week
wee
y
sent from t
ent from
performed
performed
reening.
eening. Ev
E
by 
by Invest
Investigig
ependent 
pendent rara
.1.1.
A
Response
Response
sess
sess


('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
ndergo a br
ndergo a 
.
y y only)
only) at 
at
s, and ship 
and ship
Asian
Asian-Pacif
Pac
1-day
day cycl
cyc
y
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
e time of 
d appropria
appropr
azacit
aza
idine
din
dose) and o
ose) and 
3, 3.5, 4, 6
3, 3.5, 4, 6
Schedule
Schedule
Pharm
Pharm
N
/*
(/
&(
&


('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.
 
&(/*(1(3
subjects
subjects o
35,(7$5<,1)250$7,21
7
$7
$7
$7
$7
0$
50
25
ssments an
ments an
ed.  Then, i
.  Then,
240 mL of 
240 mL 
est CC
st CC-486
-4
2 hours pos
hours p
administra
administra
is the 240 
is the 240
235
523
52
35
( 35
1(


('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
 
 
 
&(/*(1(35235,(7$5<,1)250$7,21
$7
$7
$7
0$7
0$
0
50


('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 
&(/*(1(35235,(7$5<,1)250$7,21
ument.
ument.
poorly
poorly
metastati
etastatic.c
lly afafter
te
f
1 t
n, 1982
n, 1982) se
) 
able disease
le diseas
ced by
ced by the f
th
y
pper limit o
pper limit 
range, or co
range, o
e marrow fu
marrow 
hil count 
hil count ≥ ≥
x 10
109 cells
cells
≥ 9 g/dL
≥ 9 g/dL
childbearin
childbearin
undergone a
ndergone 
orectomy
rectomy (th
(t
y
stmenopaus
enopaus
he precedi
preced
a.a.
Ha
Ha


('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).
&(/*(1(3
atat
35235,(7$5<,1)250$7,21
acepti
eptive
ve
i
the cou
the course
rse
ast dose of
ast dose o
eded.
ded.
related
related
r protocol r
protocol r
ct fro
from enro
enr
stasis. In su
stasis. In su
.  Primary
.  Primary N
y
nsidered br
nsidered br
ithin 5 year
hin 5 year
sisitu carcin
tu carcin
i
treatment 
treatment 
squamous 
quamous
 PSA <10
PSA <10
viously
viously tre
t
ing agent
g ag
history
istory of
o
y f
liac disease
liac disease
ntestinal dis
ntestinal d
bo
bolism
lism, or 
or
astrointestin
rointestin
Subject h
Subject
6.6. Subj
Subj
T


('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.
&(/*(1(35235,(7$5<,1)250$7,21
t t 
e clinical
e clinical
not recover
not reco
ays or 5 hal
s or 5
prior antica
ior antica
fieleld d radi
radiata
f the bone m
f the bone 
dititioion, l
n, labo
ab
t from part
t from part
ding the pre
ing the p
table risk if
able risk
that confo
that confo


('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;
&(/*(1(35235,(7$5<,1)250$7,21
vent 
en
ntained
tained.
ay
ays of
s of a 21
2
f
ble
ble fo
for safe
r safe
ycle 1
ycle 1; and
; an
equent
uent subj
ubj
dose for 14
se for 1
(8
(8 ounces) 
ounces) 
od (a light b
od (a light 
g days.
g days.
vent occurs
vent occu
at the subje
at the subje
Section
Section 9.9
tion in Asia
ion in A
ubjects of A
ubjects of 
y y and dete
and dete
1 subject of
subject o
ial 200 mg 
al 200 mg
cts of Asia
ts of Asi
mg
mg daily
daily, a
, a
ned as 
ed as an I
an 
ay 1) that l
1) that l
y
!
Gra
Gr


('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
&(/*
neutropenia o
neutropenia 
delay to the
delay to th
C < 0.5 
< 0.5 x 10
x 109
latatelet
l s < 25
s < 25
or ANC 
or ANC
*(1(3
rombocytope
rombocyto
nned star
ed start of 
t of 
L
( 35235,(7$5<,1)250$7,21
of the nex
of the nex
begin.
begin.
ring a dose 
ring a dose 
unacceptab
unaccepta
will
will b
l e def
e def
poses a med
oses a m
Grade 3 or
Grade 3 o
ed after th
ed after th
t Gui
Guideline
delin
se Delays
e Delays f
Recomm
Recomm
35
2
to 
1.5 x
5 x
Hold 
Hold
D
23
2
09/L
/L
( 3
*


('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.
0$
al
0 mg.
0 mg.
discontinue 
iscontinue
CC
CC-486.
486
0$
0$
1)
0$
European So
European So
ordance to AS
rdance
ytopenia with
topenia wit
cal toxicity sh
cal toxicity
should be ma
should be ma
fever, the cont
ever, the co
r.r.
IP on all of
IP on all of
period shou
period shou
ned by
d by the s
the 
y
this protoco
his protoco
an overdose
n overdo
o a
o a given s
given s
(oral
(oral) ) - an
a
dule or freq
ule or freq
ol requi
requi
l
red 
red 
i
mplete data
plete data
m
overdose w
verdose w
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.
&(/*(1(35235,(7$5<
r i
r i
5<,1)250$7,21
l the proces
the proce
nsibilit
sibilities f
ies
ropriate sec
opriate se
r or desi
or de gn
n their cu
n their c


('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.
&(/*(1(35235,(7$5<,1)250$7,21
and 
nd 
Investi
nvestigat
gat
nd E
d Europe
urope
f neutropen
f neutropen
igator
gator’s di
’s di
prior to eac
or to eac
d at the fir
at the fi
doses of 
oses of CC
CC
ations
ations an
a
pecifically
pecifically
d, or 
, or invest
investi
e, or other d
, or other 
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
y y cri
criteria
teria
i
ty and disc
and disc
e intensit
intensity a
y
s.s.
atatioion will b
will b
ects who ha
ects who h
l be efficac
be effica
d Power C
d Power C
fficacy eval
cacy eva
imat
matioion is 
is 
ow that the
ow that the
tage design
age desig
or med
median
ian P
ge,
ge 17 subj
subj
llment will
llment wil
ubjects.
ubjects. Sub
Sub
repl
ep aced.
ced.
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 
&(/*(1(35235,(7$5<,1)250$7,21
y
ment 
ment 
ol
al distribut
l distributi
be provi
be provided
d
o estimate 
o estimate 
based on t
based on
be consid
be consid
e considere
e consider
me of the c
me of the c
w-
w up pri
up prior 
or 
ontact.
ntact.
sed to estim
sed to estim
will be pr
ill be prov
o
l be includ
e inc
y will
y will b
l e m
e 
ents, labora
ents, labora
dose interru
dose interru
one or mor
one or mo
examinat
aminatioio
mitant medi
itant medi
verse even
erse even
worsens in
worsens in
will be 
will be
t


