A Phase 2, Open-Label, Single-Arm Rollover Study to Evaluate Long-Term Safety in Subjects Who Participated in Other Celgene Sponsored CC-486 (Oral Azacitidine) Clinical Trials in Hematological Disorders
Phase: PHASE2
Conditions: Hematologic Neoplasm, Neoplasms, Hematologic Malignancies
Sponsor: Celgene

Official Title of Study: 
A Phase 2, Open-Label, Single-Arm Rollover Study to Evaluate Long-Term Safety in Subjects Who 
Participated in other Celgene Sponsored CC-486 (Oral Azacitidine) Clinical Trials in Hematological 
Disorders 
 
NCT Number: NCT02494258 
Document Date (Date in which document was last revised): 27 Feb 2023 
 
 
 

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
1
A PHASE 2, OPEN-LABEL, SINGLE-ARM 
ROLLOVER STUDY TO EVALUATE LONG-TERM 
SAFETY IN SUBJECTS WHO PARTICIPATED IN 
OTHER CELGENE SPONSORED CC-486 (ORAL 
AZACITIDINE) CLINICAL TRIALS IN 
HEMATOLOGICAL DISORDERS
PROTOCOL NUMBER:
CC-486-GEN-001
COMPOUND NUMBER:
CC-486 (also known as
BMS-986345)
DATE FINAL:
31-MAR-2015
AMENDMENT 1.0 DATE FINAL
27 FEB 2023
EudraCT NUMBER:
2023-503272-25-00
IND NUMBER:
074618
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
2
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION
Contact Information:
Name:
Title:
Address:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
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 Trial Physician(s) or Medical Monitor or designee 
for emergency calls.
Back-up 24-hour Emergency Telephone Number: 
USA: +1-866-470-2267
International: +1-248-844-7390
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
3
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
4
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, International Conference on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations governing 
the conduct of clinical studies.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
5
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 1.0:
As of 01 Jan 2023, one subject in the United States (US) continues to receive CC-486, and there 
are no subjects in the survival follow-up phase of this study. This protocol was amended to allow 
rollover into this study for subjects outside of the US who are receiving single agent CC-486 in 
other Celgene clinical trials, tolerate the protocol-prescribed regimen, and in the opinion of the 
Investigator, may derive clinical benefit from continuing treatment with CC-486. 
Additional changes include updates of disease and compound background, investigational product
dose modification, information about permitted and prohibited concomitant medications according 
to the current version of the Investigator’s Brochure (IB), and CC-486 product information. 
Methods of contraception have been updated in the inclusion criteria for females of childbearing 
potential (FCBP) and male subjects who are sexually active with FCBP according to the latest
recommendation for pregnancy prevention for subjects treated with CC-486, which was found to 
be both teratogenic and fetotoxic in pre-clinical studies. 
Currently, there are no Celgene-sponsored CC-486 clinical trials in solid tumors that may
potentially transition subjects into this rollover study; therefore, the language related to solid tumor 
studies and disorders has been removed from the protocol.
The Protocol Summary was updated to reflect the changes made throughout the protocol.
The revision of this protocol amendment applies to all subjects currently enrolled. 
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0
Section Number & Title
Description of Change
Brief Rationale
Throughout the protocol
Table and section numbers 
updated.
Administrative update.
Title Page
Title updated to remove solid 
tumors and add the compound 
number and EudraCT number.
There are no CC-486 solid tumor 
clinical trials that may potentially 
transition subjects into the
CC-486-GEN-001 study. 
Medical Monitor / Emergency 
Contact Information
Updated contact details for the 
Medical Monitor and 24-hour 
Emergency Phone Number
Administrative change.
Celgene Therapeutic Area Head 
Signature Page
Therapeutic Area Head and title 
were updated.
Administrative change.
Section 1.1.1, Acute Myeloid 
Leukemia 
Updated background 
information and references for 
disease background of acute 
myeloid leukemia. 
Information was updated based on 
recent publications.
1.0
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1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
6
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0
Section Number & Title
Description of Change
Brief Rationale
Section 1.1.3, Solid Tumor 
Pathogenesis
Section was deleted.
There are no CC-486 solid tumors 
clinical trials that may potentially 
transition subjects into 
CC-486-GEN-001 study.
Section 1.2.1, CC-486 (Oral 
Azacitidine)
Provided updated compound 
background information for 
CC-486 (oral azacitidine).
Information was updated based on the 
most recent version of the IB.
Section 1.3.1, Study Rationale and 
Purpose
Section 3.1, Study Design
Deleted a part of the sentence 
regarding subjects with solid 
malignancies as this study will 
not include that population.
There are no CC-486 solid tumor 
clinical trials that may potentially 
transition subjects into the 
CC-486-GEN-001 study.
Section 1.4, Benefit/Risk
Assessment 
Section 1.4.1, Risk Assessment
Section 1.4.2, Benefit Assessment
Section 1.4.3, Overall Benefit/Risk 
Assessment
New sections and table added.
To incorporate stand-alone risk/
benefit assessment information into 
the protocol.
Table 3, Study Endpoints
Changed wording from “study 
termination” to “End of Trial”.
Minor wording change for clarity.
Section 3.3, End of Trial
Added 2 new criteria for End of 
Trial:
1. The date of the study 
termination by the Sponsor 
2. The date of the last 
per-protocol visit for subjects 
who are transferred to 
commercially available and/or
reimbursed CC-486 in the 
participating countries where 
CC-486 is approved by 
regulatory authorities for the 
indication that the subject is
being treated.
Updated for inclusiveness and 
accuracy.
Section 4.2, Inclusion Criteria
Section 10.4.1, Pregnancy
Appendix C, Females of 
Childbearing Potential Definitions 
and Methods of Contraception
Contraceptive requirements have 
been updated and new appendix 
added.
As per IB, CC-486 has been found in
pre-clinical studies to be both 
teratogenic and fetotoxic. Therefore,
inclusion criterion 4 has been 
modified based on Clinical Trials 
Facilitation and Coordination Group
last US Food and Drug Administration
(FDA) guidance for compounds that 
are found to be teratogenic/fetotoxic. 
1.0
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930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
7
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0
Section Number & Title
Description of Change
Brief Rationale
Table 4: Table of Events
Updated footnote related to 
pregnancy testing in the table of 
events.
The information for pregnancy testing 
has been moved from Section 6.1.7 to 
Appendix C.
Section 6.1.7, Pregnancy Testing 
(Females of Childbearing Potential 
[FCBP] Only) and Contraception 
Education
The section has been deleted 
from the body of the protocol
and following section numbers 
updated.
The information has been moved from 
the body of the protocol to 
Appendix C.
Section 6.2.1, Cycle 1 
Procedures/Assessments
Added statement that 
unscheduled visits may be 
performed if deemed necessary 
by the Investigator.
An additional clarification to the study 
procedures was added.
Section 6.3.2, Survival Follow-up or 
Long-term Follow-up
Updated end of trial criteria.
For internal consistency with the end 
of trial criteria in the other sections of 
the protocol.
Section 7.1, Description of 
Investigational Product
Added a 300-mg tablet option to 
the list.
To align with the current version of 
CC-486 product information.
Section 7.2.3, Investigational 
Product Administration
Administration and ingestion of 
oral azacitidine tablets have been 
updated.
Information was updated based on 
most recent version of the IB.
Section 7.2.4, Missing Doses
More information regarding 
missed doses has been added.
Information was updated based on 
most recent version of the IB.
Section 7.2.6, Dose Modifications
Removed the option for 
600 mg/day to 500 mg/day.
There are no studies with a 600-mg 
exposure that would roll over into this 
protocol.
Table 5, Criteria for Interrupting or 
Resuming Study Treatment
Revised criteria for interrupting 
or resuming Study Treatment.
Information was updated based on 
most recent version of the IB.
Section 8.1, Permitted Concomitant 
Medications and Procedures
Parenteral flu vaccinations are 
permitted, and information 
regarding coronavirus 2019 
(COVID-19) vaccinations has 
also been added.
Clarification added in the context of 
viral infections risk (including 
COVID-19 pandemic).
Section 8.2: Prohibited Concomitant 
Medications and Procedures
Drug-drug interactions have not 
been studied with CC-486, and 
live COVID-19 vaccines should 
generally not be administered to 
a participant during the study.
Information was updated based on 
most recent version of the IB.
Clarification added in the context of 
COVID-19 pandemic risk. 
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
8
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0
Section Number & Title
Description of Change
Brief Rationale
Section 9.1, Overview
The 2 following sentences were 
removed:
“In addition, where appropriate, 
a total column will be included 
to summarize subjects across 
treatment regimens”.
“All statistical analyses specified 
in this protocol will be 
conducted using SAS® Version 
9.2 or higher unless otherwise 
specified”.
Information updated considering the 
sample size based on number of 
subjects in parent CC-486 studies.
The statistical analysis will be 
provided in the statistical analysis plan 
(SAP).
Section 9.3, Sample Size and Power 
Considerations
Deleted prior section of efficacy 
evaluable population.
Minor rewording of the sample 
size.
Information updated considering the 
sample size based on number of 
subjects in ongoing parent CC-486 
studies.
The statistical analysis will be 
provided in the SAP.
Section 9.5, Subject Disposition
Removed the sentence "A 
summary of subjects enrolled by 
site will be provided." This
information will be moved to the 
statistical analysis plan (SAP).
Updated as information will be found 
in the SAP.
Section 9.6, Overall Survival
Removed previous section of 
Efficacy Analysis.
Specified that overall survival 
(OS) analysis will be performed 
for subjects if the sample size 
and number of deaths allows for 
meaningful results.
Efficacy analysis to be performed in 
the parent CC-486 studies. Only OS 
analysis may be performed depending
on sample size. 
The statistical analysis will be 
provided in the SAP.
Section 9.7, Safety Analysis
Revised statement so that safety 
analysis will be performed on 
subjects who meet the safety 
population definition.
Definition of safety population is 
provided in Section 9.2.2. 
Section 10.1, Monitoring, 
Recording, and Reporting of 
Adverse Events
Adverse events of special 
interest will be collected if 
applicable and required from the 
parent CC-486 study.
Adverse events (AEs) that occur 
after consent related to 
COVID-19 must be reported.
Clarification added in the context of 
requirements of parent CC-486 
studies.
Clarification added in the context of 
COVID-19 pandemic risk.
1.0
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930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
9
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0
Section Number & Title
Description of Change
Brief Rationale
Section 10.1, Monitoring,
Recording, and Reporting of 
Adverse Events
Section 10.2.1, Seriousness
Section 10.4.1, Females of 
Childbearing Potential
Section 10.5, Reporting of Serious 
Adverse Events
Section 10.5.1, Safety Queries
Section 10.6, Expedited Reporting 
of Adverse Events
Updates to adverse event 
reporting have been added.
Updated information regarding AE 
reporting.
Section 11.2, Study Discontinuation
Added new criteria for study 
discontinuation.
Added new criteria for overall 
comprehensiveness.
Section 13.9, Sponsor Commitment 
to Diversity in Clinical Trials
Added a new section to align 
with Sponsor commitment to 
diversity in clinical trials.
To align with Sponsor practices and to 
comply with European Union Clinical 
Trial Regulation (EU-CTR)
requirements.
Section 14.4, Data Protection, Data 
Privacy, and Data Security
Added a new section regarding 
data practices.
To align with Sponsor practices and to 
comply with EU-CTR requirements.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
10
PROTOCOL SUMMARY
Study Title
A Phase 2, Open-label, Single-arm Rollover Study to Evaluate Long-term Safety in Subjects Who 
Participated in Other Celgene Sponsored CC-486 (oral azacitidine) Clinical Trials in 
Hematological Disorders.
Indication
Rollover study supporting hematological disorder indications from Celgene-sponsored CC-486 
(also known as BMS-986345) protocols eligible for participation in the study. 
Objectives
Primary Objectives: To evaluate the long-term safety of CC-486 (oral azacitidine) in subjects who 
have received CC-486 as monotherapy in other Celgene-sponsored clinical trials and whom the 
Investigators feel may derive clinical benefit from continuing treatment with CC-486. 
Secondary Objectives: To follow subjects treated with CC-486 or placebo (in parent CC-486 
study) for survival if required by the parent CC-486 study protocol.
Study Design
The open-label, multicenter, multinational rollover study is intended to evaluate the safety of CC-
486, while providing continued treatment with CC-486 for subjects who are receiving single agent 
CC-486 at the time of transition to the rollover study and tolerated the protocol prescribed regimen 
in Celgene-sponsored trials, and whom in the opinion of the Investigator may derive clinical 
benefit from continuing treatment with CC-486.  
The study design is described in detail in Section 3.1
The study will be conducted in compliance with International Conference on Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Study Population
All subjects participating in a Celgene CC-486 sponsored study whether on active CC-486 or 
placebo, and as described in Section 4 of this protocol may participate in this study.
In order to receive investigational product (IP) in this protocol, subjects must have previously 
participated in a CC-486 study and who, in the opinion of the Investigator may derive clinical 
benefit from continuing treatment with CC-486 monotherapy.  The subject must not have been 
discontinued from receiving IP in the parent CC-486 protocol prior to entering this study. 
In addition, any subject who had received CC-486 or placebo in a parent CC-486 protocol but had 
been discontinued from IP and were in survival follow-up in the parent CC-486 study, may be 
rolled over into this protocol and will continue to be followed for survival as in the parent CC-486 
protocol. 
In order to enter the survival follow-up in the Follow-up Phase of the rollover study, subjects must 
have been enrolled into a parent CC-486 study where monitoring for survival is required.
1.0
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930200125
1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
11
Length of Study
The study will terminate and relevant subjects will discontinue from the study when CC-486 
receives regulatory approval in the indication for which they are being treated, and is also 
commercially available and reimbursed such that the subject’s access to CC-486 is neither 
interrupted nor discontinued by the relevant local healthcare provider.
The End of Trial is defined as the following, whichever is the later date:

the date of the last visit of the last subject to complete the post-treatment follow-up, 

the date of receipt of the last data point from the last subject that is required for primary 
and/or secondary analysis, as pre-specified in the protocol, 

the date of the study termination by the Sponsor,

the date of the last per-protocol visit for subjects who are transferred to commercially 
available and/or reimbursed CC-486 in the participating countries where CC-486 is 
approved by regulatory authorities for the indication that subject is being treated.
Study Treatments
Subjects will receive CC-486 during the treatment phase of the study. The dose and schedule of 
CC-486 in this study will be dictated by the single agent CC-486 dose received at the time of 
transitioning in the parent CC-486 study, taking into account the subject’s last dose and schedule 
of CC-486 in the parent CC-486 study. In the Celgene-sponsored, placebo-controlled, parent CC-
486 studies requiring survival follow-up, subjects who received placebo may transition into this 
study; however, they will not receive CC-486 treatment. These subjects, with consent, will be 
followed for survival.
Overview of Survival Follow-up Assessment
Survival data will be collected for subjects transitioning from parent CC-486 studies, if defined in 
the protocol of the parent CC-486 study.
Overview of Key Safety Assessments
All subjects will be monitored for safety throughout the study. Safety variables include the 
following:

Physical examination (PE)

Vital signs

Clinical laboratory measurements, including hematology, serum chemistry and pregnancy tests 
(if applicable) 

Concomitant medications/procedures

Adverse events (AEs)

