Conditions: Leukemia, Myeloid Isocitrate Dehydrogenase
Keywords: AG-221 CC-90007 Efficacy Safety Leukemia Acute myeloid meukemia Isocitrate dehydrogenase 2 mutation Enasidenib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 319
Healthy volunteers: no

Brief summary:
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the efficacy and safety of AG-221 versus conventional care regimens (CCRs) in subjects 60 years or older with acute myeloid leukemia (AML) refractory to or relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase (IDH2) mutation.

Detailed description:
Acute myeloid leukaemia (AML) is a form of cancer that is common in older patients. Mutations in the isocitrate dehydrogenase enzyme 2 (IDH2) have been found in approximately 15% of patients with AML.

The outcome of first line chemotherapy treatment is poor and many patients fail to attain complete remission (CR, ie refractory) or will eventually relapse. There is no single standard of care for relapsed or refractory AML. Since the prognosis is very poor there is a great need for new therapies.

Inhibition of the mutant IDH2 enzyme may represent a promising targeted therapy for AML. AG-221 is a small molecule inhibitor of the IDH2 enzyme, designed to preferentially target the mutant IDH2 variants. Data from the ongoing first-in-human study has shown AG-221 to be generally well tolerated and demonstrated CR in patients with IDH2 mutation positive relapsed or refractory AML.

The study purpose is to test the safety and efficacy of AG-221 compared with conventional care regimens (CCR), which include best supportive care (BSC) only, azacitidine plus BSC, low-dose cytarabine plus BSC or intermediate-dose cytarabine plus BSC, in patients with late stage AML refractory to or relapsed after second or third line therapy and positive for the IDH2 mutation. Patients will be randomly assigned to receive open-label tablets of AG-221 or one of the CCR on continuous 28-day treatment cycles. The trial duration is expected to be 78 months which includes 42 months enrollment, approximately 7 months treatment and a follow-up period.

Study procedures include: vital signs, physical exams, ECGs, ECHO, urine/blood samples, bone marrow aspirates and/or biopsies and peripheral blood to test for IDH2 and assess treatment response. Bone marrow, blood, cheek swab samples will be used for genetic tests.

This study is being sponsored by Celgene Corporation. Approximately 316 participants will take part in the study.

Arms:
arm 1: Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC. arm 2: Continuous 28-day cycles of BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) plus BSC. Subjects will be assigned by the investigator to one of the CCR treatment options based on the investigator's assessment of subjects' eligibility.

Interventions: intervention 1: AG-221 intervention 2: BSC intervention 3: Azacitidine intervention 4: Low-dose cytarabine (LDAC) intervention 5: Intermediate-dose cytarabine (IDAC)
Intervention descriptions: intervention 1: Continuous 28-day cycles of AG 221 100 mg orally (PO) once a day (QD) for 28 days intervention 2: Best supportive care includes, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support intervention 3: continuous 28-day cycles of azacitidine 75 mg/m2/day SC for 7 days, plus BSC intervention 4: continuous 28-day cycles of cytarabine 20 mg SC twice a day (BID) for 10 days, plus BSC intervention 5: 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, plus BSC; only BSC given after IDAC therapy concludes per standard institutional practice

Protocol document:
Prot_000.pdf: 
Official Title of Study: 
A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-
90007) Versus Conventional Care Regimens in Older Subjects with Late Stage Acute Myeloid Leukemia 
Harboring an Isocitrate Dehydrogenase 2 Mutation 
 
 
 
PROTOCOL(S) AG-221-AML-004 
 
NCT Number: NCT02577406 
  
Document Date (Date in which document was last revised): November 30, 2017 


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
1
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
 
A PHASE 3, MULTICENTER, OPEN-LABEL, 
RANDOMIZED STUDY COMPARING THE EFFICACY 
AND SAFETY OF AG-221 (CC-90007) VERSUS 
CONVENTIONAL CARE REGIMENS IN OLDER 
SUBJECTS WITH LATE STAGE ACUTE MYELOID 
LEUKEMIA HARBORING AN ISOCITRATE 
DEHYDROGENASE 2 MUTATION
The “IDHENTIFY” Trial
PROTOCOL NUMBER:
AG-221-AML-004
DATE FINAL:
13 Aug 2015
AMENDMENT 1.0:
11 Oct 2016
AMENDMENT 2.0:
30 Nov 2017
EudraCT NUMBER:
2015-000344-42 
IND NUMBER:
117631 (Enasidenib [AG-221, 
CC-90007]) 
064251 (Azacitidine)
SPONSOR NAME/ ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
2
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:     
Title:       
Address: 
                
Phone:    
E-mail:   
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
3
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
4
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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 Council on 
Harmonisation (ICH) Good Clinical Practices Guidelines, and local regulations 
governing the conduct of clinical studies.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
5
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name:_______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
6
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of
AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects with Late Stage
Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation.
Indication
Treatment of subjects 60 years or older with acute myeloid leukemia (AML) refractory to or 
relapsed after second- or third-line AML therapy and positive for an isocitrate dehydrogenase 2
(IDH2) mutation
 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
7
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Objectives
Primary

To determine the primary efficacy, measured as overall survival (OS), of AG-221 
compared with conventional care regimens (CCRs) in subjects 60 years or older with 
AML refractory to or relapsed after second- or third-line AML therapy and positive 
for an IDH2 mutation
Secondary

To determine the supporting efficacy of AG-221 compared with CCRs

To determine the safety and tolerability of AG-221 compared with CCRs

To determine the effect of AG-221 compared with CCRs on Health-related Quality-
of-Life (HRQoL)
Study Design
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the 
efficacy and safety of AG-221 versus CCRs in subjects 60 years or older with AML refractory to 
or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation.
Screening procedures are to occur within 28 days prior to the start of study treatment and after 
the informed consent form (ICF) is signed.  Diagnosis of AML disease and AML disease status 
at screening will be based on local review of pathology and cytogenetics.  Positivity of IDH2 
gene mutation in bone marrow aspirate and/or peripheral blood will be confirmed centrally at 
screening. (Note: in the event that the central laboratory result is delayed and precludes acute 
clinical management of a subject who has confirmed IDH2 gene mutation by local evaluation, 
the subject may be eligible for randomization with approval by the Medical Monitor.)
Following review of eligibility, subjects will be assigned by the investigator to one of the CCR 
treatment options based on the investigator’s assessment of subjects’ eligibility.  The CCR 
treatment options include best supportive care (BSC) only, azacitidine subcutaneously (SC) plus 
BSC, low-dose cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC)
intravenously (IV) plus BSC.  The CCR treatment option chosen and the reason(s) for selecting 
the CCR treatment option will be recorded for all subjects prior to randomization.
Following the selection of a CCR treatment option, subjects will be randomized centrally in a 1:1 
ratio to receive either the AG-221 treatment or the CCR treatment option pre-selected by the 
investigator.  Randomization will be stratified by prior intensive therapy for AML (yes versus 
no), primary refractory (ie, morphologic complete remission [CR], CR with incomplete 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
8
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
neutrophil recovery [CRi] or CR with incomplete platelet recovery [CRp] has never been 
attained) (yes versus no), and prior allogeneic hematopoietic stem cell transplantation (HSCT)
for AML (yes versus no).
Study treatment starts within 3 days after randomization.  No crossover between any of the 
treatment options, including the CCR treatment options, will be permitted during the course of 
study treatment.
Assessments during study treatment include efficacy, safety, HRQoL,
 
  
A retrospective central review of all bone marrow aspirates and/or biopsies, peripheral blood 
smears and cytogenetics collected during the study will be conducted by personnel blinded to 
subject treatment.  The central assessments will be used in the statistical analyses.  Disagreement 
between central and local assessments will be adjudicated by a third party reviewer and the
adjudicated assessment will be used in the statistical analyses.
Response to treatment and hematologic improvement (HI) will be assessed by the investigators 
and retrospectively by a blinded Independent Response Assessment Committee (IRAC) 
according to modified International Working Group (IWG) AML Response Criteria
(Appendix F) and IWG myelodysplastic syndromes HI criteria (Appendix H), respectively.
Dosing interruptions, dosing delays or dose modifications may occur for managing toxicities 
and/or augmenting treatment response during study treatment (refer to Section 7.2).
Subjects can continue to receive study treatment provided that they benefit from study treatment 
and all protocol-specified criteria for continuing study treatment are met.  Study treatment will
be discontinued if the investigator has alternative therapies (eg, HSCT) and/or considers study 
treatment to be no longer beneficial to the subject, or the rapidity of change of disease state 
renders it unacceptable for further study treatment in the judgment of the investigator.  Refer to 
Section 11.1 for sufficient reasons for discontinuing a subject from study treatment.
The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, 
the investigator may contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
All subjects who have received at least one dose of study treatment should undergo end of
treatment (EOT) evaluations (Section 6.2.3) when study treatment is discontinued.  The reason 
for discontinuation will be recorded in the electronic case report form (eCRF) pages and in the 
source document.
All subjects discontinued from study treatment for any reason other than withdrawal of consent 
for follow-up will continue to be assessed for adverse events (AEs), concomitant medications, 
concomitant procedures, transfusions, 
 response, hematologic 
improvement, subsequent AML therapies and survival.  Refer to Section 6.3 for details regarding 
the assessments scheduled after the EOT visit.
The study will be conducted in compliance with International Council on Harmonisation (ICH) 
Good Clinical Practices (GCPs).
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
9
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Study Population
This study will enroll 316 subjects 60 years or older with AML refractory to or relapsed after 
second- or third-line AML therapy and positive for an IDH2 mutation.
Length of Study
The expected duration of this study is approximately 78 months, including an enrollment period 
of approximately 42 months, followed by approximately 7 months of treatment and/or 
posttreatment follow-up to reach the total number of events (see below Statistical Methods 
Section and Section 9) required for a fully-powered analysis of OS.
The End of Trial is defined as either the date of 36 months from the last subject randomized date, 
or the date when all subjects discontinued from study treatment and no subject is available for 
survival follow-up,  whichever is the later date. 
Study Treatments
The options in the CCR treatment arm include:

BSC only: continuous 28-day cycles of BSC.  Best supportive care includes, but is 
not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome 
associated with therapy of mutant IDH inhibition (ie, IDH differentiation syndrome),
anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional 
support (refer to Section 7.1.5 and Section 8 for details);

Azacitidine SC plus BSC: continuous 28-day cycles of azacitidine 75 mg/m2/day SC
for 7 days, plus BSC;

LDAC SC plus BSC: continuous 28-day cycles of cytarabine 20 mg SC twice a day
(BID) for 10 days, plus BSC;

IDAC IV plus BSC: 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 
6 days, per standard institutional practice, plus BSC; only BSC given after IDAC 
therapy concludes per standard institutional practice. (Note: any local standard 
regimen different from the above specification will need review and approval by the 
Medical Monitor.)
Subjects randomized to the AG-221 treatment arm will receive continuous 28-day cycles of 
AG-221 100 mg orally (PO) once a day (QD) for 28 days, plus BSC.  Dose escalation to 200 mg
may occur for augmenting treatment response (detailed in Section 7.2.1.2).
Study treatments as described above can continue until the End of Trial, unless discontinued for 
any of the reasons detailed in Section 11.1.
Overview of Key Efficacy Assessments
The primary efficacy endpoint is OS.  
The key secondary efficacy endpoints include overall response rate and event-free survival.  
Response will be assessed retrospectively by a blinded IRAC through collection of central
hematology parameters, central assessments of bone marrow aspirates and/or biopsies, peripheral
blood smears and cytogenetics, and results of other pertinent tests.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
10
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Overview of Key Safety Assessments
Safety assessments include physical examination, vital signs, electrocardiogram, hematology, 
serum chemistry, cardiac markers, fasting (preferred) lipid panel, pregnancy testing (for females 
of childbearing potential only), AEs, concomitant medications, concomitant procedures and 
transfusions.  After screening, echocardiogram, urinalysis and coagulation will be repeated as 
clinically indicated.
Statistical Methods
The primary efficacy endpoint of OS is defined as time from randomization to death due to any 
cause.  The equality of overall survival cures will be compared between the AG-221 and CCR 
treatment arms using a stratified log-rank test.  Assuming a median OS of 5.6 months in the CCR 
treatment arm (Roboz, 2014), a median OS of 8 months in the AG-221 treatment arm (42.9% 
improvement), and a drop-out rate of approximately 9%, this design requires 250 deaths and 316
subjects (158 per treatment arm) to be randomized in order to achieve 80% power to detect a 
constant hazard ratio of 0.7 and demonstrate a statistically significant difference in OS at a Type 
I error rate of 0.05 (two-sided).  An interim analysis for superiority will be conducted at 65% 
information (ie, 163 deaths) based on Lan-DeMets version of the O’Brien-Fleming alpha 
spending function.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
11
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................26
3.
OVERALL STUDY DESIGN ................................................................................29
3.1.
Study Design ..........................................................................................................29
3.1.1.
Screening Phase......................................................................................................29
3.1.2.
Treatment Phase .....................................................................................................30
3.1.3.
Follow-up Phase .....................................................................................................31
3.1.4.
Interim Analysis .....................................................................................................31
3.1.5.
Data Monitoring Committee ...................................................................................32
3.2.
Study Duration for Subjects....................................................................................32
3.3.
End of Trial ............................................................................................................32
4.
STUDY POPULATION.........................................................................................34
4.1.
Number of Subjects ................................................................................................34
4.2.
Inclusion Criteria....................................................................................................34
4.3.
Exclusion Criteria...................................................................................................36
5.
TABLE OF EVENTS.............................................................................................39
6.
PROCEDURES......................................................................................................45
6.1.
Screening Phase......................................................................................................45
6.2.
Treatment Phase .....................................................................................................48
6.2.1.
Baseline..................................................................................................................51
6.2.2.
Unscheduled Visits.................................................................................................51
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
12
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
6.2.3.
End of Treatment....................................................................................................51
6.3.
Follow-up Phase .....................................................................................................52
6.4.
Safety Assessment ..................................................................................................53
6.4.1.
Adverse Events.......................................................................................................54
6.4.2.
Urinalysis, Coagulation, Hematology, Serum Chemistry, Cardiac Markers 
and Fasting (Preferred) Lipid Panel.........................................................................54
6.5.
Efficacy Assessment...............................................................................................54
6.5.1.
Disease Status or Response to Study Treatment ......................................................54
6.5.2.
Hematologic Improvement .....................................................................................55
6.5.3.
Survival..................................................................................................................55
6.9.
Quality-of-Life .......................................................................................................56
7.
DESCRIPTION OF STUDY TREATMENTS........................................................58
7.1.
Description of Investigational Product(s)................................................................58
7.1.1.
AG-221 ..................................................................................................................58
7.1.2.
Azacitidine .............................................................................................................58
7.1.3.
Low-dose Cytarabine..............................................................................................58
7.1.4.
Intermediate-dose Cytarabine .................................................................................58
7.1.5.
Best Supportive Care Only .....................................................................................59
7.2.
Treatment Administration and Schedule .................................................................59
7.2.1.
AG-221 Treatment..................................................................................................60
7.2.1.1.
Dispensation and Administration of AG-221 ..........................................................60
7.2.1.2.
Dose Modifications for AG-221..............................................................................60
7.2.1.3.
Reference Toxicities During AG-221 Treatment.....................................................61
7.2.1.4.
Initiation of Each AG-221 Treatment Cycle............................................................63
7.2.2.
Azacitidine Treatment.............................................................................................64
7.2.2.1.
Dose Modifications for Azacitidine ........................................................................64
7.2.3.
Low-dose Cytarabine Treatment.............................................................................66
7.2.4.
Intermediate-dose Cytarabine Treatment.................................................................66
7.2.5.
Best Supportive Care Only Treatment.....................................................................67
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
13
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.3.
Method of Treatment Assignment...........................................................................67
7.4.
Packaging and Labeling..........................................................................................67
7.5.
Investigational Product Accountability and Disposal ..............................................67
7.6.
Investigational Product Compliance........................................................................68
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................70
8.1.
Permitted Concomitant Medications and Procedures...............................................70
8.2.
Prohibited Concomitant Medications and Procedures..............................................70
8.3.
Restricted Concomitant Medications and Procedures..............................................71
8.4.
Required Concomitant Medications and Procedures................................................72
9.
STATISTICAL CONSIDERATIONS ....................................................................73
9.1.
Overview................................................................................................................73
9.2.
Study Population Definitions ..................................................................................73
9.2.1.
Intent-to-Treat Population.......................................................................................73
9.2.2.
Modified Intent-to-Treat Population .......................................................................73
9.2.3.
Safety Population....................................................................................................73
9.3.
Sample Size and Power Considerations...................................................................74
9.4.
Background and Demographic Characteristics........................................................74
9.5.
Subject Disposition.................................................................................................74
9.6.
Efficacy Analysis....................................................................................................74
9.6.1.
Primary Efficacy Analysis ......................................................................................75
9.6.2.
Secondary Efficacy Analyses..................................................................................75
9.6.2.1.
Key Secondary Efficacy Analyses ..........................................................................75
9.6.2.2.
Additional Secondary Efficacy Analyses ................................................................76
9.7.
Safety Analysis.......................................................................................................77
9.8.
Interim Analysis .....................................................................................................77
9.9.
Other Topics...........................................................................................................78
9.9.1.
Data Monitoring Committee ...................................................................................78
9.9.2.
Steering Committee ................................................................................................78
9.9.3.
Health-Related Quality-of-Life ...............................................................................78
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
14
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
10.
ADVERSE EVENTS..............................................................................................80
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................80
10.2.
Evaluation of Adverse Events.................................................................................80
10.2.1.
Seriousness.............................................................................................................80
10.2.2.
Severity/Intensity....................................................................................................82
10.2.3.
Causality ................................................................................................................82
10.2.4.
Duration .................................................................................................................83
10.2.5.
Action Taken..........................................................................................................83
10.2.6.
Outcome.................................................................................................................83
10.3.
Abnormal Laboratory Values..................................................................................83
10.4.
Pregnancy...............................................................................................................83
10.4.1.
Females of Childbearing Potential ..........................................................................84
10.4.2.
Male Subjects.........................................................................................................84
10.5.
Reporting of Serious Adverse Events......................................................................84
10.5.1.
Safety Queries ........................................................................................................85
10.6.
Expedited Reporting of Adverse Events..................................................................85
11.
DISCONTINUATIONS .........................................................................................87
11.1.
Treatment Discontinuation......................................................................................87
11.2.
Study Discontinuation ............................................................................................87
12.
EMERGENCY PROCEDURES.............................................................................89
12.1.
Emergency Contact.................................................................................................89
12.2.
Emergency Identification of Investigational Products .............................................89
13.
REGULATORY CONSIDERATIONS...................................................................90
13.1.
Good Clinical Practice............................................................................................90
13.2.
Investigator Responsibilities ...................................................................................90
13.3.
Subject Information and Informed Consent.............................................................91
13.4.
Confidentiality........................................................................................................91
13.5.
Protocol Amendments.............................................................................................91
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
15
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
13.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................91
13.7.
Ongoing Information for Institutional Review Board/ Ethics Committee ................92
13.8.
Termination of the Study ........................................................................................92
14.
DATA HANDLING AND RECORDKEEPING.....................................................94
14.1.
Data/Documents .....................................................................................................94
14.2.
Data Management...................................................................................................94
14.3.
Record Retention....................................................................................................94
15.
QUALITY CONTROL AND QUALITY ASSURANCE........................................96
15.1.
Study Monitoring and Source Data Verification......................................................96
15.2.
Audits and Inspections............................................................................................96
16.
PUBLICATIONS ...................................................................................................97
17.
REFERENCES.......................................................................................................98
18.
APPENDICES......................................................................................................103
Appendix A:  Table of Abbreviations......................................................................................103
Appendix B:  World Health Organization Classification of Acute Myeloid Leukemia.............109
Appendix C:  Acute Myeloid Leukemia Risk Status................................................................110
Appendix D:  Eastern Cooperative Oncology Group (ECOG) Performance Status ..................111
Appendix E:  New York Heart Association Classification for Congestive Heart Failure ..........112
Appendix F:  International Working Group Acute Myeloid Leukemia Response Criteria ........113
Appendix G:  Definitions of Prior Line of AML Therapy........................................................114
Appendix H:  Hematologic Improvement According to the International Working Group 
for Myelodysplastic Syndromes............................................................................115
Appendix I:  European Organization for Research and Treatment of Cancer Quality-of-
Life questionnaire (Version 3.0) ...........................................................................116
Appendix J:  EQ-5D-5L Health Questionnaire (English Version for the UK) ..........................118
Appendix K:  Subcutaneous Preparation and Administration of Azacitidine............................120
Appendix L:  Azacitidine Dose Modifications due to Hematologic Toxicity – Subjects 
without Reduced Baseline Blood Counts ..............................................................124
Appendix M:  Azacitidine Dose Modifications due to Hematologic Toxicity – Subjects 
with Reduced Baseline Blood Counts ...................................................................125
Appendix N:  Cytochrome Sensitive Substrates.......................................................................126
Appendix O:  Transporter Sensitive Substrates........................................................................127
Appendix P:  Monitoring of Liver Function.............................................................................128
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
16
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
LIST OF TABLES
Table 1:
Study Objectives.....................................................................................................26
Table 2:
Study Endpoints .....................................................................................................26
Table 3:
Table of Events.......................................................................................................39
Table 4:
Abbreviations and Specialist Terms......................................................................103
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
17
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................33
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
18
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
19
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
20
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
21
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
22
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
23
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
24
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
25
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
26
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
2.
STUDY OBJECTIVES AND ENDPOINTS
Table 1:
Study Objectives
Primary Objective
The primary objective of the study is

To determine the primary efficacy, measured as overall survival (OS), of AG-221 compared 
with conventional care regimens (CCRs) in subjects 60 years or older with AML refractory to 
or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation
Secondary Objective(s)
The secondary objectives are

To determine the supporting efficacy of AG-221 compared with CCRs

To determine the safety and tolerability of AG-221 compared with CCRs

To determine the effect of AG-221 compared with CCRs on Health-related Quality-of-Life
Table 2:
Study Endpoints
Endpoint
Name 
Description
Timeframe
Primary 
Overall survival
Time from randomization to death due 
to any cause
Up to ~ 49 months
Secondary
Overall response rate
Rate of MLFS + CR + CRi + CRp + PR 
according to modified IWG AML 
response criteria (Appendix F)
Up to ~ 49 months
Rate of CR/CRh (assessed by the 
Sponsor only and based on laboratory 
dataset; Appendix F).
Up to ~ 49 months
Event-free survival
Time from randomization to 
documented morphologic relapse, PD 
according to modified IWG AML 
response criteria (Appendix F) or death 
from any cause, whichever occurs first
Up to ~ 49 months
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
27
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Timeframe
Secondary
(continued)
Duration of response
Time from the first documented 
MLFS/CR/CRi/CRp/PR to documented 
morphologic relapse, PD  according to 
modified IWG AML response criteria 
(Appendix F) or death due to any cause, 
whichever occurs first
Up to ~ 49 months
Time from the first documented 
CR/CRh to documented morphologic 
relapse, PD according to modified IWG 
AML response criteria (Appendix F) or 
death from any cause, whichever occurs 
first
Up to ~ 49 months
Time to response
Time from randomization to first 
documented MLFS/CR/CRi/CRp/PR 
according to modified IWG AML 
response criteria (Appendix F)
Up to ~ 49 months
Time from randomization to first 
documented CR/CRh (Appendix F)
Up to ~ 49 months
Treatment mortality at 30 
and 60 days
Rate of death from any cause within 
30 and 60 days of initiation of study 
treatment
At 30 and 60 days
after treatment 
start
One-year survival
The probability of survival at 1 year 
from randomization 
Up to ~ 49 months
Overall remission rate
Rate of CR + CRi + CRp according to 
modified IWG AML response criteria 
(Appendix F)
Up to ~ 49 months
Complete remission rate
Rate of CR according to modified IWG 
AML response criteria (Appendix F)
Up to ~ 49 months
Hematologic improvement 
rate
Rate of HI-N + HI-P + HI-E according 
to IWG MDS HI criteria (Appendix H)
Up to ~ 49 months
Rate of HSCT
Rate of bridge-to-HSCT through study 
treatment
Up to ~ 49 months
Time to treatment failure
Time from randomization to 
discontinuation of study treatment due 
to any cause
Up to ~ 49 months
Safety and tolerability
Type, frequency, severity, seriousness 
and relationship of adverse events to 
study treatments; vital signs; ECG; 
clinical laboratory evaluations
Up to ~ 78 months
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
28
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 2:
Study Endpoints (Continued)
Endpoint
Name 
Description
Timeframe
Secondary
(continued)
HRQoL
European Organization for Research 
and Treatment of Cancer Quality-of-
Life  questionnaire (EORTC QLQ-C30) 
(Appendix I) and EuroQoL Group 
EQ-5D-5L instrument (Appendix J)
Up to ~ 49 months
Abbreviations: AML = acute myeloid leukemia; CR = morphologic complete remission; CRh = morphologic 
complete remission with partial hematologic recovery; CRi = morphologic complete remission with incomplete 
neutrophil recovery; CRp = morphologic complete remission with incomplete platelet recovery; ECG = 
electrocardiogram; EORTC= European Organization for Research and Treatment of Cancer; 
HI = hematologic improvement; HI-E = hematologic improvement erythroid response; 
HI-N = hematologic improvement neutrophil response; HI-P = hematologic improvement platelet response; 
HRQoL = Health-related Quality of Life; HSCT = hematopoietic stem cell transplantation; IWG = International 
Working Group; MDS = myelodysplastic syndromes; MLFS = morphologic leukemia-free state; 
 PR = partial remission; PD = progressive disease.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
29
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the 
efficacy and safety of AG-221 versus CCRs in subjects 60 years or older with AML refractory to 
or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation.
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.
The study consists of a Screening Phase, a Treatment Phase and a Follow-up Phase.
Figure 1 provides a schematic of the overall study design.
3.1.1.
Screening Phase
Screening procedures are to occur during the Screening Phase within 28 days prior to the start of 
study treatment and after the informed consent form (ICF) is signed.  
Diagnosis of AML disease according to World Health Organization (WHO) classification 
(Appendix B) and AML disease status at screening according to modified International Working 
Group (IWG) AML Response Criteria (Appendix F) will be based on local review of pathology 
and cytogenetics.  
A retrospective central review of screening bone marrow aspirates and/or biopsies, peripheral
blood smears and cytogenetics will be conducted by personnel blinded to study treatment. The 
central cytogenetic review will provide standardized analysis and reporting for all subjects, 
regardless of the laboratory performing the initial analysis (local or central; Section 6.1).  The 
central assessments will be used to confirm AML disease status at screening. If the central and 
local reviews disagree on AML disease status of a subject at screening, a third party reviewer 
will adjudicate and make the final assessment.  If the subject was centrally confirmed to be 
ineligible for the study, the subject will be allowed to remain in the study, but will be excluded 
from the modified intent-to-treat (mITT) population (Section 9.2.2).  Instructions for submission 
slides of bone marrow aspirate (and/or biopsy) and peripheral blood smear, and pertinent reports 
to central review are provided in the Study Reference Manual and Study Central Laboratory 
Manual.
Positivity of IDH2 gene mutation in bone marrow aspirate and/or peripheral blood will be 
confirmed centrally at screening. (Note: in the event that the central laboratory result is delayed 
and precludes acute clinical management of a subject who has confirmed IDH2 gene mutation by 
local evaluation, the subject may be eligible for randomization with approval by the Medical 
Monitor.)
Following review of eligibility, subjects will be assigned by the investigator to one of the CCR 
treatment options based on the investigator’s assessment of subjects’ eligibility.  The CCR 
treatment options include best supportive care (BSC) only, azacitidine SC plus BSC, LDAC SC 
plus BSC, or IDAC IV plus BSC:
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
30
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