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ure, and to
ure, and t
be collecte
be collecte
t limited to
limited to
ata:
ta:
n, coefficie
, coeffici
x) will be pr
x) will be p
ppropriate.
propriate
tructions fo
uctions fo
ided to the
ded to th
ured using 
ured using
pics
pics
Steering C
Steering C
erim Effica
erim Effica
ly. The inte
y. The inte


('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);
&(/*(1(35235,(7$5<,1)250$7,21
rom
ome
mptoms of 
mptoms of 
be reporte
be reporte
th an AE sh
h an AE sh
overdose.)
erdose
should be 
should be
n the sequel
the seque
lting 
ing in the
and CRF bu
nd CRF b
dy
dy.  Assess
.  Assess
ect’s clinic
ect’s clinic
physical ex
hysical e
gator
ator from 
from t
and those S
and tho
ng related t
ng related 
the CRF an
he CRF an
Safet
Safety y wi
w ti
ropri
ropriate m
ate
uation of
uation of
nvest
nvestigator
igator
Seriou
Seriou
serious adv
erious adv
!


('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.
&(/*(1(35235,(7$5<,1)250$7,21
or 
ve. 
ve. 
E should be
E should be
wever, hos
wever, ho
administrat
dministra
ati
ation
on not a
usision
on as ro
as r
n
rolonged h
rolonged
e SAE.
e SAE.
elelated inve
ated inve
tory
ory tests, b
tests, 
y
hospitaliza
hospitaliz
olongat
olongatioion o
n 
e of an AE.
e of an AE
hat is plann
hat is pl
nted in the 
nted in the 
zati
ation f
on for 
or 
f
lect
lective tre
ive tre
nrelated to
nrelated to
Emerge
Emerg
unles
unl
f an AE i
f an AE is c
s
must be c
must be c


('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.
&(/*(1(35235,(7$5<,1)250$7,21
calal
stance may
tance may
e usually re
 usually r
ble
ble
y, significan
significan
red, hospi
red, hospiti
y of a speci
y of a spec
we
wever, may
ver, m
erio
erion is no
no
ria associ
a associa
uide f
de for def
or de
f
ne the rela
ne the rela
as Not Susp
s Not Sus
Mean
Mea
adm
adm
Suspected:
Suspected:


('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 
&(/*(1(35235,(7$5<,1)250$7,21
icable
able
comit
mitant
ant
AEs.
AEs.
parti
participat
cipat
covered or d
overed or
AE
AE if th
the a
udy
dy;
interruption
interruptio
ant clinical 
ant clini
y l
y aboratory
aborato
rious adver
ous adve
y i
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
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 
&(/*(1(35235,(7$5<,1)250$7,21
r 
form
form.
gator
ator
of f th
the seri
e seri
ther approp
ther approp
e SAE Rep
e SAE Rep
ed, without
d, withou
he Invest
Inves igi
to Celgene 
Celgene
Investigato
Investig
form
orm.
86 beco
bec me
me
pregnant f
pregnant f
female par
female par
hcare prof
hcare prof
the course 
the course 
ress any
s any co
co
y
Serious A
Serious A
criterion for
riterion 
rded on the
rded on t
ty y wi
with
th
i in 2
in 2
riate metho
iate metho
ertains to in
ertains to in
stigator
gator is r
is r
equi
equiremen
remen
i
dy (f(f
y
rom
rom
f
thth
m
investigat
nvestigatioio
that are 
at are
F)


('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).
&(/*(1(35235,(7$5<,1)250$7,21
business 
siness 
e the expec
e the expe
vest
estigator
igat
’s
ons (SUSA
ns (SUSA
32.2.
elgene or it
elgene or 
latory
atory Auth
Auth
y
irect
irective 20
ive 20
n of advers
n of adve
an use (EN
an use (EN
ase under st
se under st
sidered to b
idered to
pedited saf
pedited s
entative
entative sha
sha
ed of being
ed of bein
rious and u
rious an
ng fro
ng from tet
subject
subjects in
s in
,
uired by
ired by l
y oc
o
ew serious a
w serious 
Investi
Investigat
gat
corresponde
orresponde
inform
nformat


('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.
&(/*(1(35235,(7$5<,1)250$7,21
CRF and i
CRF and
sponsibilit
sponsibili y
wever, prio
wever, pri
and forwar
and forwar
n
red sufficie
red suffic
consent
onsen
follow
follow-up
-up
otocol
ocol vivi
l
ol
ol
Other
Other
eason for d
eason for


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ot be
ot 
ed on
d on
ntatives are
ntatives are
Celgene/C
Celgene/Co
nly
nly b
y e used
e used
or or design
r or desig
nal Produ
nal Pro
d on the pa
d on the pa


('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.
&(/*(1(35235,(7$5<,1)250$7,21
in 
authori
authorititi
i es
es
ical Practic
ical Practic
evaluate an
valuate
study
ud are a
re
study
study-relate
rel
s and other 
and othe
dy-
dy-rel
related d
ated
of all subje
of all sub
dy.  Subject
y.  Subjec
uments.
uments.
of the
of the Inve
Inve
ve queries a
queries 
ital charts, 
al charts
st ensure t
st ensure 
rmation a
mation 
obtain infor
obtain info
lated proce
ated proc
that inform
hat inform
formed con
formed con
the date.  T
he date.  T
and by the
and by the
y, m
, must be 
ust be
m
n addit
n additioion, 
n,
inform
nformed
ed
mend
end


('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.
ain
arch
arch
or written a
or written a
versio
version oc
n oc
the Investi
Inves
able.
ble. Amen
Ame
be submitt
be submit
dent Ethic
ent Ethi
nform
nformed co
d c
e IRB/EC w
e IRB/EC w
nd the site 
nd the site 
. If applicab
 If appli
alal ll egal
egal req
l
ststigator
igator by
b
nd legal req
nd legal re
presentativ
presentat
and their o
and their
ns and quali
ns and qu
ming that th
ming that th
B General 
B General 
oval by the 
oval by the 
ble), study
le), study
nts review
nts review
cially signe
cially signe
hihical and l
cal and 
The IRB
he IR
en


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<,1)250$7,21
e;e;
ed risk to su
ed risk to su
reasonable
asonable
e appropria
e appropr
uthori
horititi
i es, e
es,
o discont
o discontinu
inu
ns such as
ns such a
ta collect
a collectioi
;
protocol
protocol.