Pregnancy testing (for females of childbearing potential subjects)
1.0
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930200125
1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
12
During treatment phase of the study, PE, vital signs, and clinical laboratory assessments are 
performed (these data will be captured in the source documents only). Concomitant 
medications/procedures and AEs are reported in the clinical case report form database. 
All subjects will be monitored for AEs; starting from the time the subject signs the informed 
consent form until 28 days after the last dose of study treatment.
Statistical Methods
This open-label, single-arm rollover study is designed to evaluate long-term safety in subjects who 
participated in monotherapy clinical trials of CC-486 (oral azacitidine) in myeloid disorders.
Analysis Populations
The Safety population includes all enrolled subjects who were determined eligible to receive IP in 
this rollover study. The Safety population will be used for all safety analysis. Subjects will be 
analyzed according to the treatment actually received.
Sample Size 
The size of this study will be defined by the number of subjects rolling over to this study from 
parent CC-486 studies.
Overall Survival
Overall survival analysis will be performed if it is required by the parent CC-486 protocol, and if
the sample size of subjects and number of deaths allow to conduct the appropriate analysis.
Safety Analyses
All subjects in the safety population will be included in the safety analyses. Safety and tolerability 
will be monitored through continuous reporting of AEs and serious adverse events, deaths, and 
incidence of subjects experiencing AEs resulting in dose reductions, dose interruptions, and/or 
premature discontinuation of IP. Adverse events and concomitant medications/procedures will be 
tabulated and summarized across the study as one group, by treatment regimen, if applicable.
Interim Analysis
There is no interim analysis planned for this study.
1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
13
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 1.0:............................................5
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 1.0.........................................5
PROTOCOL SUMMARY ........................................................................................................10
TABLE OF CONTENTS..........................................................................................................13
LIST OF TABLES....................................................................................................................16
LIST OF FIGURES ..................................................................................................................17
1.
INTRODUCTION..................................................................................................18
1.1.
Disease Background ...............................................................................................18
1.1.1.
Acute Myeloid Leukemia.........................................................................................18
1.1.2.
Myelodysplastic Syndromes ....................................................................................19
1.2.
Compound Background ..........................................................................................20
1.2.1.
CC-486 (Oral Azacitidine)......................................................................................20
1.3.
Rationale ................................................................................................................23
1.3.1.
Study Rationale and Purpose..................................................................................23
1.3.2.
Rationale for the Study Design................................................................................24
1.4
Benefit/Risk Assessment ........................................................................................24
1.4.1
Risk Assessment......................................................................................................24
1.4.2
Benefit Assessment..................................................................................................25
1.4.3
Overall Benefit/Risk Conclusion .............................................................................26
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................26
3.
OVERALL STUDY DESIGN ................................................................................27
3.1.
Study Design ..........................................................................................................27
3.1.1.
Study Entry/Screening Assessment Phase................................................................27
3.1.2.
Treatment Phase.....................................................................................................27
3.1.3.
Follow-up Phase.....................................................................................................28
3.2.
Study Duration for Subjects....................................................................................30
3.3.
End of Trial ............................................................................................................30
4.
STUDY POPULATION.........................................................................................30
4.1.
Number of Subjects ................................................................................................30
4.2.
Inclusion Criteria....................................................................................................30
4.3.
Exclusion Criteria...................................................................................................32
5.
TABLE OF EVENTS.............................................................................................33
6.
PROCEDURES......................................................................................................35
6.1.
Study Entry/Screening Assessment Phase...............................................................35
6.1.1.
Demographics ........................................................................................................35
6.1.2.
Clinical Assessments...............................................................................................35
6.1.3.
Physical Examination .............................................................................................36
6.1.4.
Vital Signs, Body Weight, and Height Measurements..............................................36
6.1.5.
Hematology ............................................................................................................36
6.1.6.
Serum Chemistry ....................................................................................................36
6.1.7.
Assessing Adverse Events .......................................................................................37
6.1.8.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures .............................................................................................................38
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
14
6.1.9.
Information to be Collected on Subjects Who do not Meet Eligibility Criteria 
(Not Applicable to Subjects Who Enter Follow-up Phase of the Study)....................38
6.2.
Treatment Phase .....................................................................................................38
6.2.1.
Cycle 1 Procedures/Assessments.............................................................................38
6.2.1.1.
Cycle 2 and Beyond Procedures/Assessments (if Subject is Visiting the 
Clinic) ....................................................................................................................39
6.2.1.2.
Cycle 2 and Beyond Procedures/Assessments (if Subject is Not Visiting the 
Clinic) ....................................................................................................................39
6.2.2.
End of Treatment....................................................................................................40
6.3.
Follow-up Phase (Disregard if Not Applicable) ......................................................40
6.3.1.
Safety Follow-up.....................................................................................................40
6.3.2.
Survival Follow-up or Long-term Follow-up...........................................................41
7.
DESCRIPTION OF STUDY TREATMENTS........................................................41
7.1.
Description of Investigational Product(s)................................................................41
7.2.
Treatment Administration and Schedule .................................................................41
7.2.1.
Investigational Product Treatment Schedule...........................................................41
7.2.2.
Investigational Product Dispensation .....................................................................42
7.2.3.
Investigational Product Administration...................................................................42
7.2.4.
Missing Doses ........................................................................................................42
7.2.5.
Overdose ................................................................................................................43
7.2.6.
Dose Modifications.................................................................................................43
7.2.7.
Re-treatment Criteria..............................................................................................46
7.3.
Method of Treatment Assignment...........................................................................46
7.4.
Packaging and Labeling..........................................................................................46
7.5.
Investigational Product Accountability and Disposal ..............................................46
7.6.
Investigational Product Compliance........................................................................47
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................48
8.1.
Permitted Concomitant Medications and Procedures...............................................48
8.2.
Prohibited Concomitant Medications and Procedures..............................................49
8.3.
Required Concomitant Medications and Procedures................................................50
9.
STATISTICAL CONSIDERATIONS ....................................................................50
9.1.
Overview................................................................................................................50
9.2.
Study Population Definitions ..................................................................................50
9.2.1.
Enrolled Population ...............................................................................................50
9.2.2.
Safety Population....................................................................................................50
9.3.
Sample Size and Power Considerations...................................................................50
9.4.
Background and Demographic Characteristics........................................................51
9.5.
Subject Disposition.................................................................................................51
9.6.
Overall Survival .....................................................................................................51
9.7.
Safety Analysis.......................................................................................................51
9.8.
Interim Analysis .....................................................................................................51
9.9.
Other Topics...........................................................................................................52
10.
ADVERSE EVENTS..............................................................................................52
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................52
10.2.
Evaluation of Adverse Events.................................................................................53
10.2.1.
Seriousness.............................................................................................................53
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10.2.2.
Severity/Intensity ....................................................................................................54
10.2.3.
Causality ................................................................................................................55
10.2.4.
Duration.................................................................................................................55
10.2.5.
Action Taken...........................................................................................................55
10.2.6.
Outcome .................................................................................................................55
10.3.
Abnormal Laboratory Values..................................................................................55
10.4.
Pregnancy...............................................................................................................56
10.4.1.
Females of Childbearing Potential .........................................................................56
10.4.2.
Male Subjects .........................................................................................................56
10.5.
Reporting of Serious Adverse Events......................................................................57
10.5.1.
Safety Queries ........................................................................................................57
10.6.
Expedited Reporting of Adverse Events..................................................................57
11.
DISCONTINUATIONS .........................................................................................58
11.1.
Treatment Discontinuation......................................................................................58
11.2.
Study Discontinuation ............................................................................................59
12.
EMERGENCY PROCEDURES.............................................................................59
12.1.
Emergency Contact.................................................................................................59
12.2.
Emergency Identification of Investigational Products .............................................59
13.
REGULATORY CONSIDERATIONS...................................................................60
13.1.
Good Clinical Practice............................................................................................60
13.2.
Investigator Responsibilities ...................................................................................60
13.3.
Subject Information and Informed Consent.............................................................61
13.4.
Confidentiality........................................................................................................61
13.5.
Protocol Amendments.............................................................................................61
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................61
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................62
13.8.
Termination of the Study ........................................................................................62
13.9.
Sponsor Commitment to Diversity in Clinical Trials...............................................63
14.
DATA HANDLING AND RECORDKEEPING.....................................................63
14.1.
Data/Documents .....................................................................................................63
14.2.
Data Management...................................................................................................63
14.3.
Record Retention....................................................................................................63
14.4.
Data Protection, Data Privacy, and Data Security....................................................64
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................65
15.1.
Study Monitoring and Source Data Verification......................................................65
15.2.
Audits and Inspections............................................................................................66
16.
PUBLICATIONS ...................................................................................................66
17.
REFERENCES.......................................................................................................67
18.
APPENDICES........................................................................................................71
APPENDIX A
TABLE OF ABBREVIATIONS.............................................................71
APPENDIX B
RECOMMENDATIONS FOR MANAGEMENT OF 
TREATMENT-INDUCED DIARRHEA ................................................74
APPENDIX C
FEMALES OF CHILDBEARING POTENTIAL DEFINITIONS 
AND METHODS OF CONTRACEPTION ............................................................75
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LIST OF TABLES
Table 1:
Risk Assessment.....................................................................................24
Table 2:
Study Objectives ....................................................................................26
Table 3:
Study Endpoints .....................................................................................26
Table 4:
Table of Events ......................................................................................33
Table 5:
Criteria for Interrupting or Resuming Study Treatment...........................44
Table 6:
Abbreviations and Specialist Terms........................................................71
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................29
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1.
INTRODUCTION 
1.1.
Disease Background 
1.1.1.
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a malignancy of the myeloid precursor cell line, characterized
by the rapid proliferation of abnormal cells, which accumulate in the bone marrow and interfere
with the production of normal blood cells. Approximately 21,450 people were estimated to have 
been diagnosed with AML in 2019 in the United States (US) and 10,920 subjects were estimated 
to have died from the disease (Siegel, 2019). In Europe, the occurrence of newly diagnosed AML 
is estimated at approximately 18,000 cases annually (Rodriguez-Abreu, 2007). Worldwide, the
incidence of AML is highest in the US, Australia, and Western Europe (Redaelli, 2003). Acute
myeloid leukemia is mostly a disease of older individuals with a median age of approximately 68
years at diagnosis and median age of 72 years at death (National Cancer Institute, 2019).
AML is generally classified as de novo or secondary when arising following exposure to prior
cytotoxic chemotherapy or after a history of prior myelodysplastic syndromes (MDS) or other
antecedent hematologic disorder. The pathogenesis of AML at the genetic level is also
heterogeneous. Comprehensive profiling of genetic alterations in AML will enhance disease
classification, risk stratification, and prognosis, and ultimately allow more precise therapeutic
interventions.
It is estimated that 35% to 40% of patients with myelodysplastic syndromes (MDS) will go on to 
develop AML, and the disease is often refractory to current therapy (Silverman, 2000). Preexisting 
myelodysplastic or myeloproliferative disorders are common in older patients with AML, 
occurring in 24% to 40% of cases (Gajewski, 1989). Acute myeloid leukemia patients with 
antecedent hematologic disease have a lesser response to therapy than those with de novo disease 
(Gajewski, 1989; Leith, 1997).
Treatment of AML is divided into two phases:  induction of remission and post remission therapy. 
For more than 30 years, the combination of cytarabine and anthracycline has been the mainstay of 
treatments to induce remission (Löwenberg, 1999; Tallman, 2005). For patients eligible for 
intensive induction chemotherapy, the combination of cytarabine and anthracycline has been the 
mainstay of treatments to induce remission (National Comprehensive Cancer Network [NCCN]
AML, 2021; Döhner, 2017). First-line induction therapy of cytarabine 100 to 200 mg/m2 × 7 days 
followed by either idarubicin 12 mg/m2× 3 days or daunorubicin 45 to 90 mg/m2× 3 days, referred 
to as “7+3 protocol,” is the backbone of conventional treatment for patients who can tolerate 
intensive chemotherapy. In patients under 60 years, complete remission (CR) rates can be achieved 
in 75% to 90% of patients usually with one course of treatment, and the overall 5-year survival is 
approximately 50% (Burnett, 2005).
Although induction chemotherapy produces morphologic CRs in about 60% to 80% of younger
adults and 40% to 50% of older adults with newly-diagnosed AML, there is a substantial 
population of patients who will fail to attain CR (ie, refractory) (Mangan, 2011). Even for those 
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who attain CR after induction treatment, a significant portion will eventually relapse, leading to 
only about 29% relapse-free survival at 3 years (Yanada, 2007).
In elderly patients with AML, defined as older than 60 years, conventional cytotoxic intensive
chemotherapy has been associated with CR rates of approximately 45%, without durability and
with higher early treatment-related mortality and shorter survival, with a median survival between 
7 to 12 months (Dombret, 2008; Jabbour, 2006). Elderly patients with AML have significant 
comorbidities, an increased frequency of adverse cytogenetic abnormalities, performance status, a 
higher incidence of AML arising from MDS, and resistance to conventional treatments. For these 
reasons, elderly patients may not be candidates for standard intensive induction chemotherapy 
regimens (DiNardo, 2019; Pettit, 2015).
Patients considered ineligible for intensive induction chemotherapy are generally patients older
than 75 years of age or those 60 to 75 years old with significant comorbidities, poor performance
status, or with complex cytogenetic abnormalities (DiNardo, 2019; Milligan, 2006; Pettit, 2015;
Tallman, 2019). Treatment options for patients who are not candidates for intensive induction
chemotherapy and who do not have actionable mutations include: low-intensity therapies, such as 
low-dose cytarabine (LDAC), hypomethylating agents (HMAs; azacitidine or decitabine),
supportive care only, glasdegib in combination with LDAC, or the venetoclax combination
regimens with HMAs or LDAC (Kucukyurt, 2019; LeBlanc, 2019; Tallman, 2019).
Current approaches to post remission therapy include consolidation chemotherapy, hematopoietic 
stem cell transplant (HSCT) and maintenance therapy.
1.1.2.
Myelodysplastic Syndromes
Myelodysplastic syndromes encompass heterogeneous collection of hematopoietic stem cell 
disorders primarily affecting older adults. Myelodysplastic syndromes are typically characterized 
by bone marrow hyperplasia and peripheral cytopenias that manifest clinically as anemia, 
neutropenia and/or thrombocytopenia of variable frequency and severity. Anemia is the most 
frequent laboratory finding and it often progresses to red blood cell (RBC) transfusion dependence. 
Other less common presenting clinical features related to the cytopenias are an increased risk of 
infection and/or hemorrhage, and a potential to progress to AML (Catenacci, 2005). It is estimated 
that 5 cases per 100,000 persons per year are diagnosed with MDS (NCCN, 2015). The elderly are 
particularly vulnerable with annual incidence rates between 26 and 48 cases per 100,000 persons 
per year (NCCN, 2015).
Myelodysplastic syndromes are classified according to World Health Organization (WHO) criteria 
by pathologic features on bone marrow examination (Vardiman, 2009). Myelodysplastic 
syndromes are also categorized into one of 4 risk groups (Low, Intermediate-1 [INT-1], 
Intermediate-2 [INT-2], and High risk) according to the International Prognostic Scoring System 
(IPSS) based on cytogenetic features, number of cytopenias and bone marrow blast percentages 
(Greenberg, 1997). Overall survival and risk of progression to AML is significantly different in 
the 4 risk groups (Greenberg, 1997). The Low and INT-1 groups tend to have a better prognosis 
than do subjects with INT-2 or High risk disease, with the median survival for patients in these 
risk groups being 5.7 years (Low), 3.5 years (INT-1), 1.2 years (INT-2) and 0.4 years (High) 
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(Greenberg, 1997). The median time for 25% of patients to progress to AML is 9.4, 3.3, 1.1, and 
0.2 years, respectively, in the Low, INT-1, INT-2 and High risk groups (Greenberg, 1997).
The mainstay of therapy in IPSS lower-risk (Low or INT-1 risk) MDS has been supportive care, 
which includes the use of RBC and/or platelet transfusions, treatment of infections, and the use of 
erythropoiesis stimulating agents (ESAs) such as epoetin alfa or darbepoietin, plus hematopoietic 
growth factors such as granulocyte colony-stimulating factor (G-CSF) when needed (Silverman,
2000). As the outcome of patients with lower-risk MDS is not improved by early introduction of 
allogeneic hematopoietic stem cell transplantation (HSCT) (Cutler, 2010), allogeneic HSCT is 
recommended at the time of disease progression for lower-risk MDS patients (NCCN, 2015).
1.2.
Compound Background
1.2.1.
CC-486 (Oral Azacitidine)
Azacitidine is an analog of the naturally occurring pyrimidine nucleoside cytidine and is classified 
as an antimetabolite.
Azacitidine injectable is marketed worldwide under the trade name Vidaza® (azacitidine for
injection). Azacitidine injectable was first approved in the US on 19 May 2004 for the following
5 subtypes of myelodysplastic syndrome (MDS) per the French American-British classification
system: refractory anemia (RA) or RA with ringed sideroblasts (if accompanied by neutropenia or 
thrombocytopenia or requiring transfusions), RA with excess blasts (RAEB), RAEB in 
transformation, and chronic myelomonocytic leukemia (CMML). Azacitidine injectable is 
approved in the US for both subcutaneous (SC) and intravenous (IV) routes of administration. 
Azacitidine (SC use only) was approved in the European Union (EU) on 17-Dec-2008 for the 
treatment of adult patients who are not eligible for hematopoietic stem cell transplantation (HSCT) 
with intermediate-2 (INT-2) and high-risk MDS according to the IPSS, CMML with 10% to 29% 
marrow blasts without myeloproliferative disorder, and AML with 20% to 30% blasts and 
multilineage dysplasia, according to the World Health Organization (WHO) classification. In 
addition, the following indication of AML with > 30% marrow blasts, according to the WHO 
classification, was added and revised by the European Commission decisions adopted on 28-Oct-