BSC only: continuous 28-day cycles of BSC.  Best supportive care includes, but is 
not limited to, hydroxyurea for leukocytosis and/or differentiation syndrome 
associated with therapy of mutant IDH inhibition (ie, IDH Differentiation Syndrome), 
anti-infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional 
support (refer to Section 7.1.5 and Section 8 for details);

Azacitidine SC plus BSC: continuous 28-day cycles of azacitidine 75 mg/m2/day SC
for 7 days, plus BSC;

LDAC SC plus BSC: continuous 28-day cycles of cytarabine 20 mg SC BID for
10 days, plus BSC;

IDAC IV plus BSC: 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 
6 days, per standard institutional practice, plus BSC; only BSC given after IDAC
therapy concludes per standard institutional practice. (Note: any local standard 
regimen different from the above specification will need review and approval by the 
Medical Monitor.)
The CCR treatment option chosen and the reason(s) for selecting the CCR treatment option will 
be recorded for all subjects prior to randomization.
Following the selection of a CCR treatment option, subjects will be randomized centrally in a 1:1 
ratio to receive either the AG-221 treatment or the CCR treatment option pre-selected by the 
investigator.  Randomization will be stratified by prior intensive therapy for AML (yes versus 
no), primary refractory (ie, CR, CRi or CRp has never been attained) (yes versus no), and prior 
allogeneic HSCT for AML (yes versus no).
Approximately 316 eligible subjects will be enrolled with 158 subjects per treatment arm.
3.1.2.
Treatment Phase
Study treatment starts within 3 days after randomization.  No crossover between any of the 
treatment options, including the CCR treatment options, will be permitted during the course of 
study treatment.
Assessments during study treatment include efficacy, safety, Health-related Quality-of-Life 
(HRQoL) questionnaires, 
 
.
A retrospective central review of all bone marrow aspirates and/or biopsies, peripheral blood 
smears and cytogenetics collected after the start of study treatment will be conducted by 
personnel blinded to subject treatment.  The central cytogenetic review will provide standardized 
analysis and reporting for all subjects, regardless of the laboratory performing the initial analysis 
(local or central).  The central assessments will be used in the statistical analyses.  Disagreement 
between central and local assessments will be adjudicated by a third party reviewer and the
adjudicated assessment will be used in the statistical analyses.  Instructions for submission slides
of bone marrow aspirate (and/or biopsy) and peripheral blood smear, and pertinent reports to 
central review are provided in the Study Reference Manual and Study Central Laboratory 
Manual.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
31
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Response to treatment and hematological improvement (HI) will be assessed by the investigators 
and by a blinded Independent Response Assessment Committee (IRAC) according to modified 
IWG AML Response Criteria (Appendix F) and IWG myelodysplastic syndromes (MDS) HI
criteria (Appendix H), respectively.
Dosing interruptions, dosing delays or dose modifications may occur for managing toxicities 
and/or augmenting treatment response during study treatment (refer to Section 7.2 for details).
Subjects can continue to receive study treatment provided that they benefit from study treatment 
and all protocol-specified criteria for continuing study treatment are met.  Study treatment will
be discontinued if the investigator has alternative therapies (eg, HSCT) and/or considers the 
study treatment to be no longer beneficial to the subject, or the rapidity of change of disease state 
renders it unacceptable for further study treatment in the judgment of the investigator.  Study 
treatment will be discontinued if females of childbearing potential (FCBPs) become pregnant 
during the study. Refer to Section 11 for events that are considered sufficient reasons for 
discontinuing a subject from study treatment.
The decision to discontinue a subject, which will not be delayed or refused by the Sponsor, 
remains the responsibility of the treating physician. However, prior to discontinuing a subject, 
the investigator may contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
All subjects who have received at least one dose of study treatment should undergo end of
treatment (EOT) evaluations (Section 6.2.3) when study treatment is discontinued.  The reason 
for discontinuation will be recorded in the electronic case report form (eCRF) pages and in the 
source document.
3.1.3.
Follow-up Phase
All subjects discontinued from study treatment for any reason other than withdrawal of consent 
for follow-up will continue to be assessed for AEs, concomitant medications, concomitant 
procedures, transfusions, 
 response, hematologic improvement, 
subsequent AML therapies and survival.  Refer to Section 6.3 for details regarding the 
assessments scheduled after the EOT visit.  Females of childbearing potential should avoid 
becoming pregnant for 4 months after the last study treatment (6 months after the last dose of 
cytarabine), and male subjects and their partners should avoid conception for 4 months after the 
last study treatment (6 months after the last dose of cytarabine; 6 months after the last dose of 
azacitidine in Canada).
3.1.4.
Interim Analysis
The study will have one interim analysis for superiority (Section 9.8).  The interim efficacy 
analysis will be performed by an external independent third party and the results will be kept 
strictly confidential in order to maintain the integrity of the study.  The interim results will be 
provided to an independent Data Monitoring Committee (DMC) who will review and give 
advice to the Sponsor regarding the study conduct. The analysis results will not be disseminated 
among investigators and those directly involved with the study conduct.    
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
32
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
3.1.5.
Data Monitoring Committee
An external independent unblinded DMC with multi-disciplinary representation will evaluate 
safety and interim efficacy in compliance with a prospective charter which contains the details of 
the DMC responsibilities, authorities and procedures.
3.2.
Study Duration for Subjects 
Study participation for each subject is approximately up to 78 months, an enrollment period of 
approximately 42 months including a screening period for up to 28 days, followed by 
approximately 7 months of treatment and/or posttreatment follow-up to reach the total number of 
events (see Section Section 9) required for a fully-powered analysis of OS.
3.3.
End of Trial
The End of Trial is defined as either the date of 36 months from the last subject randomized date, 
or the date when all subjects discontinued from study treatment and no subject is available for 
survival follow-up,  whichever is the later date.
The Sponsor may consider closing the trial when data supporting key endpoints and objectives of 
the study have been analyzed, and the availability of a roll-over or extension protocol exists into 
which any subjects who remain on study treatment may be consented and continue to receive 
access to study treatment.  Such a protocol would be written for a compound that would not yet 
be commercially available.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
33
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Figure 1:
Overall Study Design
                                                                                        
Key: AML = acute myeloid leukemia; BSC = best supportive care; CCR = conventional care regimen; CR = morphologic 
complete remission; CRi = morphologic complete remission with incomplete neutrophil recovery; CRp = morphologic 
complete remission with incomplete platelet recovery; EOT = end of treatment; HSCT = hematopoietic stem cell 
transplantation; IDAC = intermediate-dose cytarabine; IDH2 = isocitrate dehydrogenase isoform 2; IV = intravenously; LDAC 
= low-dose cytarabine; PD = progressive disease; PO = orally; SC = subcutaneously.
* Stratification factors: prior intensive therapy for AML (yes versus no), primary refractory (yes versus no), and prior allogeneic 
HSCT for AML (yes versus no).
Randomization* 1:1
N = 316
End of Treatment
Treat continuously unless discontinued early for 
evidence of PD, death, unacceptable toxicity, HSCT or 
withdrawal from study treatment.
Follow-up
Follow-up for adverse events, concomitant medications, concomitant 
procedures, 
transfusions, 
response, 
hematologic improvement, subsequent AML therapies, response / disease 
status to subsequent AML therapies and survival.  Refer to Section 6.3 for 
details regarding the assessments scheduled after the EOT visit.
CCR Arm
BSC only; or
Azacitidine SC plus BSC; or 
LDAC SC plus BSC; or
IDAC IV plus BSC
N = 158
AG-221 Arm
AG-221 PO plus BSC
N = 158
Screening (Day -28 to Day -1)
Eligibility Check

≥ 60 years old

AML refractory to or relapsed after second- /third-line AML therapy
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
34
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 316 subjects 60 years or older with AML refractory to or relapsed after second-
or third-line AML therapy and positive for an IDH2 mutation will be enrolled worldwide.
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥60 years of age at the time of signing the ICF
2. Subject has primary (ie, de novo) or secondary (progression of MDS or 
myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO
classification (Appendix B)
3. Subject has received second- or third-line of AML therapy (see Appendix G for the 
definition of prior AML line; note that, for subjects having AML secondary to prior 
higher risk [Intermediate-2 or High risk according to the International Prognostic Scoring 
System] MDS treated with a hypomethylating agent [eg, azacitidine or decitabine], the 
hypomethylating therapy can be counted as a line if there is disease progression to AML 
during or shortly [eg, within 60 days] after the hypomethylating therapy.)
4. Subject has the following disease status:
a.
Refractory to or relapsed after second- or third-line of intensive therapy for AML 
(eg, the “7 + 3” regimen):
at least 5% leukemic blasts in bone marrow (the minimum number of treatment 
cycles of the intensive therapy is per the investigator’s discretion); or
b. Refractory to or relapsed after second- or third-line low-intensity AML therapy
(eg, LDAC, azacitidine or decitabine):
at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles
5. Subject is eligible for and willing to receive the pre-selected CCR treatment option, 
according to the investigator's assessment (Note: Subjects with degenerative and toxic 
encephalopathies, especially after the use of methotrexate or treatment with ionizing 
radiation, should not receive cytarabine.)
6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 
2 (Appendix D)
7. Subject has IDH2 gene mutations tested centrally (using the “investigational use only” 
PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and peripheral 
blood, and confirmed positive in bone marrow aspirate and/or peripheral blood. (Note: in 
the event that the central laboratory result is delayed and precludes acute clinical 
management of a subject who has confirmed IDH2 gene mutation by local evaluation, the 
subject may be eligible for randomization with approval by the Medical Monitor.)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
35
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
8. Subject has adequate organ function defined as:

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) 
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT)
≤3 x upper limit of normal (ULN), unless considered due to leukemic organ 
involvement, following review by the Medical Monitor; and

Serum total bilirubin ≤1.5 x ULN, unless considered due to Gilbert’s syndrome (eg, a 
gene mutation in UGT1A1) or leukemic organ involvement, following review by the 
Medical Monitor; and

Creatinine clearance 30 mL/min based on the Modification of Diet in Renal Disease 
(MDRD) glomerular filtration rate (GFR):
GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 if 
female) × (1.212 if African American)
9. Females of childbearing potential (FCBP)* may participate, providing they meet the 
following conditions:

Agree to practice true abstinencefrom sexual intercourse or to use highly effective 
contraceptive methods (eg, combined [containing estrogen and progestogen] or 
progestogen-only associated with inhibition of ovulation, oral, injectable, 
intravaginal, patch, or implantable hormonal contraceptive; bilateral tubal occlusion; 
intra-uterine device; intrauterine hormone-releasing system; or male partner 
sterilization [note that vasectomized partner is a highly effective birth control method 
provided that partner is the sole sexual partner of the FCBP trial participant and that 
the vasectomized partner has received medical assessment of the surgical success]) at 
screening and throughout the study, and for 4 months following the last study 
treatment (6 months following the last dose of cytarabine); and

Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) 
pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and

Have a negative serum or urine (investigator’s discretion under local regulations)
β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to the 
start of study treatment in the Treatment Phase (note that the screening serum 
pregnancy test can be used as the test prior to the start of study treatment in the 
Treatment Phase if it is performed within the 72-hour timeframe).
10. Male subjects must agree to practice true abstinence** from sexual intercourse or to the 
use of highly effective contraceptive methods (as described above) with non-pregnant 
                                                            
* A female of childbearing potential is a sexually mature woman who 1) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at 
least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months).  
True abstinence is only accepted as a method of contraception when it is the preferred and usual lifestyle of the 
subject.  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method are not considered to be acceptable methods of 
contraception.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
36
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
female partners of childbearing potential at screening and throughout the course of the 
study, and should avoid conception with their partners during the course of the study and 
for 4 months following the last study treatment (6 months following the last dose of 
cytarabine; 6 months following the last dose of azacitidine in Canada)
11. Subject must understand and voluntarily sign an ICF prior to any study-related 
assessments/procedures being conducted
12. Subject is 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 enrollment:
1. Subject is suspected or proven to have acute promyelocytic leukemia based on 
morphology, immunophenotype, molecular assay, or karyotype (Appendix B)
2. Subject has AML secondary to chronic myelogenous leukemia (CML; Appendix C)
3. Subject has received a targeted agent against an IDH2 mutation
4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to the 
start of study treatment.  Note that hydroxyurea is allowed prior to the start of study 
treatment for the control of leukocytosis (however, hydroxyurea should not be given 
within 72 hours prior to and after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5 half-lives, 
whichever is longer, prior to the start of study treatment
6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on 
immunosuppressive therapy post HSCT at the time of screening, or with clinically 
significant graft-versus-host disease (GVHD).  The use of a stable dose of oral steroid 
post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from prior 
therapies
8. Subject has or is suspected of having central nervous system (CNS) leukemia.  
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is 
suspected during screening.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as 
ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics, antiviral therapy, and/or other treatment)
10. Subject has immediately life-threatening, severe complications of leukemia such as 
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated 
intravascular coagulation
11. Subject has significant active cardiac disease within 6 months prior to the start of study 
treatment, including New York Heart Association (NYHA) class III or IV congestive 
heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke; or left 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
37
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated 
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment
12. Subject has prior history of malignancy, other than MDS, MPN or AML, unless the 
subject has been free of the disease for ≥ 1 year prior to the start of study treatment.  
However, subjects with the following history/concurrent conditions are allowed:

Basal or squamous cell carcinoma of the skin

Carcinoma in situ of the cervix

Carcinoma in situ of the breast

Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, 
metastasis clinical staging system)
13. Subject is known seropositive or active infection with human immunodeficiency virus 
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other 
conditions that limit the ingestion or gastrointestinal absorption of drugs administered 
orally
15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or 
diastolic BP > 100 mmHg)
16. Subject is a pregnant or lactating female
17. Subject has known or suspected to have hypersensitivity to any of the components of 
study treatment
18. Subject is taking those medications (listed in Section 8.2) that are known to prolong QT 
interval unless the subject can be transferred to other medications at least 5 half-lives 
prior to the start of study treatment
19. Subject has QTc interval (ie, Fridericia’s correction [QTcF]) ≥450 ms or other factors 
that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, 
hypokalemia, family history of long QT interval syndrome) at screening
20. Subject is taking the following sensitive CYP substrate medications that have a narrow 
therapeutic range are excluded from the study unless the subject can be transferred to 
other medications at least 5 half-lives prior to the start of study treatment: paclitaxel and 
docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine 
(CYP2D6), theophylline, and tizanidine (CYP1A2)  
21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive 
substrate rosuvastatin should be excluded from the study unless the subject can be 
transferred to other medications at least 5 half-lives prior to the start of study treatment
22. Subject has any significant medical condition, laboratory abnormality, or psychiatric 
illness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, which 
places the subject at unacceptable risk if he/she were to participate in the study
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
38
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
24. Subject has any condition that confounds the ability to interpret data from the study
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
39
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
5.
TABLE OF EVENTS
Table 3:
Table of Events
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Days -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Informed Consent
c
IVRS Registration and Calls

d



Inclusion & Exclusion Criteria

e, f
Demographics

Initial AML Diagnosis

Prior AML Therapies

AML Disease Status
g
Central Testing of IDH2 Gene 
Mutations on BMA and PB
g
Medical History

Prior Medications and 
Procedures
h
Eligibility of CCR Options
i
EORTC QLQ-C30 and 
EQ-ED-5L




ECOG Performance Status





Physical Exam j





Vital Signs









Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
40
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 3:
Table of Events (Continued)
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Height

Body Weight





BSA Calculation k




ECHO l
m
As clinically indicated
12-Lead ECG l






Pregnancy Test (FCBP only) n
o
l, p
l
l
l
Urinalysis o

As clinically indicated
Coagulation Laboratory o

Hematology Laboratory o









q
Chemistry Laboratory o






UGT1A1 Gene Mutation Test o
(for Diagnosis of Gilbert’s 
syndrome; refer to Section 4.2)

Cardiac Markers o
f
r
Fasting (preferred) Lipid Panel o

s
Adverse Event
Continuous starting after signing ICF until 28 days after the last study treatment or until the EOT visit, whichever is longer
Concomitant Medications and 
Procedures
Continuous until 28 days after the last study treatment or until the EOT visit, whichever is longer
Transfusions
u
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
41
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 3:
Table of Events (Continued)
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
BMA for Assessing Disease 
Status /Response to Treatment v
g
w
x
y
z
q
BMB dd
g
w
x
y
z
q
PB Smear
g
w
x
y
z
q
Cytogenetics Testing
g
w, ee
x, ee
y, ee
z, ee
q, ee
Response and HI
w
x
y
z
q
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
42
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 3:
Table of Events (Continued)
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Treatment Accountability jj
kk



IP Dispensation



Treatment Administration
See Section 7.2 for details
Survival Follow-up
ll
Subsequent AML Therapies/ 
Response / Disease Status to 
Subsequent AML Therapies per 
Investigator 
ll
Abbreviations: AML = acute myeloid leukemia; β- hCG = β-subunit of human chorionic gonadotropin; BMA = bone marrow aspirate; BMB = bone marrow 
biopsy; BSA = body surface area; CCR = conventional care regimen; CR = morphologic complete remission; CRi = morphologic complete remission with 
incomplete neutrophil recovery; CRp = morphologic complete remission with incomplete platelet recovery; ECHO = echocardiogram; eCRF = electronic case 
report form; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC= European Organization for Research and Treatment of 
Cancer; FCBP = female of childbearing potential; EOT = End of Treatment; HI = hematologic improvement; HRQoL = Health-related Quality of Life; 
HSCT = hematopoietic stem cell transplantation; ICF = informed consent form; IDH2 = isocitrate dehydrogenase isoform 2; IP = investigational product; 
IVRS = Interactive Voice Response System; IWG = International Working Group;
 PB = peripheral blood; PD = progressive disease; 
SOC = standard of care; UGT1A1 = uridine diphosphate-glucuronosyltransferase 1 family, polypeptide A1.
a Study Treatment is to be initiated on Day 1 of each treatment cycle.  One treatment cycle (one month) is considered as 28 days (ie, 4 weeks).  Unless noted 
otherwise, an administrative window of ± 3 days is permitted for all subsequent visits after the start of study treatment in the Treatment Phase.  Day 1 of 
Cycles 2 and beyond may be delayed from Day 28 of the prior cycle in order for subjects to recover from toxicity and meet criteria for initiating each treatment 
cycle (Section 7.2).  The study visit window for EOT or monthly-scheduled survival follow-up is ± 7 days.  
b See Section 6.2.3 for details.
c Including informed consent for mandatory genetic testing 
.
d The subject should start study treatment (ie, Day 1 of Cycle 1) within 3 days after randomization.
e Subject should continue to be eligible for study entry prior to the start of study treatment on Day 1 of Cycle 1.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
43
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
f Cycle 1 only.
g See Section 6.1 for details regarding collecting BMA, BMB, PBS and cytogenetics at screening for assessing AML disease status, collecting BMA and PB at 
screening for central testing IDH gene mutations
. In the event that the 
central laboratory result is delayed and precludes acute clinical management of a subject who has confirmed IDH2 gene mutation by local evaluation, the 
subject may be eligible for randomization with approval by the Medical Monitor.
h All prior medications (prescription and non-prescription) taken and treatment procedures received from the 4-week period (ie, 28 days) prior to starting study 
treatment (including those prior to the start of study treatment on Day 1 of Cycle 1), and all prior anticancer therapies, regardless of discontinuation date of 
treatment.
i Documentation of CCR treatment option selected by the investigator must occur prior to randomization.
j Source documented only.
k The BSA calculation is per the Dubois & Dubois formula: BSA (m2) = weight (kg)0 425 x height (cm)0 725/139.2.  Where applicable, the dose should be 
calculated on Day 1 of each treatment cycle.
l These assessments will be done locally.
m The screening ECHO does not need to be repeated if a prior ECHO or multi-gated acquisition (MUGA) scan has been performed within 28 days prior to the 
start of study treatment.
n Pregnancy test is required for all FCBPs (see Section 4.2 for the definition).  Serum β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) will be performed
centrally at screening.  For FCBP subjects, a local serum or urine (investigator’s discretion under local regulations) β- hCG pregnancy test (sensitivity of at 
least 25 mIU/mL) is to be done within 72 hours prior to study treatment administration on Day 1 of every treatment cycle in the Treatment Phase and at the 
EOT visit.  Negative results are required for study treatment administration.
o These assessments will be done centrally.  Fasting is recommended, particularly for subjects who experience clinically meaningful elevations of lipids, per the 
investigator’s assessment.
p A local serum or urine (investigator’s discretion under local regulations) pregnancy test (sensitivity of at least 25 mIU/mL) is to be done within 72 hours prior 
to the start of study treatment in the Treatment Phase for FCBP only (note that the screening central serum pregnancy test can be used as the test prior to the 
start of study treatment in the Treatment Phase if it is performed within the 72-hour timeframe).
q Whenever response/disease status is assessed in the Follow-up Phase (ie, every 12 weeks [± 28 days]).  See Section 6.3 for details.
r Day 1 (± 14 days) of every 3rd cycle (eg, Cycles 3, 6, 9, etc) or more frequently per standard institutional practice. Not necessary for the EOT visit if last 
performed within 14 days.
s Day 1 of Cycle 3 and Day 1 (± 28 days) of every 6th cycle (eg, Cycles 6, 12, 18, etc) or more frequently per standard institutional practice.  Not necessary for 
the EOT visit if last performed within 28 days.
u Including type, number of units, reasons and date of transfusions taken ≤ 8 weeks prior to the start of study treatment through 28 days after the last study 
treatment or until the EOT visit, whichever is longer.  Thereafter, transfusions will continue to be collected until the initation of the first subsequent AML
therapy after discontinuation from study treatment, death, lost to follow-up, withdrawal of consent for further data collection, or the End of Trial, whichever 
occurs first.  
v In addition to the frequency specified in the table, samples will also be collected if clinically indicated (eg, confirmation of CR/CRi/CRp, morphologic relapse 
after CR/CRi/CRp or PD by a repeated bone marrow assessment at least 1 month later) or required for toxicity assessment.
w Within 7 days prior to study treatment administration on Day 1 of Cycle 2.
x Within 7 days prior to study treatment administration on Day 1 of Cycle 3.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
44
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
y Within 7 days prior to study treatment administration on Day 1 of Cycle 5 and Day 1 of every 2nd cycle thereafter (eg, Cycles 7, 9, etc).
z Not necessary for the EOT visit if last performed within 28 days.
dd A bone marrow biopsy can be collected in conjunction with an aspirate if it is standard institutional practice.  A bone marrow biopsy must be collected if 
adequate aspirate is not attainable.
ee If the bone marrow aspirate is obtained for confirming CR/CRi/CRp, morphologic relapse after CR/CRi/CRp or PD, a sample of the bone marrow aspirate is to 
be sent to the local or central cytogenetics laboratory (for sites without local analysis capability) for standard metaphase preparation and analysis of a minimum 
of 20 metaphase cells.  A bone marrow biopsy can be used for cytogenetics testing if adequate aspirate is not attainable (note that specific handling of the 
biopsy is required for cytogenetics testing).
jj Including diary cards, if utilized.  See Section 7.6 for details.
kk Cycle 2 only.
ll Every 4 weeks (± 7 days) for survival follow-up until death, lost to follow-up, withdrawal of consent for further data collection or the End of Trial, whichever 
occurs first.  Subsequent AML therapies and investigator-assessed response/disease status to subsequent AML therapies should be collected at the same time 
schedule.  See Section 6.3 for details.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
45
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
6.
PROCEDURES
Any questions regarding the protocol should be directed to the Medical Monitor or designee.
Written ICFs must be obtained before any study evaluations are performed and any samples are 
collected per local regulations during the course of the study. 
6.1.
Screening Phase
Screening evaluations start from ICF signing and must be completed within 28 days prior to the
start of study treatment, unless noted otherwise below.  Screening laboratory values must 
demonstrate subject eligibility, but may be repeated within the screening window, if necessary.  
The following will be performed at screening as specified in the Table of Events, Table 3, after 
written ICFs have been obtained:

Registration of screening in IVRS

Inclusion and exclusion criteria

Demographics (age, sex, race, and ethnicity)

Information supporting the initial diagnosis of AML by local pathology and 
cytogenetics review, including reports of bone marrow aspirate and/or biopsy, 
peripheral blood smear, cytogenetics and other tests if pertinent

Prior AML therapies including surgery, radiation, systemic or any other therapy for 
the subject’s AML disease, particularly induction/re-induction/salvage
chemotherapies, consolidation or maintenance therapies, HSCT, low-intensity AML 
therapies such as azacitidine, decitabine or LDAC, or other medications considered 
supportive care for AML, regardless of discontinuation date of treatment

Information supporting CR/CRi/CRp attained during prior AML therapies by local 
pathology and cytogenetics review, including reports of bone marrow aspirate and/or 
biopsy, peripheral blood smear, cytogenetics, and other pertinent tests

AML disease status at screening determined by local pathology and cytogenetics 
review and confirmed retrospectively by central review.  Therefore, bone marrow 
aspirate (or biopsy if adequate aspirate is not attainable) must be collected at 
screening so slides of bone marrow aspirate (and/or biopsy) and peripheral blood 
smear are available for both the local and the central pathology reviewers.  A bone 
marrow biopsy can be collected in conjunction with an aspirate if it is standard 
institutional practice.  Whenever a bone marrow sample is collected, a peripheral
blood smear is to be prepared.  In addition, a sample of the screening bone marrow 
aspirate is to be sent to the local or central cytogenetics laboratory (for sites without 
local analysis capability) for standard metaphase preparation and analysis of a 
minimum of 20 metaphase cells.  A bone marrow biopsy can be used for cytogenetics 
testing if adequate aspirate is not attainable (note that specific handling of the biopsy 
is required for cytogenetics testing).
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
46
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
The retrospective central review of screening bone marrow aspirates and/or biopsies, 
peripheral blood smears and cytogenetics will be conducted by personnel blinded to 
study treatment. The central assessments will be used to confirm AML disease status 
at screening. If central review and local review disagree on AML disease status of a 
subject at screening, a third party reviewer will adjudicate and make the final 
assessment.  If the subject was centrally confirmed to be ineligible for the study, the 
subject will be allowed to remain in the study, but will be excluded from the modified 
intent-to-treat (mITT) population (Section 9.2.2).
Instructions for submission slides of bone marrow aspirate (and/or biopsy) and 
peripheral blood smear, and pertinent reports for central review are provided in the 
Study Reference and/or Study Central Laboratory Manual.