('06'RF1XPEHU
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;
&(/*(1(35235,(7$5<,1)250$7,21
on as 
n as 
macy
acy, and
, and
elgene
elgene stan
stan
hrough use 
ugh us
es in the da
s in the da
nnel, if nece
nel, if nec
witithin the s
hin 
stigator
stigator fo
for
region and 
egion and
CH regi
CH region,
on,
pment of th
pment of th
ed above or
d above o
ments incl
ents inc
nsent docum
nsent docum
catatioion code
n cod
ll co
ll commu
mmun
osisititi
i on of
on of thth
f
cord of all 
ord of all
representat
representat
!
List of
List of
Inv
Inv
t


('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.
&(/*(1(35235,(7$5<,1)250$7,21
e
ities.
ties.
destruction
destruction


('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.
&(/*(1(35235,(7$5<,1)250$7,21
fter 
ter 
udy
dy
udy
dy, a
, a
formed 
formed 
itoring will
itoring wil
ropriate
ropriate
ts, the facil
s, the facil
and all oth
nd all 
tive in acco
ive in acc
on that i
n that s a
rce doc
ce docume
um
d/or his/her 
d/or his/he
queries by t
queries by t
d consents, 
consents, 
roper recor
oper reco
udy
udy-specifi
specifi
s
ng procedu
ng procedu
presentative
resentative
Celgene S
Celgene
s.
quired to p
quired to
 CRFs and
CRFs and
ect
ectioions by I
ns by I
thorized rep
thorized rep
dits and/or 
ts and/or 
i
ing an inspe
ng an inspe


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


('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
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 
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 
metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 
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 
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.
&(
th
&(/*(1(35235,(7$5<,1)250$7,21
atat-
753 patient
753 patien
haryngeal
haryngeal
HNS
NS-ESMO
ESMO
. Ann Onco
. Ann On
demethylat
demethylat
1.
otherapy
therapy f
y or
f
:244
244-249.
-249.
of capecita
of capecita
eated wit
ated with
et al.
et al. Cape
Cap
ase II study
ase II study
et al.
et al. Mul
M ti
l
carcino
carcinom
dy. J Clin O
dy. J Clin 
Leong SS, 
Leong SS, 
d ty
d type.
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.
Lo KW, Chung GTY, To KF, et al. Acquired genetic and epigenetic alterations in 
nasopharyngeal carcinoma. In: Busson P, ed. Nasopharyngeal Carcinoma. New York, 
NY:Springer New York;2013:61-81.
Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of 
advanced nasopharyngeal carcinoma. Cancer 2005;103:22-31.
Mendenhall WM, Werning JW, Pfister DG. Treatment of head and neck cancer. In: DeVita VT 
Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. 
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 
disseminated nasopharyngeal carcinoma. Ann Oncol 2011;22:718-722.
Okada T, Nakamura M, Nishikawa J, et al. Identification of genes specifically methylated in 
Epstein-Barr virus-associated gastric carcinomas. Cancer Sci 2013;104:1309-1314.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic 
nasopharyngeal carcinoma. Eur J Cancer 2003;39:1535-1541.
Paulson EJ, Speck SH. Differential methylation of Epstein-Barr virus latency promoters 
facilitates viral persistence in healthy seropositive individuals.  J Virol 1999;73:9959-9968.
Robertson KD, Ambinder RF. Methylation of the Epstein-Barr virus genome in normal 
lymphocytes.  Blood 1997;90:4480-4484.
Salamon D, Takacs M, Ujvari D, et al. Protein-DNA binding and CpG methylation at nucleotide 
resolution of latency-associated promoters Qp, Cp, and LMP1p of Epstein-Barr virus. J Virol 
2001;75:2584-2596.
Sham JS, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases 
from nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1993;26:787-792.
Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma; orderly neck node spread. Int J Radiat 
Oncol Biol Phys 1990;19:929-933.
Shiu WCT, Tsao SY. Efficacy of 4'-epidoxorubicin in advanced nasopharyngeal carcinoma. Clin 
Trials J 1989;26:419.
Simon R. Optimal two-Stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-
10.
Tierney R, Kirby H, Nagra J, et al. The Epstein-Barr virus promoter initiating B-cell 
transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5.  
J Virol 2000;74:10458-10467.
&(/*(1(35235,(7$5<,1)250$7,21
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
9:1535
9:1535-15
-15
ioion of Eps
n of Eps
oposit
opositive
ive ini
ylat
ylatioion of th
n o
0-4484.
-44
 D, et al.
D, et al. P
ated prom
ated prom
YK, Cho
K, Choy y D
geal carcin
geal carcin
oy y D, 
D, Wei
Wei
l Phys 199
Phys 199
l
WCT, Tsao
WCT, Tsao
als J 1989;
ls J 1989;
Si
Simo
m n R.
n R.
0


('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.
Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of
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.
&(/*(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.
&(/*(1(35235,(7$5<,1)250$7,21
7
$7
$7
$7
$7
work of a 
ork of a 
0$
activities. U
activities
5
han 50% of w
an 50%
)2
onfined to b
nfined to 
1)
,1
5<


('06'RF1XPEHU
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.
8VHU1DPH

7LWOH

'DWH:HGQHVGD\2FWREHU$0(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
&(/*(1(35235,(7$5<,1)250$7,21
PH
PH
  

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 


',6&/2685(
5('$&7('25,*,1$/35272&2/
&&13&
$3+$6(08/7,&(17(5,17(51$7,21$/6,1*/($50678'<72$66(66
7+(6$)(7<$1'()),&$&<2)6,1*/($*(17&&25$/$=$&,7,',1(
,135(9,286/<75($7('68%-(&76:,7+/2&$//<$'9$1&('25
0(7$67$7,&1$623+$5<1*($/&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,
ILIL
5,(7$5<,1)250$7,21
6
1(
1(
5
5
RWEHVKDUHG
RWEHVKDUHG
FKHUVDQGSD
KHUVDQ
JXO
JXODWLRQVUH
DWLRQVU
DORUF
RUFRQWUDF
RQWUDF
WRFHUWDLQSD
FHUWDLQS
DLQLQIRUPDW
LQLQIRUPDW
&HOJHQH¶VF
&HOJHQH¶V
SULQFLSOHV
SULQFLSOHV
H\ VSDFHPD
VSDFHPD
FDWLRQRIL
FDWLRQRIL
QFRQILGHQ
FRQILG
WLD
WL
DLQLGHQWLILD
LQLGHQWLI
OVRPD\FRQ
OVRPD\FRQ
LVJHQHUDWLQ
VJHQHUDWL
DWWDFKPHQWV
WWDFKPHQ
RIWKHUHSR
RIWKHUH
W&HOJHQHY
&HOJHQHY
KDWLQIRUPDW
KDWLQIRUPD
DERXWRXUY
DERXWRXU
RQDERXW&H
DERXW&H
QGDWKWWSZ
QGDWKWWSZ


('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
ided to yo
and ethics co
and ethics co
regarded as c
garded as c
not be disclose
not be disclos
ons to whom 
ns to whom
5235,(7$5<,1)250$7,21
S 
S 
cit
citidine)
idine
001
001
14
4-001745-
-001745
122556
122556
Celelge
g
86
86
52
52
/*
/*


('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: 
&(/*(1(35235,(7$5<,1)250$7,21
0
50
25
)2
er should o
r should
Medical M
Medic
enter:
enter:
$5
7$5