2015 and 29-Jun-2016, accordingly. As of 18-Jan-2022, azacitidine injectable is approved in 85 
countries, including the US and EU. Depending on the country, azacitidine injectable is approved 
for SC use only or for both SC and IV administration.
Azacitidine has also been formulated for oral administration. CC-486 (ONUREG, oral 
azacitidine), also known as BMS-986345, is approved in many regions including the United States
(US), Canada, European Union (EU), and United Kingdom for continued treatment of adult 
patients with AML who achieved first complete remission (CR) or complete remission with 
incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not 
able to complete intensive curative therapy (ONUREG® USPI, 2020). Oral azacitidine was 
approved in Canada on 05-Jan-2021 for maintenance therapy in adult patients with AML who 
achieved CR or CRi following induction therapy with or without consolidation treatment, and who 
are not eligible for HSCT. On 17-Jun-2021, the ethics committee (EC) granted the Marketing 
Authorization for ONUREG for maintenance therapy in adult patients with AML who achieved 
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CR or CRi following induction therapy with or without consolidation treatment, and who are not 
candidates for, including those who choose not to proceed to, HSCT.
CC-486 is being developed and is currently being evaluated in clinical trials, either as a single 
agent or in combination with other drugs for the treatment of hematological malignancies. The oral 
formulation provides an opportunity for a more convenient home administration than the 
hospital/clinic setting.
Azacitidine has strong in vitro and in vivo antileukemic activity at cytotoxic concentrations and 
the ability to induce differentiation at lower concentrations in hematopoietic and non-
hematopoietic cell lines. The cytotoxic effects of azacitidine may result from multiple 
mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA 
and DNA, and activation of DNA damage pathways. The ability of azacitidine to cause 
differentiation can be attributed to its activity as a hypomethylating agent. The degree of 
methylation of cytosine residues in DNA has been demonstrated to play a role in gene expression.  
Indeed, cytosine hypermethylation of the genes critical to ensure orderly cell proliferation and 
maturation (differentiation) is frequently found in primary neoplasms and tumor cell lines (Zingg, 
1997). Therefore, use of an inhibitor of DNA methylation, such as azacitidine, would be a rational 
approach for the treatment of various malignancies including AML, MDS and CMML to revert 
these epigenetic aberrations in the malignant clone and to re-establish the antiproliferative signals 
that were extinguished by hypermethylation.  Recent data (Tsai, 2012) support the concept that 
DNA hypomethylating agents at low doses can reprogram the aberrant epigenetic state of cancer 
cells to elicit sustained antitumor activity. Preliminary data from the AZA-PH-GL-2003-CL-001
survival study with Vidaza in higher-risk MDS patients found from an analysis of pretreatment 
bone marrow methylation density that the overall survival (OS) benefit observed with azacitidine 
versus the conventional care regimen (CCR) was independent of methylation status of the 5 genes 
analyzed (CDKN2B [p15], SOCS1, CDH1 [E-cadherin], TP73, and CTNNA1 [α-catenin]). 
However, increasing methylation was associated with worse OS and patients with lower levels of 
methylation treated with azacitidine had the best OS, suggesting they may derive greater benefit 
from azacitidine.
Parenteral azacitidine has been extensively studied in MDS and AML. In MDS it has been shown 
in a large, randomized Phase 3 trial of higher-risk MDS patients to provide a survival advantage 
of 9.4 months over CCRs and thus altering the natural course of MDS. The median OS of 
azacitidine-treated patients was 24.5 months compared with 15.0 months for the combined CCR 
group, which included best supportive care (BSC), low-dose cytarabine, and intensive 
chemotherapy (Fenaux, 2009). The clinical experience of azacitidine in AML is smaller, but 
positive efficacy results have been obtained. In a subset of 113 patients with WHO-defined AML 
(mean age 70 years, 24% with unfavorable karyotype, median bone marrow blasts 23%) from the 
larger MDS study discussed above, the median OS was 24.5 months (n = 55) in the azacitidine 
arm compared with 15.0 months (n = 58) in the CCR (Fenaux, 2008; Fenaux, 2009). Additionally,
the outcome was not significantly different in patients with unfavorable karyotypes, although the 
sample size was small.  Silverman et al, using WHO AML criteria for diagnosis, reported a median 
OS of 19.3 months (n = 27) in azacitidine treated patients compared with 12.9 months (n = 25) in 
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patients who received BSC (Silverman, 2006). Additionally, Goldberg et al reported on 33 patients 
who received azacitidine (n = 11, median age 74) or 7 + 3 intensive chemotherapy (n = 22, median 
age 67 years). Median blast counts at baseline were 42% in the azacitidine group and 65% in the 
intensive chemotherapy group. The median OS was 13.2 months in azacitidine-treated patients 
compared with 9.2 months in intensive chemotherapy patients (Goldberg, 2006). All of the above 
mentioned studies used the standard azacitidine dose of 75 mg/m2/day for 7 days.
An oral formulation of azacitidine (CC-486) entered clinical testing in 2006 in subjects with MDS, 
CMML, and AML. The AZA PH US 2007 CL 005 study has shown that CC-486 is bioavailable 
and produces cumulative exposures (area under the concentration curve [AUC]) that are 30% to 
60% of the exposure achieved with the labeled dose and schedule of Vidaza. A maximum 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 also 
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. Daily 
doses of 300 mg have proven to be tolerated on both the 14 and 21 out of 28-day schedules with 
myelosuppression, gastrointestinal 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 endpoint, to determine DNA hypomethylating activity of CC-486. In Part 1 of 
the study, CC-486 administration for the first 7 days of a 28-day cycle reduced DNA methylation 
in the blood, with maximum hypomethylation achieved on Day 15 (8 days after the last dose), and 
methylation levels returned to near-baseline values by the end of cycle. In Part 2 of the study, DNA 
methylation levels in blood were measured to determine the DNA hypomethylating activity of CC-
486 when administered orally at 300 mg once daily (QD) for 14 or 21 days of 28-day cycles. 
Subjects treated with CC-486 for 21 days had DNA hypomethylation that persisted through the 
end of cycle. This contrasts with the lack of persistent hypomethylation at the end of cycle when 
treated with CC-486 for only 7 days, thus providing mechanistic support for treating beyond 7 
days. In summary, CC-486 is biologically active, reducing DNA methylation when administered 
at low doses on extended schedules.
The primary analysis of a controlled Phase 3 study assessing the efficacy of CC-486 to treat 
subjects with IPSS lower-risk MDS (AZA-MDS-003) has been completed. Subjects were 
randomized 1:1 to receive 300 mg CC-486 or placebo QD for the first 21 days of each 28-day 
treatment cycle. The primary efficacy endpoint of red blood cell (RBC) transfusion independence 
with a duration of 56 days (8 weeks) or longer in subjects with IPSS lower-risk MDS with RBC 
transfusion-dependent anemia and thrombocytopenia was achieved in 31% of subjects treated with 
CC-486 (n = 107) compared to 12% of subjects treated with placebo (n = 109), with a statistically 
significant difference of almost 19% (p = 0.0005). The median duration of RBC transfusion 
independence for subjects treated with CC-486 was 11.1 months with a median onset of 
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2.4 months. In addition, subjects treated with CC-486 demonstrated significant clinical benefit 
across multiple other parameters measured, namely, hematologic improvement–erythroid response 
(10.9% rate difference, CC-486 group over placebo group), hematologic improvement-platelet
response (17.0% rate difference, CC-486 group over placebo group), hemoglobin increase, and 
increase in platelet counts. Approximately 50% fewer subjects experienced progression to AML 
in the CC-486 group compared to the placebo group. Overall survival was assessed as an interim 
analysis at the time of the primary analysis and demonstrated no significant or clinically 
meaningful difference in survival between the 2 treatment groups with a hazard ratio (HR) 1.03 
(p = 0.8759) (Garcia-Manero, 2021).
The efficacy of CC-486 as a maintenance therapy in subjects with AML aged 55 years or older 
who were in remission following induction/consolidation therapy and were not eligible for HSCT 
was assessed in a controlled Phase 3 study (CC-486-AML-001). Results of the primary analysis 
were positive; the primary efficacy endpoint of OS and the key secondary efficacy endpoint of 
relapse-free survival (RFS) were both significantly improved in the CC-486 group (stratified 
log-rank test p = 0.0009 for OS and p = 0.0001 for RFS). Treatment with CC-486 (n = 238) resulted 
in a median OS of 24.7 months, a clinically meaningful increase of 9.9 months over placebo
(14.8 months), and a 31% reduction in the risk of death. The median RFS was 10.2 months for the 
CC-486 group and 4.8 months for the placebo group, with a clinically meaningful difference in 
median RFS of 5.3 months with CC-486 treatment. The stratified HR was 0.65 (95% confidence 
interval: 0.52, 0.81), indicating a 35% reduction in risk of relapse or death for the CC-486 group, 
which demonstrated the benefit of CC-486 as maintenance therapy for the treatment of AML. CC-
486 was associated with significantly lower rates of hospitalization events compared to placebo 
(0.48 events per person-year for the CC-486 group and 0.64 events per person-year for the placebo 
group [nominal p = 0.0068]) and number of days hospitalized (7.89 days per person year for 
CC-486 compared to 13.36 days per person-year for placebo, nominal p < 0.0001) (Wei, 2020).
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event profile of the 
investigational product (IP).
1.3.
Rationale
1.3.1.
Study Rationale and Purpose
The proposed open-label, multicenter, multinational rollover study is intended to evaluate the long-
term safety of CC-486, while providing continued treatment with CC-486 for subjects who 
received single agent CC-486 in Celgene-sponsored trials, and who in the opinion of the 
Investigator may derive clinical benefit from continuing treatment with CC-486.  
CC-486 provides an opportunity to deliver azacitidine at lower systemic doses over a more 
prolonged schedule than can be practically achieved with parenteral therapy. In addition, CC-486 
can be taken at home rather than in the hospital/clinic setting representing an opportunity for 
patients with various hematological malignancies including AML and MDS, under adequate 
control or in remission and may offer better quality of life and possibly a survival advantage.
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1.3.2.
Rationale for the Study Design
This open-label, multicenter, non-randomized study is designed to evaluate long-term safety of 
CC-486 and at the same time provides continued access to CC-486 for eligible subjects who were 
previously enrolled and treated with single agent CC-486 in a parent CC-486 protocol and did not 
meet the criteria for discontinuation described in the parent CC-486 study protocol, and are still 
deriving clinical benefit (as assessed by Investigator). These subjects may therefore potentially 
benefit from continued treatment with CC-486. In this study subjects will initiate treatment with 
CC-486 at the dose and schedule of the last visit of the parent CC-486 study. Treatment will 
continue until progression of disease or disease relapse or as long as the subject is deriving clinical 
benefit, as judged by the Investigator, or upon commercial availability of CC-486 for the indication 
in the participating country.
1.4
Benefit/Risk Assessment
Detailed information about the known and expected benefits and risks and reasonably anticipated 
AEs of CC-486 can be found in the Investigator’s Brochure.
1.4.1
Risk Assessment
Table 1:
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention(s)
The known risks associated with CC-486
treatment classified as very common (a
10% or more chance that this will 
happen) include neutropenia, leukopenia,
febrile neutropenia, thrombocytopenia,
infections (including pneumonia or
infections of the upper respiratory tract),
nausea, vomiting, diarrhea, abdominal or 
upper abdominal pain, constipation,
asthenia, fatigue, pyrexia, decreased
appetite, weight decreased, and pain 
(including arthralgia, back pain, pain in 
extremity).
The reported AEs in global
study oral azacitidine AZA-
MDS-003 were consistent 
with the known safety profile 
of azacitidine. There were no 
new safety signals or
unexpected safety findings 
observed with the oral 
azacitidine regimen.
The proposed safety
monitoring (Section 10.1),
and toxicity management guidance
(Table 5) will minimize the risks 
for the subjects in this study.
Study Procedures
There are no study-specific procedures 
that have been identified as potential risks
to subjects of this study.
N/A
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Table 1:
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Other
The COVID-19 pandemic has been 
identified as a potential risk to clinical 
study subjects in general.
It is not known whether taking
CC-486 increases the risk of
SARS-CoV-2 infection or the
duration or severity of 
COVID-19.
The study has been designed with 
study visits that allow for close 
monitoring of the subjects’ safety 
throughout the clinical study
(Table 4, Section 6), and 
unscheduled visits may be 
performed if clinically indicated
(Section 6)孱
To facilitate enhanced reporting of 
COVID-19 events that occur 
during the study, all AEs and SAEs 
reported after the time of consent 
that are related to SARS-CoV-2 or
COVID-19 infection must be
reported (Section 10.1).
Individual benefit-risk
considerations remain the
responsibility of the Investigator. 
Investigators should apply clinical
judgment, and these risks should 
be considered when enrolling a
participant.
Abbreviations: AE = adverse event; COVID-19 = coronavirus disease 2019; N/A = not applicable; SAE = serious 
adverse events; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
1.4.2
Benefit Assessment
Oral azacitidine is the first therapy used in the maintenance setting to provide statistically 
significant and clinically meaningful improvements in both OS and recurrence-free survival (RFS)
in patients with AML in remission following induction chemotherapy with or without 
consolidation. Oral CC-486 has a manageable safety profile and represents a new therapeutic 
standard for patients with AML in remission (Wei, 2019).
Oral azacitidine has demonstrated a clinical benefit in MDS subjects with a decreased risk of 
progression to AML and a potential correction of the peripheral blood cytopenias, including the 
correction of packed red blood cells (pRBCs) or platelet transfusion dependence. While a benefit 
of overall survival has not been demonstrated by using CC-486, it can elicit pRBC transfusion 
independence in heavily pre-transfused MDS patients.
Therefore, the development of CC-486 offers an oral alternative to conventional HMA (including 
injectable azacitidine) and provides a treatment option for patients with AML and those patients 
with MDS who have exhausted symptomatic treatments and are in need for a disease-modifying 
treatment. The oral formulation provides an opportunity for a more convenient home 
administration than the injectable azacitidine that requires the hospital/clinic setting.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
26
1.4.3
Overall Benefit/Risk Conclusion
Taking into account the measures to minimize risk to subjects in this study, the potential risks 
identified in association with oral azacitidine are justified by the anticipated benefits that may be 
afforded to subjects with myeloid disorders. The Sponsor will evaluate the benefit/risk profile of 
the study on an ongoing basis. This evaluation will be based on all available data with particular 
attention to AEs or other safety trends in this or any other clinical study of CC-486 whose nature,
severity, and/or frequency suggest that subjects would be exposed to an unreasonable and 
significant risk of illness or injury; and new nonclinical data which suggest unreasonable and 
significant risk of illness or injury. If such evaluation suggests that the risk/benefit profile of the 
study has become unfavorable to subjects, the Sponsor will pause enrollment and/or treatment until 
further evaluation of data, and interaction with the appropriate Health Authority(ies) can take place 
on potential actions. Such actions may include (but are not limited to) study continuation, 
substantial amendment, or termination of the study. However, no available safety information has 
been identified which would alter the currently known benefit/risk profile for azacitidine.
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 2:
Study Objectives
Primary Objective
The primary objective of the study is to evaluate the long-term safety of CC-486 (oral azacitidine) in subjects who 
have received CC-486 as monotherapy in other Celgene-sponsored clinical trials and whom the Investigators feel 
may derive clinical benefit from continuing treatment with CC-486. 
Secondary Objective(s)
The secondary objective is to follow subjects treated with CC-486 or placebo (in parent CC-486 study) for 
survival if required by the parent CC-486 study protocol.
Exploratory Objective(s)
None.
Table 3:
Study Endpoints
Endpoint
Name 
Description
Timeframe
Primary 
Safety
Type, frequency, severity and relationship of treatment 
emergent adverse events to investigational product
At End of Trial
Secondary 
Survival
Time from randomization until death from any cause
At End of Trial 
Exploratory
None
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
27
3.
OVERALL STUDY DESIGN
3.1.
Study Design
The open-label, multicenter, multinational rollover study is intended to evaluate the long-term 
safety of CC-486, while providing continued treatment with CC-486 for subjects who are receiving 
single agent CC-486 at the time of transition to rollover study and tolerated the protocol prescribed 
regimen in Celgene-sponsored trials, and who, in the opinion of the Investigator, may derive 
clinical benefit from continuing treatment with CC-486.  Subjects’ survival will also be followed 
if required by the parent CC-486 study protocol. If approved by Celgene, subjects from any 
ongoing or future Celgene sponsored CC-486 studies in hematological disorders will be included 
in this protocol.
The overall study design is described in Figure 1.
3.1.1.
Study Entry/Screening Assessment Phase
Once a subject gives written consent, the subject may enter the Study Entry/Screening Assessment 
Phase. During this period, the subject will undergo safety and other assessments to reconfirm 
eligibility for the study. Assessments conducted during the End of Study visit in the parent CC-
486 study may be used if these are the same assessments specified in this rollover protocol and fall 
within the required timeframe. Once the subject has fulfilled the required assessment in the Study 
Entry/Screening Assessment Phase, the subject will enter the Treatment Period.
To ensure no gaps in IP dosing, subjects should start study entry/screening assessment procedures
within 7 days of the End of Study visit from their parent CC-486 study. Ideally, Day 1 of the first 
cycle in the rollover study should occur on the same day as the End of Study visit from the parent 
CC-486 study.  A subject’s transition into the rollover study should not exceed more than 45 days 
after the End of Study visit of the parent CC-486 study.
Assessments performed as part of the End of Study visit from parent CC-486 study do not need to 
be repeated on Day 1 of the rollover study if performed within 7 days.  
Please refer to Section 6.1 and Table 4 for all assessments to be performed during the Study 
Entry/Screening Assessment Phase.
3.1.2.
Treatment Phase
Subjects who meet all inclusion and none of the exclusion criteria will be evaluated at the clinic 
on the intended Day 1 (ie, predose) for study entry/screening assessments.
The dose and schedule of CC-486 in this study will be dictated by which parent CC-486 study the 
subject participated in, taking into account their last single agent dose and schedule of CC-486 in 
the parent CC-486 study. For some subjects, a formulation change of the IP from capsule 
formulation to tablet formulation must occur after enrolling into this rollover study. 
Safety will be monitored throughout the study from the time informed consent is obtained until 28 
days after the last dose of CC-486. 
Subjects will continue participation in this rollover protocol until disease relapse or progressive 
disease is documented, until a withdrawal criterion (Section 11) is met, or until CC-486 is 
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
28
commercially available in the participating country for the indication that the subject is being 
treated. Only subjects whose parent CC-486 studies require follow-up for survival, will be 
followed for overall survival.
If a subject discontinues from the study for any reason, the subject must undergo the required 
safety follow-up procedures/assessments as described in Table 4 after the decision to permanently 
discontinue treatment.
Subjects who received placebo in the randomized parent CC-486 clinical trials will not receive 
CC-486 treatment. Once consented, these subjects will directly enter survival follow-up in the 
Follow-up Phase of the rollover study.
3.1.3.
Follow-up Phase 
All subjects who received CC-486 in this protocol, and discontinue from the Treatment Phase, will 
enter safety follow-up in the Follow-up Phase of the study.  These subjects will be followed for 28 
days after the last dose of IP for the assessment of safety related parameters and adverse event 
(AE) reporting, as well as serious adverse events (SAEs) made known to the Investigator at any 
time thereafter that are suspected of being related to IP.  
Subjects whose parent CC-486 studies require follow-up for survival will be followed for overall 
survival in this study. Subjects who received placebo in the randomized parent CC-486 clinical 
trials may transition into the rollover protocol; however, they will not receive CC-486 treatment.  
Once consented, these subjects will directly enter survival follow-up in the Follow-up Phase of the 
rollover study.  
Additionally, all subjects, regardless of treatment with single agent CC-486 or placebo, who 
discontinued from the treatment phase but are continuing in the follow-up phase of the parent CC-
486 study, will also be followed for survival in the rollover study. Once consented, these subjects 
will directly enter survival follow-up in the Follow-up Phase of the rollover study.  
During the follow-up phase of the study, subjects will be followed for survival every month for 
the first year and then every 3 months until death, withdrawal of consent for further follow-up, 
study termination, or until a subject is lost to follow-up, according to the parent CC-486 protocol 
requirements. New anticancer therapies should be collected at the same time schedule.
Survival/long-term 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.
The study will be conducted in compliance with the International Council on Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
29
Figure 1:
Overall Study Design
AE = adverse event; CBC = complete blood count; ICF = informed consent form; IP = investigational product; SAE = serious adverse event.
1 Follow-up for Survival is for subjects indicated.  Follow-up for survival will not have the Safety Follow-up.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
30
3.2.
Study Duration for Subjects
Subjects will continue to receive IP in this rollover study until disease relapse, documented disease 
progression, unacceptable toxicity; death, withdrawal of consent, or until study termination. 
Subjects transitioning from parent CC-486 studies with survival follow-up will require survival 
follow-up in this rollover study. Subjects who discontinue CC-486 due to an AE will be followed 
until resolution of the AE or return to baseline.
If the subject discontinues from study treatment for any reason, the subject must undergo the 
required assessments as soon as possible after the decision to permanently discontinue treatment. 
Subjects may also be discontinued from the study if CC-486 becomes commercially available in 
the participating countries for the indications for which subjects are being treated.
3.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
post-treatment follow-up, the date of receipt of the last data point from the last subject that is 
required for primary and/or secondary endpoint analysis, as pre-specified in the protocol, the date 
of the study termination by the Sponsor, or the date of the last per-protocol visit for subjects who 
are transferred to commercially available and/or reimbursed CC-486 in the participating countries 
where CC-486 is approved by regulatory authorities for the indication that the subject is being 
treated, whichever is the later date.
The study will close once CC-486 becomes commercially available in the participating countries 
for the indications that the subjects are being treated and reimbursed such that the subject’s access 
to CC-486 is neither interrupted nor discontinued by the relevant local healthcare provider.
4.
STUDY POPULATION
4.1.
Number of Subjects 
The total number of subjects and sites cannot be clearly determined or estimated as the number of 
studies from which subjects will roll over into the present study is not yet known. Subjects who 
received or will be receiving single agent CC-486 from any ongoing or future CC-486 studies 
selected by Celgene Corporation may be included in this protocol.  
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be given IP in the study:
1. Previously participated in, and received CC-486, and continues to fulfill the eligibility criteria 
in one of the parent CC-486 clinical trials.
The Investigator believes the subject is tolerating treatment with CC-486 monotherapy and 
continued CC-486 treatment is of benefit to the subject.
2. Understand and voluntarily sign an informed consent document prior to any study-related 
assessments or procedures being conducted.
3. Willing and able to adhere to the study visit schedule and other protocol requirements.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
31
4. Reproductive Status