Subject has IDH2 gene mutations tested centrally in samples of bone marrow aspirate 
and peripheral blood, and confirmed positive in bone marrow aspirate and/or
peripheral blood. (Note: in the event that the central laboratory result is delayed and 
precludes acute clinical management of a subject who has confirmed IDH2 gene 
mutation by local evaluation, the subject may be eligible for randomization with 
approval by the Medical Monitor.)  
The detection and identification of IDH2 mutations (if present) will be assessed by 
Abbott RealTime IDH2 using a partially automated system entailing extraction and 
amplification of deoxyribonucleic acid (DNA) with specific primers and probes. The 
device (test) has been developed by Abbott Molecular Inc. and is used to detect and 
identify IDH2 mutations in subjects’ bone marrow aspirate and peripheral blood 
specimens. The commercial test, which has been approved by FDA, is equivalent to 
the investigational test in the study. 
Refer to the Study Reference and/or Study Laboratory Manual for sample collection, 
processing, storage, and shipment procedures.

Medical history including all relevant current medical conditions and medical 
conditions diagnosed/ occurring prior to screening

Prior medications including those taken ≤ 28 days prior to the start of study treatment
and all prior anticancer therapies, regardless of discontinuation date of treatment

Prior procedures including those occurring ≤ 28 days prior to the start of study 
treatment and all prior anti-cancer procedures, regardless of discontinuation date of 
treatment

Documentation of the CCR treatment option selected by the investigator prior to 
randomization

ECOG performance status

Physical examination: information about the screening physical examination must be 
present in the subject’s source documentation.  Significant findings must be included 
on the appropriate eCRF page.

Vital signs including temperature, blood pressure, pulse rate and respiratory rate
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
47
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Height (only collected once at screening)

Body weight

Body surface area (BSA) calculation per the Dubois & Dubois formula: 
BSA (m2) = weight (kg)0.425 x height (cm)0.725/139.2

The following laboratory assessments will be done locally:
-
ECHO (not required if a prior ECHO or MUGA scan has been performed 
within 28 days prior to the start of study treatment)
-
12-lead ECG will be assessed by a physician trained in ECG interpretation as 
normal, abnormal - not clinically significant, or abnormal - clinically 
significant.  Intervals including PR, QRS, QT and RR will be collected, as 
well as heart rate and rhythm.  Abnormal finding(s) will be reported on the 
appropriate eCRF page.  For a given subject, ECG interpretations should be 
conducted by the same physician throughout the study as much as possible, 
with a consistent approach for the QT interval analysis (eg, pre-cordial leads 
and lead II).

The following laboratory assessments will be done centrally:
-
Serum β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) is required
for all FCBPs (see Section 4.2 for the definition)
-
Urinalysis including examination by a standard dipstick test for specific 
gravity, glucose, ketones, blood, pH, and protein, and microscopic analysis if 
indicated
-
Coagulation test including prothrombin time (PT) with international 
normalized ratio (INR) and partial thromboplastin time (PTT)
-
Hematology panel including complete blood count (CBC) with differential, 
including red blood cell (RBC) count, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC), white blood cell (WBC) 
count (with differential), absolute neutrophil count (ANC) and platelet count
-
Chemistry panel including sodium, potassium, calcium, magnesium, chloride, 
phosphorus, CO2, bicarbonate, blood urea nitrogen (BUN), creatinine, 
glucose, albumin, total protein, alkaline phosphatase (ALP), bilirubin (total 
and direct), uric acid, lactate dehydrogenase (LDH), AST/SGOT, ALT/SGPT, 
gamma glutamyl transpeptidase (GGT), amylase and lipase
-
UGT1A1 gene mutation test performed on peripheral blood samples for 
diagnosis of Gilbert’s syndrome (refer to the inclusion criterion regarding
serum total bilirubin in Section 4.2)

Assessing AEs
 start when the subject signs the ICF

Transfusion history including the type, number of units, reason, and date of
transfusions for the 8 weeks prior to the start of study treatment
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
48
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Information to be Collected on Screening Failures
The informed consent date, demographics, and reason subject did not qualify for the study will 
be collected for all subjects determined to be screen failures.  Adverse events experienced by 
screen failure subjects will be collected from the date of signing consent to the day the subject is 
confirmed to be a screen failure.  This information will be captured in the subject’s source 
documents and appropriate eCRF(s).
Randomization
Eligible subjects will be randomized in a central IVRS in a 1:1 ratio to receive either the AG-221 
treatment or the CCR treatment option pre-selected by the investigator.  Randomization will be 
stratified by prior intensive therapy for AML (yes versus no), primary refractory (yes versus no), 
and prior allogeneic HSCT for AML (yes versus no).  
The study treatment should be initiated within 3 days after randomization.  
6.2.
Treatment Phase
The subject should continue to be eligible for study entry prior to the start of study treatment on 
Day 1 of Cycle 1.  Study Treatment is to be initiated on Day 1 of each treatment cycle.  One 
treatment cycle (one month) is considered as 28 days (ie, 4 weeks).  Unless noted otherwise, an 
administrative window of ± 3 days is permitted for all subsequent visits after the start of study 
treatment in the Treatment Phase.  Day 1 of Cycles 2 and beyond may be delayed from Day 28 
of the prior cycle in order for subjects to recover from toxicity and meet criteria for initiating 
each treatment cycle (see Section 7.2 for details).
The following evaluations will be performed during study treatment at the frequency specified in
the Table of Events, Table 3, or more frequently if clinically indicated. The evaluations should 
be performed prior to dosing on scheduled clinical visit day, unless otherwise specified.  For 
each evaluation, the same parameters as required at screening or on Day 1 of Cycle 1 should be 
evaluated.

Registration of the start of each treatment cycle in IVRS (where applicable)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
49
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

HRQoL (EORTC QLQ-C30 and EQ-ED-5L questionnaires; Section 6.9)

Treatment accountability (where applicable; also refer to Section 7.5)

ECOG performance status

Physical examination, vital signs and body weight.  Significant findings are to be 
reported on the appropriate eCRF page.

Body surface area calculation.  Where applicable, the dose should be calculated on 
Day 1 of each treatment cycle.

The following laboratory assessments will be done locally:
-
ECHO if clinically indicated
-
12-lead ECG.  Abnormal finding(s) will be reported on the appropriate eCRF
page.
-
A serum or urine (investigator’s discretion under local regulations) β-hCG 
pregnancy test (sensitivity of at least 25 mIU/mL) is to be done within 
72 hours prior to study treatment administration on Day 1 of each treatment 
cycle (for FCBPs only; note that the central serum pregnancy test at screening 
can be used as the test prior to the start of study treatment in the Treatment
Phase if it is performed within the 72-hour timeframe).  The subject may not 
receive study treatment until the investigator has verified that the result of the 
pregnancy test is negative.

The following laboratory assessments will be done centrally:
-
Urinalysis and/or coagulation test if clinically indicated
-
Hematology panel
-
Chemistry panel
-
Cardiac marker troponin I
-
Fasting (preferred) lipid panel including total cholesterol, low-density 
lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-
C), triglycerides.  Fasting is recommended, particularly for subjects who 
experience clinically meaningful elevations of lipids, per the investigator’s 
assessment.

Continuous evaluations of AEs, 
 concomitant 
medications and procedures, and transfusions

Bone marrow aspirate (or biopsy if adequate aspirate is not attainable) samples will 
be collected for assessing response during study treatment.  As specified in the Table 
of Events, Table 3, the frequency is within 7 days prior to study treatment 
administration on Cycles 2 and 3, every 2nd cycle thereafter (eg, Cycles 5, 7, 9, etc), 
and if clinically indicated (eg, confirmation of CR/CRi/CRp, morphologic relapse 
after CR/CRi/CRp or PD by a repeated bone marrow assessment at least 1 month 
later) or required for toxicity assessment.  A bone marrow biopsy can be collected in 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
50
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
conjunction with an aspirate if it is standard institutional practice or if clinical 
indicated (eg, evaluation of bone marrow cellularity).  Whenever a bone marrow 
sample is collected, a peripheral blood smear is to be prepared.  In addition, whenever 
a bone marrow aspirate is obtained for confirming CR/CRi/CRp, morphologic relapse 
after CR/CRi/CRp or PD, a sample of the bone marrow aspirate is to be sent to the 
local or central cytogenetics laboratory (for sites without local analysis capability) for 
standard metaphase preparation and analysis of a minimum of 20 metaphase cells.  A 
bone marrow biopsy can be used for cytogenetics testing if adequate aspirate is not 
attainable (note that specific handling of the biopsy is required for cytogenetics 
testing).  Bone marrow aspirate and/or biopsy, peripheral blood smear and 
cytogenetics collected after the start of study treatment for response assessment must 
be available for both local and central review.  Instructions for submission slides of 
bone marrow aspirate (and/or biopsy) and peripheral blood smear, and pertinent 
reports for central review are provided in the Study Reference and Study Central 
Laboratory Manuals

Response to treatment and HI will be assessed whenever bone marrow samples are 
collected for response assessment (see above)
 

Treatment dispensing and administration (where applicable; refer to Section 7)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
51
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
6.2.1.
Baseline
Unless noted otherwise for a particular assessment, results obtained just prior to the start of study 
treatment on Day 1 of Cycle 1 will serve as the baseline values.  If not available, the most recent 
screening results prior to the start of study treatment on Day 1 of Cycle 1 will be considered the 
baseline values.  Transfusions history includes the type, number of units, reason, and date of
transfusions for the 8 weeks prior to the start of study treatment on Day 1 of Cycle 1.  EORTC 
QLQ-30 and EQ-5D are to be completed prior to the start of study treatment on Day 1 of Cycle 1
and prior to interaction with study personnel.
6.2.2.
Unscheduled Visits
Should it become necessary to repeat an evaluation (eg, laboratory tests or ECG), the results of 
the repeat evaluations should be entered as appropriate in additional unscheduled visit pages of 
the eCRF.
6.2.3.
End of Treatment
An EOT evaluation will be performed for subjects who are withdrawn from study treatment for 
any reason as soon as possible after the decision to permanently discontinue study treatment has 
been made.  An administrative window of ± 7 days is permitted for the EOT visit, unless noted 
otherwise.  If a subject is discontinued during a regularly-scheduled visit, all EOT evaluations 
should be completed at that visit.
The following evaluations will be performed as specified in the Table of Events, Table 3.  For 
each evaluation, the same parameters as required at screening or on Day 1 of Cycle 1 should be 
evaluated.

Registration of treatment discontinuation in IVRS

HRQoL (EORTC QLQ-C30 and EQ-ED-5L questionnaires)

Treatment accountability (where applicable; refer to Section 7.5)

ECOG performance status 

Physical examination, vital signs and body weight.  Significant findings are to be 
reported on the appropriate eCRF page.

The following laboratory assessments will be done locally:
-
ECHO if clinically indicated
-
12-lead ECG
-
A serum or urine (investigator’s discretion under local regulations) β-hCG 
pregnancy test (sensitivity of at least 25 mIU/mL) (for FBCPs only)

The following laboratory assessments will be done centrally:
-
Urinalysis and/or coagulation test if clinically indicated
-
Hematology panel
-
Chemistry panel
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
52
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
-
Cardiac marker (not necessary for the EOT visit if it was last performed 
within 14 days unless clinically indicated)
-
Fasting (preferred) lipid panel (not necessary for the EOT visit if it was last 
performed within 28 days unless clinically indicated)

Evaluations of AEs, 
 concomitant medications, 
concomitant procedures and transfusions (monitored through 28 days after the last 
study treatment or until the EOT visit, whichever is longer)

Bone marrow aspirate and/or biopsy, peripheral blood smear and, if applicable, 
cytogenetics, for response assessment (not necessary for the EOT visit if it was last 
performed within 28 days unless clinically indicated)

Response to treatment and HI will be assessed if bone marrow samples are collected 
for assessing response at the EOT visit (see above)
6.3.
Follow-up Phase
All subjects discontinued from study treatment for any reason other than withdrawal of consent 
for follow-up will continue to have the following assessments in the Follow-up Phase:

AEs, 
 concomitant medications, concomitant 
procedures and transfusions for 28 days after the last study treatment or the EOT
visit, whichever is longer.  
Thereafter, SAEs made known to the investigator at any time that are suspected of 
being related to study treatment, as described in Section 10.1.  

Transfusions 
will continue to be collected until the
initation of the first subsequent AML therapy after discontinuation from study 
treatment, death, lost to follow-up, withdrawal of consent for further data collection, 
or the End of Trial, whichever occurs first.

Bone marrow aspirate and/or biopsy, peripheral blood smear and, if applicable, 
cytogenetics, available for both local and central review for assessing response or 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
53
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
disease status, every 12 weeks (± 28 days) or more frequent if clinically indicated
until PD, the initation of the first subsequent AML therapy after discontinuation of 
study treatment, death, lost to follow-up, withdrawal of consent for further data 
collection, or the End of Trial, whichever occurs first.  

Response/disease status and HI will be assessed whenever bone marrow samples are 
collected for assessing response or disease status (see above)

Survival follow-up every 4 weeks (± 7 days) until death, lost to follow-up, 
withdrawal of consent for further data collection, or the End of Trial, whichever 
occurs first.  Subsequent AML therapies should be collected at the same schedule as 
survival follow-up.

Investigator-assessed response/ disease status to subsequent AML therapies will be 
collected. Specifically, the best response to a subsequent AML therapy and the first 
date achieving the best response, and progressive disease/relapse date during or after 
a respective subsequent AML therapy should be reported.  

Survival follow-up, subsequent AML therapies, and response/ disease status to 
subsequent AML therapies may be conducted by record review (including public 
records) and/or telephone contact with the subject, family, or the subject’s treating 
physician.

Females of childbearing potential should avoid becoming pregnant for 4 months after 
the last study treatment (6 months after the last dose of cytarabine), and male subjects 
and their partners should avoid conception for 4 months after the last study treatment
(6 months after the last dose of cytarabine; 6 months after the last dose of azacitidine
in Canada).
6.4.
Safety Assessment
Safety assessments include physical examination, vital signs, ECG, hematology, serum 
chemistry, cardiac markers, fasting (preferred) lipid panel, pregnancy testing (for FCBP subjects 
only), AEs, concomitant medications and procedures, and transfusions, will be performed at the 
frequency specified in Table 3 or more frequently if clinically indicated.  After screening, 
ECHO, urinalysis and coagulation will be performed if clinically indicated.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
54
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
6.4.1.
Adverse Events
Refer to Section 10 for AE reporting.  Information about common side effects already known 
about AG-221 and azacitidine can be found in the respective IBs or will be communicated 
between IB updates in the form of Investigator Notifications.  Refer to United Kingdom (UK) 
Summary of Product Characteristics (SmPC) for information about common side effects already 
known about cytarabine.  This information about common side effects will also be included in 
the subject ICF and should be discussed with the subject as needed during the study.
6.4.2.
Urinalysis, Coagulation, Hematology, Serum Chemistry, Cardiac Markers and
Fasting (Preferred) Lipid Panel
All samples should be sent to the central laboratory.  In the event that an immediate laboratory 
assessment is required to acutely manage a subject (eg, monitoring ALT increases of ≥ 3 x ULN; 
Appendix P), local laboratory tests may be used.  In addition to collecting the local laboratory 
sample, a second sample should be collected and sent to the central laboratory.
Refer to Section 10.3 for information regarding abnormal laboratory values or whether test 
results constitute an AE.
6.5.
Efficacy Assessment
6.5.1.
Disease Status or Response to Study Treatment
Bone marrow aspirate (or biopsy if adequate aspirate is not attainable) samples will be collected 
for assessing disease status or response to study treatment at the frequency specified in Table 3
or more frequently if clinically indicated.  
A bone marrow biopsy can be collected in conjunction with an aspirate if it is standard 
institutional practice or if clinical indicated (eg, evaluation of bone marrow cellularity).  
Whenever a bone marrow sample is collected, a peripheral blood smear is to be prepared.  
In addition, whenever a bone marrow aspirate is obtained for confirming CR/CRi/CRp, 
morphologic relapse after CR/CRi/CRp or PD, a sample of the bone marrow aspirate is to be sent 
to the local or central cytogenetics laboratory (for sites without local analysis capability) for 
standard metaphase preparation and analysis of a minimum of 20 metaphase cells.  A bone 
marrow biopsy can be used for cytogenetics testing if adequate aspirate is not attainable (note 
that specific handling of the biopsy is required for cytogenetics testing).  
Bone marrow aspirate and/or biopsy, peripheral blood smear and cytogenetics collected 
throughout study must be available for both local and central review.  A retrospective central 
review of all bone marrow aspirates and/or biopsies, peripheral blood smears and cytogenetics 
collected throughout study will be conducted by personnel blinded to subject treatment.  The 
central cytogenetic review will provide standardized analysis and reporting for all subjects, 
regardless of the laboratory performing the initial analysis (local or central).  The central 
assessments will be used in the statistical analyses.  Disagreement between central and local 
assessments will be adjudicated by a third party reviewer and the adjudicated assessment will be 
used in the statistical analyses.
Response to study treatment will be assessed by the investigators and retrospectively by a 
blinded IRAC according to modified IWG AML response criteria (Appendix F) through 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
55
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
collection of central hematology parameters, central assessments of bone marrow aspirates 
and/or biopsies, peripheral blood smears and cytogenetics, and results of other pertinent tests.
Instructions for submission slides of bone marrow aspirate (and/or biopsy) and peripheral blood 
smear, and pertinent reports for central review are provided in the Study Reference and Study 
Central Laboratory Manuals.
In addition, investigator-assessed response/ disease status to subsequent AML therapies will be 
collected (see the details in Section 6.3). 
6.5.2.
Hematologic Improvement
Hematologic improvement will be assessed by the investigators and retrospectively by a blinded
IRAC according to IWG MDS HI criteria (Appendix H) through collection of transfusion 
records and central hematology parameters.
6.5.3.
Survival
Refer to Section 6.3 for survival follow-up.
 
 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
56
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
6.9.
Quality-of-Life
Two instruments, the European Organization for Research and Treatment of Cancer Quality-of-
Life questionnaire (EORTC QLQ-C30) and EuroQoL Group EQ-5D, will be used for HRQoL.  
The EORTC QLQ-30 (Aaronson, 1993) is a validated quality of life measure applicable to 
subjects with any cancer diagnosis.  It is composed of 30 items that address general physical 
symptoms, physical functioning, fatigue and malaise, and social and emotional functioning.  
Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales 
indicating better function and higher scores on symptom scales indicating worse symptoms.  The 
EORTC QLQ-C30 is available in many languages.  This instrument takes 10 to 15 minutes to 
administer.  The EORTC QLQ-C30 data will be captured using a portable electronic tablet 
computer.  See Appendix I for an example.
The EQ-5D is a standardized instrument for use as a measure of health outcome.  It provides a 
simple descriptive profile and a single index value for health status, and is applicable to a wide 
range of health conditions and treatments.  The EQ-5D is available in many languages and it 
takes approximately 5 minutes to complete.  EQ-5D data will be captured using a portable 
electronic tablet computer.  See Appendix J for an example.
It is important that every subject completes all assessments of EORTC QLQ-30 and EQ-5D at 
every specified time point, prior to dosing and prior to interaction with study personnel, to 
minimize the amount of missing data.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
57
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
58
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product(s)
7.1.1.
AG-221
AG-221 will be supplied by Celgene and labeled appropriately as investigational product (IP) for 
this study.
Celgene Corporation will supply AG-221 50-, 100-, 150- and 200-mg free-base equivalent 
strength 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 high density polyethylene (HDPE) bottles with a desiccant (silica 
gel) canister and child resistant closures with heat induction seal.  All tablets should be 
swallowed whole, and should not be broken or chewed.
Bottles of AG-221 tablets must be stored according to the package label.  The storage area 
should be secure and have limited access.  AG-221 tablets will be monitored by the Sponsor for 
stability for the duration of the study.   
7.1.2.
Azacitidine 
Azacitidine will be supplied by Celgene Corporation as a sterile lyophilized powder containing 
100 mg of azacitidine and 100 mg of mannitol per vial.
Detailed instructions for preparation of SC azacitidine are provided in Appendix K.
7.1.3.
Low-dose Cytarabine
Subjects randomized to LDAC treatment and located in countries where LDAC is designated as 
non-investigational product (NIP) may have cytarabine sourced locally by the clinical site.  
Subjects randomized to LDAC treatment and located in countries where LDAC is designated as 
IP will have cytarabine supplied and packaged by Celgene Corporation.  
Please refer to the UK SmPC for more details on available formulations, preparation of SC 
cytarabine, storage conditions (eg, refrigeration), the approved indications, known precautions, 
warnings, and adverse reactions of cytarabine.
7.1.4.
Intermediate-dose Cytarabine
Subjects randomized to IDAC treatment and located in countries where IDAC is designated as 
NIP may have cytarabine sourced locally by the clinical site.  Subjects randomized to IDAC 
treatment and located in countries where IDAC is designated as IP will have cytarabine supplied 
and packaged by Celgene Corporation.
Please refer to the UK SmPC for more details on available formulations, preparation of IV 
cytarabine, storage conditions (eg, refrigeration), the approved indications, known precautions, 
warnings, and adverse reactions of cytarabine.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
59
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.1.5.
Best Supportive Care Only
Refer to Section 8 for details regarding BSC. Please refer to local prescribing information and 
local therapeutic guidelines for more details on available formulations, preparation, storage 
conditions (eg, refrigeration), the approved indications, known precautions, warnings, and 
adverse reactions of BSC (see the current version of prescribing information).
7.2.
Treatment Administration and Schedule
Study treatment is to be initiated on Day 1 of each treatment cycle.  The subject may not receive 
study treatment for each treatment cycle until all Day 1 procedures have been completed and all 
doses of study treatment from the prior treatment cycle are accounted for (where applicable).  
For FCBP subjects, a serum or urine (investigator’s discretion under local regulations) β-hCG 
pregnancy test (sensitivity of at least 25 mIU/mL) must be performed within 72 hours prior to 
study treatment administration on Day 1 of each treatment cycle and verified negative.
No crossover between any of the treatment options, including the CCR treatment options, will be 
permitted during the course of study treatment. Any AML therapy other than the study-
prescribed treatment is prohibited during the course of study treatment.
Subjects will be monitored for hematologic toxicity and non-hematologic toxicity with the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.03) used as a guide for the grading of severity.  Dosing interruptions or 
delays, or dose modifications may occur for managing toxicities and/or augmenting treatment 
response during study treatment.
Overdose, as defined for this protocol, refers to AG-221, azacitidine and cytarabine dosing only.
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of AG-221, azacitidine and cytarabine assigned to a given subject, regardless of any 
associated adverse events or sequelae.
PO:
any amount over the protocol-specified dose
IV:
10% over the protocol-specified dose 
SC:
10% 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 eCRF.  See Section 10 for the 
reporting of AEs associated with overdose.
Subjects can continue to receive study treatment provided that they benefit from study treatment 
and all protocol-specified criteria for continuing study treatment are met.  Study treatment will
be discontinued if the investigator has alternative therapies (eg, HSCT) and/or considers study 
treatment to be no longer beneficial to the subject, or the rapidity of change of disease state 
renders it unacceptable for further study treatment in the judgment of the investigator.  
Refer to Section 11.1 for events that are considered sufficient reasons for discontinuing a subject 
from study treatment.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
60
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.2.1.
AG-221 Treatment
Subjects randomized to the AG-221 treatment arm will receive continuous 28-day cycles of 
AG-221 100 mg PO QD for 28 days.  In addition, subjects may receive BSC per standard 
institutional practice and as deemed necessary by the investigator.  In order to optimally benefit 
from the AG-221 treatment, the investigator should aim to treat subjects for at least 6 cycles or as 
long as subjects continue to benefit from the treatment until the End of Trial. Subjects may be 
discontinued from the treatment for any of the reasons detailed in Section 11.1.
7.2.1.1.
Dispensation and Administration of AG-221
AG-221 will be dispensed on Day 1 of each treatment cycle and a quantity of AG-221 only 
sufficient for one treatment cycle will be dispensed.  Subjects should be instructed to open the 
AG-221 packaging as close as possible to when they are going to take AG-221, inspect each 
AG-221 tablet and only take tablets that are totally intact (subjects should be instructed to return 
any tablet not totally intact to the clinic).    
Subjects should be instructed to take their daily dose at approximately the same time each day.  
Each dose should be taken with a glass of water and consumed over as short a time as possible.  
Subjects should be instructed to swallow tablets whole and to not chew the tablets.  
All efforts should be made to administer AG-221 on all of the scheduled days of each 28-day 
treatment cycle.  A dose missed earlier in a day can be made up later that day as long as it is 
taken within 6 hours after the missed dose.  If more than 6 hours have elapsed, then that dose 
should be omitted, and the subject should resume treatment with the next scheduled dose.  Any 
missed doses should not be taken beyond the last scheduled day of AG-221 administration, but 
should be returned by the subject for AG-221 accountability.
If vomiting occurs shortly after a dose of AG-221 is administrated, that dose should not be made 
up later the same day.  The subject should continue with the dosing schedule on the next day and 
inform the investigator about the vomiting event at the next visit.
7.2.1.2.
Dose Modifications for AG-221
The investigator should contact the Medical Monitor for guidance on AG-221 dose modification, 
if needed.
Dose modification due to toxicities
If a certain level of toxicity (eg, Section 7.2.1.3) is observed after initiation of AG-221 treatment
and considered as possibly or probably related to AG-221 treatment, AG-221 dosing can be 
interrupted or delayed.  Upon resolution of the toxicity, dosing may be resumed with a one-level 
dose reduction from 100 mg QD to 50 mg QD.  Any subject who is unable to tolerate 50 mg QD 
of AG-221 should be discontinued from study treatment.
If treatment is modified during the course of the study and benefit is demonstrated with a 
reduced level of dose, then that dose level should be maintained during the subsequent treatment 
cycles that are given unless toxicity develops.  However, once reduced, if there is a need for 
augmenting treatment response as defined below, the AG-221 dose may be subsequently 
re-escalated back to the starting dose (ie, 100 mg QD), provided that the starting dose is tolerable.
  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
61
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Dose escalation for augmenting treatment responses
The AG-221 dose for the subsequent treatment cycles that are given may be increased from 
100 mg QD to 200 mg QD if the following occurs:

ANC < 0.5 x 109/L after being on AG-221 for the first cycle without ≥Grade 3 AEs 
suspected by the investigator to be related to AG-221; or

no partial remission (PR) achieved after being on AG-221 for at least 2 cycles without 
≥Grade 3 AEs suspected by the investigator to be related to AG-221; or

evidence of morphologic relapse or PD
If benefit is demonstrated with an increased level of dose, then that dose level should be 
maintained during the subsequent treatment cycles that are given.  However, once increased, the 
AG-221 dose may be reduced if a certain level of toxicity (eg, Section 7.2.1.3) is observed and 
considered as possibly or probably related to AG-221 treatment.  A maximum of 3 steps of 
AG-221 dose reduction, stepwise first from 200 mg QD to 150 mg QD, second from 150 mg QD 
to 100 mg QD, and then last from 100 mg QD to 50 mg QD, are permitted in the event of 
toxicities, depending on the dose that the subject is on.  Once reduced, the AG-221 dose should 
not be re-escalated unless there is evidence of morphologic relapse or PD.  Any subject who is 
unable to tolerate 50 mg QD of AG-221 should be discontinued from study treatment.
7.2.1.3.
Reference Toxicities During AG-221 Treatment
Hematologic toxicities
Hematologic toxicities include clinically significant hematologic toxicities of cytopenia (> 50% 
decrease from baseline [defined in Section 6.2.1]) and/or marrow cellularity < 5% on Day 28 or 
later from the start of AG-221 treatment in a treatment cycle without evidence of leukemia.
Non-hematologic toxicities
Non-hematologic toxicities include all clinically significant non-hematologic toxicities of 
≥Grade 3 with the exception of ≥Grade 3 blood bilirubin increases in subjects with a UGT1A1 
mutation.  In subjects with a UGT1A1 mutation, blood bilirubin increases of > 5 × ULN may be 
considered clinically significant.
QT Prolongation
Subjects who experience prolongation of the heart rate-corrected QT interval, Fridericia’s
correction (QTcF) to > 480 msec (Grade ≥2) while treated with AG-221, should be promptly 
evaluated for causality of the QTc prolongation and managed according to the following 
guidelines:

Levels of electrolytes (potassium, calcium and magnesium) should be checked and 
supplementation given to correct any values outside the normal range.

Concomitant therapies should be reviewed and adjusted as appropriate for medication 
with known QT prolonging effects.

If no other cause is identified and the investigator believes it is appropriate, 
particularly if QTc remains elevated (after above measures have been implemented, 
or as determined by the investigator), AG-221 treatment may be interrupted, and an 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
62
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
ECG should be rechecked in approximately 1 week after the QTc prolongation was 
first observed or more frequently as clinically indicated. 
-
If QTc has recovered or improved and the investigator believes it is safe to do 
so, a re-challenge with AG-221 should be considered if held.  ECGs should be
conducted at least weekly (eg, at every scheduled visit) for 2 weeks following 
QTc reduction ≤480 msec.
-
If Grade 2 (QTcF > 480 and ≤ 500 msec), the dose of AG-221 may be reduced 
without interruption of dosing. The AG-221 dose may be re-escalated to the 
prior dose in ≥14 days after QT prolongation has decreased to ≤ Grade 1.

If this is the second occurrence of QT prolongation, administration of 
AG-221 should continue at a reduced dose (ie, the dose may not be re-
escalated).
-
If Grade 3 (QTcF > 500 msec), hospitalization for continuous cardiac 
monitoring and evaluation by a cardiologist should both be considered.  
Dosing with AG-221 will be interrupted. If QTc returns to within 30 msec of 
baseline or < 450 msec within 14 days, treatment may be resumed at a 
reduced dose.  The AG-221 dose cannot be re-escalated following dose 
reduction for Grade 3 QTcF prolongation unless the prolongation was 
associated with an electrolyte abnormality or concomitant medication.
-
If Grade 4 (QTcF > 500 msec or > 60 msec change from baseline with torsade 
de pointes or polymorphic ventricular tachycardia or signs/symptoms of 
serious arrhythmia), subjects should be admitted to the hospital for continuous 
cardiac monitoring and discharged only after review by a cardiologist.  Dosing 
with AG-221 should be permanently discontinued.
IDH Differentiation Syndrome
Subjects treated with AG-221 (enasidenib) have experienced symptoms of differentiation 
syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute 
respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or 
peripheral edema, lymphadenopathy, bone pain, and hepatic or renal dysfunction. If 
differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic 
monitoring until symptom resolution.
If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (eg, 
dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement.  Taper 
corticosteroids only after resolution of symptoms.  Symptoms of differentiation syndrome may 
recur with premature discontinuation of corticosteroid treatment.  If severe pulmonary symptoms 
requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours 
after initiation of corticosteroids, interrupt enasidenib until signs and symptoms are no longer 
severe.  Hospitalization for close observation and monitoring of patients with pulmonary and/or 
renal manifestation is recommended. Enasidenib can be resumed when signs and symptoms 
improve to Grade 2 or lower.
Further information on diagnosis and treatment of IDH differentiation syndrome can be found in 
the current version of IDH differentiation syndrome guidance documents. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
63
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Noninfectious Leukocytosis 
Subjects with hematologic malignancies treated with enasidenib may experience rapid myeloid 
cell proliferation, presenting as an increase in WBC count without evidence of infection or signs 
of IDH differentiation syndrome.
Blood counts should be assessed for noninfectious leukocytosis (defined as WBC greater than 
30 x 109/L) prior to the initiation of enasidenib and monitored at a minimum of every 2 weeks 
for at least the first 3 months during treatment.  Any abnormalities should be managed promptly. 
Treatment with hydroxyurea should be initiated, as per standard institutional practices. Interrupt 
enasidenib if leukocytosis is not improved with hydroxyurea, and then resume enasidenib at 
100 mg daily when WBC is less than 30 x 109/L. 
Tumor Lysis Syndrome
Subjects with hematologic malignancies treated with enasidenib may experience tumor lysis 
syndrome.  Manage any abnormalities promptly.  If enasidenib-related toxicity is Grade 3 or 
more, interrupt enasidenib until toxicity resolves.
Gastrointestinal Disorders
Appropriate monitoring and management of GI disorders, such as diarrhea, nausea, and 
vomiting, is required.
Elevated Serum Bilirubin
Hyperbilirubinemia is induced by enasidenib inhibition of UGT1A1, the enzyme responsible for 
the metabolism of bilirubin (a condition similar to Gilbert’s syndrome). 
Patients with Gilbert’s syndrome genotype treated with enasidenib experienced earlier onset of 
bilirubin elevation following treatment initiation, as compared to patients with normal UGT1A1 
genotype.  With continuing treatment, maximum severity of bilirubin elevation was similar in 
patients with Gilbert’s syndrome and patients with normal UGT1A1 genotype. Reference 
toxicities of hyperbilirubinemia during AG-221 treatment is described in Section 7.2.1.3, and
dose modification due to hyperbilirubinemia Section 7.2.1.2. 
7.2.1.4.
Initiation of Each AG-221 Treatment Cycle
Subjects will have laboratory assessments performed to evaluate renal, hepatic and hematologic 
function prior to starting each AG-221 treatment cycle (including Cycle 1).
In order to proceed to the next AG-221 treatment cycle, subjects should manifest recovery of 
hematologic and non-hematologic toxicities (see Section 7.2.1.3).  If the subject does not meet 
these criteria, the start of the next cycle will be delayed, BSC initiated and the subject evaluated 
regularly per standard institutional practice and as deemed necessary by the investigator.  If there 
is a delay of more than 28 days (ie, 4 weeks) in the start of the next AG-221 treatment cycle, the
Medical Monitor should be consulted for the risks and benefits of continuing AG-221 treatment.  
Subjects who experience persistent Grade ≥3 toxicity that is assessed as possibly or probably 
related to AG-221 treatment may continue AG-221 treatment if, in the opinion of the investigator 
and the Medical Monitor, the subject is experiencing clinical benefit from AG-221 treatment.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
64
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.2.2.
Azacitidine Treatment
Subjects randomized to the azacitidine treatment option will receive continuous 28-day cycles of 
azacitidine 75 mg/m2/day SC for 7 days until the End of Trial, unless they are discontinued from 
the study treatment for any of the reasons detailed in Section 11.1.  In addition, subjects may 
receive BSC per standard institutional practice and as deemed necessary by the investigator.  In 
the event 2 or fewer doses are missed (eg, skipping weekend dosing per standard institutional 
practice), dosing should continue so the subject receives the full 7 days of therapy.  If 3 or more 
days are missed, the investigator should contact the Medical Monitor and a decision on dosing 
will be made on a case-by-case basis. The dose of azacitidine should be calculated on Day 1 of 
each treatment cycle.  The dose during a treatment cycle should not be amended.
7.2.2.1.
Dose Modifications for Azacitidine
The first treatment cycle of azacitidine should always be given at 100% of the dose, ie, 75 mg/m2
SC, regardless of the subject’s laboratory values (provided that the subject is allowed to enroll in 
the study based on the inclusion and exclusion criteria).  
Subjects should be monitored for hematologic toxicity and renal toxicity; a delay in starting the 
next treatment cycle or dose reduction as described below may be necessary.  If the dose of 
azacitidine is modified during the course of the study (see below) and benefit is demonstrated at 
a dose lower than 75 mg/m2, that dose should be maintained during subsequent cycles that are 
given (unless toxicity develops).  The investigator should contact the Medical Monitor for 
guidance on azacitidine dose modification, if needed.
Azacitidine dose modifications due to nonhematological toxicity
Following receipt of any dose of azacitidine, subsequent treatment cycles may be delayed if a 
certain level of toxicity occurs after the previous dose.  Any subject who experiences a non-
hematological AE of Grade 3 or 4 that is an escalation from his or her status at baseline (defined 
in Section 6.2.1) should have azacitidine temporarily discontinued until the toxicity grade returns 
to less than Grade 3.  Azacitidine should be permanently discontinued if the non-hematological 
toxicity persists as Grade 3 or 4 for more than 21 days, despite the temporary interruption of 
azacitidine.
Dose modifications due to hematological toxicity
Treatment with azacitidine is associated with anemia, neutropenia and thrombocytopenia, 
particularly during the first 2 cycles.  Complete blood counts should be performed as specified in
Table 3 and as needed to monitor response and toxicity.
Recovery is defined as an increase of cell line(s) where hematological toxicity was observed of 
at least half of the difference of nadir and the baseline count plus the nadir count (ie, blood count 
at recovery ≥ Nadir Count + (0.5 x [Baseline count – Nadir count]).
Subjects without reduced baseline blood counts (ie, WBC ≥3.0 x 109/L, 
ANC ≥1.5 x 109/L, and platelets ≥75.0 x 109/L) prior to the first treatment
If hematological toxicity is observed following azacitidine treatment, the next cycle of 
azacitidine therapy should be delayed until the platelet count and the ANC have recovered.  If 
recovery is achieved within 14 days, no dose adjustment is necessary.  However, if recovery has 
not been achieved within 14 days, the dose should be reduced according to the following table.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
65
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Following dose modifications, the cycle duration should return to 28 days.  The reduced dose 
should be maintained during subsequent cycles that are given (unless toxicity develops).  A flow 
diagram for the determination of azacitidine dose adjustment in subjects without reduced 
baseline blood counts is provided in Appendix L.
Nadir Counts
% Dose in the next course if 
recoverya is not achieved in next 14 
days
Absolute Neutrophil Count (x109/L) 
≤ 1.0
> 1.0
Platelets (x109/L) 
≤ 50.0
> 50.0
50%
100%
a Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])
Subjects with reduced baseline blood counts (ie, WBC count < 3.0 x 109/L or 
ANC < 1.5 x 109/L or platelets < 75.0 x 109/L) prior to the first treatment
Following azacitidine treatment, if the decrease in WBC or ANC or platelets from that prior to 
treatment is less than 50%, or greater than 50% but with an improvement in any cell line 
differentiation, the next cycle should not be delayed and no dose adjustment made.
If the decrease in WBC or ANC or platelets is greater than 50% from that prior to treatment, with 
no improvement in cell line differentiation, the next cycle of azacitidine therapy should be 
delayed until the platelet count and the ANC have recovered. If recovery is achieved within 
14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 
14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is > 50%, 
no dose adjustments should be made. If bone marrow cellularity is ≤ 50%, treatment should be 
delayed and the dose reduced according to the following table:
Bone Marrow Cellularity
% Dose in the next course if recoverya
is not achieved in next 14 days
Recovery ≤ 21 days
Recovery > 21 days
15 – 50%
< 15%
100%
100%
50%
33%
a Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])
Following dose modifications, the cycle duration should return to 28 days.  The reduced dose 
should be maintained during subsequent cycles that are given (unless toxicity develops).  A flow 
diagram for the determination of azacitidine dose adjustment in subjects with reduced baseline 
blood counts is provided in Appendix M.
Renal dysfunction during azacitidine therapy
In previous studies, renal abnormalities ranging from elevated serum creatinine to renal failure 
and death were reported rarely in subjects treated with intravenous azacitidine in combination 
with other chemotherapeutic agents.  In addition, renal tubular acidosis, defined as a fall in serum 
bicarbonate to < 20 mmol/L in association with an alkaline urine and hypokalemia (serum 
potassium < 3 mmol/L) developed in 5 subjects with CML treated with azacitidine and 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
66
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
etoposide.  If unexplained reductions in serum bicarbonate (< 20 mmol/L) occur, the dose should 
be reduced by 50% on the next course.  Similarly, if unexplained elevations in serum creatinine 
or BUN to ≥ 2-fold above baseline values and above upper limit normal occur, the next cycle 
should be delayed until values return to normal or baseline and the dose should be reduced by 
50% on the next treatment cycle.  The reduced dose should be maintained during subsequent 
cycles that are given (unless toxicity develops).
Necrotizing fasciitis during azacitidine therapy
Necrotizing fasciitis, including fatal cases, have been reported in subjects treated with 
intravenous azacitidine. Azacitidine therapy should be discontinued in subjects who develop 
necrotizing fasciitis, and appropriate treatment should be promptly initiated.
7.2.3.
Low-dose Cytarabine Treatment
Subjects randomized to the LDAC treatment option will receive continuous 28-day cycles of 
cytarabine 20 mg SC BID for 10 days until the End of Trial, unless they are discontinued from 
the study treatment for any of the reasons detailed in Section 11.1.  In addition, subjects may 
receive BSC per standard institutional practice and as deemed necessary by the investigator.  
Before subjects commence each treatment cycle with LDAC, they should manifest adequate 
platelet and neutrophil recovery (ie, platelets and neutrophils should return approximately to 
baseline levels).  Individual patients differ considerably regarding their ability to regenerate bone 
marrow cellularity after chemotherapy.  In case of myelotoxicity with unacceptable cytopenia 
and poor regeneration 2 weeks after the last dose of LDAC, the start of the next treatment cycle 
can be delayed up to 2 weeks.  In the event of prolonged (ie, more than 2 weeks) and severe
(ie, Grade 4) neutropenia or thrombocytopenia, complicated by a Grade 4 infection or clinically 
significant bleeding, the duration of LDAC treatment can be reduced to 7 days, per investigators’ 
discretion.  The investigator should contact the Medical Monitor for guidance on LDAC dose 
modification, if needed.
7.2.4.
Intermediate-dose Cytarabine Treatment
Subjects randomized to IDAC treatment option will receive 28-day cycles of cytarabine 0.5 to 
1.5 g/m2/day IV for 3 to 6 days, per standard institutional practice, unless they are discontinued 
from the study treatment for any of the reasons detailed in Section 11.1.  In addition, subjects 
may receive BSC per standard institutional practice and as deemed necessary by the investigator.  
Subjects may only receive BSC if IDAC therapy concludes per standard institutional practice.  
(Note: any local standard regimen different from the above specification will need review and 
approval by the Medical Monitor.)
The dose of cytarabine should be calculated on Day 1 of each treatment cycle.  Before subjects 
commence each treatment cycle with IDAC, they should manifest adequate platelet and 
neutrophil recovery as well as recovery of non-hematologic toxicities, per standard institutional 
practice.  Treatment modification of IDAC due to toxicity should be performed according to 
Cytarabine UK SmPC or per standard institutional practice. The investigator should contact the 
Medical Monitor for guidance on IDAC modification, if needed.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
67
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
7.2.5.
Best Supportive Care Only Treatment
Subjects randomized to the BSC only treatment option will receive continuous 28-day cycles of 
BSC per standard institutional practice and as deemed necessary by the investigator until the End 
of Trial, unless they are discontinued from the study treatment for any of the reasons detailed in 
Section 11.1.  Refer to Section 8 for details about BSC.  
7.3.
Method of Treatment Assignment
Following review of eligibility, subjects will be assigned by the investigator to one of the CCR 
treatment options based on the investigator’s assessment.  Thus the investigator should evaluate 
prior to randomization whether a subject has any potential contraindications to any of the CCR
treatment options based on the azacitidine IB and cytarabine UK SmPC, and which CCR 
treatment option would be the most suitable for the subject.  If, in the investigator’s opinion, the 
subject is contraindicated to receive AG-221 treatment, the subject is not to be randomized.  
Following the selection of a CCR treatment option, subjects will be randomized centrally in a 1:1 
ratio to receive either the AG-221 treatment or the CCR treatment option pre-selected by the 
investigator.  Randomization will be stratified by prior intensive therapy for AML (yes versus 
no), primary refractory (yes versus no), and prior allogeneic HSCT for AML (yes versus no).
No crossover between any of the treatment options, including the CCR treatment options, will be 
permitted during the course of study treatment.
7.4.
Packaging and Labeling
This is an open-label study.  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 
The investigator(s) or designee(s) is responsible for taking an inventory of each shipment of IP
received, and comparing it with the accompanying IP accountability form.  The investigator(s) or 
designee(s) will verify the accuracy of the information on the form, sign and date it, retain a copy 
in the study file, and return a copy to Celgene.  
At the study site, all IPs will be stored according to the storage conditions described on the IP 
packaging label in a locked, safe area to prevent unauthorized access.  The IP must be stored at 
controlled temperature and a temperature log must be maintained in the source documents.
Investigational product (and comparator product in countries where comparator is designated as 
NIP) accountability is the responsibility of the investigator and designee.  Applicable 
information such as lot number, tablet or vial count, and expiration date should be collected, as 
well as information provided by the subject or the caregiver (eg, subject dosing diary).  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
68
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
The investigator(s) or designee(s) is responsible for accounting for all IPs received at the site and 
issued to and returned by the subject during the course of the study according to applicable 
regulatory requirements.  
Investigational product (and comparator product in countries where comparator is designated as 
NIP) issued to and returned by the subject will be assessed before drug dispensing for each 
subsequent treatment cycle and at EOT.  This should occur as soon as possible after subjects 
have completed all scheduled doses of study treatment.
Any unused IP must be returned by a study subject and retained by the investigative site for 
accountability to be conducted by a Celgene representative (or designee).  If any IP is lost or 
damaged, its disposition should be documented.  At the periodic monitoring visits, a Celgene 
representative (or designee) will conduct IP (and comparator product in countries where 
comparator is designated as NIP) accountability and address any discrepancies.  Upon 
satisfactory reconciliation of all IPs (and comparator product in countries where comparator is 
designated as NIP), the Celgene representative (or designee) will authorize for the product to be 
either returned or destroyed at the site.  At the conclusion of the study a final reconciliation will 
be conducted and all remaining IP will be counted, and reconciled with dispensing records, 
destruction records, returns and other documents.  The Celgene representative (or designee) will 
ensure that a final drug accountability to the unit dose level (ie, tablet or vial) is conducted.  
Documentation of this accountability and any discrepancies will be prepared and placed in both 
the investigator study file and the central clinical study file.
Celgene (or designee) will review with the investigator and relevant site personnel the process 
for IP (and comparator product in countries where comparator is designated as NIP) return, 
disposal, and/or destruction including responsibilities for the site versus Celgene (or designee).  
If IP is to be destroyed via the site’s process, a copy of the site’s standard operating procedure 
(SOP) for drug destruction will be collected by the Sponsor (or designee).  Any site without a 
Sponsor (or designee) approved destruction SOP and process will be required to return IP (and 
comparator product in countries where comparator is designated as NIP) to Celgene.  Any 
revisions to a site’s destruction process must be provided and approved by the Sponsor (or 
designee) prior to implementation on this protocol.
7.6.
Investigational Product Compliance
Study treatment on scheduled clinic visit days will be administered in the clinic by study site 
personnel after all pre-dose assessments (Section 6.2) have been completed.  

Subjects will self-administer all other AG-221 doses in the Treatment Phase.  
Documentation of AG-221 dosing during treatment may be recorded in a study 
specific diary card.  AG-221 administration diary cards may be provided by the 
Sponsor to study site personnel, who will in turn distribute them to study subjects 
randomized to receive AG-221 treatment.  If study specific diary cards are utilized, 
study site personnel will enter the scheduled daily doses, the number of tablets to be 
taken each day and any other applicable information, and will review the dosing 
information with the subject (or legally authorized representative).  If study specific 
diary cards are utilized, subjects (or legally authorized representative) will be asked to 
record AG-221 dosing information and to bring the diary card and unused tablets in 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
69
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
the bottle (or the bottle if it is empty) with them to all clinic visits.  A diary card and 
tablet compliance check will be performed by study personnel if study specific diary 
cards are utilized.  Diary cards, if utilized, must be saved and kept with the source 
documentation.  Study site personnel will perform an AG-221 administration 
compliance check and record this information in the subject’s source documentation 
and on the appropriate eCRF page.

Administration of all other doses of azacitidine, LDAC, IDAC or BSC in the 
Treatment Phase is per standard institutional practice.    
Accurate recording of study treatment administration (including preparation, dosing and any 
changes in dosage administration such as interruption or reduction in dosing due to an AE) will 
be made in the appropriate section of the subject’s eCRF and source documents.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
70
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
8.
CONCOMITANT MEDICATIONS AND PROCEDURES
All prior and concomitant medications (prescription and non-prescription) taken and treatment 
procedures received from the 4-week period (ie, 28 days) prior to starting study treatment up to 
28 days after the last study treatment must be recorded on the appropriate eCRF page(s).  
Particularly, all prior anti-cancer treatments should be recorded regardless of discontinuation 
date of treatment.
For information regarding other drugs that may interact with study treatment and affect its 
metabolism, 
 or excretion, see the respective IBs and/or Cytarabine UK SmPC.
8.1.
Permitted Concomitant Medications and Procedures
Supportive care may be used per standard institutional practice and as deemed necessary by the 
investigator.  Supportive care includes prophylactic antibiotics, antifungal and/or antiviral 
agents, analgesics, antiemetics, antipyretics, RBC transfusions (packed RBC or whole blood), 
single donor or pooled donor platelet transfusions and nutritional support.  
The use of erythropoiesis stimulating agents (ESAs) is permitted according to the American 
Society of Clinical Oncology Guidelines (Rizzo, 2010).  
The use of myeloid growth factors (granulocyte-colony stimulating factor [G-CSF] and 
granulocyte-macrophage colony-stimulating factor [GM-CSF]) may be given to support subjects 
who have developed Grade 4 neutropenia or Grade 3 neutropenia with fever and/or infection. 
Treatment with hydroxyurea is allowed after the start of study treatment for the control of 
leukocytosis and/or if subjects experience IDH Differentiation Syndrome (Section 7.2.1.3) 
during the course of study treatment.  However, hydroxyurea should not be given within the 
72 hours prior to and after azacitidine administration.  
Steroids are allowed for the treatment of IDH Differentiation Syndrome, if warranted, as 
standard of care. The use of chronic low-dose steroids to treat an underlying medical condition 
that is not a malignancy is permitted during the course of study treatment.
It is recommended that an antiemetic medication such as a serotonin 5-HT3 receptor antagonist 
(eg, ondansetron) be taken 30 minutes prior to azacitidine administration during Cycle 1. If 
nausea/vomiting is not significant, further antiemetic prophylaxis may not be needed.  
Pretreatment or posttreatment with a serotonin 5-HT3 receptor antagonists, or other locally 
available and appropriate antiemetic medication, will be considered concomitant treatment and 
should be recorded on the appropriate subject’s eCRF.  Treatment with antidiarrheal medications 
is recommended at the first sign of diarrhea. Premedication with antidiarrheal medication for 
subsequent doses of azacitidine may be appropriate. Pretreatment and posttreatment with 
antidiarrheal medication will be considered concomitant treatment and should be recorded on the 
appropriate subject’s eCRF.
8.2.
Prohibited Concomitant Medications and Procedures
Systemic anti-cancer therapy (excluding hydroxyurea) is not permitted during the course of study 
treatment.  Hydroxyurea is allowed after the start of study treatment for the control of 
leukocytosis and/or if subjects experience IDH Differentiation Syndrome during the course of 
study treatment.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
71
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
If AML therapy other than the study-prescribed treatment is required for treatment of the 
subject’s AML disease, the subject should be discontinued from study treatment.  
The following therapies are not permitted during the course of azacitidine treatment:

Oral retinoids (topical retinoids are permitted)
The following therapies are not permitted during the course of AG-221 treatment:

Corticosteroids, with the exception of topical cutaneous, ophthalmic, nasal, and 
inhalational steroids.  Note that short course steroid therapy will be permitted to treat 
co-morbidities such as IDH Differentiation Syndrome.  The use of a stable dose of 
oral steroids post HSCT and/or topical steroids for ongoing skin GVHD is permitted.