('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.  
,1
,1)250$7,21
0$
0$
50
s content to
conten
,1


('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.
&(/*(1(35235,(7$5
$5
$5<,1)250$7,21
0$
0$
50
s study
s study at m
at
y
, informed 
nformed
ocedures, in
edures, i
Go
Good Clin
od C
ct of clinica
of clinic
$5


('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.
&(/*(1(35235,(7$5<
5<
5<,1)
wi
wi
1)250$7,21
0$
0$
50
th
th
i
ICH G
ICH 
h
ghout the st
out the st
5<


('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.
&(/*(1(35235,(
r, internat
r, interna io
ated
ated subjec
sub
previous
previous
bjects will b
jects will
t (
t (> 4 respo
4 res
subjects
subjects ba
n addi
addititi
i on
on
t will be st
t will be st
ulation
ulation
dy
dy will
will
y
be c
be 
l
lyly different
differen
y
wo o pri
prior 
o reg
reg
7$5<,1)250$7,21
inically or 
inically o
py
py.
CC
CC-486 in
4
Length
Length
(7$
,(7


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ry day
y day
valuable
valuable fof
e tested. If 
e tested. If
AEs l
AEs leadin
eadi
equent subj
quent subj
on, unacce
n, unacce
refusal, phy
fusal, ph
progressio
progressio
1 gui
1 gu deline
deline
and then ev
nd then e
or wi
or with
th
i draw
draw
puted
uted tom
omog
wit
with suprac
h sup
minat
na ion wi
n w
cans will b
cans will b
ntnticancer
nce t
wed every
wed every 8
y
er occurs f
occurs f
Safety Asse
afety As
ts will be m
will be m
d Consent 
d Consent
cal condit
cal conditi
aminat
aminatioion
Epstein
Epstein-B
Group 
roup


('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 
&(/*(1(35235,(7$5<,1)250$7,21
ment for 
ment for 
have
have
fficacy Eva
ficacy 
f
s > 5 month
s > 5 month
ts will be ac
s will be a
be stopped
be stopped
This
This Phase
as
ed in 51 su
ed in 51 su
yields a ma
yields a m
40%. Afte
40%. Aft
80%
80% (60%)
(60%
on the
on the effica
ef
RR will be b
R will be
onfidence in
nfidence i
based on the
ased on t
ovi
ov ded.
ed.
bilit
bility will
y will
s (SAEs)
(SAEs) l
ons, dose in
ns, dose in
eive one or
eive one o
ical examin
ical exami
ncomitant 
ncomitant 
All
All adve
dv
nc


('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
&(/*(1(35235,(7$5<,1)250$7,21
7
....... 18
18
...........
.......... 19
1
.............
............
..............
............
.............
............
................
..........
..............
.............
.............
.........
..............
...
..............
..........
......
...............
..............
.............
.............
.......
.............
.........
..............
.............
..............
.........
EVENTS
VENT
URES
URES......
ment Per
ment Perioi
nd of Trea
nd of Trea
Fo
Follo
llow
.
Eff
Effif
.2.2.
.2.2
.3.
.3.


('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
&(/*(1(35235,(7$5<,1)250$7,21
6
.......37
3
..........
.... 39
3
..............
...........
..............
............
.............
.............
..............
............
... ...........
......
.............
.....
............
.............
..... ..........
.......
y and Dispo
and Dispo
ce............
..........
IONS AND
ONS AND
edications 
ications 
nt Medi
M
cat
c
itant Medi
tant Med
i
L ANALY
ANALY
..............
..........
y Popul
Popul
y
atition
on
ample Si
ple Si
m
ze
ze
Backgro
Backgro
Subj
Su
0.6.
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 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
&(/*(1(35235,(7$5<,1)250$7,21
9
.......50
5
..........
.... 50
5
..............
...........
..............
............
.............
.............
..............
............
.............
......
..........
..... ...
..............
...........
.............
.............
..........
...............
..............
..........
.............
..........
URES
RES....
..............
.........
ficati
fication of
on of
RY CONSI
Y CONS
nical Pract
cal Pra i
igator Res
igator Res
ubject Info
ubject Info
Confide
Confide
Prot
Pro
4.6.
4.6.
7


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
13
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
&(/*(1(35235,(7$5<,1)250$7,21
1
.......62
6
..........
.... 63
6
..............
...........
tus
us..........
.......


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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
15
CC-486-NPC-001 Final: 11 July 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 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.
&(/*(1(35235,(7$5<,1)250$7,21
asal
sal
the lungs.
the lungs.
upper surfa
upper surf
sa of 
sa of 
harynx abu
harynx abu
the m
the muscle
uscle
m
e pharyngea
haryng
an irre
n irregular
gula
system des
system d
mo
mon subt
n subty
in so
in some
me are
ar
ca are diag
a are dia
zing ty
zing type
pe
y
(A
btype.
btype.
heast Chin
heast Chin
Asia, North
sia, North
g immigran
g immigra
ot exactly u
ot exactly u
lude
ude th
the pr
e p
et ri
et rich in s
ch in s
PC cells
PC cells an
an
have high 
have high
tigens. The
igens. Th
several ye
everal ye
nes
nes


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
17
CC-486-NPC-001 Final: 11 July 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 
ecludes ear
ecludes ea
disease
disease
, 1993
, 1993; Sha
Sh
lvement at
lvement at
s is to bone
is to bo
d rate in ax
d rate in a
herapy
herapy alal
y
on
ry f
y or 
or 
f
resi
resid
diatatioion the
n th
r the primar
r the primar
e retreated w
e retreated 
d radiation 
radiation
e site of re
e site of
e or local re
 or local r
py shoul
y should b
d
py
py remains 
remains
y
especially 
specially
stages (IIB
stages (IIB
ith local an
th local a
survival an
survival an
hs and 4
and 4 toto
%.
%. Isolated
Isolated
ar survival 
r survival 
plplatatinum
inum-b
ecomm
ecomm


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
18
CC-486-NPC-001 Final: 11 July 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 
&(/*(1(35235,(7$5<,1)250$7,21
es
es
c
the
he
studi
studies,
es,
ecan have
ecan have
and capeci
and capeci
months 
months (F
ang, 2008
ang, 2008)
008 and rep
008 and r
val o
val of f 12.8
12
ies, m
es
ostly
ostly
ucleoside cy
cleoside
sis and met
sis and m
d by the US
by the US
ish
sh (FAB) 
(FAB
proved by
proved b t
y
mia (A
mia (AML)
r hematopo
hematopo
 (IV
IV) or 
or su
ioav
oavaila
ailable
b
rati
ration into 
on into 
cts wi
ts with
ti
DN
D
h
nance of DN
ance of DN
tic changes
change
ate the stab
ate the sta
st recogni
st recogniz
group to c
group to c
nd is a
nd is a