Investigators shall counsel females of childbearing potential (FCBP) (as defined in Appendix 
C) and male subjects who are sexually active with FCBP, on the importance of pregnancy 
prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity 
occurring due to transmission of study intervention, present in seminal fluid, to a developing 
fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.

The investigator shall evaluate the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention.

Local laws and regulations may require the use of alternative and/or additional contraception 
methods.

Both male and female subjects must use an efficient method of contraception throughout the 
transition time frame after the last dose of CC-486 in the parent CC-486 study and prior to the 
first dose of CC-486 in this study without interruption. Once the subject is in the new study, 
contraception will be continued throughout participation in the new study and for a period after 
treatment completion (at the specified time frames for women and men, respectively).
a) Female Subjects:
i)
Female subjects must have documented proof that they are not of childbearing 
potential.
(1) Females who are not of childbearing potential are exempt from contraceptive 
requirements.
ii) Females of childbearing potential may participate, provided that the subject meets the 
following conditions:
(1) Have two negative pregnancy tests as verified by the investigator prior to starting 
study treatment. She must agree to ongoing pregnancy testing during the course of 
the study, and after end of study treatment. This applies even if the subject practices 
true abstinence from heterosexual contact.
(2) Either commit to true abstinence from heterosexual contact (which must be 
reviewed on a monthly basis and source documented) or agree to use and be able 
to comply with highly effective contraception without interruption, during 
screening, during the study treatment (including dose interruptions), and for 6 
months after discontinuation of study treatment, or longer if required for each 
compound and/or by local regulations.
b) Male Subjects:
Males who are sexually active with FCBP must agree to follow instructions for method(s) 
of contraception as described below and included in the informed consent form (ICF).
i)
Azoospermic males are not exempt from contraceptive requirements and will be 
required to always use a latex or other synthetic condom during any sexual activity (eg, 
vaginal, anal, oral) with FCBP, even if the subject has undergone a successful 
vasectomy or if the partner is pregnant.
ii) Male subjects are required to use a condom during the intervention period and for at 
least 90 days after the last dose of study intervention.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
32
iii) Female partners of male subjects should be advised to use a highly effective method of 
contraception during the study intervention period and for at least 90 days after the last 
dose of study intervention for the male participant.
iv) Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent 
from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, 
oral) during the intervention period and for at least 90 days after the last dose of study 
intervention.
v) Male subjects must refrain from donating sperm during the intervention period and for 
at least 90 days after the last dose of study intervention.
vi) Breastfeeding partners of male subjects should be advised to consult their health care 
provider about using appropriate highly effective contraception during the time the 
male participant is required to use condoms.
Subjects must satisfy the following criteria to participate in the Survival Follow-up phase:
1. In order to be enrolled for the survival follow-up in the Follow-up Phase of the rollover study, 
subjects must have been in a parent CC-486 study where monitoring for survival was required 
and have signed informed consent for follow-up phase. 
2. Understand and voluntarily sign an informed consent document for this study (CC-486-GEN-
001).
3. Willing and able to adhere to the study visit schedule and other protocol requirements.
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from receiving IP in the study:
1. Concomitant use of drugs that are prohibited (listed in the protocol).
2. Prior chemotherapy (including injectable azacitidine) or radiotherapy or any investigational 
agent after the last dose of CC-486 administered as part of the parent CC-486 study.
3. Subjects have met one or more criteria for discontinuation as stipulated in the parent CC-486 
study.
4. Subjects received CC-486 in combination with another compound during a parent CC-486 
study (Subjects form multi-arm parent CC-486 studies will be allowed to enroll into the 
rollover study, if the subject is receiving single-agent CC-486 at the time of transition into the 
rollover study).
5. A subject’s transition into rollover study ≥ 45 days after End of the Study visit of the parent 
CC-486 study
6. Pregnant or lactating females.
There are no exclusion criteria to prevent entry or remaining on the follow-up phase of this study.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
33
5.
TABLE OF EVENTS
Table 4:
Table of Events
Events
Study 
Entry/Screening 
Assessments Phase 
Treatment Phase a
Follow-up Phase a
Day -21 to Day -1
Cycle 1 
Day 1
Day 1 of Each 
Subsequent Cycle 
(if clinic visit)
Non-clinic Visits 
(prior to starting 
subsequent cycles)b
End of 
Treatment Safety Follow-up c
Survival 
Follow-up
Sign Informed Consent
X
-
-
-
-
-
-
Inclusion/Exclusion Criteria
X
-
-
-
-
-
-
Demographics d
X
-
-
-
-
-
-
Determine IP Dose and Schedule e, d
X
-
-
-
-
-
-
Physical Examination f
X
X
X
-
X
X
-
Vital Signs, Body Weight and Height f
X
X
X
-
X
X
-
Clinical Assessment g
X
X
X
-
X
X
-
Hematology h
X
X
X
X
X
X
-
Serum Chemistry i 
X
X
X
X
X
X
-
Pregnancy Test j, d/Contraception Education j
X
X
X
X
X
X
-
Assessing Adverse Events k, d
X
X
X
-
X
X
-
Concomitant Medications/Procedures d
X
X
X
X
X
X
-
Dispense IP l, d
-
X
X
X
-
-
-
IP Diary Card
-
X
X
X
-
-
-
Collect Unused CC-486 m
-
-
X
-
X
-
-
Review IP Diary Card m
-
-
X
-
X
-
-
Subject Contact during Non-clinic Visits b
-
-
-
X
-
-
-
Survival Follow-up n, d
-
-
-
-
-
X
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRF = case report form; FCBP = females of child-bearing potential; IP = investigational product; RT-
PCR = reverse transcription polymerase chain reaction.
a
7-day window for all visits, unless otherwise specified.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
34
b
When local, state and federal regulations allow for a site to ship IP to a subject’s home, clinic visits are not necessary at every cycle, provided the following procedures 
are performed prior to dispensing (shipping) IP:  

Hematology and serum chemistry assessments may be done locally and results sent to Investigator and/or site.  