The following medications that are known to prolong QT interval: amiodarone, 
arsenic trioxide, astemizole, azithromycin, bepridil, chloroquine, chlorpromazine, 
cisapride, citalopram, clarithromycin, disopyramide, dofetilide, domperidone, 
droperidol, erythromycin, escitalopram, flecainide, halofantrine, haloperidol, 
ibutilide, levomethadyl, mesoridazine, methadone, moxifloxacin, pentamidine, 
pimozide, probucol, procainamide, quinidine, sevoflurane, sotalol, sparfloxacin, 
terfenadine, thioridazine, or vandetanib

Sensitive CYP substrate medications that have a narrow therapeutic range: paclitaxel 
and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19), 
thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2)

The BCRP transporter-sensitive substrate rosuvastatin
The following therapies are not permitted during the course of cytarabine treatment:

5-Flurocytosine (the antifungal efficacy of 5-Fluorocytosine has been shown to be 
abolished during cytarabine therapy)

Live or live-attenuated vaccines (Administration of these vaccines may result in 
serious or fatal infections. Killed or inactivated vaccines may be administered; 
however, the response to such vaccines may be diminished.)
8.3.
Restricted Concomitant Medications and Procedures
The following therapies are restricted during the course of AG-221 treatment:

Coadministration of CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP3A4, 
and CYP1A2 substrates other than those listed in Section 8.2 should be used only if 
medically necessary (refer to Appendix N for a list of CYP substrates)

Coadministration of P-gp or BCRP substrates, OAT, OATP1B and OCT2 substrates 
other than those listed in Section 8.2 should be used only if medically necessary (refer 
to Appendix O for a list of transporter substrates)

Given the solubility profile of AG-221, the exposure can be much lower for subjects 
with elevated gastric pH. Thus antacids, H2 blockers, or proton pump inhibitors
should be used only if medically necessary and with at least 4 hours of elapsed time
after AG-221 administration.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
72
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

As an inhibitor of UGT1A1, AG-221 may slow down the metabolism of drugs that 
are substrates for UGT1A1, such as irinotecan, ezetimibe, raloxifene, and raltegravir.  
If this applies, especially in subjects who develop hyperbilirubinemia, it might be 
necessary to lower the doses for UGT1A1 substrates or switch to alternate therapies, 
or otherwise monitor for AEs associated with the respective products.
8.4.
Required Concomitant Medications and Procedures
Not applicable.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
73
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
9.
STATISTICAL CONSIDERATIONS
The sections below provide an overview of the proposed statistical considerations and analyses.  
The final statistical analysis methods will be documented in detail in the statistical analysis plan
(SAP).
9.1.
Overview
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the 
efficacy and safety of AG-221 versus CCRs in subjects 60 years or older with AML refractory to 
or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation.
All data will be summarized by treatment group.  In addition, where appropriate, a total column 
will be included to summarize subjects across treatment groups.  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 group unless 
otherwise specified.  In general, missing data will not be imputed unless otherwise specified.
All statistical analyses specified in this protocol will be conducted using SAS® Version 9.2 or 
higher unless otherwise specified.
9.2.
Study Population Definitions
9.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population includes all subjects who are randomized to treatment, 
regardless of whether they received treatment or not.
9.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all subjects who have met all eligibility 
criteria and experienced no major protocol deviations during the study, received at least one dose 
of study treatment and had at least one treatment response assessment performed.  This definition 
will be further clarified and detailed in the final SAP prior to database lock.
9.2.3.
Safety Population
The safety population includes all randomized subjects who received at least 1 dose of study 
treatment.  Because BSC only treatment may consist of blood products or antibiotics, etc,
administered only as needed, subjects who are randomized to the BSC only treatment option will 
be included in the safety population if they have had at least 1 post-randomization assessment.  
The safety population will be used for all safety analyses.  Subjects will be analyzed according to 
the treatment actually received.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
74
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
9.3.
Sample Size and Power Considerations
The equality of overall survival curves will be compared between the AG-221 and CCR 
treatment arms using a stratified log-rank test. Subjects will be randomized to receive AG-221 
treatment or a CCR treatment option pre-selected by the investigator in a 1:1 ratio.  Assuming a 
median OS of 5.6 months in the CCR treatment arm (Roboz, 2014), a median OS of 8 months in 
the AG-221 treatment arm (42.9% improvement), and a drop-out rate of approximately 9%, this 
design requires 250 deaths and 316 subjects (158 per treatment arm) to be randomized in order to 
achieve 80% power to detect a constant hazard ratio (HR) of 0.7 and demonstrate a statistically 
significant difference in OS at a Type I error rate of 0.05 (two-sided).  It is assumed that the OS 
distribution is exponential with a constant failure rate and that accrual rate is 3 subjects per 
month for the first 12 months and 9 subjects per month afterwards. The interim analysis for 
superiority will be conducted at 65% information (ie, 163 deaths) based on Lan-DeMets version 
of the O’Brien-Fleming alpha spending function.
9.4.
Background and Demographic Characteristics
Demographic and baseline disease characteristics will be summarized by treatment group for the 
ITT, mITT and safety populations.  Subjects’ age, height, weight, and continuous baseline 
characteristics will be summarized using descriptive statistics (N, mean, SDev, median, 
minimum, maximum), while age group, 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, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percent for both treatment 
and follow-up phases.  A summary of subjects enrolled by site and by country will be provided. 
Protocol deviations/violations will be summarized using frequency tabulations.  Supportive 
corresponding subject listings will also be provided.
9.6.
Efficacy Analysis
All efficacy analyses will be performed on the ITT population.  Key secondary efficacy analysis 
will be performed on the mITT population as supportive evidence and to assess the robustness of 
the efficacy findings.  Subjects will be analyzed according to randomized treatment group. Refer 
to Section 2 for the primary and secondary efficacy endpoints, respectively.
In order to perform hypothesis testing on multiple endpoints while controlling the overall Type I 
error rate, a closed, sequential testing approach is proposed with the endpoints to be tested in a 
pre-specified order.  The primary efficacy endpoint of OS will be tested first at a two-sided 
significance level of 0.05.  If superiority of AG-221 is demonstrated in OS, then each of the key 
secondary endpoints of overall response rate (ORR) and event-free survival (EFS), in the pre-
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
75
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
specified priority order will be tested, each at a two-sided 0.05 significance level once the 
superiority of the previous endpoint is established.
9.6.1.
Primary Efficacy Analysis
The primary efficacy endpoint of OS is defined as the time between randomization and death 
from any cause.  All subjects will be followed until drop-out, death or End of Trial.  Drop-out 
may be due to withdrawal of consent from further data collection or loss to follow-up.  Subjects 
who drop-out or are alive at End of Trial will have their OS times censored at the time of last 
contact, as appropriate.
The analysis of the primary endpoint will use the stratified log-rank test in the ITT population. 
This test will provide the pivotal p-value summarizing the comparison of the two OS curves of 
AG-221 and CCRs.  Subjects will be analyzed as they were randomized, regardless of the actual 
treatment received. The stratification used for the log-rank test will be the same stratification 
used for randomization. The corresponding stratified Cox proportional hazards regression model 
with treatment as the only term will be used to estimate the hazard ratio and a 95% confidence 
interval.
The assumption of proportional hazards will be tested by a time-dependent Cox model with the 
interaction of treatment and time. A significant interaction indicates that the proportional hazard 
assumption is violated. Under such circumstance, restricted mean survival time and piecewise 
Cox regression will be adopted to estimate treatment effect. Generalized Wilcoxon test will be 
utilized as a sensitivity analysis when treatment difference occurs early rather than late during 
the Follow-up period.
In order to assess the impact of subsequent enasidenib treatment in the CCR arm, sensitivity 
analyses of OS will be conducted following ICH E9 (R1) addendum, in which strategies to 
address intercurrent events are described. To be specific, Hypothetical Strategy, eg, regression-
based imputation method (Luo, 2016) and Rank Preserve Structure Failure Time model 
(Robins, 1991), Principal Stratum Strategy, eg, Inverse Probability of Censoring Weighted 
method (Robins, 2000), and While on Treatment Strategy to censor subjects at the time of 
crossover will be adopted to provide supporting evidence when appropriate. In addition, to assess 
the impact of subsequent transplantation, a sensitivity analysis of OS will be conducted in which 
subjects who have subsequent transplantation will be censored at the time of transplantation after 
study treatments.
9.6.2.
Secondary Efficacy Analyses
The time-to-event secondary efficacy variables will be analyzed similarly to the primary efficacy 
variable with or without stratification when appropriate.  Kaplan-Meier (KM) methods will be 
used to estimate time-to-event curves, unless otherwise specified.  Counts and percentages will 
be used to describe categorical secondary variables.
9.6.2.1.
Key Secondary Efficacy Analyses
The key secondary efficacy endpoints include ORR and EFS assessed by a blinded IRAC 
according to modified IWG AML response criteria (Appendix F).  Overall response rate will be 
compared by Cochran-Mantel-Haenszel test.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
76
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Overall response rate is defined as the rate of morphologic leukemia-free state (MLFS) + CR + 
CRi + CRp + PR according to modified IWG AML response criteria (Appendix F).
Event-free survival is defined as the interval from the date of randomization to the date of 
documented morphologic relapse after CR/CRi/CRp, PD or death from any cause, whichever 
occurs first.  Subjects who are alive without any of these events will be censored at the date of 
their last response assessment.
9.6.2.2.
Additional Secondary Efficacy Analyses
The other secondary endpoints include duration of response, time to response, rates of overall 
remission, CR and HI assessed by an IRAC according to modified IWG AML response criteria
(Appendix F) and IWG MDS HI criteria (Appendix H), treatment mortality at 30 and 60 days, 
one-year survival, rate of HSCT and time to treatment failure.  The definitions of these additional
secondary efficacy endpoints are listed below and in Section 2.
Duration of response is defined as time from first documented MLFS/CR/CRi/CRp/ PR to
documented morphologic relapse after CR/CRi/CRp/ PD or death due to any cause, whichever 
occurs first.  Subjects without morphologic relapse, PD or death due to any cause will be 
censored at the date of the last response assessment.
Time to response is defined as time from randomization to first documented MLFS/CR/CRi/CRp/
/PR.  Subjects without a MLFS/CR/CRi/CRp/ PR will be censored at the date of the last response 
assessment.
Treatment mortality at 30 and 60 days is defined as rate of death from any cause within 30 or 
60 days of initiation of study treatment.
One-year survival is defined as the probability of survival at 1 year from randomization.
Overall remission rate is defined as rate of CR + CRi + CRp according to modified IWG AML 
response criteria (Appendix F).
Complete remission rate is defined as rate of CR according to modified IWG AML response 
criteria (Appendix F).
Hematologic improvement rate is defined as rate of neutrophil response (hematologic 
improvement neutrophil response [HI-N]) + platelet response (hematologic improvement platelet 
response [HI-P]) + erythroid response (hematologic improvement erythroid response [HI-E]) 
according to IWG MDS HI criteria (Appendix H).
Rate of HSCT is defined as rate of bridge-to-HSCT through study treatment.
Time to treatment failure is defined as time from randomization to discontinuation of study 
treatment due to any cause.
The rate of CR/CR with partial hematologic recovery (CRh; Appendix F) and duration of 
CR/CRh will be analyzed using the statistical methods mentioned above or other statistical 
methods as appropriate.  Note: CRh is not available for the investigator’s assessment and will be 
assessed by the Sponsor only and based on laboratory dataset.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
77
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
9.7.
Safety Analysis
All safety analyses will be performed on the safety population.
Adverse events will be summarized by the Medical Dictionary for Regulatory Activities
(MedDRA) system organ class and preferred term.  Treatment-emergent AEs leading to death, 
TEAEs leading to discontinuation from treatment, CTCAE Grade 3 or Grade 4 TEAEs, TEAEs 
any CTCAE grade, TEAEs related to study treatment and serious TEAEs will be summarized 
separately. 
Clinical laboratory results will be listed and summarized descriptively by treatment group, which 
will also include a display of change from baseline.  Laboratory values outside of the normal 
ranges will be identified.  Clinically significant hematologic and nonhematologic laboratory 
abnormalities that meet Grade 3 or Grade 4 criteria according to the CTCAE will be listed and 
summarized.  Graphical display of select laboratory parameters over the course of the study will 
be provided where useful to assist in the interpretation of results.
Vital sign measurements will be listed for each subject at each visit collected.  Descriptive 
statistics for vital signs, both observed values and changes from baseline, will be summarized by 
treatment group.
Electrocardiograms will be analyzed for QTc intervals, QTc > 480 and > 500, increase > 30 and 
> 60 msec.
9.8.
Interim Analysis
The interim analysis for superiority will be performed when approximately 65% of the expected 
number of deaths (ie, 163 deaths) have been reported.  The interim efficacy analysis will be 
performed by an independent third party and the results will be kept strictly confidential in order 
to maintain the integrity of the study.  The interim results will be provided to the DMC who will
review and give advice to the Sponsor regarding the study conduct. The analysis results will not 
be disseminated among investigators and those directly involved with the study conduct.
The Type I error rate will be controlled at the overall one-sided 0.025 level by using an O’Brien-
Fleming monitoring boundary with a Lan-DeMets alpha spending function. The decision rules 
are as follows: 

65% of expected events
Stop for superiority if one-sided p-value ≤0.0055 (HR ≤0.6715)

100% of expected events 
Claim success if one-sided p-value ≤0.0233 (HR ≤0.7775)
The actual levels used will depend on the actual number of events observed at the interim and the 
final analyses.  Based on the study assumptions, the superiority interim is projected to occur 
approximately 37 months after the first subject is randomized and 256 subjects have been 
accrued.
At the time of the interim analysis, the overall death rate will be evaluated relative to the study 
assumptions and enrollment into the study may be increased to ensure that the required number 
of 250 deaths can be reached in a reasonable time period.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
78
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
9.9.
Other Topics
9.9.1.
Data Monitoring Committee
An external DMC will be convened that will include medical hematologists/oncologists with 
experience in treating subjects with AML and a statistician, all of whom are not otherwise 
involved in the study conduct. During the course of the study, the DMC will review the safety 
data regularly as well as safety and efficacy data in accordance with the guidelines for the 
preplanned interim analysis.  An independent third party will prepare the reports of aggregate 
data summaries and individual subject data listings, as appropriate, to the DMC members for 
each scheduled meeting. Operational details for the DMC will be detailed in the DMC charter.
9.9.2.
Steering Committee
The conduct of this trial will be overseen by a steering committee, presided over by the 
coordinating Principal Investigator and if possible the representative Regional Investigators from 
countries participating in this study.  The steering committee will serve in an advisory capacity to 
the Sponsor.  Operational details for the steering committee will be detailed in a separate steering 
committee charter.  
Note: The steering committee is separate from the DMC.
9.9.3.
Health-Related Quality-of-Life
Two instruments, the EORTC QLQ-C30 and EuroQoL Group EQ-5D, will be used for HRQoL.  
Scoring for EORTC QLQ-C30 and EQ-5D, and methods to address missing values will be 
accomplished according to directions provided by the instrument developers.  Detailed analysis 
plans will be described in the subject-reported outcome statistical plan.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
79
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
80
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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 eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
Abuse, withdrawal, sensitivity or toxicity to 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 eCRF.  See Section 7.2 for the definition of overdose. Any sequela of an accidental or 
intentional overdose of study treatment should be reported as an AE on the AE eCRF. If the 
sequela of an overdose is an SAE, then the sequela must be reported on an SAE report form and 
on the AE eCRF. The overdose resulting in the SAE should be identified as the cause of the 
event on the SAE report form and eCRF but should not be reported as an SAE itself.
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary.  There is no known specific antidote for overdose of IP. 
Actual treatment should depend on the severity of the clinical situation and the judgment and 
experience of the treating physician.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or findings from 
other tests and/or procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP or until the EOT visit, whichever is longer, 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 eCRF and in the subject’s 
source documents.  All SAEs must be reported to Celgene Drug Safety within 24 hours of the 
investigator’s knowledge of the event by facsimile, or other appropriate method, using the SAE 
Report Form, or approved equivalent form.  
10.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all AEs 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);
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
81
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions);

Is a congenital anomaly/birth defect;

Constitutes an important medical event.
Important medical events are defined as those occurrences that may not be immediately life-
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

a standard procedure for protocol therapy administration.  However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

the administration of blood or platelet transfusion as routine treatment of studied 
indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE.

a procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy, 
sampling for laboratory tests, bone marrow sampling).  However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
SAE.

hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

a procedure that is planned (ie, planned prior to start of treatment on study); must be 
documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

an elective treatment of or an elective procedure for a pre-existing condition, 
unrelated to the studied indication, that has not worsened from baseline. 

emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
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.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
82
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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 4.03);
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.
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 AE 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 AE.  ‘Reasonable possibility’ means there is 
evidence to suggest a causal relationship between the IP and the 
AE.
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.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
83
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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 study treatment 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.
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a SAE.
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  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.  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
84
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
10.4.1.
Females of Childbearing Potential
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, or within 4 months of the subject’s last dose of IP (6 months following the last dose of 
cytarabine), 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 female subject should be referred to an obstetrician-gynecologist, preferably one 
experienced in reproductive toxicity for further evaluation and counseling.
The investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the investigator 
should report the abnormal outcome as an AE.  If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety by facsimile, or other appropriate 
method, within 24 hours of the investigator’s knowledge of the event using the SAE Report 
Form, or approved equivalent form.
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs.  In addition, any infant death after 28 days that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety by 
facsimile, or other appropriate method, within 24 hours of the investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form.
10.4.2.
Male Subjects
If a female partner of a male subject taking IP becomes pregnant while the male subject is on IP, 
or within 4 months of the male subject’s last dose of IP (6 months following the last dose of 
cytarabine; 6 months following the last dose of azacitidine in Canada), the male subject taking IP
should notify the investigator, and the pregnant female partner should be advised to call their 
healthcare provider immediately.  Where applicable, the IP may need to be discontinued in the 
male subject, but may be resumed later at the discretion of the investigator and the Medical 
Monitor.
10.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method (eg, via email), using the SAE Report Form, or approved equivalent 
form.  This instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study
(from the time the subject signs informed consent until 28 days after the last study treatment or 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
85
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
until the EOT visit, whichever is longer) or any SAE made known to the investigator at anytime 
thereafter that are suspected of being related to IP.  Serious AEs occurring prior to treatment 
(after signing the ICF) will be captured.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data should be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety.  
Where required by local legislation, the investigator is responsible for informing the Institutional 
Review Board/Ethics Committee (IRB/EC) of the SAE and providing them with all relevant 
initial and follow-up information about the event. The investigator must keep copies of all SAE 
information on file including correspondence with Celgene and the IRB/EC.
10.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
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 AG-221 or azacitidine based on AG-221 (enasidenib) IB or 
Azacitidine IB, respectively.
In the US, all suspected unexpected serious adverse reactions (SUSARs) will be reported in an 
expedited manner in accordance with 21 CFR 312.32.
For countries within the European Economic Area (EEA), Celgene or its authorized 
representative will report in an expedited manner to Regulatory Authorities and Ethics 
Committees concerned, SUSARs in accordance with Directive 2001/20/EC and the Detailed 
Guidance on collection, verification and presentation of adverse reaction reports arising from 
clinical trials on IPs for human use (ENTR/CT3) and also in accordance with country-specific 
requirements.  
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP, specifically, the Cytarabine UK
SmPC.
Events of disease progression for the disease under study (including deaths due to disease 
progression for indications that are considered to be fatal) will be assessed as AEs and will not 
be reported as expedited safety reports to regulatory authorities.
Celgene or its authorized representative shall notify the investigator of the following information
(In Japan, Celgene KK shall notify the Heads of the Institutes in addition to the investigators):

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);
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
86
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity.

In Japan, measures taken in foreign countries to ensure subject safety, study reports 
that indicate potential risk of cancer, etc, or biannual SAE report according to the 
local regulations.
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.)
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
87
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
11.
DISCONTINUATIONS
11.1.
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from study 
treatment:

Adverse event

Progressive disease (Appendix F)

Withdrawal by subject from study treatment

Death

Lost to follow-up

Allogeneic HSCT

Pregnancy

Other (to be specified on the eCRF)
Although progressive disease is considered a sufficient reason for discontinuing a subject from 
study treatment, the investigator may consider continuing study treatment until the investigator 
has alternative therapies (eg, allogeneic HSCT) and/or considers study treatment to be no longer 
beneficial to the subject, or the rapidity of change of disease state renders it unacceptable for 
further study treatment in the judgment of the investigator.
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 for progressive disease, or any other reason if not listed above, the investigator may 
contact the Medical Monitor and forward appropriate supporting documents for review and 
discussion.  The reason for discontinuation of study treatment should be recorded in the eCRF 
and in the source documents.  
Discontinued subjects will not be replaced.
11.2.
Study Discontinuation
Discontinuation from study treatment should be considered distinct from discontinuation from 
the study.  All subjects discontinued from study treatment for any reason other than withdrawal 
of consent for follow-up, death or lost to follow-up will be followed in the Follow-up Phase of 
the study (Section 6.3).  Every attempt should be made to collect all data during the Follow-up 
Phase unless subjects discontinue from the study.
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Screen failure
-
IDH2 mutation negative
-
Other
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
88
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Adverse event

Withdrawal by subject from study

Death

Lost to follow-up

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
89
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
12.
EMERGENCY PROCEDURES
12.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/contract 
research organization Medical Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
12.2.
Emergency Identification of Investigational Products
This is an open-label study; therefore, IP will be identified on the package labeling.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
90
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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.  Celgene staff or an authorized representative will evaluate and approve all 
investigators who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Celgene information. The investigator should maintain 
a list of Sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an ICF and are 
screened for entry into the study.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the 
information provided by Celgene on public registry websites) is considered Celgene confidential 
information.  Only information that is previously disclosed by Celgene on a public registry 
website may be freely disclosed by the investigator or its institution, or as outlined in the Clinical 
Trial Agreement.  Celgene protocol, amendment and IB information is not to be made publicly 
available (for example on the investigator’s or their institution’s website) without express written 
approval from Celgene.  Information proposed for posting on the investigator’s or their 
institution’s website must be submitted to Celgene for review and approval, providing at least 5 
business days for review.
At the time results of this study are made available to the public, Celgene will provide 
investigators with a summary of the results that is written for the lay person. The investigator is 
responsible for sharing these results with the subject and/or their caregiver as agreed by the 
subject.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
91
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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
Celgene affirms the subject's right to protection against invasion of privacy and to be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the investigator to obtain such permission in 
writing from the appropriate individual.
13.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
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 Celgene or its authorized 
representative after documentation on all ethical and legal requirements for starting the study has 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
92
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
been received by Celgene or its authorized representative. This documentation must also include 
a list of the members of the IRB/EC and their occupation and qualifications. If the IRB/EC will 
not disclose the names, occupations and qualifications of the committee members, it should be 
asked to issue a statement confirming that the composition of the committee is in accordance 
with GCP. For example, the IRB General Assurance Number may be accepted as a substitute for 
this list. Formal approval by the IRB/EC should mention the protocol title, number, amendment 
number (if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a Coordinating Investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or Coordinating Investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
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 AEs 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
Celgene reserves the right to terminate this study prematurely at any time for reasonable medical 
or administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities, etc).
The Sponsor may end the trial when all key endpoints and objectives of the study have been 
analyzed, and the availability of a roll-over or extension protocol exists into which any subjects
who remain on study may be consented  and continue to receive access to AG-221.  Such a 
protocol would be written for a compound that would not yet be commercially available.
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment;

GCP noncompliance;

Inaccurate or incomplete data collection;
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
93
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Falsification of records;

Failure to adhere to the study protocol.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
94
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
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 investigational product are complete, accurate, filed and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy, and 
the laboratories, as well as copies of eCRFs or CD-ROM.
14.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). This data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
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, screening log (if applicable), and enrollment log;

Record of all communications between the investigator and the IRB/EC;

Composition of the IRB/EC;

Record of all communications between the investigator, Celgene, and their authorized 
representative(s);

List of Sub-investigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures;

Copies of CRFs (if paper) and of documentation of corrections for all subjects;

IP accountability records;

Record of any body fluids or tissue samples retained;