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
19
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 
&(/*(1(35235
n Solid
olid Tu
n combinat
n combinat
psed or ref
ed or ref
of this two
of this tw
ys 1 to 14 o
 1 to 14 o
AZA
ZA-ST
ST-0
-0
subjects re
ubjects re
300 mg w
300 mg w
itaxel was a
itaxel was 
ncountered
ncountered
nab-
na
pacli
pacli
com
com
5,(7$5<,1)250$7,21
ring
ng
aily
ily and tw
and tw
y
fashio
fashion. 
n. C
mulat
mulative ex
ive e
tely
ely 40%
40% an
espect
espectively
ivel
day
ay sc
sc
y
hed
h
being the m
being the m
n lelevelsls ini b
hypo
hypomet
methy
hy
ally act
lly active,
ve
.
5,(
35,


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
20
CC-486-NPC-001 Final: 11 July 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).
&(/*(1(35235,(7$5<,1)250$7,21
aluable
uable
hers had 
hers had
in subjects
n subject
ovocative, 
ovocativ
ZA
Z -ST
ST-00
-0
The ongoin
he ongoin
hich
hich 5 are 
are
and 3 subj
and 3 subj
subject
subject rep
rep
re encourag
re encoura
86 treatmen
86 treatme
informat
informatioio
sm, clinical
sm, clinical
shown pro
shown pro
C-486 w
486 was 
ay
ay cycle wi
cycle w
odifying ag
difying a
s in subject
in subjec
pported
pported in t
in t
Frequent
Freque
!
Gen
Gen
!


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
21
CC-486-NPC-001 Final: 11 July 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.
&(/*(1(35235,(7$5<,1)250$7,21
, 2004
, 2004).).
nt the
nt the
ird d
i
line set
line 
QD for 21 
D for 21 
neutropenia
utropeni
day
day schedu
sche
proposal is
roposal 
200 mg da
200 mg d
creasing th
creasing th
l be fo
l be follo
llow
NPC who 
NPC who 
d the encou
the encou
86 as
86 as a a sin
s


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
22
CC-486-NPC-001 Final: 11 July 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
 
&(/*(1(35235,(7$5<,1)250$7,21
netetics
i
lected 
ected 
)25
1)2


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
23
CC-486-NPC-001 Final: 11 July 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.
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
 
 
&(/*(1(35235,(7$5<,1)250$7,21
eri
eria a
dy
dy treatm
treatm
y
e
nse using
se using
eatment to 
tment to
rgent adver
rgent adve
, , Grade
Grade 3 a
3
normalities
normalities
subset of 
subset of
s
235
523
35
( 3
(1(
*(1


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
24
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
$5<,1)250$7,21
nts s
n’s 
n s
ut of the fi
ut of the f
en
en th
the stud
e stud
es out of 17
es out of 17
will be base
will be bas
bjects who 
ects wh
r. . Subjects 
Subject
y reason oth
reason ot
jects who p
ects w
n, or as d
n, or as
ST
ST v1.1 1 init
i it
d d disease p
disease p
w-up
up. All su
. All 


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
25
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.
&(/*(1(35235,(7$5<,1)250$7,21
5,(7$5<,1)250$7
   
FS 
month
1)
tm
tment is ex
ent is e
population
populatio
nitori
tori
i
ng of 
ng o
ssio
ss
n (if ap
n (if 
r analysis, 
r analysi
nd of Tri
nd of Tri
of Trial is 
Trial i
or the date
or the date
mary
mary, secon
, seco
Stati
Statistical
ical A
subjects
ubject


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
26
CC-486-NPC-001 Final: 11 July 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
&(/*
pri
prietet
/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
0$
quent 
en
es
es
25
25
25
25
1
)2
< ,
<
---
5<
$
---
--
$5
7$
----
7$
7$
7$
7$
---
---
(7
5,
----
5,
5,
5,
5,
As needed
s neede
35
52
Conti
Conti
52
52
52
52
8d from 
m
eening)
eening)
3
X
1(
(1
C
*(
*(
*(
/*(


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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
---
&(/*(1(
pri
prietet
1(
(w/in72 hou
w/in72 ho
( 35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
X
1)
< ,
X
< ,
< ,
< ,
< ,
----
5<
X
$5
7$
X
7$
7$
7$
7$
-----
(7
5, 7
---
5,
5,
5,(
5,
----
35
X
2
52
--
52
52
52
52
35
(
1(


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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
---
---
&(/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
pri
prietet
Fo
Follo
7,2
$7
0$
5
E
50
25
1)
Cycle 1 Day
ycle 1 Da
disease prog
disease pro
f consent
f consent
,1
X
5<
$
ASSESSME
ASSESS
$
---
--
(7$
7$
7$
5, 7
---
---
5,
5,
5,(
5,
Xh,j
h j
23
52
X**
X**
52
52
52
52
INVEST
INVES
35
3
-----
1(
(1


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
29
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.
&(/
pri
prietet
(/*(1(35235,(7$5<,1)250$7,21
e Corpora
e Corpora
21
Fo
Follo
7,2
$7
0$
5
E
50
25
1)
---
---
,1
< ,
----
5<
$ <
mputed tomo
mputed to
childbearing 
childbearing
teractive
eractiv re
hin
hin.
ust occur wit
ust occur
ons are perfo
s are perfo
irst treatment
rst treatmen
e first treatm
e first treatm
base at screen
ase at scre
visit, that pa
visit, tha
creening and 
reening and
screening; re
screening; re
s prior to the 
s prior to the 
dose, a urine 
se, a urine 
negative.
egative.
screening or
eening o
3 Day
3 Da 1, Cy
, Cy
y
n be submitt
n be submitt


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
30
CC-486-NPC-001 Final: 11 July 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 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 
&(/*(1(35235,(7$5<,1)250$7,21
tory
ry
ndow if 
dow if 
(Table
Table 1),)
nosi
osis, stagin
s, stagin
nicit
ic y-y-if all
if al
ct number r
number r
radi
radiatation, s
n
vant medic
vant medic
ded)
ded)
cedures (in
cedures
ant m
nt medica
edic
pt for those 
t for thos
aminat
amina ion (
n
gns (includ
gns (includ
stern Coope
tern Coop
Appendix A
Appendix A
!
12-
2-lead
lead
!
Re
Re


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
31
CC-486-NPC-001 Final: 11 July 2014
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 
&(/*(1(35235,(7$5<,1)250$7,21
Day
Day 1
y
ecti
ection 
on 6.5
6 5
y 1
y
romboplast
ombop
(and D1 of 
and D1 of
ts of 
of childb
child
creening. U
creening. 
igibilit
igibility y wi
nancy test d
nancy test d
for IP adm
for IP adm
ns s afafter
ter
f
th
the
omi
mitted if S
tted if 
i
od
od
atment upo
atment 
ys of signin
ys of signin
indow of ±
dow of ±
es are 21 da
es are 21 da
ing evaluat
ng evaluat
The evaluat
evalua
fied:
fied:
!
C


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
32
CC-486-NPC-001 Final: 11 July 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)
!
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)
&(/*(1(35235,(7$5<,1)250$7,21
g dose
dose
ectition
on 6.4
6.4)
done in Sta
one in Sta
ectction 6.3
6.3)
pririor to dosi
or to dos
ch cycle if 
h cycle if 
houl
hould be p
d be 
possible aft
ossible a
s should al
s should a
ll be perfor
ll be perfor
minat
minatioion (in
ns
omitant me
omitant m
Concomitan
Concomitan
ECOG 
ECOG
!
IRT
IRT
!