Site personnel will telephone the subject to inquire about and record adverse events (AEs), concomitant medications/procedures and information from the IP 
diary – ie, any missed days/doses.  Review of the IP diary for all cycles should be performed when subjects return to the clinic.   

The Investigator will review the laboratory test results, recorded as AEs, concomitant medication and IP dosing information. 

If the Investigator agrees, the subject may be dispensed another cycle of IP and arrangements will be made with the site pharmacy to ship IP to the subject’s 
home.  Additional IP diaries should be given to the subject during a clinic visit or shipped with the IP.

Coordination of the timing of the laboratory tests, telephone call to the subject and shipment of the IP should be considered to avoid delays in starting the next 
cycle of treatment.  

If the subject communicates that he or she experienced an AE which the Investigator suspects may be serious, the subject will be instructed to return to the clinic 
for evaluation by the Investigator before continuing IP or receiving another cycle of IP.  If the subject experienced a serious adverse event (SAE) the Investigator 
must report the event as described in Section 10.2.

Subjects must have clinic visits at least once every 3 cycles.  
c
Safety Follow-up visit occurs approximately 28 days after the last dose of IP.
d
Data should be collected in the CRF.
e
Subject’s last dose and schedule in the parent CC-486 study will be starting dose and schedule in this study.  Should be recorded in the CRF.
f
Assessment if deemed necessary. This may include physical examination, vital signs, body weight – however, data will not be collected in the CRF but recorded in the 
source documents. Clinically significant abnormal findings should be recorded as AEs in the clinical database.
g
Clinical assessment may be performed less frequently than every clinic visit, however, subjects must have clinical assessment at least every third cycle.  
h
Hematology: hemoglobin, hematocrit, red blood cell (RBC) count with indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], and mean 
corpuscular hemoglobin concentration [MCHC]), white blood cell (WBC) count with absolute and percent differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils and myeloblasts [percent only]), platelet count.  This information is required for safety monitoring only and laboratory test results will not be 
collected in the clinical database as described in Section 10.3.
i
Serum chemistry of albumin, alkaline phosphatase, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), 
phosphorous, potassium, magnesium, serum glutamic oxaloacetic transaminase (SGOT [AST]), serum glutamic pyruvic transaminase (SGPT [ALT]), sodium, total and 
direct/indirect bilirubin, total protein, and uric acid. This information is required for safety monitoring only and laboratory test results will not be collected in the clinical 
database as described in Section 10.3
j
For details on Contraception Education, please refer to Appendix C. For FCBP, a medically supervised serum pregnancy test is to be obtained and verified negative at 
screening. Note that the screening 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 time 
frame. The subject may not receive IP until the investigator has verified that the result of the pregnancy test is negative. Serum pregnancy test during screening should 
be submitted to the local laboratory. Females under the age of 55 years must have a serum follicle-stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause. 
This will be collected locally at screening.
k
Please refer to Section 6.1.7. 
l
Only one cycle of IP may be dispensed at one time.  Subjects who received placebo in the parent CC-486 study will not receive IP.
m For subjects who do not visit clinic monthly, IP accountability and review of IP diary card is done during clinic visits.
n
Overall survival measurements will include survival and disease status, and anticancer treatment not previously reported.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
35
6.
PROCEDURES
All of the required assessments are indicated in Table 4 with an “X” for the assessments to be 
performed during that visit.  All data obtained from these assessments must be present in the 
subject’s source documentation.  Assessments and sample analysis will be performed locally and 
are described in detail below.
Additional assessments may be necessary in some subjects based on the parent CC-486 study 
protocol.  These assessments may be performed at the discretion of the treating physician 
according to the local clinical practices and must be documented in the subject’s source 
documentation.
6.1.
Study Entry/Screening Assessment Phase
To ensure no or minimal gaps in IP dosing for subjects transitioning into the rollover protocol, 
study entry/screening assessment procedures should start immediately after discontinuation from 
the parent CC-486 study.  Ideally, Day 1 of the first cycle in the rollover study should occur on the 
same day as the End of Study visit from the parent CC-486 study. Assessments performed as part 
of the End of Study visit from the parent CC-486 study do not need to be repeated on Day 1 of the 
rollover study if performed within 7 days (excluding the pregnancy testing for FCBP, which must 
be completed within 72 hours of Day 1 of each cycle).  
Written informed consent must be obtained before any study-specific procedures are performed
and any samples are collected.  Study entry/screening assessments to confirm eligibility must take 
place within 21 days prior to enrollment. To ensure that inclusion and exclusion criteria are 
satisfied, eligibility for each subject will be reviewed by the sponsor prior to enrollment. Failure 
to meet any entry criterion excludes a subject from enrollment into the study.  
Please refer to Section 6.1.9 for information to be collected on subjects who could not meet 
eligibility criteria.
Although PE, vital signs and clinical laboratory assessments are performed and must be present in 
the subject’s source documentation, only concomitant medications/procedures and AEs are 
reported in the clinical CRF database.
6.1.1.
Demographics
The subject number and protocol identifier from the parent CC-486 study, the subject number from 
this rollover study, date of birth, sex, race, and ethnicity will be recorded on the respective CRF(s) 
during Study Assessment/Screening Phase.
6.1.2.
Clinical Assessments
Clinical assessment should be performed if deemed necessary by the Investigator for the clinical 
management of the subject.  Assessment by the Investigator may be performed less frequently than 
at the beginning of each cycle, however, subjects must have clinical assessment as stipulated in 
Table 4 at least every third cycle; although pregnancy testing for FCBP must be performed, and 
verified as negative, prior to the subject starting every new cycle.  
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
36
6.1.3.
Physical Examination
Information about the PE must be present in the subject’s source documentation.  Although a PE is 
performed, it is not reported in the database.
Please refer to Table 4 for specific time points of this assessment. 
6.1.4.
Vital Signs, Body Weight, and Height Measurements
Vital signs include blood pressure, pulse, body temperature, body weight, and respiratory rate.  
Height is collected only during Study Entry/Screening Assessment Phase.  Although vital signs, 
body weight, and height measurements are performed and recorded in the source documentation, 
they are not reported in the database.
Please refer to Table 4 for specific time points of these assessments.  
6.1.5.
Hematology
A complete blood count (CBC) for the hematology assessment includes:

red blood cell (RBC) count

hemoglobin

hematocrit

mean corpuscular volume (MCV)

mean corpuscular hemoglobin (MCH)

mean corpuscular hemoglobin concentration (MCHC)

red cell distribution width (RDW)

platelet count

white blood cell (WBC) count with differential:

absolute and/or percent neutrophils

absolute and/or percent lymphocytes

absolute and/or percent monocytes

absolute and/or percent eosinophils

absolute and/or percent basophils

percent myeloblasts, if reported.
Hematology samples will be analyzed by the local laboratory.  Any or all laboratory assessments 
may be repeated more frequently if clinically indicated.  Please refer to Table 4 for specific time 
points of this assessment. Although hematology samples are collected, analyzed and recorded in the 
source documentation, they are not reported in the database.
6.1.6.
Serum Chemistry
Serum chemistry assessments include:

potassium

sodium

chloride
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
37

bicarbonate 

calcium

magnesium

phosphorus

blood urea nitrogen (BUN)

creatinine

glucose

albumin

total protein

alkaline phosphatase

lactate deyhydrogenase (LDH)

uric acid

total and direct/indirect bilirubin 

aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT) 

alanine aminotransferase (ALT) or serum glutamic pyruvic transaminase (SGPT)
Serum chemistry samples will be analyzed by the local laboratory.  Any or all laboratory 
assessments may be repeated more frequently if clinically indicated.  Please refer to Table 4 for 
specific time points of this assessment. Although serum chemistry samples are collected, analyzed 
and recorded in the source documentation, they are not reported in the database.
.
6.1.7.
Assessing Adverse Events
Adverse events will be collected beginning on the date the informed consent is signed.  Adverse 
events will be recorded on the respective CRF(s).  All subjects will be monitored for AEs during 
the study as outlined in Section 10.  Please refer to Section 10 for details regarding monitoring, 
recording, and reporting of AEs, including serious adverse events (SAEs).
For subjects entering the CC-486-GEN-001 rollover study, ongoing AEs at the time of the End of 
Study visit from the parent CC-486 study should be left as ongoing and should not be recorded 
again in the rollover protocol AE CRF unless there is a worsening in the intensity of the ongoing 
AE.  Adverse events with an onset date between the End of Study visit from the parent CC-486 
study and up to the time of signing the informed consent of the rollover study should be recorded 
in the AE CRF for the parent CC-486 study, if the AE occurred within 28 days after the last dose 
of IP in the parent CC-486 study. Only new AEs with an onset date on or after the signing of the 
informed consent in the rollover study should be recorded in the rollover study AE CRF.  If a 
previously reported AE during the parent CC-486 study worsens during the rollover study, then 
the AE should be recorded as a new AE with a higher grade on the rollover AE CRF. All subjects 
will be monitored for AEs from the signing of the informed consent through 28 days following the 
date of last dose of CC-486 in the rollover protocol.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
38
6.1.8.
Concomitant Medications/Significant Non-drug Therapies/Concomitant 
Procedures
All prescription or over-the-counter medications and therapeutic procedures administered during 
Study Entry/Screening Assessment Phase and until 28 days after the last dose of the IP must be 
recorded on the respective CRF.  Please refer to Table 4 for specific time points of this assessment.  
6.1.9.
Information to be Collected on Subjects Who do not Meet Eligibility 
Criteria (Not Applicable to Subjects Who Enter Follow-up Phase of the 
Study) 
The following must be collected for all subjects who provide informed consent, but fail eligibility 
criteria and are not enrolled in the treatment phase of the study:

informed consent date;

reason subject did not qualify for the study;

Investigator’s signature. 
Any adverse events experienced by subjects who do not meet eligibility criteria will be collected 
from the date of signing informed consent to the day the subject is declared a screen failure.  This 
information is to be captured in the subject’s source documents and appropriate CRF(s).  Relevant 
information will also be recorded on a study entry/screening assessment log.
6.2.
Treatment Phase
Once eligibility is confirmed, the investigative site should contact Integrated Response 
Technology (IRT) and the IP (CC-486) to subjects will be assigned via IRT.  The dose and schedule 
of CC-486 in this study will be dictated by which parent CC-486 study the subject participated in, 
taking into account their last dose and schedule of CC-486 in the parent CC-486 study. For some 
subjects, a formulation change of the IP from capsule formulation to tablet formulation may occur 
after enrolling into this rollover study. 
Subjects who received placebo in the parent CC-486 clinical trials may transition into the rollover 
protocol, however, they will not receive CC-486 treatment.  Once consented these subjects will 
directly enter the follow-up phase of the rollover study and will be followed for survival.
6.2.1.
Cycle 1 Procedures/Assessments
Cycle 1 Day 1 predose assessments may be waived, if subjects had their End of Study assessments 
and/or study entry/screening assessments performed within 7 days of Cycle 1 Day 1. The 
pregnancy test can be waived for FCBP only if it was performed within 72 hours prior to IP 
administration.

Clinical assessment by Investigator

Hematology

Serum chemistry

Pregnancy test for FCBP/contraception education

Collect concomitant medications/procedures

AE assessment
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
39

IP dispensing (for 28-day cycle)

Provide IP diary card
Clinical assessment by the Investigator will be performed at clinic visits. This may include PE, 
vital signs, and body weight but data will not be collected in the CRF. Clinically significant 
abnormal findings on these assessments should be recorded as AEs in the clinical database. 
Unscheduled visits may be performed if deemed necessary by the Investigator.
6.2.1.1.
Cycle 2 and Beyond Procedures/Assessments (if Subject is Visiting the 
Clinic)

Clinical assessment by Investigator 

Hematology 

Serum chemistry

Pregnancy test for FCBP/contraception education

Collect concomitant medications/procedures

AE assessment

Review IP diary card from prior cycle(s) which includes antiemetic premedication use

Drug accountability – collect unused oral azacitidine

IP dispensing (for 28-day cycle)

Provide IP diary card
Clinical assessment by the Investigator will be performed at clinic visits.  This may include PE, 
vital signs, and body weight but data will not be collected in the CRF.  Clinically significant 
abnormal findings on these assessments should be recorded as AEs in the clinical database. 
6.2.1.2.
Cycle 2 and Beyond Procedures/Assessments (if Subject is Not Visiting 
the Clinic) 
When local, state and federal regulations allow for a site to ship IP to a subject’s home, clinic visits 
are not necessary at every cycle, provided the following procedures are done prior to dispensing 
(shipping) one cycle of IP (this does not include FCBP, who must visit the clinic before each cycle 
for pregnancy testing):  

Hematology and serum chemistry may be done locally with results sent to the 
Investigator and/or site.  

Site personnel will telephone the subject to inquire about and record AEs, concomitant 
medications/procedures and information from the IP diary – ie, any missed days/doses.  
Review of the IP diary for all cycles should be performed when the subject returns to 
the clinic.   

The Investigator will review the laboratory test results, recorded AEs, concomitant 
medication and IP dosing information.  

If the Investigator agrees, the subject may be dispensed another cycle of IP and 
arrangements will be made with the site pharmacy to ship IP to the subject’s home.  
Additional IP diaries should be given to the subject during a clinic visit or shipped with 
the IP.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
40

Coordination of the timing of the laboratory tests, telephone call to the subject and 
shipment of the IP should be considered to avoid delays in starting the next cycle of 
treatment.  