All other source documents (subject records, hospital records, laboratory records, 
etc.); 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
95
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial).
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. The 
investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
96
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
15.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and SOPs.
15.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study.  All aspects of the study are reviewed with the investigator and the staff at a study
initiation visit and/or at an investigators’ Meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRFs, 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, eCRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRFs 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 eCRFs 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.
15.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs  to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/ECs, regulatory authorities (eg, Food and Drug Administration
[FDA], European Medicines Agency [EMA], Health Canada) and company authorized 
representatives.  The investigator should make every effort to be available for the audits and/or 
inspections.  If the investigator is contacted by any regulatory authority regarding an inspection, 
he/she should contact Celgene immediately.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
97
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
16.
PUBLICATIONS
As described in Section 13.2, all protocol- and amendment-related information, with the 
exception of the information provided by Celgene on public registry websites, is considered 
Celgene confidential information and is not to be used in any publications.  Celgene protocol-
related information proposed for use in a publication must be submitted to Celgene for review 
and approval, and should not be utilized in a publication without express written approval from 
Celgene, or as described in the Clinical Trial Agreement.  
Celgene will ensure Celgene-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results.  At a minimum, this applies to 
results from all Phase 3 clinical studies, and any other study results of significant medical 
importance.  This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results may also be presented at one or more medical congresses, and may be used for 
scientific exchange and teaching purposes.  Additionally, this study and its results may be 
submitted for inclusion in all appropriate health authority study registries, as well as publication 
on health authority study registry websites, as required by local health authority regulations.  
Eligibility for external authorship, as well as selection of first authorship, will be based on 
several considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation and/or publication development.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
98
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
17.
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European
Organization for Research and Treatment for Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85(5):365-76.
American Heart Association 1994 Revisions to Classification of Functional Capacity and 
Objective Assessment of Patients With Diseases of the Heart. American Heart Association 
website. Available at: 
http://my.americanheart.org/professional/StatementsGuidelines/ByTopic/TopicsD-H/Functional-
Capacity-and-Obj-Assessment-of-Patients-With-Diseases-of-the-
Heart_UCM_424309_Article.jsp. Accessed 05 Aug 2015.
.  
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642-9.  
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al.  
Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood 2006;108(2):419-25.
Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
Accessed 05 Aug 2015.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
99
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Food and Drug Administration Drug Development and Drug Interactions Website: Table 7.  
Examples of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow Therapeutic 
Range (7/28/2011).  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm. Accessed 05 Aug 2015.
Food and Drug Administration Drug Development and Drug Interactions Website: Table 13.  
Examples of In Vivo Substrates for Selected Transporters (7/28/2011).  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm. Accessed 05 Aug 2015.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
100
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.  International scoring 
system for evaluating prognosis in myelodysplastic syndromes [published erratum appears in 
Blood 1998;91(3):1100]. Blood 1997;89(6):2079-88.
Luo X, Li M, Wu C, Xu Q, Chen G, Dornseif BE, et al. A proposed approach for analyzing post-
study therapy effect in survival analysis. J Biopharm Stat 2016;26(4):790-800.
Managan JK, Luger SM. Salvage therapy for relapsed or refractory acute myeloid leukemia. 
Ther Adv Hematol. 2011;2(2):73-82.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. 
Am J Clin Oncol. 1982;5(6):649-55.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
101
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. American Society 
of Hematology/American Society of Clinical Oncology clinical practice guideline update on the 
use of epoetin and darbepoetin in adult patients with cancer. Blood 2010;116(20):4045-59.
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Commun Stat Theory Methods 1991;20(8):2609-31.
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in an AIDS 
clinical trial with inverse probability of censoring weighted (IPCW) long-rank tests. 
Biometrics 2000;56(3): 779-88.
Roboz GJ, Rosenblat T, Arellano M, Gobbi M, Altman JK, Montesinos P, et al. International 
randomized phase III study of elacytarabine versus investigator choice in patients with 
relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2014;32(18):1919-26.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
102
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Swerdlow, SH, Campo, E, Harris, NL, Jaffe, ES, Pileri, SA, Stein, H, et al. editors. WHO 
Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: 
IARC Press; 2008;109-39.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 
revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute 
leukemia: rationale and important changes. Blood 2009;114(5):937-51.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
103
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
18.
APPENDICES
Appendix A:  Table of Abbreviations
Table 4:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ACS
Acute coronary syndrome
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
BCRP
Breast cancer resistance protein
β-hCG
β-subunit of human chorionic gonadotropin
BID
Twice a day
BP
Blood pressure
BMA
Bone marrow aspirate
BMB
Bone marrow biopsy
BSA
Body surface area
BSC
Best supportive care
BUN
Blood urea nitrogen
CBC
Complete blood count
CCR
Conventional care regimen
CI
Confidence interval
CML
Chronic myelogenous leukemia
CNS
Central nervous system
CO2
Carbon dioxide
CR
Morphologic complete remission
CRh
Morphologic complete remission with partial hematologic recovery
CRi
Morphologic complete remission with incomplete neutrophil recovery
CRp
Morphologic complete remission with incomplete platelet recovery
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
104
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
CYP
Cytochrome
DNA
Deoxyribonucleic acid
DMC
Data Monitoring Committee
EBV
Epstein-Barr virus
EC
Ethics Committee
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EEA
European Economic Area
EFS
Event-free survival
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of treatment
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte-colony stimulating factor
GFR
Glomerular filtration rate
GGT
Gamma glutamyl transpeptidase
GI
Gastrointestinal
GM-CSF
Granulocyte macrophage colony-stimulating factor
GVHD
Graft-versus-host disease
HBV
Hepatitis B virus
HCV
Hepatitis C virus
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
105
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
HDPE
High density polyethylene
HI
Hematologic improvement
HI-E
Hematologic improvement erythroid response
HI-N
Hematologic improvement neutrophil response
HI-P
Hematologic improvement platelet response
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRQoL
Health-related Quality-of-Life
HSCT
Hematopoietic stem cell transplantation
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonisation
IDAC
Intermediate-dose cytarabine
IDH
Isocitrate dehydrogenase
IDH2
Isocitrate dehydrogenase 2
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
IRAC
Independent Response Assessment Committee
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenously
IVRS
Interactive voice response system
IWG
International Working Group
KM
Kaplan-Meier
LDAC
Low-dose cytarabine
LDL-C
Low-density lipoprotein cholesterol
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
106
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
MDS
Myelodysplastic syndromes
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified intent-to-treat
MLFS
Morphologic leukemia-free state
MPN
Myeloproliferative neoplasm
MUGA
Multi-gated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIP
Non-investigation product
NYHA
New York Heart Association
OAT
Organic anion transporter 
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
P-gp
P-glycoprotein
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
107
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PO
Orally
PR
Partial remission
PT
Prothrombin time
PTT
Partial thromboplastin time
QD
Once a day
QTc
Heart rate-corrected QT
QTcF
QTc with Fridericia’s correction
RBC
Red blood cell
SAE
Serious adverse event
SAP
Statistical analysis plan
SC
Subcutaneous
SD
Stable disease
SDev
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
UDP
Uridine diphosphate
UGT1A1
UDP-glucuronosyltransferase 1 family, polypeptide A1
UK
United Kingdom
ULN
Upper limit of normal
US
United States
WBC
White blood cell
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
108
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Table 4:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
WHO
World Health Organization
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
109
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix B:  World Health Organization Classification of Acute Myeloid 
Leukemia
Acute myeloid leukemia with recurrent genetic abnormalities
Acute myeloid leukemia with t(8;21)(q22;q22); (RUNX1-RUNX1T1)
Acute myeloid leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); 
(CBFB-MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12); (PML-RARA)
Acute myeloid leukemia with t(9;11)(p22;q23); MLLT3-MLL
Acute myeloid leukemia with t(6;9)(p23q34); DEK-NUP214
Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q26.2); RPN1-EVI1
Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
Acute myeloid leukemia with gene mutations
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasma
Acute myeloid leukemia, not otherwise categorized
Acute myeloid leukemia with minimal differentiation
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Source: Swerdlow, 2008.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
110
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix C:  Acute Myeloid Leukemia Risk Status
Risk Status
Cytogenetics
Molecular Abnormalities a
Better-risk
inv(16)b, c
t(16;16)b
t(8;21)b
t(15;17)
Normal cytogenetics:
NPM1 mutation in the absence of 
FLT3-ITD or isolated biallelic 
CEBPA mutation 
Intermediate-risk
Normal cytogenetics
+8
t(9;11)
Other non-defined
t(8;21), inv(16), t(16;16):
with c-KIT d mutation
Poor-risk
Complex (≥ 3 clonal chromosomal 
abnormalities)
Monosomal karyotype
-5, 5q-, -7, 7q-
11q23 - non t(9;11)
inv(3), t(3;3)
t(6;9)
t(9;22)e
Normal cytogenetics:
with FLT3-ITD mutation f
a The molecular abnormalities included in this table reflect those for which validated assays are available in 
standardized commercial laboratories.  Given the rapidly evolving field, risk stratification should be modified 
based on continuous evaluation of research data.  Other novel genetic mutations have been identified that may 
have prognostic significance.  
b Other cytogenetic abnormalities in addition to these finding do not alter risk status.
c Paschka P, Du J, Schlenk RF, Gaidzik VI, Bullinger L, Corbacioglu A, et al. Secondary genetic lesions in acute 
myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML study group (AMLSG). 
Blood 2013; 121:170-177.
d Emerging data indicates the presence of c-KIT mutation in subjects with t(8;21), and to a lesser extent, inv(16), 
confers a high risk of relapse.  These subjects should be considered for clinical trials, if available.
e For Philadelphia+ acute myeloid leukemia (AML) t(9;22), manage as myeloid blast crisis in chronic myeloid 
leukemia (CML), with addition of tyrosine kinase inhibitors.  These subjects are excluded from study entry.
f FLT3-ITD mutations are considered to confer a significant poor outcome in subjects with normal karyotype, and 
these subjects should be considered for clinical trials where available.  There is controversy as whether FLT3-TKD 
mutations carry equally poor prognosis
Source:  
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia. 
National Comprehensive Cancer Network website.  Available at 
http://www nccn.org/professionals/physician_gls/PDF/aml.pdf.  Accessed 05 Aug 2015.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
111
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix D:  Eastern Cooperative Oncology Group (ECOG) Performance 
Status
Eastern Cooperative Oncology Group (ECOG) Performance Status
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and about 
more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair.
5
Dead.
Source:  Oken, 1982.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
112
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix E:  New York Heart Association Classification for Congestive Heart 
Failure
Functional Capacity
Class I.  Subjects with cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.
Class II.  Subjects with cardiac disease resulting in slight limitation of physical activity.  They are 
comfortable at rest.  Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.
Class III.  Subjects with cardiac disease resulting in marked limitation of physical activity.  They are 
comfortable at rest.  Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain.
Class IV.  Subjects with cardiac disease resulting in inability to carry on any physical activity without 
discomfort.  Symptoms of heart failure or the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased.
Source: American Heart Association, 1994.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
113
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix F:  International Working Group Acute Myeloid Leukemia 
Response Criteria
Hematologic Response According to modified IWG Criteria for AML
Category
Definition
Morphologic Complete Remission (CR)
Defined as less than 5% blasts in a BM aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. There should be no blasts with 
Auer rods and absence of extramedullary disease.  Plus, all the following 
conditions should be met:

ANC ≥ 1 x 109/L (1,000/μL)

Platelet count ≥ 100 x 109/L (100,000/μL)

Independent of red cell transfusions for ≥ 1 week immediately 
before each response assessment
Morphologic Complete Remission with 
Incomplete Neutrophil Recovery (CRi) a
Defined as all criteria of CR except the following:

ANC < 1 x 109/L (1,000/μL)
Morphologic Complete Remission with 
Incomplete Platelet Recovery (CRp) a
Defined as all criteria of CR except the following:

Platelet count < 100 x 109/L (100,000/μL)
Morphologic Complete Remission with 
Partial Hematologic Recovery (CRh) a
Defined as all criteria of CR except the following:

ANC > 0.5 x 109/L (500/μL); and

Platelet count > 50 x 109/L (50,000/μL)
Morphologic Leukemia-free State 
(MLFS)
Defined as less than 5% blasts in a BM aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. There should be no blasts with 
Auer rods and absence of extramedullary disease
Partial Remission (PR)
Defined as all hematologic criteria of CR with a > 50% decrease in the 
percentage of BM blasts to 5% to 25% (a blast count value of < 5% may also 
be considered a partial remission if Auer rods are present) b
Cytogenetic Complete Remission (CRc)
Defined as CR/CRi/CRp with a reversion to a normal karyotype in cases with 
an abnormal karyotype at baseline, based on evaluating ≥ 20 metaphase BM 
cells
Morphologic Relapse after CR/CRi/CRp a
Defined as one of the following conditions:

Reappearance of ≥5% blasts in the BM not attributable to any other 
cause (eg, BM regeneration after consolidation therapy); or 

Development of extramedullary disease
Not evaluable (NE) a
Defined as without a posttreatment response assessment
Stable Disease (SD) a
Defined as failure to meet any of the above criteria and not meeting the 
criteria of progressive disease (see below)
Progressive Disease (PD) a
Defined as one of the following conditions:

For subjects with 5 to 70% BM blasts at baseline: a > 50% increase 
of BM blast count percentage from baseline to ≥ 20%; or

For subjects with > 70% BM blasts at baseline: a doubling of 
absolute blast count in peripheral blood from baseline to ≥ 10 x 
109/L (10,000/μL); or

Development of new extramedullary disease since last response 
assessment
Progressive disease is to be confirmed by 2 consecutive response assessments 
separated by at least 1 month.  The date of progressive disease is defined as 
the first date that one of three conditions listed above was met.
AML = Acute Myeloid Leukemia; ANC= Absolute Neutrophil Count; BM= Bone Marrow; IWG= International Working Group.
a Modification to IWG response criteria.  Note: CRh is not available for the investigator’s assessment and will be assessed by the 
Sponsor only and based on laboratory dataset.
b If the pre-treatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a value between
5% and 25%; if the pre-treatment blast percentage was 20% to less than 49%, they must decrease by at least half to a value of 
more than 5%.
Notes:  Deletions to the IWG response criteria are not shown.  
Source: Cheson, 2003.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
114
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix G: Definitions of Prior Line of AML Therapy
A line of AML therapy is defined as cytotoxic chemotherapy or low-intensity therapy, single 
agent or in combination, delivered with the intent to induce remission and/or prolong survival.  
If remission is not induced by the first cycle (eg, cytarabine 100-200 mg/m2 continuous infusion 
for 7 days), the second cycle is modified (eg, cytarabine 1 to 3 g/m2 every 12 hours for 3 to 
7 days) with the intent to induce remission, then the subject has received two different lines of 
AML therapy.  Treatment modifications with the intent to manage toxicity are not counted as 
separate lines.  
The line used for re-induction for first relapse is also regarded as a second line even if the same 
drugs are given at the same doses as for the first remission induction, since the disease 
characteristics have changed from diagnosis to relapse.
Post-remission strategies (regimens) such as consolidation or maintenance are not counted as 
separate lines.
Transplantation is considered as a line if given with the intent to induce remission.  However, 
transplantation as a post-remission strategy is not considered a separate line as it is regarded as 
consolidation.
Hydroxyurea is not counted as a separate line.
Note that, for subjects having AML secondary to prior higher risk (Intermediate-2 or High risk 
according to the International Prognostic Scoring System [see below]) MDS treated with a 
hypomethylating agent [eg, azacitidine or decitabine], the hypomethylating therapy can be 
counted as a line if there is disease progression to AML during or shortly (eg, within 60 days) 
after the hypomethylating therapy.
International Prognostic Scoring System for MDS
Prognostic Variable
Score Value
0
0.5
1.0
1.5
2.0
Bone Marrow Blasts (%)
< 5
5-10
-
11-20
21-30
Karyotype
a
Good
Intermediate
Poor
-
-
Cytopenias
b
0 or 1
2 or 3
-
-
-
a Good:  normal, -Y, del(5q), del(20q); Poor:  complex (3 abnormalities) or chromosome 7 anomalies; 
Intermediate:  other abnormalities.
b Defined as:  Hemoglobin < 100 g/L, absolute neutrophil count < 1.5 x 109/L, and platelet count < 100 x 109/L.
Note:  Scores for risk groups are as follows:  Low = 0; INT-1 = 0.5-1.0; INT-2 = 1.5-2.0; and High:  2.5.
Source: Greenberg, 1997.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
115
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix H:  Hematologic Improvement According to the International 
Working Group for Myelodysplastic Syndromes
Hematologic Improvement According to IWG Criteria
Hematologic improvement a
Response criteria (responses must last at least 8 week)b
Erythroid Response (HI-E) 
(pre-treatment, < 11 g/dL) 

Hemoglobin increase by ≥1.5 g/dL

Relevant Reduction in units of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8 week compared with the pretreatment 
transfusion number in the previous 8 week
Note: Only RBC transfusions given for a hemoglobin of ≤9.0 g/dL on treatment 
will count in the RBC transfusion response evaluation b
Platelet Response  (HI-P)
(pre-treatment, < 100 X 
109/L) 

Absolute increase of ≥30 X 109/L for subjects starting with > 20 X
109/L platelets 

Increase from < 20 X 109/L to > 20 X 109/L and by at least 100% b  
Neutrophil Response (HI-N)
(pre-treatment, < 1.0 X
109/L) 

At least 100% increase and an absolute increase > 0.5 X 109/Lb  
Progression or Relapse After 
HI c
At least 1 of the following:

At least 50% decrease from maximum response levels in granulocytes 
or platelets

Reduction in hemoglobin by ≥1.5 g/dL

Transfusion dependence
HI-E = hematologic improvement erythroid response; HI-N = hematologic improvement neutrophil response; HI-P = 
hematologic improvement platelet response; IWG = International Working Group; RBC = red blood cell.
a Pre-treatment counts averages of at least 2 measurements (not influenced by transfusions, ie, no RBC transfusions for 2 weeks 
and no platelet transfusions for 1 week) ≥1 week apart (modification).  
b Modification to IWG (2000) response criteria.
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet responses be 
reported overall as well as by the individual response pattern.
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter to grams per 
liter, multiply grams per deciliter by 10.  
Source:  Cheson, 2006.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
116
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix I: European Organization for Research and Treatment of Cancer 
Quality-of-Life questionnaire (Version 3.0)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
117
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix I:  European Organization for Research and Treatment of Cancer
Quality-of-Life questionnaire (Version 3.0) (Continued)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
118
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix J:  EQ-5D-5L Health Questionnaire (English Version for the UK)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
119
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix J:  EQ-5D-5L Health Questionnaire (English Version for the UK)
(Continued)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
120
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix K: Subcutaneous Preparation and Administration of Azacitidine
Recommendations for Safe Handling 
Azacitidine is a cytotoxic medicinal product and, as with other potentially toxic compounds, 
caution should be exercised when handling and preparing azacitidine suspensions. Procedures 
for proper handling and disposal of anticancer medicinal products should be applied.  If 
reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash 
with soap and water. If it comes into contact with mucous membranes, flush thoroughly with 
water.
Overview of Two Methods for Preparing Injection 
Azacitidine degrades rapidly at room temperature following reconstitution; therefore the 
azacitidine suspension should be prepared immediately before use (Method A) or should be 
refrigerated immediately after reconstitution (Method B). 
Method A:
The total time from reconstitution to administration should be no greater than 
45 minutes (60 minutes in the US):
1. Reconstitute (see next page for instructions).  Record time of reconstitution. 
2. Prior to administration to the subject, the nurse/doctor must check the time of
reconstitution.  If elapsed time is greater than 45 minutes (60 minutes in the US), the dose 
should be discarded appropriately and a new dose prepared.
3. Nurse or doctor must administer dose to subject and record time of administration. 
Method B:
If the product must be reconstituted in advance of the dose, it should be prepared as 
follows: 
1. Reconstitute.  Record time of reconstitution.
2. Place in refrigerator (2°C to 8°C [36°F to 46°F]) immediately.  Record time of placement 
in refrigerator.  If the suspension is prepared using water for injections that has not been 
refrigerated (2°C to 8°C [36°F to 46°F]), the suspension may be held under refrigerated
conditions for a maximum of 8 hours (22 hours if the suspension is prepared using 
refrigerated water for injections).
3. When ready to administer, remove from refrigerator.  Record time.  If elapsed time held 
in refrigerator is over the maximum hours as defined above, the suspension should be 
discarded appropriately and a new dose prepared. 
4. The syringe filled with reconstituted suspension should be allowed, up to 30 minutes 
prior to administration, to reach a temperature of approximately 20°C to 25°C (68°F to 
77°F).
5. Prior to administration to the subject, the nurse/doctor must check the time of removal 
from the refrigerator.  If elapsed time is more than 30 minutes, the dose should be 
discarded appropriately and a new dose prepared.
6. Nurse or doctor must administer dose to subject and record time of administration.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
121
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix K:  Subcutaneous Preparation and Administration of Azacitidine
(Continued)
Preparing the suspension for subcutaneous administration:
1. Assemble the following supplies:

Vial(s) of azacitidine; 

Vial(s) of sterile water for injection;

Nonsterile surgical gloves;

Alcohol wipes;