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
33
CC-486-NPC-001 Final: 11 July 2014
!
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.
&(/*(1(35235,(7$5<,1)250$7,21
sion, start o
sion, start o
ollo
llowed fo
wed fo
n Section
Section 6
s (± 5 day
(± 5 d
er occurs fi
r occurs fi
w anticancer
anticanc
radiati
radiation, 
on, 
d review (i
review (
or the
r the subje
subje
s
luat
luatioions) sh
s) 
y 6
y
weeks (
weeks (
weeks 
weeks un
u
from the e
from th
formed 
ormed ≤ 28
ng.
ng. Evalua
Evalua
vest
vestigator
igator
dent 
dent radio
radiololo
Assess
Assess
esponse wil
sponse wil
assessmen
ssessmen
he head
e hea


('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
&(/*(1(35235,(7$5<,1)250$7,21
as SD 
s SD 
a brain sca
brain sc
) at a sel
at a select
ect
ship CC
hip CC-48
acific
acific islan
islan
cycle will b
ycle wil
onal
na 6 subj
6 subj
scalated to 
scalated to 
ubjects wil
ubjects wi
taking ant
taking anti
sessments (
sessments (
of day.  Th
of day.
priate CRF
iate CRF
ine PK ass
ne PK ass
nd over the 
d over th
4, 6, and 8
4, 6, and
dule of Pha
ule of Ph
armacokin
rmacokin
Nomina
Nomina
(1
*(
/*
(/
&(
&


('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.
 
 
 
&(/*(1(
1(
1(
1(
1(
(1
*(
352
ts only
only.
,(7$5<,1)250$7,21
7
$7
$7
$7
0$7
and 
and proce
proce
n, if applic
, if ap
of water
of water a
486 with 2
486 with 
post
post-dose.
tration
tratio .  Th
T
40 mL of w
 mL of 
5,(
35,
235
23
52
52
35
( 3
1(
1
(/
&


('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 
&(/*
h
/*(1(35235,(7$5<,1)250$7,21
ument.
ument.
poorly
poorly
metastati
etastatic.c
lly afafter
te
f
1 t
n, 1982
n, 1982) se
) 
able disease
le diseas
ced by
ced by the f
th
y
pper limit o
pper limit 
range, or co
range, o
e marrow fu
e marrow 
hil count 
hil count ≥ ≥
x 10
109 cells
cells
≥ 9 g/dL
≥ 9 g/dL
childbearin
childbearin
undergone a
undergone 
orectomy
rectomy (th
(t
y
stmenopaus
enopaus
e preced
precedi
a.a.
Ha
Ha


('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).
&(/*(1(3
atat
35235,(7$5<,1)250$7,21
acepti
eptive
ve
i
the course
the course
ast dose of
ast dose o
eded.
ded.
related
related
r protocol r
protocol r
ct fro
from enro
enr
tasis. In
tasis. In su
su
.  Primary
.  Primary N
y
nsidered br
nsidered br
ithin 5 year
hin 5 year
sisitu carcin
tu carcin
i
treatment 
treatment 
squamous 
quamous
 PSA <10
PSA <10
viously
viously tre
t
ing agent
g ag
history
istory of
o
y f
liac disease
liac disease
ntestinal dis
ntestinal d
bo
bolism
lism, or 
or
astrointestin
rointestin
Subject h
Subject
6.6. Subj
Subj
T


('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.
&(/*(1(35235,(7$5<,1)250$7,21
t t 
e clinical
e clinical
not recover
not reco
ays or 5 hal
s or 5
prior antica
ior antica
fieleld d radi
radiata
f the bone m
f the bone 
dititioion, l
n, labo
ab
t from pa
t from partrt
a
ding the pre
ing the p
table risk if
able risk
that confo
that confo


('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;
&(/*(1(35235,(7$5<,1)250$7,21
vent 
en
ntained
tained.
ay
ays of
s of a 21
2
f
ble
ble fo
for safe
r safe
ycle 1
ycle 1; and
; an
equent
uent subj
ubj
dose for 14
se for 1
nces) of roo
nces) of roo
mach or wi
ach or witi
n PK samp
n PK sam
an-
n-Pacific
Pacific
f Asian
Asian-Pac
Pac
erminat
rminatioion
of Asian
f Asian-Pa
g dose will b
dose wil
an-Pacific I
Pacific 
at the di
at the discr
sc
IP
IP-related 
related
eads to per
eads to pe
rade 4 neut
rade 4 neut
requi
requiriri
i ng h
ng 
!
Grade
rade
!
A


('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
&(/*(1
penia or throm
enia or throm
to the planne
o the planne
x 109/L
/L
s < 25 
s < 25 x 10
109/
ANC < 0.5 x
NC < 0.5 x
he initiation
he initiation
nvestigato
vestiga
SF
SF
(1(35235,(7$5<,1)250$7,21
ext 
ex
se reduction
e reductio
table toxicit
able toxic
defined as a
efined as 
medical risk
dical risk
or 4 hema
or 4 he
the 3
he 3rd
r epi
epi
ines due to 
ines due to
ys s for Toxic
for Tox
mendation
mendation
(7
ld CC
ld CC-486 u
486 u
Delay 
Delay ≤7
≤
d
Delay 8
Dela
Delay
Dela
5,(
2
openia 
openia 
of a Cycle
of a Cycle
52
(1


('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, 
&(/*(1(35235,(7$5<,1)250$7,21
0$
0$
0$
Medical
dical
MO 
O
significant bl
significant 
nacted.
nacted.
ropriately acc
opriately
f the subject i
the subject 
heduled day
eduled d
be added
added af
for IP acco
for IP ac
rs to CC
s to CC-48
48
ned as 
ned as any
an
regardless 
regardles
unt over the
unt over the
basis, an o
asis, an
le or freque
le or fre
drug admin
drug adm
dental or in
dental or in
Method o
Method o
s who enter
s who ente
ects will rec
cts will re
All IP will b
All IP will b
accounta
ccounta


('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.
&(/*(1(35235,(7$5<,1)250$7,21
he subject’
e subject
ountable
ountable fof
during the c
uring the


('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.
&(/*(1(35235,(7$5<,1)250$7,21
and 
nd 
Investi
nvestigat
gat
nd E
d Europe
urope
f neutropen
f neutropen
igator
gator’s di
’s di
prior to eac
or to eac
d at the fir
at the fi
doses of 
oses of CC
CC
ations
ations an
a
pecifically
pecifically
d, or 
, or invest
investi
e, or other d
, or other 
Concomita
Concom