If the subject communicates that he or she experienced an AE which the Investigator 
determines to be serious, the subject will be instructed to return to the clinic for 
evaluation by the Investigator before continuing IP or receiving another cycle of IP.  If 
the subject experienced an SAE the investigator must report the event per Section 10.2
of the protocol.
Subjects must have clinic visits at least once every 3 cycles, except for a subject who is an FCBP. 
Any subject who is an FCBP must visit the clinic at the beginning of each cycle.  
The study events schedule is described in Table 4.
6.2.2.
End of Treatment
End of Treatment evaluation will 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. 
The following evaluations will be performed as specified in the Table of Events (Table 4):

Clinical assessment by Investigator 

Hematology

Serum chemistry

Pregnancy test for FCBP/contraception education

Collect concomitant medications/procedures 

Adverse events assessments

Collect any unused CC-486 and perform drug accountability (discontinuation from 
treatment visit)

Review IP diary card from prior cycle(s) which includes antiemetic premedication use 
(discontinuation from treatment visit)
Clinical assessment by the Investigator will be performed at clinic visits.  This may include PE, 
vital signs, and body weight but data will not be collected in the CRF.  Clinically significant 
abnormal findings on these assessments should be recorded as AEs in the clinical database. 
6.3.
Follow-up Phase (Disregard if Not Applicable)
6.3.1.
Safety Follow-up 
All subjects will be followed for 28 days after the last dose of IP for AE reporting, as well as SAEs 
made known to the Investigator at any time thereafter that are suspected of being related to IP, as 
described in Section 10.1.
The following evaluations will be performed as specified in the Table of Events (Table 4):

Clinical assessment by Investigator

Hematology
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
41

Serum chemistry

Pregnancy test for FCBP/contraception education

Collect concomitant medications/procedures 

Adverse events assessments
Clinical assessment by the Investigator will be performed at clinic visits. This may include PE, 
vital signs, and body weight but data will not be collected in the CRF. Clinically significant 
abnormal findings on these assessments should be recorded as AEs in the clinical database. 
6.3.2.
Survival Follow-up or Long-term Follow-up 
Only those subjects whose parent CC-486 study required follow-up for survival will be followed 
for overall survival. During the follow-up phase of the study, subjects will be followed for survival 
every month for the first year and then every 3 months until death, withdrawal of consent for 
further follow-up, study termination, until a subject is lost to follow-up, according to the parent 
CC-486 protocol requirements.
New anticancer therapies should be collected at the same time schedule.
Survival/long-term 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.
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
The Sponsor will supply CC-486 100-, 150-, 200-, and 300-mg tablets for oral administration. 
Each tablet is formulated using excipients that are generally regarded as safe and are used in 
marketed drug products.
All tablets will be packaged in blister cards.  Only sufficient IP for one cycle of treatment will be 
provided to each subject at the start of each treatment cycle.  All tablets should be swallowed 
whole, and should not be broken or chewed.
IP will be shipped, and subjects instructed to store IP, at ambient temperatures as directed on the 
package label. Shelf-life evaluation of the intact blister card is ongoing.  The IP will be monitored 
for stability for the duration of the study.
7.2.
Treatment Administration and Schedule
7.2.1.
Investigational Product Treatment Schedule
The dose and schedule of CC-486 in this study will be dictated by which parent CC-486 study the 
subject participated in. The subjects will continue at the same dose, schedule or frequency used 
for the last dose of CC-486 given in the parent CC-486 study. For some subjects, a formulation 
change of the IP from capsule formulation to tablet formulation will occur after enrolling into this 
rollover study. 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, or as administered in the parent CC-486 study.  Subjects may continue to receive 
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
42
the protocol-prescribed therapy for as long as they benefit from the treatment or until treatment is 
discontinued for reasons detailed in Section 11. 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.
7.2.2.
Investigational Product Dispensation
Investigational product will be dispensed on Day 1 of each treatment cycle.  Only 1 cycle of IP 
will be dispensed to the subject on Day 1 of each treatment cycle.  
The subject may not receive IP for each treatment cycle until all Day 1 procedures have been 
completed and all IP from the previous cycle are to be accounted for (where applicable). During 
subject’s non clinic visit cycles, IP accountability information (any missed days/doses) will be 
collected over telephone by the site personnel, and verified during the subject’s next clinic visit 
(subjects will be instructed to record all dosing information in the subject’s IP dairy on an ongoing 
basis). 
When local, state and federal regulations allow for a site to ship IP to a subject’s home, only one 
cycle of IP may be shipped each time.  
Female subjects of childbearing potential must visit the clinic every cycle. For FCBP subjects, a 
pregnancy test must be performed and verified as negative within 72 hours prior to IP 
administration on Day 1 of each new cycle.
7.2.3.
Investigational Product Administration
Investigational product administration will be accurately recorded including, but not limited to, 
date of administration, dose, and any changes in dose administration (eg, interruption or reduction 
in dose due to an AE).
The initial dose of CC-486 in the CC-486-GEN-001 protocol is to be taken at the same dose, 
schedule and frequency used for the last dose of CC-486 given in the parent CC-486 study. 
Investigational product will be administered by the study site personnel in the clinic on Day 1 of 
Cycle 1. The subject will self-administer all other IP doses in the treatment phase.  
Antiemetic medication (not a required study medication) may be taken 30 minutes prior to IP 
administration. Subject should ingest IP with approximately 240 mL (8 ounces) of room 
temperature water. Oral azacitidine tablets should not be split or crushed. Investigational product 
can be taken on an empty stomach or with food. If following CC-486 administration an emesis 
event occurs, subjects should not take additional IP on that same day, but return to the normal time 
of dose administration the following day. It is recommended that the subject receives an antiemetic 
30 minutes prior to each CC-486 dose for the first 2 treatment cycles. Antiemetic prophylaxis may 
be omitted after 2 cycles if there is no nausea or vomiting.
7.2.4.
Missing Doses
All efforts should be made to administer IP on all of the scheduled days of each of the scheduled 
days of the treatment cycle. A dose should be administered at about the same time each day. If a 
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
43
dose of CC-486 is missed or is not taken at the usual time, the dose should be administered as soon 
as possible on the same day and returned to the normal time of dose administration on the following 
day. Two doses should not be taken on the same day. Any missed doses during that cycle should 
not be taken after the last scheduled day of administration for the cycle, but instead should be 
returned by the subject for IP accountability.
7.2.5.
Overdose
Overdose, as defined for this protocol, refers to CC-486 dosing only. 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of CC-486 assigned to a given subject, regardless of any associated AEs or sequelae:  

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 CRF.  See Section 10.1 for the 
reporting of AEs associated with overdose.
7.2.6.
Dose Modifications
Subjects should be monitored for toxicity using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0, as a guide for the grading of 
severity.  
At the discretion of the Investigator, all dose modifications due to toxicity in individual subjects 
may be performed as described in the parent CC-486 study protocol or can follow the steps 
provided below in this protocol (Table 5:.
Dose modification is only available at the beginning of each cycle (ie, intra-cycle dose 
modification is not allowed).
Dose Adjustment Guidelines For Subjects Who Are on QD Schedule
All subjects who experience significant toxicity possibly or probably related to oral azacitidine 
should have the dose of oral azacitidine reduced in 100 mg increments to a minimum dose of 100 
mg/day, irrespective of the starting dose, in a stepwise fashion as follows
from 500 mg/day to 400 mg/day

from 400 mg/day to 300 mg/day

from 300 mg/day to 200 mg/day
from 200 mg/day to 100 mg/day
Dose Adjustment Guidelines for Subjects Who Are on BID Schedule
All subjects who are on a twice a day (BID) schedule and who experience significant toxicity 
possibly or probably related to oral azacitidine should have the dose of oral azacitidine reduced to 
a minimum dose of 100 mg BID, irrespective of the starting dose, in a stepwise fashion as follows:
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
44
• from 300 mg BID to 200 mg BID
•
from 200 mg BID to 100 mg BID
Dose Schedule Modification
If toxicity persists even after a step-wise dose reduction to a minimum of 100 mg QD or 100 mg 
BID, a maximum of two treatment schedule modifications is permitted for subjects who are on a 
21-day schedule
•
from 21 to 14 days, 
•
then 14 days to 7 days 
and a single treatment schedule modification for subjects who are on a 14-day schedule
•
from 14 to 7 days 
is permitted in the event of continuing toxicity that does not respond to dose reduction.  
For subjects who are already on a 7-day dosing schedule no further reduction in the dosing 
schedule of 100 mg daily is permitted.
If toxicities persist or recur even after the dose is reduced to a minimum dose of 100 mg and the 
dose schedule is reduced to 7 days, oral azacitidine should be discontinued.  The Sponsor’s 
Medical Monitor must be consulted prior to any dose reduction step or treatment termination.  
The decision to modify a dose or a subject’s treatment schedule should first be discussed with the 
Medical Monitor or designee.  Subjects should not receive less than 100 mg IP or be scheduled to 
receive treatment for less than 7 days.  
Table 5:
Criteria for Interrupting or Resuming Study Treatment
Toxicity (NCI CTCAE 
Toxicity Grade)
Resolution
Grade 4 neutropenia or 
Febrile Neutropenia
≥Grade 3
First Occurrence:
•
Interrupt dose. Resume the treatment cycle at the same dose once 
neutrophils return to Grade 2 or lower.
•
The use of supportive care such as G-CSF, as clinically indicated, may be 
considered孱
Occurrence in 2 Consecutive Cycles:
•
Interrupt dose. After neutrophils return to Grade 2 or lower, resume the 
treatment cycle at a reduced dose as indicated in Section 7.2.6.
•
If a subject continues to experience the toxicity after dose reduction, 
reduce the treatment duration by 7 days.
•
If the toxicity continues or re-occurs after dose and schedule reduction, 
discontinue oral azacitidine.
•
The use of supportive care such as G-CSF, as clinically indicated, may be 
considered.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
45
Table 5:
Criteria for Interrupting or Resuming Study Treatment
Toxicity (NCI CTCAE 
Toxicity Grade)
Resolution
Grade 4 thrombocytopenia or 
Grade 3 thrombocytopenia 
with bleeding
First Occurrence:

Interrupt dose. Resume the treatment cycle at the same dose once platelets 
return to Grade 2 or lower.
Occurrence in 2 Consecutive Cycles:

Interrupt dose. After platelets return to Grade 2 or lower, resume the 
treatment cycle at a reduced dose as indicated in Section 7.2.6.

If a subject continues to experience the toxicity after dose reduction, 
reduce the treatment duration by 7 days.

If the toxicity continues or reoccurs after dose and schedule reduction, 
discontinue oral azacitidine.
Diarrhea, nausea or vomiting
≥Grade 3

Interrupt dose. Resume the treatment cycle at the same dose once toxicity 
has resolved to Grade 1 or lower.

Use supportive care such as anti-emetic therapy and treat diarrhea at the 
onset of symptoms.

If event reoccurs, interrupt dose until resolved to Grade 1 or lower. 
Reduce the dose as indicated in Section 7.2.6.

If a subject continues to experience the toxicity after dose reduction, 
reduce the treatment duration by 7 days.

If the toxicity continues or re-occurs after dose and schedule reduction, 
discontinue oral azacitidine.

Follow recommendations in Appendix B for treatment-induced diarrhea.
Other non-hematological AEs 
Grade 3

Interrupt dose and provide medical support according to local 
recommendation. Resume treatment cycle at same dose once toxicity has
resolved to Grade 1 or lower.

If the event reoccurs, interrupt dose until resolved to Grade 1 or lower and 
reduce dose as indicated in Section 7.2.6.

If a subject continues to experience the toxicity after dose reduction, 
reduce the treatment duration by 7 days.