5 mL syringe(s) with 18-gauge needle(s); and

Additional 25-gauge needle(s) for subcutaneous injection.
2. Document the sequence number of vial(s) on the source document.
3. Wash and dry hands and put on gloves.
4. Remove the syringe from its protective wrapper by peeling back the paper label.
5. Remove the plastic cover from the sterile water vial and use an alcohol wipe to clean the 
rubber top.  Do not touch the rubber top after it is cleaned.
6. Remove the plastic cover from the azacitidine vial, shake the vial to break up the 
lyophilized cake, and use a fresh alcohol wipe to clean the rubber top.  Do not touch the 
rubber top after it is cleaned. 
7. Remove the plastic cap from the 18-gauge needle and attach to the syringe.  Never touch 
the needle.
8. Pull the plunger back to the 4 mL mark to draw air into the syringe.
9. Insert the needle through the rubber top of the sterile water vial and push the plunger all 
the way in.
10. Leave the needle/syringe in the vial and turn the vial upside down.  Make sure the needle 
tip is below the level of the liquid.  Pull the plunger back to draw 4 mL of sterile water 
into the syringe, making sure to purge any air trapped within the syringe. 
11. Pull the needle/syringe out of the vial and set the vial down.
12. Insert the needle of the syringe with sterile water through the rubber top of the azacitidine 
vial and slowly inject the 4 mL of sterile water into the vial.  Document the preparation 
and administration time interval.  The preparation time begins when the sterile water is 
added to the vial of azacitidine.  Record the exact time in the pharmacy and other 
applicable records.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
122
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix K:  Subcutaneous Preparation and Administration of Azacitidine 
(Continued)
13. Remove the syringe and needle.  The vial should be vigorously shaken until a uniform 
cloudy suspension is achieved.  The reconstituted product is a homogeneous, cloudy 
suspension, free of agglomerates.  The product should be discarded if it contains large 
particles or agglomerates.  Do not filter the suspension after reconstitution since this 
could remove the active substance.  It must be taken into account that filters are present 
in some adapters, spikes, and closed systems; therefore such systems should not be used 
for administration of the drug after reconstitution.  After reconstitution each milliliter of 
suspension will contain 25 mg of azacitidine (100 mg/4 mL).
14. Using an alcohol wipe, clean the rubber top and insert a new needle and syringe.  Turn 
the vial upside down. Make sure the needle tip is below the level of the liquid.  Pull the 
plunger back to withdraw the amount of drug required for the proper dose, making sure to 
purge any air trapped within the syringe. 
15. Pull the needle/syringe out of the vial.  Properly dispose of the needle according to local 
pharmacy standard operating procedures and other applicable guidelines.
16. Remove a fresh subcutaneous needle (recommended 25-gauge) for injection from its 
paper wrapper and firmly attach it to the syringe, being careful to not touch the tip of the 
syringe.
17. If needed (doses over 100 mg) repeat all the above steps for preparation of the 
suspension.  For doses greater than 100 mg (4 mL), the dose should be equally divided 
into 2 syringes (eg, dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe).  All 
syringes should be prepared prior to starting administration.
The contents of the dosing syringe must be re-suspended immediately prior to administration.  
The temperature of the suspension at the time of injection should be approximately 20°C to 25°C 
(68°F to 77°F).  To re-suspend, vigorously roll the syringe between the palms until a uniform, 
cloudy suspension is achieved.  The product should be discarded if it contains large particles or 
agglomerates.  Azacitidine is supplied in single-use vials that cannot be used more than once. 
After removing the dose needed, dispose of all used sterile water vials and needles appropriately. 
All partially used and empty vials should not be retained, but disposed of in accordance with 
local requirements. Each vial number and amount used per subject should be carefully 
documented in the applicable site and pharmacy records. 
Subcutaneous injection of suspension
1. Select the site(s) for injection: either of the upper arms, thigh, or abdomen.  Injection sites 
within an injection area must be different from 1 injection to the next. 
2. Rub the area with a fresh alcohol wipe in an outward circular motion.
3. Remove the plastic cap from the subcutaneous needle, being careful to not touch the 
needle. 
4. Pinch a 2-inch fold of skin at the injection site between your thumb and forefinger.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
123
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix K:  Subcutaneous Preparation and Administration of Azacitidine 
(Continued)
5. Insert the needle at a 90angle until it is completely inserted.
6. Pull back on the plunger slightly to check for blood.  If blood appears in the syringe, 
withdraw the syringe and select another site, then repeat steps 2, 4, 5, and 6.
7. If no blood appears in the syringe, push the plunger forward and inject the drug.
8. Withdraw the syringe and swab the area with alcohol.
9. If needed (doses over 100 mg) repeat all the above steps for subcutaneous injection of the 
suspension.  A new location should be selected for administration of each part of the 
dose.  Document location(s) of dose(s) administered.
10. New injections should be given at least 1 inch or 2.5 cm from an old injection site and 
never into areas where the site is tender, bruised, red, or hard.
11. The details of the dose administration should be recorded in the applicable record(s).  
When doses exceed 100 mg and/or more than 1 injection is administered, the “time of 
subcutaneous injection” should be recorded as the time of completion of the last 
injection.
12. Appropriately dispose of all needles and syringes in accordance with local requirements.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
124
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix L:  Azacitidine Dose Modifications due to Hematologic Toxicity –
Subjects without Reduced Baseline Blood Counts
Hematological toxicity 
observed in a given cycle
Delay the next cycle 
until platelet count 
and ANC have 
recovered
Subjects without reduced baseline blood counts*
Reduce dose
No dose
adjustment needed
Nadir counts
% dose to give in next cycle
ANC (x 109/L)
Platelets (x 109/L)
1
50
50%
> 1
> 50
100%
* White blood cells (WBC) ≥3.0 x 109/L and absolute neutrophil count (ANC) ≥1.5 x 109/L and platelets ≥75.0 x 109/L prior to the first treatment
** Recovery = counts nadir count + (0.5 x [Baseline count – nadir count])
Following dose adjustments, cycle duration should return to 28 days
Recovery** not achieved within 14 days
Recovery** achieved within 14 days
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
125
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix M:  Azacitidine Dose Modifications due to Hematologic Toxicity –
Subjects with Reduced Baseline Blood Counts
Delay the next cycle 
until platelet count 
and ANC have 
recovered
Subjects with reduced baseline blood counts*
Delay treatment 
and adjust dose
Determine bone
marrow cellularity
Bone marrow 
cellularity
% dose to give in next cycle
Recovery** 21 days
Recovery** > 21 days
15-50%
100%
50%
< 15%
100%
33%
* White blood cells (WBC) < 3.0 x 109/L or absolute neutrophil count (ANC) < 1.5 x 109/L or platelets < 75.0 x 109/L prior to the first treatment
**
(
)
Following dose adjustments, cycle duration should return to 28 days
Reduction in WBC/ ANC/ platelets
from that prior to treatment > 50%,
with no improvement 
in cell line differentiation
Recovery** achieved within 14 days
No dose
adjustment needed
Hematological 
toxicity observed in 
a given cycle
No dose
adjustment needed
No delay or dose
adjustment needed
Reduction in WBC/ ANC/ platelets
from that prior to treatment < 50%,
or > 50%, with improvement 
in cell line differentiation
Recovery** not achieved within 14 days
≤50%
> 50%
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
126
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix N:  Cytochrome Sensitive Substrates
From Food and Drug Administration (FDA) Drug Development and Drug Interactions Website: 
Table 7. Examples a of Sensitive In Vivo Cytochrome (CYP) Substrates and CYP Substrates with 
Narrow Therapeutic Range (7/28/2011)
CYP 
Enzymes
Sensitive substrates b
Substrates with narrow therapeutic range c
CYP1A2
Alosetron, caffeine,
Theophylline, tizanidine
duloxetine, melatonin, ramelteon,
tacrine, tizanidine
CYP2B6 d
Bupropion, efavirenz
CYP2C8
Repaglinide e
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, 
S-mephenytoin
S-mephenytoin
CYP3A f
Alfentanil, aprepitant, budesonide, 
buspirone, conivaptan, darifenacin, 
darunavir, dasatinib, dronedarone, 
eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, 
lopinavir, lovastatin, lurasidone, 
maraviroc, midazolam, nisoldipine, 
quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, 
tipranavir, triazolam, vardenafil, 
grapefruit juice
Alfentanil, astemizole g, cisapride g,
cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus, terfenadine g
CYP2D6
Atomoxetine, desipramine, 
dextromethorphan, metoprolol, 
nebivolol, perphenazine, tolterodine, 
Venlafaxine
Thioridazine
a Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499.htm.  Accessed 05 Aug 2015.
b Sensitive CYP substrates refer to drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when co-administered with a known CYP inhibitor.
c CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (e.g., Torsades de Pointes).
d The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 inhibitor, but they represent 
the most sensitive substrates studied with available inhibitors evaluated to date.
e Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 substrate if the inhibition of 
OATP1B1 by the investigational drug has been ruled out.
f Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of P-gp, the observed 
increase in exposure could be due to inhibition of both CYP3A and P-gp.
g Withdrawn from the United States market because of safety reasons.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
127
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix O:  Transporter Sensitive Substrates
From Food and Drug Administration (FDA) Drug Development and Drug Interactions Website: 
Table 13. Examples of In Vivo Substrates for Selected Transporters a (7/28/2011)
Transporter
Gene
Substrate
P-gp
ABCB1
Aliskiren, ambrisentan, colchicine, dabigatran 
etexilate, digoxin, everolimus, fexofenadine, 
imatinib, lapatinib, maraviroc, nilotinib, 
posaconazole, ranolazine, saxagliptin, 
sirolimus, sitagliptin, talinolol, tolvaptan, 
topotecan
BCRP
ABCG2
Methotrexate, mitoxantrone, imatinib, 
irinotecan, lapatinib, rosuvastatin, 
sulfasalazine, topotecan
OATP1B1
SLCO1B1
Atrasentan, atorvastatin, bosentan, ezetimibe, 
fluvastatin, glyburide, SN-38 (active 
metabolite of irinotecan), rosuvastatin, 
simvastatin acid, pitavastatin, pravastatin, 
repaglinide, rifampin, valsartan, olmesartan
OATP1B3
SLCO1B3
Atorvastatin, rosuvastatin, pitavastatin, 
telmisartan b, valsartan, olmesartan
OCT2
SLC22A2
Amantadine, amiloride, cimetidine, dopamine, 
famotidine, memantine, metformin, pindolol, 
procainamide, ranitidine, varenicline, 
oxaliplatin
OAT1
SLC22A6
Adefovir, captopril, furosemide, lamivudine, 
methotrexate, oseltamivir, tenofovir, 
zalcitabine, zidovudine
OAT3
SLC22A8
Acyclovir, bumetanide, ciprofloxacin, 
famotidine, furosemide, methotrexate, 
zidovudine, oseltamivir acid, (the active 
metabolite of oseltamivir), penicillin G, 
pravastatin, rosuvastatin, sitagliptin
a Please note this is not an exhaustive list. For an updated list, see the following link: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/uc
m080499 htm.  Accessed 05 Aug 2015.
b Selective for OATP1B3.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Protocol AG-221-AML-004
Celgene Corporation
128
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
Appendix P:  Monitoring of Liver Function
Subjects with ALT increases of ≥ 3 x ULN will be monitored as follows:

Liver function tests (ie, ALP, ALT, AST, total bilirubin and GGT) should be repeated 
within 3 days of the initial ALT finding, 2 to 3 times weekly until ALT level is stable, 
and weekly thereafter 

Additional diagnostic follow-ups include: 

Focused medical history, including detailed review of prior history of liver and/or 
biliary disorders, concurrent symptoms, all concomitant medications (eg, 
acetaminophen-containing medications, over-the-counter or herbal medications, 
nutritional supplements) including any changes in medications, and alcohol use 

Hepatitis serology (anti-HAV antibody, HBsAg, HBcAb, HBsAb, anti-HCV 
antibody, HCV RNA)

Profiling of EBV, CMV and autoantibodies (eg, ANAs, anti-smooth muscle 
antibodies) 

Complete physical examination

Liver ultrasound and other imaging follow-ups as appropriate

Additional evaluations as appropriate (eg, PT with INR and PTT)
Key: ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANA = antinuclear antibody; AST = aspartate 
aminotransferase; CMV = Cytomegalovirus ; EBV = Epstein-Barr virus; GGT = gamma glutamyl transpeptidase; 
HAV = hepatitis A virus; HBV = hepatitis B Virus; HBcAb = anti-HBV core antibody; HBsAb = anti-HBV 
surface antibody; HBsAg = HBV surface antigen; HCV = hepatitis C virus; INR = international normalized ratio; 
PT = prothrombin time; PTT = partial thromboplastin time; RNA = ribonucleic acid; ULN = upper limit of  
normal.
Approved
1.0
v


EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Friday, 01 December 2017, 08:46 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
3
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Sample size was increased and statistical considerations were updated.
AG-221 (enasidenib) was approved by the Food and Drug Administration (FDA) in the United 
States (US) for the treatment of adult patients with relapsed or refractory AML with an isocitrate 
dehydrogenase 2 (IDH2) mutation as detected by an FDA-approved test.  This approval may 
allow subjects in the conventional care regimen arm to receive commercially available AG-221 
(enasidenib), leading to statistical power loss in detecting the treatment effect on overall survival.  
To remedy this statistical power loss, Study AG-221-AML-004 increased sample size from 280 
to 316 subjects and updated statistical considerations (eg, event size was increased from 193 to 
250 deaths, etc). (Refer to the Protocol Summary, Section 3.1.1, Figure 1, Section 4.1, and 
Sections 9.3, 9.6.1, and 9.8.)

Study duration was updated.
The expected duration of this study was changed from approximately 28 months to 78 months 
because the enrollment period was extended from 24 months to 42 months to increase the sample 
size as mentioned above, and to submit the final study report and data set with 3 years of follow-
up per the Post Marketing Requirements by the FDA (NDA 209606 APPROVAL 1-Aug-2017 
Reference ID: 4132874). Accordingly, the definition of the End of Trial has been updated as 
either the date of 36 months from the last subject randomized date, or the date when all subjects 
discontinued from study treatment and no subject is available for survival follow-up, whichever
is the later date. (Refer to the Protocol Summary, Table 2, Sections 3.2 and 3.3.)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
4
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

Fasting (preferred) lipid panel was added at 2 more timepoints.
Fasting (preferred) lipid panel was added on Day 1 of Cycles 2 and 3 to allow for monitoring 
lipid changes during early cycles of study treatment. (Refer to Table 3.)

The fasting requirement for lipid panel was updated.
The most recent European guideline indicates that non-fasting blood samples are sufficient for 
assessing plasma lipid profiles (Nordestgaard, 2016).  Thus, the fasting requirement for lipid 
panel was updated, particularly for subjects who experience clinically meaningful elevations of 
lipids, per the investigator’s assessment. (Refer to Table 3 and Section 6.2.)

Frequency of assessing disease status in the follow-up phase was reduced.
The frequency for disease status assessment was reduced from every 8 weeks to every 12 weeks
to reduce subjects’ burden during follow-up.  (Refer to Section 6.3.)

Data collection of investigator-assessed response/ disease status to subsequent AML 
therapies was added. 
This will allow for evaluate of disease response to subsequent AML therapies after subjects 
discontinue study treatment.  For example, subjects who had refractory disease status before the 
study treatment might achieve good disease control from subsequent AML therapy after 
exposure to AG-221. This would provide scientifically meaningful data regarding the sensitivity 
to subsequent AML therapy after exposure to study treatment, and general disease status after 
study treatment.  (Refer to Table 3 and Section 6.3.)

Fasting requirement for taking AG-221 was removed.
This change was made based on emerging pharmacokinetics and safety data from a human food 
effect study (Study AG221-C-002) and two Phase 1/2 dose escalation studies (AG221-C-001 and 
AG221-C-003) which showed that the increase of AG-221 exposure by food is not considered as 
clinically meaningful. Accordingly, as recommended by the FDA, the US prescribing 
information does not include a fasting requirement for AG-221 administration. (Refer to 
Section 7.2.1.1.)

Reference toxicities during AG-221 therapy were updated.
These changes were made based on the current AG-221 IB. (Refer to Section 7.2.1.3.)

Restricted concomitant medications during AG-221 therapy were updated.
Restricted concomitant medications during AG-221 therapy were updated based on the current 
AG-221 IB. (Refer to Section 8.3.)
The amendment also includes several other minor clarifications and corrections:

Celgene therapeutic area head signature page was updated on page 3.   

Three new references were cited in Section 9.6.1 (Primary Efficacy Analysis) and 
have been included in Section 17.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
5
AG-221-AML-004 Amendment 2.0 Final: 30 Nov 2017

The commercial test to detect IDH2 mutations has been approved by FDA since 
August 2017. The explanation was added in Section 6.1. 

Other clarifications, corrections of minor typographical errors and incidental 
formatting changes were made throughout the document.
2.
REFERENCES
Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, et al.  Fasting is not 
routinely required for determination of a lipid profile: clinical and laboratory implications 
including flagging at desirable concentration cut-points-a joint consensus statement from the 
European Atherosclerosis Society and European Federation of Clinical Chemistry and 
Laboratory Medicine.  Eur Heart J. 2016 Jul 1;37(25):1944-58.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
3
AG-221-AML-004 Amendment 1.0 Final: 11 Oct 2016
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Best supportive care was clarified to be given according to local prescribing 
information and local therapeutic guidelines.
This clarification was at the request of the French National Agency for Medicines and Health 
Products Safety (ANSM).  (Refer to the Protocol Summary, Sections 3.1.1 and 7.1.5.)

A special condition of allowing confirmation of  isocitrate dehydrogenase (IDH) 
gene mutation locally was added
In the event that the central laboratory result is delayed and precludes acute clinical management 
of a subject who has confirmed IDH2 gene mutation by local evaluation, the subject may be 
eligible for randomization with approval by the Medical Monitor.  (Refer to Protocol Summary, 
Sections 3.1.1 and 4.2 [inclusion criterion #7].)

Management of differentiation syndrome during AG-221 therapy was updated.
In the upcoming version of the Medical Dictionary for Regulatory Activities (MedDRA), the 
preferred term of differentiation syndrome associated with therapy of mutant isocitrate 
dehydrogenase (IDH) inhibition will be IDH Differentiation Syndrome.  Thus the term for 
differentiation syndrome during AG-221 therapy was changed from “Differentiation-like 
Syndrome” to “IDH Differentiation Syndrome".  Diagnosis and treatment of IDH Differentiation 
Syndrome during AG-221 therapy was also updated with a reference to a supplemental guidance 
document.  (Refer to Protocol Summary, Sections 3.1.1, 7.2.1.3 and 8.)

A note was added to clarify the intermediate-dose cytarabine (IDAC) regimen
Any local standard regimen different from the IDAC regimen specified in the protocol will need 
review and approval by the Medical Monitor.  (Refer to Protocol Summary, Sections 3.1.1 and 
7.2.4.)

For subjects having acute myeloid leukemia (AML) secondary to prior higher risk 
(Intermediate-2 or High risk according to the International Prognostic Scoring 
System) myelodysplastic syndromes (MDS) treated with a hypomethylating agent 
(eg, azacitidine or decitabine), the hypomethylating therapy can be counted as a 
line/regimen if there is disease progression to AML during or shortly (eg, within 60 
days) after the hypomethylating therapy.
As hypomethylating therapy is approved for higher risk (Intermediate-2 or High risk according 
to the International Prognostic Scoring System) MDS and AML (approvals vary by country), and 
secondary AML with prior MDS treated with hypomethylating therapy has the median overall 
survival only about 4 months, as poor as those who have failed second- or third-line AML 
therapy, this amendment will count the hypomethylating therapy for higher risk MDS as a 
line/regimen if there is disease progression to AML during or shortly (eg, within 60 days) after 
the hypomethylating therapy.  (Refer to Sections 
4.2 [inclusion criterion #9] and 17, and 
Appendix G.)  
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
4
AG-221-AML-004 Amendment 1.0 Final: 11 Oct 2016
 

Caution of AG-221 phototoxicity was removed.
AG-221 does not possess phototoxicity potential based on its exposure to BALB/c-3T3 mouse 
fibroblasts in the presence of ultraviolet (UV) radiation.  Thus caution of AG-221 phototoxicity 
was removed. (Refer to Sections 
7.2.1.3.)

A new response criterion, morphologic complete remission with partial hematologic 
recovery (CRh) was added.
The new response criterion, CRh is defined as all criteria of morphologic CR except that absolute 
neutrophil count (ANC) > 0.5 x 109/L (500/μL) and platelet count > 50 x 109/L (50,000/μL).  
This criterion will be assessed by the Sponsor only and based on laboratory dataset.  (Refer to 
Table 2, Section 9.6.2.2, and Appendix F.)

The formula for creatinine clearance calculation was updated
The Cockcroft-Gault formula was replaced by the Modification of Diet in Renal Disease
(MDRD) glomerular filtration rate (GFR).  (Refer to Section 4.2 [inclusion criteria #8])

The requirement for cytarabine pregnancy prevention was updated for female 
subjects and male subjects with their partners.
These updates were made at the request of health authorities in reference to the contraceptive 
recommendations in the summary of product characteristics (SmPC) of cytarabine (ie, effective 
contraception during treatment and up to 6 months after stopping it). (Refer to Sections 3.1.3, 4.2 
[inclusion criteria #9 and #10], 6.3, and 10.4.)

The requirement for the minimum number of treatment cycles was clarified for 
subjects refractory to, or relapsed after, second- or third-line/regimen of intensive 
therapy for AML.
This clarification was made at the request of the ANSM.  Intensive therapy as the second- or 
third-line/regimen for AML subjects 60 years or older (as required by the study) would need 
extensive customization which could be best achieved through the treating physician’s 
assessment.  Thus, the protocol does not specify the minimum number of treatment cycles 
required to define refractory or relapsed disease after intensive therapy as the second- or third-
line/regimen for AML. (Refer to Section 4.2 [inclusion criterion #4a].)

The eligibility of subjects to the conventional care regimen (CCR) treatment option 
was further clarified that subjects with degenerative and toxic encephalopathy
should not receive cytarabine.
This addition was made at the request of the ANSM in reference to the section of 
Contraindications in the SmPC of cytarabine. (Refer to Section 4.2 [inclusion criterion #5].)

The definition of  females of childbearing potential (FCBPs) was updated.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
5
AG-221-AML-004 Amendment 1.0 Final: 11 Oct 2016
This update was made in reference to “Recommendations related to contraception and pregnancy 
testing in clinical trials” by Clinical Trial Facilitation Group (CTFG). (Refer to Section 4.2 
[inclusion criterion #9].)

Effective contraceptive methods were clarified.
This clarification was made in reference to “Recommendations related to contraception and 
pregnancy testing in clinical trials” by CTFG. (Section 4.2 [inclusion criteria #9 and #10].)

True abstinence was incorporated into the requirement for pregnancy prevention.
This update was made at the request of Medicines and Healthcare products Regulatory Agency 
(MHRA). (Refer to Section 4.2 [inclusion criteria #9 and #10])

Management of leukocytosis with hydroxyurea was updated.
The threshold of white blood cell (WBC) count was removed to allow control of leukocytosis 
with hydroxyurea per standard institutional practice. (Refer to Sections 4.2 [exclusion 
criterion #4], 7.2.1.3 and 8.)

Exclusion of subjects taking specific medications known to prolong QT interval 
was clarified
Subjects taking specific medications that are known to prolong QT interval will be excluded 
unless the subjects can be transferred to other medications at least 5 half-lives prior to the start of 
study treatment.  (Refer to Section 4.3 [exclusion #18].)

A guideline for monitoring liver function was added
The guideline was added as an example of acute clinical management.  (Refer to Section 6.4.2 
and Appendix P.)

Management of gastrointestinal disorders during AG-221 therapy was added.
This addition was made at the request of the ANSM in reference to the current AG-221 IB and in 
line with the IB. (Refer to Section 7.2.1.3.)

A recommendation of the minimum number of AG-221 treatment cycles was added.
Preliminary data from the Phase 1/2 study (ie, AG-221-C-001) showed that response to treatment 
with AG-221 may frequently be delayed.  Thus it is recommended that subjects receive at least 
6 cycles of AG-221 treatment in order to optimally benefit from the treatment. (Refer to 
Section 7.2.1.)

Definitions of hematologic toxicities were clarified.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
6
AG-221-AML-004 Amendment 1.0 Final: 11 Oct 2016
These clarifications were made to allow continuous AG-221 treatment cycles without delays due 
to disease-related hematologic toxicities.  (Refer to Section 7.2.1.3.)

Criteria for initiating subsequent AG-221 treatment cycle was updated.
This update was made to allow continuous AG-221 treatment cycles without delays due to 
disease-related adverse events. (Refer to Section 7.2.1.4.)

The definition of subjects without reduced baseline blood counts was updated.
These updates were made at the request of the ANSM in reference to the current Azacitidine IB 
and in line with the IB. (Refer to Section 7.2.2.1 and Appendix L.)

Management of necrotizing fasciitis during azacitidine therapy was added.
This addition was made at the request of the ANSM in reference to the azacitidine SmPC. (Refer 
to Section 7.2.2.1.)

Guidelines of concomitant treatment of gastrointestinal side effects during 
azacitidine treatment were added.
Recommended concomitant treatment of nausea, vomiting and/or diarrhea during azacitidine 
treatment was added. (Refer to Section 8.1.)

Administration of live or live-attenuated vaccines was added as a prohibited 
concomitant medication during the course of cytarabine therapy.
This addition was made at the request of the ANSM in reference to the section “Special warnings 
and precautions for use” in the cutarabine SmPC. (Refer to Section 8.2.)

Administration of 5-Fluorocytosine was added as a prohibited concomitant 
medication during the course of cytarabine therapy.
This addition was made at the request of the ANSM in reference to the section of Interaction 
with medicinal products and forms of interaction in the cytarabine SmPC. (Refer to Section 8.2.)
The amendment also includes several other minor clarifications and corrections:

Medical monitor contact information and Celgene therapeutic head signature page 
were updated on pages 2 and 3.

Citations of AG-221 and azacitidine IBs were removed in Section 17 and the links to 
these citations (in the Protocol Summary, and Sections 
 10.6) were abolished 
to allow reference to the current IBs.   
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Summary of Changes AG-221-AML-004
Celgene Corporation
7
AG-221-AML-004 Amendment 1.0 Final: 11 Oct 2016

Multi-gated acquisition (MUGA) scan was removed as an assessment during 
screening and/or treatment.  However, a prior MUGA scan performed within 28 days 
prior to the start of study treatment can be used for study entry.  These changes were 
reflected in the Protocol Summary, Table 3, and Sections 6.1, 6.2, and 6.4.

The window for bone marrow aspirate and/or biopsy, peripheral blood smear and, if 
applicable, cytogenetics, during the Treatment Phase was clarified in the footnotes 
“w”, “x” and “y” of Table 3 to be consistent with Section 6.2.

The window for bone marrow aspirate and/or biopsy, peripheral blood smear and, if 
applicable, cytogenetics, during the Follow-up Phase was corrected in Section 6.3 to
± 14 days to be consistent with the footnote “q” of the Protocol, Table 3, Table of 
Events.

The parameters of chemistry and cardiac marker panels were updated.

Truncated sentences in Sections 8.1 and 10.6 were completed.

The elapsed time from azacitidine reconstitution to administration in Method A of 
Appendix K was updated with addition of the specification in the United States.

Specification of azacitidine reconstitution with refrigerated water was added in 
Method B of Appendix K.

Corrections of minor typographical errors and incidental formatting changes were 
made throughout the document.
Approved
1.0
v

SAP_001.pdf: 
Official Title of Study: 
A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of AG-221 (CC-
90007) Versus Conventional Care Regimens in Older Subjects with Late Stage Acute Myeloid Leukemia 
Harboring an Isocitrate Dehydrogenase 2 Mutation 
 
 
 