('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.
&(/*(1(35235,(7$5<,1)250$7,21
1.1.1
y y cri
criteria
teria
i
ty and disc
and disc
e intensit
intensity a
y
s.s.
atatioion will b
will b
ects who ha
ects who h
l be
be efficac
effica
d Power C
d Power C
fficacy eval
cacy eva
imat
matioion is 
is 
ow that the
ow that the
tage design
age desig
or median
r median P
ge,
ge 17 subj
subj
llment will
llment wil
ubjects.
ubjects. Sub
Sub
repl
ep aced.
ced.
51
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 
&(/*(1(35235,(7$5<,1)250$7,21
y
ment 
ment 
ol
al distribut
l distributi
be pr
be provi
ovided
d
o estimate 
o estimate 
based on t
based on
l be consid
l be consid
e considere
e consider
me of the c
me of the c
w-
w up pri
up prior 
or 
ontact.
ntact.
sed to estim
sed to estim
will be prov
ill be pro
l be includ
e inc
y will
y will b
l e m
e 
ents, labora
ents, labora
dose interru
dose interru
one or mor
one or mo
examinat
aminatioio
mitant medi
itant medi
verse even
erse even
worsens in
worsens in
will be 
will be
t


('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.
&(/*(1(35235,(7$5<,1)250$7,21
ure, and to
ure, and t
be collecte
be collecte
t lim
limitited to
ed to
ata:
ta:
n, coefficie
, coeffici
x) will be pr
x) will be p
ppropriate.
propriate
tructions fo
uctions fo
ided to the
ded to th
ured using 
ured using
pics
pics
Steering C
Steering C
erim Effica
erim Effica
ly. The inte
y. The inte


('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);
&(/*(1(35235,(7$5<,1)250$7,21
ome
me
mptoms of 
mptoms of 
be reporte
be reporte
th an AE sh
h an AE sh
overdose.)
erdose
should be 
should be
n the sequel
the seque
lting 
ing in the
and CRF bu
nd CRF b
dy
dy.  Assess
.  Assess
ect’s clinic
ect’s clinic
physi
hysical
cal ex
e
l
gator
ator from 
from t
and those S
and tho
ng related t
ng related 
the CRF an
he CRF an
Safet
Safety y wi
w ti
ropri
ropriate m
ate
uation of
uation of
nvest
nvestigator
igator
Seriou
Seriou
erious
erious adv
adv
!


('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.
&(/*(1(35235,(7$5<,1)250$7,21
or 
ve. 
ve. 
E should be
E should be
wever, hos
wever, ho
administrat
dministra
ati
ation
on not a
fusio
fusion as ro
n as r
rolonged h
rolonged
e SAE.
e SAE.
elelated inve
ated inve
tory
ory tests, b
tests, 
y
hospitaliza
hospitaliz
olongat
olongatioion o
n 
e of an AE.
e of an AE
hat is plann
hat is pl
nted in the 
nted in the 
zati
ation f
on for 
or 
f
lect
lective tre
ive tre
nrelated to
nrelated to
Emerge
Emerg
unles
unl
f an AE i
f an AE is c
s
must be c
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.
&(/*(1(35235,(7$5<,1)250$7,21
calal
stance may
tance may
e usually re
 usually r
ble
ble
y, significan
significan
red, hospi
red, hospiti
y of a spe
y of a specic
wever, may
wever, m
erio
erion is no
no
ria associ
a associa
uide f
de for def
or de
f
ne the rela
ne the rela
as Not Susp
s Not Sus
Mean
Mea
adm
adm
Suspected:
Suspected:


('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
participat
cipat
covered or d
overed or
AE
AE if th
the a
udy
dy;
interruption
interruptio
ant clinical 
ant clini
y l
y aboratory
aborato
rious adver
ous adve
y i
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 
&(/*(1(35235,(7$5<,1)250$7,21
r 
form
form.
gator
ator
of f th
the seri
e seri
ther approp
ther approp
e SAE Rep
e SAE Rep
ed, without
d, withou
he Invest
Inves igi
to Celgene 
Celgene
Investigato
Investig
form
orm.
86 beco
bec me
me
pregnant f
pregnant f
female par
female par
hcare prof
hcare prof
the course 
the course 
ress any cou
ss any co
Serious A
Serious A
criterion for
riterion 
rded on the
rded on t
ty y wi
with
th
i in 2
in 2
riate metho
iate metho
ertains to in
ertains to in
stigator
gator is r
is r
equi
equiremen
remen
i
dy (f(f
y
rom
rom
f
thth
m
investigat
nvestigatioio
that are 
at are
F)


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
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).
&(/*(1(35235,(7$5<,1)250$7,21
business 
siness 
e the expec
e the expe
vest
estigator
igat
’s
ons (SUSA
ns (SUSA
32.2.
elgene or it
elgene or 
latory
atory Auth
Auth
y
irect
irective 20
ive 20
n of advers
n of adve
an use (EN
an use (EN
ase under st
se under st
sidered to b
idered to
pedited saf
pedited s
entative
entative sha
sha
ed of being
ed of bein
rious and u
rious an
ng fro
ng from tet
subject
subjects in
s in
,
uired by
ired by l
y oc
o
ew serious a
w serious 
Investi
Investigat
gat
corresponde
orresponde
inform
nformat


('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.
&(/*(1(35235,(7$5<,1)250$7,21
CRF and i
CRF and
sponsibilit
sponsibili y
wever, prio
wever, pri
and forwar
and forwar
n
red sufficie
red suffic
consent
onsen
follow
follow-up
-up
otocol
ocol vivi
l
ol
ol
Other
Other
eason for d
eason for


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
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.
&(/*(1(35235,(7$5<,1)250$7,21
ot be
ot 
ed on
d on
ntatives are
ntatives are
Celgene/C
Celgene/Co
nly
nly b
y e used
e used
or or design
r or desig
nal Produ
nal Pro
d on the pa
d on the pa


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<,1)250$7,21
in 
authori
authorititi
i es
es
ical Practic
ical Practic
evaluate an
valuate
study
ud are a
re
study
study-relate
rel
s and other 
and othe
dy-
dy-rel
related d
ated
of all subje
of all sub
dy.  Subject
y.  Subjec
uments.
uments.
of the
of the Inve
Inve
ve queries a
queries 
ital charts, 
al charts
st ensure t
st ensure 
rmation a
mation 
obtain infor
btain info
lated proce
ated proc
that inform
hat inform
formed con
formed con
the date.  T
he date.  T
and by the
and by the
y, m
, must be 
ust be
m
n addit
n additioion, 
n,
inform
nformed
ed
me
mend
nd


('06'RF1XPEHU
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.
&(/*(1(35235,(7$5<,1)250$7,21
ain
arch
arch
or written a
or written a
versio
version oc
n oc
the Investi
Inves
able.
ble. Amen
Ame
be submitt
be submit
dent Ethic
ent Ethi
nform
nformed co
d c
e IRB/EC w
IRB/EC w
nd the site 
nd the site 
. If applicab
 If appli
alal ll egal
egal req
l
ststigator
igator by
b
nd legal req
nd legal re
presentativ
presentat
and their o
and their
ns and quali
ns and qu
ming that th
ming that th
B General 
B General 
oval by the 
oval by the 
ble), study
le), study
nts review
nts review
cially signe
cially signe
hihical and l
cal and 
The IRB
The IR
en


('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.
&(/*(1(35235,(7$5<,1)250$7,21
e;e;
ed risk to su
ed risk to su
reasonable
asonable
e appropria
e appropr
uthori
horititi
i es, e
es,
o discont
o discontinu
inu
ns such as
ns such a
ta collect
a collectioi
;
protocol
protocol.