If the toxicity continues or reoccurs after dose and schedule reduction, 
discontinue oral azacitidine.
Weight Change: No treatment adjustment for weight loss or gain alone.  The reason for weight loss (eg, nausea, 
vomiting, anorexia) or weight gain (eg, peripheral edema) may require a treatment modification.
Note: Advised to follow specific criteria from the parent CC-486 protocol.
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; G-CSF = 
granulocyte colony-stimulating factor; IP = investigational product; NCI = National Cancer Institute.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
46
7.2.7.
Re-treatment Criteria
At the discretion of the Investigator, re-treatment criteria in individual subjects may be performed 
as described in the parent CC-486 study protocol or can follow the steps provided below in this 
protocol.
In order to proceed to the next cycle, subjects must continue to meet entry criteria regarding renal 
and hepatic function (see Section 7.3). Therefore, subjects will have laboratory assessments 
performed to evaluate organ function prior to starting each cycle (including Cycle 1). Because of 
the time it takes to obtain results from the central laboratory, samples should be collected early 
enough prior to the start of the next cycle in order to allow sufficient time for review. 
The start of the next cycle will be delayed if the subject does not meet entry criteria regarding renal 
and hepatic function. If there is a delay of more than 42 days (6 weeks) in the start of the next 
cycle, the Medical Monitor must be consulted. Study treatment should be discontinued if there is 
a delay of more than 56 days (8 weeks) in the start of the next cycle, unless, in the opinion of the 
Investigator and the Medical Monitor, the subject is experiencing clinical benefit. Justification for 
the subject continuing in the study must be recorded in the source documents.
The decision to discontinue a subject from IP, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, the 
Investigator may contact the Medical Monitor and forward appropriate supporting documents for 
review and discussion.
7.3.
Method of Treatment Assignment
Subjects who enter the Study Assessment/Screening Phase will be assigned a new, site specific 
subject number. All eligible subjects who enter treatment phase will receive CC-486.
All IP will be managed by the IRT system as a central subject number assignment and 
accountability tool only.
7.4.
Packaging and Labeling
The label(s) 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.
7.5.
Investigational Product Accountability and Disposal 
Investigational product accountability will be assessed by the Investigator or designee.  Applicable 
information such as lot number, tablet count and expiration date should be collected, as well as 
information provided by the subject or the caregiver (eg, subject IP dosing diary). 
Investigational product accountability should be assessed before IP dispensing for each subsequent 
treatment cycle in the treatment phase, starting on Day 1 of Cycle 2, and at the End of Treatment 
visit. During subject’s non clinic visit cycles, IP accountability information (any missed 
days/doses) will be collected over telephone by the site personnel, and verified during the subject’s 
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
47
next clinic visit (subjects will be instructed to record all dosing information in the subject’s IP 
dairy on an ongoing basis).
The Investigator(s) or designee(s) is responsible for accounting for all IP that is issued to and 
returned by the subject during the course of the study according to applicable regulatory 
requirements.  Any unused IP must be returned by a study subject and retained by the investigative 
site for accountability to be conducted by a Sponsor representative (or designee).  If any IP is lost 
or damaged, its disposition should be documented.  At the periodic monitoring visits, a Sponsor 
representative (or designee) will conduct IP accountability and address any discrepancies.  Upon 
satisfactory reconciliation of all IP, returned IP may be destroyed.  At the conclusion of the study, 
all remaining IP will be counted, reconciled with dispensing records, documented, and destroyed 
at the clinic site or allocated drug destruction location after completion of drug accountability by 
a Sponsor representative (or designee).  The Sponsor representative (or designee) will ensure that 
a final report of drug accountability to the unit dose level (ie, tablet) is prepared and placed in both 
the Investigator study file and the central clinical study file.
The Sponsor (or designee) will instruct the Investigator(s) on the return, disposal and destruction 
of IP.  A copy of the site’s standard operating procedure (SOP) for IP destruction may be collected 
by the Sponsor (or designee).  Any revisions to a site’s destruction process must be provided and 
approved by the Sponsor (or designee) prior to implementation on this protocol. Any site without 
a Sponsor (or designee) approved destruction SOP and process will be required to return IP to 
Celgene.
The Sponsor representative (or designee) will review with the Investigator and relevant site 
personnel the process for IP return, disposal, and/or destruction including responsibilities for the 
site versus the Sponsor (or designee).
7.6.
Investigational Product Compliance
Investigational product will be administered by the study site personnel in the clinic on Day 1 of 
Cycle 1. Subjects will self-administer all other IP doses in the treatment phase.  Documentation of 
dosing during treatment will be recorded in a study specific diary card.  Investigational product 
administration diary cards will be provided by the Sponsor to study site personnel, who will in turn 
distribute them to study subjects.  Study site personnel will enter the scheduled daily doses, the 
number of tablets to be taken each day and any other applicable information.  Study site personnel 
will review the dosing information with the subject (or legally authorized representative) on 
scheduled clinic visit days.  Subjects (or legally authorized representative) will be asked to record 
IP dosing information and antiemetic medication taken at home in the diary card and to bring the 
diary card and unused tablets in the blister card (or the blister card packaging even if it is empty) 
with them to scheduled clinic visits (ie, prior to the start of the next treatment cycle).  A diary card 
and tablet compliance check will be performed by study personnel.  Diary cards must be saved and 
kept with the source documentation.  Study site personnel will perform an IP administration 
compliance check and record this information in the subject’s source documentation.
During subject’s non clinic visit cycles, IP accountability information (any missed days/doses) will 
be collected over telephone by the site personnel, and verified during the subject’s next clinic visit 
1.0
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1.0
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v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
48
(subjects will be instructed to record all dosing information in the subject’s IP dairy on an ongoing 
basis).
Administration of all IP will be recorded including dispensing, dosing and any changes in dosage 
administration such as interruption or reduction in dosing due to an AE. 
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All prior and concomitant medications (prescription and non-prescription) and/or procedures that 
are administered during the Study Entry/Screening Assessment Phase prior to the start of IP 
through to the last dose of IP, or up to the End of Treatment visit, whichever period is longer, must 
be recorded on the appropriate CRF.  Significant non-drug therapies and concomitant procedures 
administered following the first dose of IP through to the last dose of IP, or up to the End of 
Treatment visit, whichever period is longer, must be recorded on the appropriate CRF.
Prior treatment with ESAs, thrombopoiesis-stimulating agent, iron-chelation therapy and other 
medications considered supportive care should be recorded regardless of the discontinuation date 
of treatment.
Concomitant medications/procedures, if considered necessary for the subject’s welfare and are 
unlikely to interfere with the IP, may be given at the discretion of the Investigator.
8.1.
Permitted Concomitant Medications and Procedures
Best supportive care may be used in combination with study treatment as deemed necessary. Best 
supportive care will include, but not be limited to, RBC and platelet transfusions, use of an ESA, 
antibiotic, antiviral, and antifungal therapy, nutritional support, and G-CSFs for subjects 
experiencing neutropenic infections, thus the risk of not providing subjects with appropriate care 
is minimized.  The use of these products will be considered as concomitant treatment and 
documented as concomitant medications, therapies or procedures.
The use of myeloid growth factors (G-CSF) and granulocyte macrophage colony-stimulating 
factor [GM-CSF]) may be permitted per the Investigator’s discretion and according to American 
Society of Clinical Oncology and European Society for Medical Oncology guidelines only for the 
treatment of neutropenic infections.  For subjects who develop an absolute neutrophil count 
(ANC) < 0.5 x 109/L, administration of prophylactic fluoroquinolone antibiotics (eg, ciprofloxacin 
or levofloxacin) or other prophylactic antibiotic treatments used as standard treatment at the site is 
allowed and must be documented as a concomitant medication on the appropriate CRF. If 
neutropenic infection occurs, treatment should consist of a broad spectrum antibiotic, and if the 
Investigator deems the use of a myeloid growth factor to be medically important, G-CSF may also 
be administered.  If myeloid growth factors are administered, they should be stopped within 4 days 
following resolution of the febrile episode.  In addition, the subject’s response to protocol-defined 
treatment should not be assessed until at least 3 weeks following the last dose of G-CSF to avoid 
confusing relapse of disease, when it may have been related to growth factor.
A serotonin (5-HT3) receptor antagonist (eg, ondansetron, or other comparable medication) may 
be administered as an antiemetic approximately 30 minutes prior to administration of IP.  
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
49
Pretreatment or posttreatment with a serotonin (5-HT3) receptor antagonist (or other antiemetic 
medication) will be considered as concomitant therapy and should be recorded on the appropriate 
CRF.
Treatment with antidiarrheal medications should be prescribed at the first sign of diarrhea. 
Premedication with antidiarrheal medication for subsequent doses of CC-486 may be appropriate 
at the Investigator’s discretion (Appendix B).
Parenteral flu vaccination is permitted.
Coronavirus disease 2019 (COVID-19) vaccines that are NOT live can be administered during the 
study, including during CC-486 treatment and after the last administration of CC-486. COVID-19 
vaccines that are NOT live should be handled in the same manner as other vaccines. The following 
are NOT considered live vaccines and the decision to vaccinate should be made by the investigator 
and subject: inactivated vaccines (eg, heat-killed and formalin-killed vaccines), subunit vaccines, 
toxoid vaccines, nucleic acid vaccines that do not encode potentially infectious virus (eg, 
Pfizer/BioNTech and Moderna COVID-19 vaccines), and replication-incompetent recombinant 
vector vaccines.
No data are available on the response to COVID-19 vaccines. Non-live COVID-19 vaccination is 
considered a simple concomitant medication within the study. However, the efficacy and safety of 
non-live vaccines (including non-live COVID-19 vaccines) in subjects receiving CC-486 in this 
trial is unknown. Please contact the Medical Monitor with any questions related to COVID-19 
vaccines.
8.2.
Prohibited Concomitant Medications and Procedures
Other investigational therapies must not be used while the subject is enrolled in the study. 
Anticancer therapy (chemotherapy, biologic or investigational therapy, immunotherapy, 
anticancer hormonal therapy, radiotherapy and surgery) other than the study treatments must not 
be given to subjects during the study. If such treatment is required, the subject must be discontinued 
from the study. 
The administration of either α-interferon and/or ribavirin, or drugs with known renal toxicity is 
prohibited during study treatment.
Drug-drug interactions have not been investigated with CC-486 in clinical studies. CC-486 does
not inhibit or induce major cytochrome P450 (CYP) enzymes and is not an inhibitor of major 
uptake and efflux drug transporters at clinically relevant concentrations; thus, oral azacitidine has 
minimal potential to cause drug-drug interactions with co-administered CYP or transporter 
substrates孱
Live COVID-19 vaccines should generally not be administered to a participant during the study, 
including during the treatment period, safety follow-up period, and within 3 months following last 
dose of IP. Live vaccines are defined as those that are capable of transmitting infectious severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or other viruses. If it cannot be 
1.0
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930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
50
determined whether or not the vaccine is live, it is recommended that the vaccine not be 
administered until it is confirmed that there is no risk of viral infectivity within the participant.
No data are available on the response to COVID-19 vaccines. The efficacy and safety of
vaccination in subjects who are receiving CC-486 are unknown. Please contact the Medical
Monitor with any questions related to COVID-19 vaccines.
Oral azacitidine should not be used interchangeably with injectable azacitidine due to differences 
in exposure, and the dose and schedule recommendations. Verify drug name, dose, and 
administration route.
8.3.
Required Concomitant Medications and Procedures
Not applicable.
9.
STATISTICAL CONSIDERATIONS
The sections below provide an overview of the proposed statistical considerations and analyses.
9.1.
Overview
The objective of the statistical analysis is to evaluate the long-term safety of single agent CC-486 
in subjects who received single agent CC-486 in other Celgene sponsored CC-486 trials.
All data will be summarized by treatment regimen. Summaries of continuous variables will present 
the number of subjects included in the analysis (N), the mean and standard deviation (SDev) of 
the mean, the median, the minimum, and the maximum statistics. Counts and percentages will be 
presented in summaries of categorical variables. The denominator for each percentage will be the 
number of subjects in the population treatment regimen unless otherwise specified. In general, 
missing data will not be imputed unless otherwise specified. 
9.2.
Study Population Definitions
9.2.1.
Enrolled Population
The Enrolled population includes all subjects who sign an informed consent.
9.2.2.
Safety Population
The Safety population includes all enrolled subjects who were determined eligible to receive IP in 
the study. The Safety population will be used for all safety analyses. Subjects will be analyzed 
according to the treatment regimen actually received.
9.3.
Sample Size and Power Considerations
The size of this study will be defined by the number of subjects rolling over to this study from 
parent CC-486 studies. 
1.0
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1.0
v
Approved
1.0
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
51
9.4.
Background and Demographic Characteristics
Subjects’ age and other continuous baseline characteristics will be summarized using descriptive 
statistics (N, mean, SDev, median, minimum, maximum), while gender, race and other categorical 
variables will be provided using frequency tabulations (count, percent) by treatment group.
9.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, screen failures, primary reason for 
screen failure, discontinued and primary reason for discontinuation, etc) will be summarized using 
frequency and percent for both treatment and follow-up phases. Protocol deviations will be 
summarized using frequency tabulations.
9.6.
Overall Survival
OS analysis will be performed if it is required by the parent CC-486 protocol, and if the sample 
size and number of deaths allow to conduct the appropriate analysis. Deaths will also be 
summarized in safety tables or listings.
Overall survival (OS), defined as the time from randomization to death from any cause, will be 
calculated using the randomization date from the parent CC-486 study and date of death, or date 
of last follow-up for censored subjects as appropriately defined in the parent study. Time to death 
from any cause is defined as the time between randomization and death from any cause. Subjects 
will be followed until dropout, death, or study closure. Drop-out may be due to withdrawal of 
consent from further data collection or lost to follow-up. Subjects who drop out or are alive at 
study closure will have their OS times censored at the time of last contact, as appropriate. 
The analysis of OS may be performed separately for each applicable parent CC-486 study. Overall 
survival curves will be estimated using Kaplan-Meier methods.
9.7.
Safety Analysis
The analysis will be conducted in the safety population. Adverse events, death, concomitant 
medications/procedures and subsequent anticancer therapies will be tabulated and summarized 
across the study, by treatment regimen.
Adverse events observed will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) classification system. The severity of the toxicities will be graded according to the 
NCI CTCAE (Version 4.0) whenever possible. The frequency of AEs will be tabulated by 
MedDRA system organ class and preferred term. Subjects having the same event more than once 
will be counted only once in frequency tabulations.  Treatment-emergent AEs (TEAEs) will be 
summarized by worst severity grade, system organ class, and preferred term. TEAEs leading to 
death or to discontinuation from treatment, TEAEs classified as CTCAE Grade 3 or Grade 4, 
TEAEs related to IP and treatment-emergent SAEs will be summarized separately. By-subject 
listings of all AEs, deaths and SAEs, regardless of when they occur, will be provided.
9.8.
Interim Analysis
There is no interim analysis planned in this study.
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1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
52
9.9.
Other Topics
Not applicable. 
10.
ADVERSE EVENTS
10.1.
Monitoring, Recording and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in 
a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section 10.3), 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 IP 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 7.2.5 for the definition of overdose.) Any sequelae of an accidental 
or intentional overdose of an IP should be reported as an AE on the AE CRF. If the sequela of an 
overdose meets SAE criteria, then it must be marked as an SAE on the electronic case report form 
(eCRF). The overdose itself should not be reported as an AE.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for CC-486 overdose.  
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring of 
any or all of the following parameters: the subject’s clinical symptoms, laboratory, pathological, 
radiological, or surgical findings, PE findings, or findings from other tests and/or procedures.
Adverse events of special interest (AESI) will be collected when applicable and if it is required in 
the parent CC-486 study protocol, and may include secondary primary malignancies, progression 
to AML for subjects with MDS, and other AESI specified in the parent CC-486 study.
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 as well as those SAEs made known to the Investigator at any time 
thereafter that are suspected of being related to IP.  Adverse events and SAEs will be recorded on 
the AE page of the CRF and in the subject’s source documents. Refer to Section 10.5 for
instructions on how to report SAEs to Drug Safety. All SAEs must be reported to the Sponsor’s
Drug Safety within 24 hours of the Investigator’s knowledge of the event.
The SAE is recorded within the eCRF and the data is transmitted electronically to the Sponsor’s 
Drug Safety within 24 hours of the Investigator’s knowledge of the event. In the event that 
electronic transmission is not available, a paper SAE Report Form will be completed and sent 
directly to the Sponsor’s Drug Safety, ensuring the event is recorded on the eCRF as well.
1.0
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1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
53
Progressive disease will not be considered as an AE for subjects with AML. However, any sign, 
symptom, or manifestation of progressive disease will be considered as an AE (if they meet any 
of the seriousness criteria, they will considered as an SAE). Progression to AML will be considered 
as an AE for subjects with MDS and be reported as an AE in the eCRF. 
In order to facilitate enhanced reporting of COVID-19 events that occur during the study, all AEs
and SAEs after the time of consent that are related to SARS-CoV-2 or COVID-19 infection must 
be reported.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all adverse events as to: 
10.2.1.
Seriousness 
An 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);

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.
1.0
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930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
54

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 start of treatment on study); must be 
documented in the source document and the CRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, unrelated 
to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above.
For each SAE, the Investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
10.2.2.
Severity/Intensity
For both AEs and SAEs, the Investigator must assess the severity/ intensity of the event. 
The severity/intensity of AEs will be graded based upon the subject’s symptoms according to the 
current active minor version of the Common Terminology Criteria for Adverse Events (CTCAE, 
Version 4.0); 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40.
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.
1.0
Approved
930200125
1.0
v
Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
55
10.2.3.
Causality
The Investigator must determine the relationship between the administration of the IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
a causal relationship of the adverse event to IP administration is 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event.
Suspected:
there is a reasonable possibility that the administration of IP 
caused the adverse event.  ‘Reasonable possibility’ means there 
is evidence to suggest a causal relationship between the IP and 
the adverse event.
Causality should be assessed and provided for every AE/SAE based on currently available 
information.  Causality is to be reassessed and provided as additional information becomes 
available.
If an event is assessed as suspected of being related to a comparator, ancillary or additional IP that 
has not been manufactured or provided by Celgene, please provide the name of the manufacturer 
when reporting the event.
10.2.4.
Duration
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event.
10.2.5.
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 dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event. 
10.2.6.
Outcome
The Investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.3.
Abnormal Laboratory Values
An abnormal laboratory value is considered to be an AE if the abnormality:

results in discontinuation from the study;

requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention; or

is judged to be of significant clinical importance, eg, one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing 
condition.
1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
56
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 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).
10.4.
Pregnancy
All pregnancies or suspected pregnancies occurring in either a female subject of childbearing 
potential or partner of childbearing potential of a male subject are immediately reportable events.  
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated βhCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 6 months or longer if required by local regulations, of the subject’s last dose of IP, 
are considered immediately reportable events.  Investigational product is to be discontinued 
immediately and the subject instructed to return any unused portion of the IP to the Investigator.  
The pregnancy, suspected pregnancy, or positive pregnancy test must be reported to Celgene Drug 
Safety immediately by email, phone or facsimile, or other appropriate method, using the Pregnancy 
Initial Report Form, or approved equivalent form.
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
The female subject should be referred to an obstetrician-gynecologist, preferably one experienced 
in reproductive toxicity for further evaluation and counseling.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the Investigator should 
report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious criteria, 
it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate method, 
within 24 hours of the Investigator’s knowledge of the event.
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 Sponsor’s Drug Safety, within 
24 hours of the Investigator’s knowledge of the event.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant while the subject is receiving 
investigational product, within 3 months, or longer if required by local regulations, of the last dose 
of IP, the male subject taking IP should notify the Investigator, and the pregnant female partner 
should be advised to call their healthcare provider immediately. The female partner should be 
referred to an obstetrician-gynecologist, preferably one experienced in reproductive toxicity for 
1.0
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1.0
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Approved
1.0
v

CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
57
further evaluation and counseling.  Male subjects should avoid fathering a child until 3 months 
after the last dose of IP, or longer if required by local regulation.  The Informed Consent Form 
(ICF) will address any country specific requirements as needed. 
10.5.
Reporting of Serious Adverse Events
Any AE that meets any serious criterion requires reporting as an SAE within 24 hours of the
Investigator’s knowledge of the event. This instruction pertains to initial SAE reports as well as
any follow-up reports.
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time the subject signs informed consent until 28 days after the last dose of IP) or any 
SAEs made known to the Investigator at anytime thereafter that are suspected of being related to 
IP.  Serious adverse events occurring prior to treatment (after signing the ICF) are to be recorded 
within the eCRF, but do not require reporting to the Sponsor’s Drug Safety.
Where required by local legislation, the Investigator is responsible for informing the Institutional 
Review Board (IRB)/Ethics Committee (EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The Investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
The SAE is recorded within the eCRF, and the data is transmitted electronically to the Sponsor’s
Drug Safety. In the event electronic transmission is not available, a paper SAE Report Form will 
be completed and sent directly to the Sponsor’s Drug Safety, ensuring the event is recorded on the 
eCRF as well.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from the Sponsor’s Drug Safety to the site via 
CRF (if electronic transmission is available), 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
10.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to CC-486 based on the Investigator Brochure.
In the United States, expedited reports sent to the Food and Drug Administration (FDA) by the 
Sponsor based on the reasonable possibility threshold are known as “Investigational New Drug 
safety reports” and will be reported in accordance with 21 CFR 312.32.
For reporting to the FDA, events that are not suspected to be related to CC-486 by the Sponsor 
will not be considered adverse reactions. As per FDA regulations, events that are anticipated in 
the study population listed in Section 10.2, will not be considered adverse reactions on individual 
assessment and will be reviewed on an aggregate basis for assessment of frequency.
For countries within the European Economic Area (EEA), the Sponsor or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics Committees 
concerned, suspected unexpected serious adverse reactions (SUSARs) in accordance with 
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
58
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.
The Sponsor 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.
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 14.3 for record retention information).
11.
DISCONTINUATIONS
11.1.
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 of treatment should be recorded in the CRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the Sponsor.  However, prior to discontinuing 
a subject, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
All subjects discontinued from protocol prescribed treatment for any reason should undergo End 
of Treatment procedures including a pregnancy test for FCBP.  Additionally, all subjects 
discontinued from protocol prescribed treatment will be followed for a period of 28 days following 
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CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
59
the last dose of IP or until the date of the last study visit, whichever is later, for the collection of 
adverse events.
For subjects who enter survival follow-up in the Follow-up Phase of the study (subjects from 
parent CC-486 protocol who require survival follow-up): During the survival follow-up in the 
Follow-up Phase, all subjects should be followed every month for the first year and then every 3 
months thereafter until study termination for collection of information on survival, disease relapse, 
and subsequent therapies, unless the subject has specifically withdrawn consent from further 
follow-up.  The Investigator must make every effort to obtain information regarding the subject’s 
survival status before determining the subject is lost to follow-up.
11.2.
Study Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the study:

Withdrawal by subject

Death

Lost to follow up

Study closure

Transfer to commercially available and reimbursed CC-486

Adverse event

Important protocol deviations

Other (to be specified in eCRF)
The reason for study discontinuation should be recorded in the CRF and in the source documents.
12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the Investigator should contact the responsible Clinical Trial 
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 Trial 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 Trial Physician(s) or Medical Monitor or designee for emergency 
calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
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13.
REGULATORY CONSIDERATIONS
13.1.
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 GCP, as described in 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.
13.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in the 
local regulations. The Sponsor staff or an authorized representative will evaluate and approve all 
Investigators who in turn will select their staff.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions,
including obligations of confidentiality of Sponsor information. The Investigator should maintain 
a list of Sub-Investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The Investigator is responsible for keeping a record of all subjects who sign an informed consent 
form (ICF) and are screened for entry into the study. Subjects who fail study entry/screening must 
have the reason(s) recorded in the subject’s source documents.
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of CRFs and queries.
The information contained in the protocol and amendments (with the exception of the information 
provided by the Sponsor on public registry websites) is considered Sponsor’s confidential 
information. Only information that is previously disclosed by Sponsor on a public registry website 
may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical Trial 
Agreement. The Sponsor protocol, amendment and IB information is not to be made publicly 
available (for example on the Investigator’s or their institution’s website) without express written 
approval from the Sponsor. Information proposed for posting on the Investigator’s or their 
institution’s website must be submitted to the Sponsor for review and approval, providing at least 
5 business days for review.
At the time results of this study are made available to the public, the Sponsor will provide 
Investigators with a summary of the results that is written for the lay person. The Investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the subject.
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Celgene Corporation
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13.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent of a subject and/or a subject’s legal representative 
prior to any study related procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study and 
of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the Investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the Investigator’s 
study files and a copy given to the study subject.
13.4.
Confidentiality
The Sponsor 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). The Sponsor
requires the Investigator to permit Sponsor’s representatives and, when necessary, representatives 
from regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the Investigator to obtain such permission in writing 
from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Sponsor’s Clinical Trial 
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.
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will be 
submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their dates 
of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is sought. 
If applicable, the documents will also be submitted to the authorities in accordance with local legal 
requirements.
Investigational product can only be supplied to an Investigator by the Sponsor or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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been received by the Sponsor or its authorized representative. This documentation must also 
include a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC 
will not disclose the names, occupations and qualifications of the committee members, it should 
be asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all ethical 
and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The Investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the Investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by the Sponsor and the 
IRB/EC prior to use.  
13.7.
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.
13.8.
Termination of the Study
The Sponsor reserves the right to terminate this study prematurely at any time for reasonable 
medical or administrative reasons. Any premature discontinuation will be appropriately 
documented according to local requirements (eg, IRB/EC, regulatory authorities, etc).
In addition, the Investigator or the Sponsor has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;

Falsification of records;

Failure to adhere to the study protocol.
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
63
13.9.
Sponsor Commitment to Diversity in Clinical Trials
The mission of the Sponsor is to transform patients’ lives through science by discovering, 
developing, and delivering innovative medicines that help them prevail over serious diseases. 
The Sponsor is committed to doing its part to ensure that patients have a fair and just opportunity 
to achieve optimal health outcomes.
The Sponsor is working to improve the recruitment of a diverse subject population with the goal 
that the clinical trial becomes more reflective of the real-world population and the people impacted 
by the diseases studied.
14.
DATA HANDLING AND RECORDKEEPING 
14.1.
Data/Documents
The Investigator must ensure that the records and documents pertaining to the conduct of the study 
and the distribution of the IP 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.
14.2.
Data Management
Data will be collected via CRF and entered into the clinical database per the Sponsor’s  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.
14.3.
Record Retention
Essential documents must be retained by the Investigator according to the period of time outlined 
in the clinical trial agreement. The Investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:

Signed ICFs for all subjects;

Subject identification code list, study entry/screening assessment 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);
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
64

List of Sub-Investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, etc.); 

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 the Sponsor 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 the Sponsor prior to destruction of any 
records. If the Investigator is unable to meet this obligation, the Investigator must ask the Sponsor 
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 or institution should take measures to prevent accidental or premature destruction of 
these documents.
14.4.
Data Protection, Data Privacy, and Data Security
The Sponsor collects and processes personal data of study subjects, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. The Sponsor ensures the privacy, 
protection, and confidentiality of such personal data to comply with applicable laws. To achieve 
these goals, the Sponsor has internal policies that indicate measures and controls for processing 
personal data. The Sponsor adheres to these standards to ensure that collection and processing of 
personal data are limited and proportionate to the purpose for which the Sponsor collects such 
personal data. This purpose is clearly and unambiguously notified to the individual at the time of 
collection of personal data. In the true spirit of science, the Sponsor is dedicated to sharing clinical 
trial information and data with subjects, medical/research communities, the media, policy makers, 
and the general public. This is done in a manner that safeguards participant privacy and informed 
consent while respecting the integrity of national regulatory systems. Clinical trial data, health-
related research, and pharmacovigilance activities on key-coded health data transferred by the 
Sponsor across national borders is done in compliance with the relevant data protection laws in 
the country and GCP requirements.
The Sponsor protects Personal Information with adequate and appropriate security controls as 
indicated under the data protection laws. To align with the recommended security standards, the 
Sponsor has adopted internal security standards and policies to protect personal data at every stage 
of its processing. 
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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To supplement these standards, the Sponsor enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
The Sponsor takes unauthorized access and disclosure of Personal Information very seriously. The 
Sponsor has adopted the security standards that include National Institute of Standards and 
Technology Cybersecurity Framework for studies in the US. The Sponsor aligns with these 
standards to continuously assess and improve its ability to protect, detect, and respond to cyber 
attacks and other unauthorized attempts to access personal data. These standards also aid in 
mitigating possible adverse effects. Furthermore, Sponsor Information Technology has defined 6 
principles to protect our digital resources and information: 
1) Responsibilities of IT Personnel
2) Securing the Sponsor Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by the Sponsor or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
The Sponsor 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 Investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Sponsor 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 Sponsor 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.
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a GCP Quality Assurance unit exists within the 
Sponsor.  Representatives of this unit will conduct audits of clinical research activities in 
accordance with the Sponsor’s SOPs to evaluate compliance with GCP 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/ECs, regulatory authorities (eg, FDA, European Medicines Agency, 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 the Sponsor immediately.
16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the exception 
of the information provided by the Sponsor on public registry websites, is considered Sponsor 
confidential information and is not to be used in any publications.  Sponsor protocol-related 
information proposed for use in a publication must be submitted to the Sponsor for review and 
approval, and should not be utilized in a publication without express written approval from the 
Sponsor, or as described in the Clinical Trial Agreement.  
The Sponsor will ensure sponsored studies are considered for publication in the scientific literature 
in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to results from 
all Phase 3 clinical studies, and any other study results of significant medical importance.  This 
also includes results relating to investigational medicines whose development programs have been 
discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on several 
considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.  
1.0
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
67
17.
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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1.0
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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1.0
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CC-486 (Oral Azacitidine, BMS-986345)
CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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18.
APPENDICES
APPENDIX A
TABLE OF ABBREVIATIONS
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the curve
β-hCG
β-subunit of human chorionic gonadotropin
BID
Twice daily
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CCR
Conventional care regimen
CMML
Chronic myelomonocytic leukemia
COVID-19
Coronavirus disease 2019
CR
Complete remission
CRF
Case report form
CRi
Complete remission with incomplete blood count recovery
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trials Facilitation and Coordination Group
CYP
Cytochrome P450
EC
Ethics Committee
eCRF
Electronic CRF
EEA
European Economic Area
EOT
End of treatment
ESA
Erythropoiesis stimulating agent
EU
European Union
FCBP
Females of childbearing potential
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
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CC-486-GEN-001
Celgene Corporation
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Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
G-CSF
Granulocyte colony-stimulating factor
GM-CSF
Granulocyte macrophage colony-stimulating factor
HMA
Hypomethylating agents
HR
Hazard ratio
HRT
Hormone replacement therapy
HSCT
Hematopoietic stem cell transplantation
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IMP
Investigational medicinal product 
IND
Investigational New Drug
INT
Intermediate
IP
Investigational product
IPSS
International Prognostic Scoring System
IRB
Institutional Review Board
IRT
Integrated Response Technology
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LAM
Lactational amenorrhea method
LDAC
Low-dose cytarabine
LDH
Lactate dehydrogenase
MDS
Myelodysplastic syndromes
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
OS
Overall survival
pRBC
Packed red blood cell
PE
Physical examination
QD
Once daily
RA
Refractory anemia
RAEB
Refractory anemia with excess blasts
RBC
Red blood cell 
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CC-486-GEN-001
Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
73
Table 6:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
RFS
Relapse-free survival
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SC
Subcutaneous
SDev
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TEAE 
Treatment-emergent adverse event
US
United States
WBC
White blood cell 
WHO
World Health Organization
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CC-486-GEN-001
Celgene Corporation
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Final: 27 Feb 2023
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APPENDIX B
RECOMMENDATIONS FOR MANAGEMENT OF TREATMENT-
INDUCED DIARRHEA
Published guidelines (Benson, 2004) were modified for consistency with the study protocol.
Key:  CBC = complete blood count; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; 
NCI = National Cancer Institute; SC = subcutaneous; TID = three times daily. 
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CC-486 (Oral Azacitidine, BMS-986345)
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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APPENDIX C
FEMALES OF CHILDBEARING POTENTIAL DEFINITIONS AND
METHODS OF CONTRACEPTION
Appendix C provides general information and definitions related to Females of Childbearing
Potential (FCBP) and methods of contraception that can be applied to most clinical trials. For 
information specific to this study regarding acceptable contraception requirements for female and 
male subjects, refer to Section 4.2 of the protocol. Only the contraception methods as described in 
Section 4.2 are acceptable for this study.
DEFINITIONS
Females of Childbearing Potential (FCBP) 
A female is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral
salpingectomy, and bilateral oophorectomy.
Female in the following categories are not considered FCBP:

Premenarchal

Premenopausal female with one of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical
records, medical examination, or medical history interview.

Postmenopausal female

A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle-stimulating hormone (FSH) level
> 40 mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH
level. The duration of the washout period is a function of the type of HRT used. Suggested
guidelines for the duration of the washout periods for HRT types are presented below. Investigators
should use their judgment in checking serum FSH levels.

1-week minimum for vaginal hormonal products (rings, creams, gels)

4-week minimum for transdermal products

8-week minimum for oral products
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Celgene Corporation
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Final: 27 Feb 2023
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH
level is > 40 mIU/mL at any time during the washout period, the woman can be considered
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the time point where the Investigational Medicinal Product
(IMP) or any active major metabolites have decreased to a concentration that is no longer
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of < 1% per year when used consistently and correctly.a

Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation and/or implantation. (This method of contraception can only be used 
by FCBP subjects in studies where hormonal contraception is permitted by the study
protocol.)b

Oral (birth control pills)

Intravaginal (rings)

Transdermal

Combined (estrogen-and progestogen-containing) hormonal contraception must begin at
least 30 days prior to initiation of study therapy.

Progestogen-only hormonal contraception associated with inhibition of ovulation. (This
method of contraception can only be used by FCBP subjects in studies where hormonal 
contraception is permitted by the study protocol.)b

Oral

Injectable

Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of
study therapy.
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of
ovulation and/or implantation. (This method of contraception can only be used by FCBP
subjects in studies where hormonal contraception is permitted by the study protocol.)b

Intrauterine device.

Intrauterine hormone-releasing system (IUS). (This method of contraception can only be
used by FCBP subjects in studies where hormonal contraception is permitted by the study 
protocol.)b,c
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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
Bilateral tubal occlusion.

Vasectomized partner
Having a vasectomized partner is a highly effective contraception method provided that the
partner is the sole male sexual partner of the FCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.
Male subjects will be required to always use a latex or other synthetic condom during any sexual 
activity (eg, vaginal, anal, oral) with FCBP, even if the subjects have undergone a successful 
vasectomy or if their partner is already pregnant or breastfeeding.

Sexual abstinence.
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.

Continuous abstinence must begin at least 30 days prior to initiation of study therapy.

It is not necessary to use any other method of contraception when complete abstinence is
elected.

FCBP subjects who choose complete abstinence must continue to have pregnancy tests, as 
specified in Section 2.

Acceptable alternate methods of highly effective contraception must be discussed in the
event that the FCBP participant chooses to forego complete abstinence.
Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM) are not acceptable methods of contraception for this study.
NOTES:
a Typical use failure rates may differ from failure rates when contraceptive methods are used consistently and
correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for subjects
in clinical studies.
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the
efficacy of the contraceptive method. Hormonal contraception is permissible only when there is sufficient
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception
would be ineffective or result in increased exposures that could be potentially hazardous. In this case, alternative
methods of contraception should be utilized.
c
IUSs are acceptable methods of contraception in the absence of definitive drug interaction studies when hormone
exposures from intrauterine devices do not alter contraception effectiveness. 
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of > 1% per year when used consistently and correctly.

Male or female condom with or without spermicide. Male and female condoms cannot be
used simultaneously.

Diaphragm with spermicide.

Cervical cap with spermicide.
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Celgene Corporation
CC-486-GEN-001 Amendment 1.0
Final: 27 Feb 2023
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
Vaginal sponge with spermicide.

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
primary mechanism of action. (This method of contraception cannot be used by FCBP
subjects in studies where hormonal contraception is prohibited.)
Unacceptable Methods of Contraception

Periodic abstinence (calendar, symptothermal, postovulation methods).

Withdrawal (coitus interruptus).

Spermicide only.

LAM.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of pregnancy information and outcome of pregnancy on the Pregnancy 
Report Form or approved equivalent form is provided in Section 10.4.1.
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