('06'RF1XPEHU
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;
&(/*(1(35235,(7$5<,1)250$7,21
on as 
n as 
macy
acy, and
, and
elgene
elgene stan
stan
hrough use 
ugh us
es in the da
s in the d
nnel, if nece
nel, if nec
witithin the s
hin 
stigator
stigator fo
for
region and 
egion and
CH region,
CH region,
pment of th
pment of th
ed above or
d above o
ments incl
ents inc
nsent docum
nsent docum
catatioion code
n cod
ll co
ll commu
mmun
osisititi
i on of
on of thth
f
cord of all 
ord of all
represen
representat
tat
n
!
List of
List of
Inv
Inv
t


('06'RF1XPEHU
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
uction


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
61
CC-486-NPC-001 Final: 11 July 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.
&(/*(1(35235,(7$5<,1)250$7,21
fter 
ter 
udy
dy
udy
dy, a
, a
formed 
formed 
itoring will
itoring wil
ropriate
ropriate
ts, the facil
s, the facil
and all oth
nd all 
tive in acco
ive in acc
on that i
n that s a
rce docume
ce docum
d/or his/her 
d/or his/he
querie
quer s by
s b t
y
d consents, 
d consents, 
roper recor
oper reco
udy
udy-specifi
specifi
s
ng procedu
ng procedu
presentative
resentative
Celgene S
Celgene
s.
quired to p
quired to
 CRFs and
CRFs and
ect
ectioions by I
ns by I
thorized rep
thorized rep
ditsts
i
and/or 
nd/or 
ing an inspe
ng an inspe


('06'RF1XPEHU
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


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
63
CC-486-NPC-001 Final: 11 July 2014
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 
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 
metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral Oncol 
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 
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.
&(/*(1(35235,(7$5<,1)250$7,21
atat-
753 patient
753 patien
haryngeal
haryngeal
HNS
NS-ESMO
ESMO
. Ann Onco
. Ann On
demethylat
demethylat
1.
otherapy
therapy f
y or
f
:244
244-249.
-249.
of
of capeci
capeci
f
tata
i
eated wit
ated with
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.
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
the head an
e head an
enne
enne


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
64
CC-486-NPC-001 Final: 11 July 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.
Lo KW, Chung GTY, To KF, et al. Acquired genetic and epigenetic alterations in 
nasopharyngeal carcinoma. In: Busson P, ed. Nasopharyngeal Carcinoma. New York, 
NY:Springer New York;2013:61-81.
Ma BB, Chan AT. Recent perspectives in the role of chemotherapy in the management of 
advanced nasopharyngeal carcinoma. Cancer 2005;103:22-31.
Mendenhall WM, Werning JW, Pfister DG. Treatment of head and neck cancer. In: DeVita VT 
Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. 
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 
disseminated nasopharyngeal carcinoma. Ann Oncol 2011;22:718-722.
Okada T, Nakamura M, Nishikawa J, et al. Identification of genes specifically methylated in 
Epstein-Barr virus-associated gastric carcinomas. Cancer Sci 2013;104:1309-1314.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
Ong YK, Heng DM, Chung B, et al. Design of a prognostic index score for metastatic 
nasopharyngeal carcinoma. Eur J Cancer 2003;39:1535-1541.
Paulson EJ, Speck SH. Differential methylation of Epstein-Barr virus latency promoters 
facilitates viral persistence in healthy seropositive individuals.  J Virol 1999;73:9959-9968.
Robertson KD, Ambinder RF. Methylation of the Epstein-Barr virus genome in normal 
lymphocytes.  Blood 1997;90:4480-4484.
Salamon D, Takacs M, Ujvari D, et al. Protein-DNA binding and CpG methylation at nucleotide 
resolution of latency-associated promoters Qp, Cp, and LMP1p of Epstein-Barr virus. J Virol 
2001;75:2584-2596.
Sham JS, Cheung YK, Choy D, et al. Computed tomography evaluation of neck node metastases 
from nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1993;26:787-792.
Sham JS, Choy D, Wei WI. Nasopharyngeal carcinoma; orderly neck node spread. Int J Radiat 
Oncol Biol Phys 1990;19:929-933.
Shiu WCT, Tsao SY. Efficacy of 4'-epidoxorubicin in advanced nasopharyngeal carcinoma. Clin 
Trials J 1989;26:419.
Simon R. Optimal two-Stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-
10.
Tierney R, Kirby H, Nagra J, et al. The Epstein-Barr virus promoter initiating B-cell 
transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5.  
J Virol 2000;74:10458-10467.
&(/*(1(35235,(7$5<,1)250$7,21
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
9:1535
9:1535-15
-15
ioion of Eps
n of Eps
oposit
opositive
ive ini
ylat
ylatioion of th
n o
0-4484.
-44
 D, et al.
D, et al. P
ated prom
ated prom
YK, Cho
K, Choy y D
geal
geal carcin
carcin
l
oy y D, 
D, Wei
Wei
l Phys 199
Phys 199
l
WCT, Tsao
WCT, Tsao
als J 1989;
ls J 1989;
Si
Simo
m n R.
n R.
0


('06'RF1XPEHU
CC-486 (Oral Azacitidine)
CC-486-NPC-001
Celgene Corporation
Confidential and Proprietary
65
CC-486-NPC-001 Final: 11 July 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.
Zhang L, Zhang Y, Huang PY, et al. Phase II clinical study of gemcitabine in the treatment of
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.
&(/*(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
66
CC-486-NPC-001 Final: 11 July 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.
&(/*(1(35235,(7$5<,1)250$7,21
7
$7
$7
$7
$7
work of a 
ork of a 
0$
activities. U
activities
5
han 50% of w
an 50%
)2
onfined to b
nfined to 
1)
,1
5<


('06'RF1XPEHU
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.
8VHU1DPH

7LWOH

'DWH)ULGD\-XO\30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
&(/*(1(35235,(7$5<,1)250$7,21