PROTOCOL(S) AG-221-AML-004 
 
NCT Number: NCT02577406 
  
Document Date (Date in which document was last revised): May 29, 2020 


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
1
STATISTICAL ANALYSIS PLAN
A Phase 3, Multicenter, Open-label, Randomized Study Comparing the Efficacy and Safety of 
AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects with Late Stage 
Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation
STUDY DRUG:
AG-221 (CC-90007)
PROTOCOL NUMBER:
AG-221-AML-004 
DATE FINAL:
29 May 2020
Prepared by:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
2
TABLE OF CONTENTS
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................6
SIGNATURE PAGE...................................................................................................................7
1.
LIST OF ABBREVIATIONS...................................................................................9
2.
INTRODUCTION..................................................................................................12
3.
STUDY OBJECTIVES...........................................................................................13
3.1.
Primary Objective...................................................................................................13
3.2.
Secondary Objectives .............................................................................................13
4.
INVESTIGATIONAL PLAN .................................................................................14
4.1.
Overall Study Design and Plan ...............................................................................14
4.2.
Study Endpoints .....................................................................................................16
4.2.1.
Primary Endpoint....................................................................................................16
4.2.2.
Secondary Endpoints ..............................................................................................16
4.2.4.
Safety Endpoints.....................................................................................................18
4.3.
Stratification, Randomization, and Blinding............................................................18
4.4.
Sample Size Determination.....................................................................................19
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................20
5.1.
Reporting Conventions ...........................................................................................20
5.2.
Analysis Populations ..............................................................................................21
5.2.1.
Intent-to-Treat Population.......................................................................................21
5.2.2.
Modified Intent-to-Treat Population .......................................................................21
5.2.3.
Safety Population....................................................................................................22
6.
SUBJECT DISPOSITION......................................................................................23
7.
PROTOCOL DEVIATIONS/VIOLATIONS ..........................................................25
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................26
8.1.
Demographics.........................................................................................................26
8.2.
Baseline Disease Characteristics and AML Diagnosis History................................26
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
3
8.2.1.
Baseline Disease Characteristics.............................................................................26
8.2.2.
AML Diagnosis History..........................................................................................27
8.3.
Medical History and Concomitant Disease..............................................................27
8.4.
Prior/Concomitant/Follow-up Medications/Procedures/Therapies...........................28
8.4.1.
Prior/Concomitant/Follow-up Medications .............................................................28
8.4.2.
Prior/Concomitant/Follow-up Procedures ...............................................................28
8.4.3.
Prior/Follow-up Anti-Cancer Therapies ..................................................................28
8.4.4.
Prior/Concomitant/Follow-up Transfusions ............................................................29
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................31
9.1.
Duration of Treatment Exposure and Duration of Treatment...................................31
9.2.
Cumulative Dose ....................................................................................................32
9.3.
Dose Intensity.........................................................................................................32
9.4.
Relative Dose Intensity...........................................................................................32
9.5.
Average Daily Dose................................................................................................33
9.6.
Dose Modification..................................................................................................33
9.7.
Compliance ............................................................................................................33
10.
EFFICACY ANALYSIS ........................................................................................34
10.1.
Multiplicity.............................................................................................................34
10.2.
Analysis of Primary Efficacy Endpoint...................................................................34
10.3.
Analyses of Secondary Efficacy Endpoints.............................................................36
10.3.1.
Key Secondary Endpoints.......................................................................................36
10.3.2.
Other Secondary Endpoints ....................................................................................39
10.4.
Subgroup Analysis..................................................................................................42
11.
SAFETY ANALYSIS ............................................................................................44
11.1.
Adverse Events.......................................................................................................44
11.2.
Adverse Events of Special Interest..........................................................................47
11.3.
Death......................................................................................................................48
11.4.
Clinical Laboratory Evaluations..............................................................................48
11.4.1.
Hematology............................................................................................................49
11.4.2.
Serum Chemistry....................................................................................................49
11.4.3.
Urinalysis ...............................................................................................................49
11.4.4.
Coagulation ............................................................................................................50
11.4.5.
Fasting Lipid Panel.................................................................................................50
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
4
11.4.6.
Cardiac Markers .....................................................................................................50
11.4.7.
Females of Childbearing Potential ..........................................................................50
11.5.
Vital Sign Measurements........................................................................................50
11.6.
Physical Examination .............................................................................................50
11.7.
Electrocardiograms.................................................................................................50
12.
INTERIM ANALYSIS...........................................................................................52
12.1.
General Information................................................................................................52
12.2.
Statistical Approaches for Control of Alpha............................................................52
13.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................54
14.
REFERENCES.......................................................................................................55
15.
APPENDICES........................................................................................................56
15.1.
Handling of Dates...................................................................................................56
15.1.1.
Calculation Using Dates .........................................................................................56
15.1.2.
Calculation of Cycles..............................................................................................57
15.2.
Date Imputation Guideline......................................................................................58
15.2.1.
Impute Missing Start/Stop Dates for Adverse Events/ Prior or Concomitant 
Medications............................................................................................................58
15.2.2.
Medical History......................................................................................................59
15.3.
Independent Response Assessment Committee .......................................................59
15.4.
Table of Events.......................................................................................................60
15.5.
International Working Group Acute Myeloid Leukemia Response Criteria .............66
15.6.
Hematologic Improvement According to the International Working Group 
for Myelodysplastic Syndromes..............................................................................68
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................9
Table 2:
Secondary Endpoints ..............................................................................................16
Table 4:
Censoring Rules for EFS ........................................................................................38
Table 5
Serum Chemistry Changes of Interest .....................................................................49
Table 6:
Fasting Lipid Changes of Interest............................................................................50
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
6
LIST OF FIGURES
Figure 1:  Overall Study Design ................................................................................................15
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
7
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE 
SAP TITLE
AG-221-AML-004 Statistical Analysis Plan
SAP VERSION, DATE
Version 2, 29 May 2020
SAP AUTHOR
{See appended electronic 
signature page}
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A PHASE 3, MULTICENTER, OPEN-LABEL, RANDOMIZED STUDY 
COMPARING THE EFFICACY AND SAFETY OF AG-221 (CC-90007) VERSUS 
CONVENTIONAL CARE REGIMENS IN OLDER SUBJECTS WITH LATE 
STAGE ACUTE MYELOID LEUKEMIA HARBORING AN ISOCITRATE
DEHYDROGENASE 2 MUTATION
INVESTIGATIONAL 
PRODUCT
AG-221 (CC-90007/ENASIDENIB)
PROTOCOL NUMBER
AG-221-AML-004
PROTOCOL VERSION, 
DATE
Amendment No 2.0, 30 Nov 2017
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
Printed Name
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
Printed Name
Date
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
8
Lead Product Safety Physician
Signature
Printed Name
Date
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
9
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
ADaM
Analysis Data Model
ADT
Analysis Date
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
AML
Acute myeloid leukemia
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical therapeutic chemical
BID
Twice a day
BMI
Body mass index
BSA
Body surface area
BSC
Best supportive care
BPM
Beats per minute
CCR
Conventional care regimen
CI
Confidence interval
CR
Morphologic complete remission
CRc
Cytogenetic Complete Remission 
CRF
Case report form
CRh
Morphologic complete remission with partial hematologic recovery
CRi
Morphologic complete remission with incomplete neutrophil recovery
CRp
Morphologic complete remission with incomplete platelet recovery
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EFS
Event-free survival
EORTC
European Organization for Research and Treatment of Cancer
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
10
Abbreviation or 
Specialist Term
Explanation
EOT
End of treatment
FCBP
Females of childbearing potential
HI
Hematologic improvement
HI-E
Hematologic improvement erythroid response
HI-N
Hematologic improvement neutrophil response
HI-P
Hematologic improvement platelet response
HLT
High-Level Term
HSCT
Hematopoietic stem cell transplantation
IDAC
Intermediate-dose cytarabine
IDH2
Isocitrate dehydrogenase isoform 2
IRAC
Independent Response Assessment Committee
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive voice response system
IWG
International Working Group
KM
Kaplan-Meier
MedDRA
Medical dictionary for regulatory activities
MLFS
Morphologic leukemia-free state
NCI
National Cancer Institute
ORR
Overall response rate
OS
Overall survival
PR
Partial remission; same as partial response
PD
Progressive disease
QTcB
Heart-rate corrected QT with Bazett’s correction
QTcF
Heart-rate corrected QT with Fridericia’s correction
SAE
Serious adverse event
SD
Stable disease
SGPT
Serum glutamic pyruvic transaminase
SMQ
Standardized MedDRA Query
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
11
Abbreviation or 
Specialist Term
Explanation
SOC
System organ class
TEAE
Treatment emergent adverse event
ULN
Upper limit of normal
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
12
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s 
protocol AG-221-AML-004 “A Phase 3, Multicenter, Open-label, Randomized Study Comparing 
the Efficacy and Safety of AG-221 (CC-90007) Versus Conventional Care Regimens (CCR) in 
Older Subjects with Late Stage Acute Myeloid Leukemia Harboring an Isocitrate 
Dehydrogenase 2 Mutation,” which was issued on 13 Aug 2015 and amended to Amendment 2.0 
on 30 Nov 2017. It contains definitions of analysis populations, derived key efficacy variables, 
and statistical methods for the analysis of efficacy and safety data.
The efficacy analyses include one interim analysis and one final analysis. Throughout this SAP, 
the treatment arms will be referred to as AG-221 and CCRs (Conventional Care Regimens). 
Treatment arm AG-221 refers to AG-221 Orally (PO) plus best supportive care (BSC). The CCR 
treatment options include BSC only, azacitidine subcutaneously (SC) plus BSC, low-dose
cytarabine (LDAC) SC plus BSC, or intermediate-dose cytarabine (IDAC) intravenously (IV) 
plus BSC. Following review of eligibility, subjects will be assigned by the investigator to one of 
the CCR treatment options based on the investigator’s assessment of subjects’ eligibility. 
Following the selection of a CCR treatment option, subjects will be randomized centrally in a 1:1
ratio to receive either the AG-221 treatment or the CCR treatment option pre-selected by the 
investigator. 
A planned interim analysis was completed in March 2019, following the reporting of 65% of the 
expected number of deaths (approximately 163 deaths).  Following this the study was continued 
to final analysis. This SAP provides a comprehensive and detailed description of the strategy,
rationale, and statistical techniques to evaluate the efficacy and safety endpoints. The purpose of 
the SAP is to ensure the credibility of the study findings by pre-specifying the statistical 
approaches to the primary efficacy analysis of study data prior to database lock for the final 
analysis. A data cut-off date for the locked database for the final analysis will be determined and 
the database will be locked after medical/scientific review of the data has been completed, 
protocol violations/deviations have been identified, and the data have been declared to be clean. 
All statistical analyses detailed in this SAP will be conducted using SAS® Version 9.2 or higher. 
The analysis methods and timing of analysis for the patient reported outcomes/quality of life 
 
 will be described in a separate pharmacoeconomics 
SAP.
 
 
 Operational details for the Data 
Monitoring Committee (DMC) during the course of the study will be discussed in a separate 
DMC charter, and will not be included in this SAP either.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
13
3.
STUDY OBJECTIVES
3.1.
Primary Objective

To determine the primary efficacy, measured as overall survival (OS), of AG-221
compared with CCRs in subjects 60 years or older with acute myeloid leukemia
(AML) refractory to or relapsed after second- or third-line AML therapy and positive
for an isocitrate dehydrogenase isoform 2 (IDH2) mutation 
3.2.
Secondary Objectives

To determine the supporting efficacy of AG-221 compared with CCRs

To determine the safety and tolerability of AG-221 compared with CCRs

To determine the effect of AG-221 compared with CCRs on Health-related 
Quality-of-Life (HRQoL)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
14
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is an international, multicenter, open-label, randomized, Phase 3 study comparing the 
efficacy and safety of AG-221 versus CCRs in subjects 60 years or older with AML refractory to 
or relapsed after second- or third-line AML therapy and positive for an IDH2 mutation. 
It is planned that approximately 316 subjects will be randomized in a 1:1 ratio to receive either 
the AG-221 treatment or the CCR treatment option pre-selected by the Investigator prior to 
randomization. Randomization will be stratified by prior intensive therapy for AML (yes versus 
no), primary refractory (i.e., morphologic complete remission [CR], CR with incomplete 
neutrophil recovery [CRi], or CR with incomplete platelet recovery [CRp] has never been 
attained) (yes versus no), and prior allogeneic hematopoietic stem cell transplantation (HSCT)
for AML (yes versus no).
The treatment options in the CCR treatment arm include:

BSC only: continuous 28-day cycles of BSC. Best supportive care includes, but is not 
limited to, hydroxyurea for leukocytosis and/or differentiation-like syndrome, anti-
infectives, analgesics, antiemetics, antipyretics, transfusions and nutritional support 
(refer to protocol Section 8 for details);

Azacitidine SC plus BSC: continuous 28-day cycles of azacitidine 75 mg/m2/day SC 
for 7 days, plus BSC;

LDAC SC plus BSC: continuous 28-day cycles of cytarabine 20 mg SC twice a day 
(BID) for 10 days, plus BSC;

IDAC IV plus BSC: 28-day cycles of cytarabine 0.5 to 1.5 g/m2/day IV for 3 to 
6 days, per standard institutional practice, plus BSC; only BSC given after IDAC 
therapy concludes per standard institutional practice.
Subjects randomized to the AG-221 treatment arm will receive AG-221 100 mg PO once a day
on Days 1 to 28 of each 28-day cycle, plus BSC. Dose escalation to 200 mg may occur for 
augmenting treatment response.
Study treatment starts within 3 days after randomization. No crossover between any of the 
treatment options will be permitted during the course of study treatment per protocol.
Dosing interruptions, delays, or dose modifications may occur for managing toxicities and/or 
augmenting treatment response during study treatment.
All subjects who have received at least one dose of study treatment should undergo 
end-of-treatment (EOT) evaluations when study treatment is discontinued. The reason for 
discontinuation will be recorded in the electronic case report form (eCRF) pages and in the 
source document.
All subjects discontinued from study treatment for any reason other than withdrawal of consent
for follow-up will continue to be assessed for adverse events (AEs), concomitant medications, 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
15
concomitant procedures, transfusions, 
 response, hematologic 
improvement (HI), subsequent AML therapies, and survival. 
The study schematic is presented in Figure 1 below.
Figure 1:  Overall Study Design
                                                                                       
Key: AML = acute myeloid leukemia; BSC = best supportive care; CCR = conventional care regimen; HSCT = 
hematopoietic stem cell transplantation; IDAC = Intermediate-dose cytarabine; IDH2 = isocitrate dehydrogenase 
isoform 2; IV = intravenously; LDAC = low-dose cytarabine; PD = progressive disease; PO = orally; SC = 
subcutaneously.
Screening (Day -28 to Day -1)
Eligibility Check

>= 60 years old

AML refractory to or relapsed after second- /third-line AML therapy

IDH2 gene mutation positive

Refer to protocol Section 4 for details
Follow-up
Follow-up for adverse events, concomitant medications, concomitant procedures,
transfusions, 
 response, hematologic improvement,
subsequent AML therapies, response/disease status to subsequent AML therapies
and survival.  Refer to protocol Section 6.3 for details regarding the assessments
scheduled after the EOT visit).
Randomization* 1:1
N = 316
End of Treatment
Treat continuously unless discontinued early for 
evidence of PD, death, unacceptable toxicity, HSCT or 
withdrawal from study treatment.
CCR Arm
BSC only; or
Azacitidine SC plus BSC; or 
LDAC SC plus BSC ; or
IDAC IV plus BSC
N = 158
AG-221 Arm
AG-221 PO plus BSC
N = 158
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
16
* Stratification factors: prior intensive therapy for AML (yes versus no), primary refractory (yes versus no), and 
prior allogeneic HSCT for AML (yes versus no).
4.2.
Study Endpoints
4.2.1.
Primary Endpoint
The primary endpoint is overall survival (OS), defined as time from randomization to death due 
to any cause. 
4.2.2.
Secondary Endpoints
The secondary endpoints are listed in Table 2 below.
Table 2:
Secondary Endpoints
Name 
Description
Overall response rate
Rate of Best Response in CR + CRi + CRp + PR 
+ MLFS according to modified IWG AML 
response criteria 
Event-free survival
Time from randomization to documented 
morphologic relapse, PD according to modified 
IWG AML response criteria or death from any 
cause, whichever occurs first
Duration of response
Time from the first documented
CR/CRi/CRp/PR/MLFS to documented 
morphologic relapse, PD according to modified 
IWG AML response criteria or death due to any 
cause, whichever occurs first
Time to response
Time from randomization to first documented
CR/CRi/CRp/PR/MLFS according to modified 
IWG AML response criteria 
Time to best response
Time from randomization to the documented 
best response of CR/CRi/CRp/PR/MLFS
according to modified IWG AML response 
criteria 
Treatment mortality at 30- and 60-day
Rate of death from any cause within 30 and 
60 days of initiation of study treatment
One-year survival
The probability of survival at 1 year
from randomization
Overall remission rate
Rate of CR + CRi + CRp according to
modified IWG AML response criteria
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
17
Name 
Description
Complete remission rate
Rate of CR according to modified IWG AML 
response criteria 
Hematologic improvement rate
Rate of HI-N + HI-P + HI-E according to IWG 
MDS HI criteria 
Rate of HSCT
Rate of bridge-to-HSCT through study treatment
Time to treatment failure
Time from randomization to discontinuation of 
study treatment due to any cause
Rate of CR/CRh
Rate of CR + CRh (Appendix 15.5)
Duration of CR/CRh
Time from the first documented CR/CRh to 
relapse according to modified IWG AML 
response criteria or death due to any cause, 
whichever occurs first
Time to CR/CRh
Time from randomization to first documented 
CR/CRh
Safety and tolerability
Type, frequency, severity, seriousness and 
relationship of adverse events to study 
treatments; vital signs; ECG; clinical laboratory 
evaluations
HRQoL
European Organization for Research and 
Treatment of Cancer Quality-of-Life 
questionnaire (EORTC QLQ-C30) and EuroQoL 
Group EQ-5D-5L instrument 
Abbreviations: AML = acute myeloid leukemia; CR = morphologic complete remission; CRi = morphologic 
complete remission with incomplete neutrophil recovery; CRp = morphologic complete remission with incomplete 
platelet recovery; CRh=morphologic complete remission with partial hematologic recovery; ECG = 
electrocardiogram; EORTC= European Organization for Research and Treatment of Cancer; HI = hematologic
improvement; HI-E = hematologic improvement erythroid response; HI-N = hematologic improvement neutrophil 
response; HI-P = hematologic improvement platelet response; HRQoL = Health-related Quality of Life; HSCT = 
hematopoietic stem cell transplantation; IWG = International Working Group; MDS = myelodysplastic syndromes; 
MLFS = morphologic leukemia-free state; PR = partial remission; PD = progressive disease.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
18
4.2.4.
Safety Endpoints
Safety assessments include physical examination, vital signs, electrocardiogram (ECG), 
hematology, serum chemistry, cardiac markers, fasting lipid panel, pregnancy testing (for 
females of childbearing potential [FCBPs] only), AEs, concomitant medications, concomitant 
procedures and transfusions. After screening, echocardiogram (ECHO), urinalysis and 
coagulation will be repeated as clinically indicated.
4.3.
Stratification, Randomization, and Blinding
Randomization will be carried out using an Interactive Voice Response System (IVRS).
Following the selection of a CCR treatment option, subjects will be randomized centrally in a 1:1 
ratio to receive either AG-221 treatment or one of the CCR treatment options pre-selected by the 
Investigator based on standard institutional practice and on evaluation of the subject’s underlying 
disease condition. To avoid potential bias, the intended treatment selection from the CCR 
treatment arm by the Investigator will be recorded for all subjects prior to randomization;
treatment assignment is not to be subsequently changed after randomization.
To further minimize the heterogeneity of treatment modalities and clinical outcomes in AML, 
randomization in this study is stratified by the following three factors that are believed to have 
the most impact to the study’s primary endpoint, OS: prior intensive therapy for AML (yes 
versus no), primary refractory (i.e., CR/CRi/CRp has never been attained) (yes versus no), and 
prior allogeneic HSCT for AML (yes versus no).
Although this is an open-label study, the interim efficacy analysis will be performed by an 
independent third party and results will be kept strictly confidential in order to maintain the 
integrity of the study. The study team will be blinded at summary-level information using actual 
treatment, i.e. no summary tables and figures will be produced or reviewed by the study team 
using actual treatment information. An independent unblinded team will produce the unblinded 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
19
results and send to an independent Data Monitoring Committee (DMC) who will review and give 
advice to the Sponsor regarding the study conduct.
4.4.
Sample Size Determination
The equality of OS curves will be compared between the AG-221 and combined CCR treatment 
arms using a stratified log-rank test. Subjects will be randomized to receive AG-221 treatment or 
a CCR treatment option pre-selected by the Investigator in a 1:1 ratio. Assuming a median OS of 
5.6 months in the CCR treatment arm, a median OS of 8 months in the AG 221 treatment arm 
(42.9% improvement), and a drop-out rate of approximately 9%, this design requires 316
subjects (158 per treatment arm) to be randomized, and 250 deaths to be observed in order to 
achieve 80% power to detect a hazard ratio (HR) of 0.7 and demonstrate a statistically significant 
difference in OS at type I error rate of 0.05 (two-sided). It is assumed that the OS distribution is 
exponential with a constant failure rate and that accrual rate is 3 subjects per month for the first 
12 months and 9 subjects per month afterwards. The interim analysis for superiority will be 
conducted at 65% information (i.e., approximately 163 deaths) based on Lan-DeMets version of 
the O’Brien-Fleming alpha spending function (DeMets and Lan, 2008)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
20
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
The following reporting conventions apply generally to tables, listings, and figures:

Data from all study centers will be combined for analysis;

Efficacy and Safety analyses will be done by treatment groups/options (AG-221
versus CCR overall and furthermore AG-221 versus, BSC Only, Azacitidine + BSC, 
LDAC + BSC, and IDAC + BSC by pre-selected CCR group). Exceptions will be 
noted in corresponding sections;

All stratified efficacy analyses will use the randomization stratification factors taken
from CRF (primary) including prior intensive therapy for AML (yes versus no), 
primary refractory (yes versus no), and prior allogeneic HSCT for AML (yes versus 
no) and repeated for stratification factors taken from IVRS.  

In stratified analysis, if stratified model does not converge due to small sample size, 
the stratification factor leads to least subjects will be dropped from the model.  If a 
stratification factor has less than 40 subjects in one of its two levels across treatment 
groups, then this factor will not be used in stratified analysis;

All statistical tests of the treatment effect will preserve a significance level of 0.05 for 
two-sided tests, unless otherwise specified;

P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be 
presented as ‘<0.0001’ and p-values that round to 1.000 will be presented as
‘>0.9999’; 

Confidence intervals (CIs) will be presented as two-sided 95% CIs unless specified 
differently in specific analysis;

Summary statistics will consist of the number and percentage of subjects (or cycles, if 
appropriate) in each category for discrete variables, and the sample size, mean, 
median, standard deviation, minimum, and maximum for continuous variables;

All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal 
places than the measured value;

All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form XX (XX.X%), where the percentage is in the 
parentheses;

All listings will be sorted for presentation in order of treatment group, study center, 
subject, and date/time of procedure or event. Subjects who are screened but not 
randomized will be listed separately as a non-randomized group;

All analysis and summary tables will have the analysis population sample size (i.e., 
number of subjects);
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
21

The day of the first dose of any study drug will be defined as Day 1; for BSC only 
subjects, Day 1 is the randomization day.

Unless noted otherwise, baseline value will be defined as the last non-missing value 
prior to or on the start of study treatment on Day 1 of Cycle 1. For subjects in the 
BSC only group, the baseline value will be defined as the last non-missing value on 
or prior to date of randomization. For subjects who are randomized but not treated, 
the baseline will be the assessment value on or prior to randomization date. 

To summarize efficacy/safety data by visit, the post-baseline results will be 
summarized by the scheduled visit or the derived visit as appropriate. 

In general, the derived visit is the same as the scheduled visit in the protocol which is
defined by study day; data that is closest to derived visit (before and after) will be 
used as the value for that visit. In case that two data collected at the equal distance to 
the derived visit, the later one will be used.  

Calculation of Cycles:
The start date of each treatment cycle will be calculated based on study drug exposure 
records for each subject, except for BSC only subjects. The start date of the first cycle 
will be the earliest date the subject receives any study drug or the date of randomization 
for subjects receiving BSC only. Once the start dates, e.g., S1, S2, S3… are calculated, the 
end date of each cycle is calculated as the day before the start date of the following cycle,
i.e., Ei = Si+1 -1. For subjects receiving BSC only, each cycle has a defined length of 28 
days; for the last cycle, the end date will be calculated as the date of discontinuation from 
the treatment period. The cycle number for each date of interest, e.g., adverse event (AE) 
will be calculated based on event start date and the cycle window start and end dates. If 
an event date is on or after Si and before Si+1, the corresponding cycle number will be i.
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population includes all subjects who are randomized to treatment, 
regardless of whether they received treatment or not.
5.2.2.
Modified Intent-to-Treat Population
The modified intent-to-treat (mITT) population includes all subjects who have met all eligibility 
criteria and experienced no major protocol deviations during the study, received at least one dose 
of study treatment (except for BSC subjects) and had at least one post-randomization treatment 
response assessment performed. Major protocol deviations leading to exclusion from the mITT 
population are defined as any of the following:

Had at least one inclusion/exclusion criteria violation; 

Disease status at screening not confirmed by retrospective central review;  

Initial study treatment given is not the one assigned in randomization; 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
22

Did not have at least one post-randomization efficacy assessment performed; 
5.2.3.
Safety Population
The safety population includes all randomized subjects who received at least 1 dose of study 
treatment. Because BSC only treatment may consist of blood products or antibiotics, etc. 
administered as needed, subjects who are randomized to the BSC arm option will be included in 
the safety population if they have had at least 1 safety assessment after randomization. The safety 
population will be used for all safety analyses and drug exposure. Subjects will be analyzed 
according to the initial treatment actually received.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
23
6.
SUBJECT DISPOSITION
Subject disposition (analysis population allocation, entered, discontinued, along with primary
reason for discontinuation) will be summarized using frequency and percent for both treatment
and follow-up phases. Enrollment by country and site will also be summarized.
The disposition of subjects will be summarized with counts and percentages. A summary of 
subject disposition will be presented by treatment group for the following analysis populations:

ITT population

mITT population 

Safety population
A listing of reasons for exclusion from the mITT population will be provided. A separate listing 
will be provided for subjects who were not randomized (screen failures) with reasons for 
screening failure. 
Reasons for treatment discontinuation will be collected on the case report form (CRF) and will 
be summarized for all randomized subjects with the following categories:

Death

Adverse event

Pregnancy

Progressive disease

Withdrawal by subject 

Non-compliance with study drug

Lost to follow-up

Study terminated by Sponsor

Transition to commercially available treatment

Physician decision

Disease relapse

Protocol violation (to be specified on the eCRF)

Other (to be specified on the eCRF)

Other: Hematopoietic Stem Cell Transplantation
Reasons for study discontinuation will be collected on the CRF and will be summarized for all 
randomized subjects and all subjects who enter the follow-up phase with the following 
categories:
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
24

Screen failure

Death

Adverse event

Pregnancy

Progressive disease 

Withdrawal by subject

Lost to follow up

Study terminated by sponsor

Transition to commercially available treatment

Physician decision

Disease relapse

Protocol violation (to be specified on the eCRF)

Other (to be specified on the eCRF)
Additional summaries will be provided for number of subjects per randomization stratum by 
randomized treatment group, as well as number of subjects by study site.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
25
7.
PROTOCOL DEVIATIONS/VIOLATIONS
The protocol deviations/violations will be identified and assessed by clinical research physician 
or designee following company standard operational procedure. These protocol 
deviations/violations will be summarized by treatment group for the ITT population. 
Protocol deviations and violations will be reviewed prior to database hard lock. Major protocol 
violations will be used to determine the mITT population (defined in Section 5.2.2).  
Major protocol deviations and violations will be summarized using frequency tabulations. A by-
subject listing of subjects with all protocol deviations/violations in the ITT population will be 
provided. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
26
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographic and baseline disease characteristics will be summarized by treatment group and 
overall for the ITT, mITT and safety populations, and for Bridge to HSCT subjects in safety 
population.
Individual subject listings will be provided to support the summary tables.
8.1.
Demographics
Age (year), height (cm), weight (kg), body mass index (kg/m2), body surface area (m2), and other
continuous baseline characteristics will be summarized using descriptive statistics (N, mean, 
standard deviation, median, minimum, maximum), while age group ≥60 years and <70 years, 
≥70 years and <80 years, ≥80 years), gender, ethnicity, race, geographic region and other 
categorical variables will be provided using frequency tabulations (count, percent) by treatment 
group and overall.
Age or year of birth will be recorded on CRF. Where age is not recorded, age will be calculated 
as follows: Age = year of informed consent – year of birth.
Body mass index (BMI) will be calculated as follows: BMI (kg/m2) = weight in kg / (height in 
m)2.
If not collected in CRF, body surface area (BSA) will be calculated per the Dubois & Dubois 
formula: BSA (m2) = weight (kg)0.425 x height (cm)0.725/139.2.
8.2.
Baseline Disease Characteristics and AML Diagnosis History
The number and percentage of subjects in each of the following categories will be summarized 
by treatment group and overall. Continuous variable will be summarized by mean, standard 
deviation, median, minimum, and maximum.
Depending on the way in which data is collected, information on the same CRF page will be 
listed in one listing. Multiple listings will be provided for the information above.
8.2.1.
Baseline Disease Characteristics
1. IDH2 gene mutate type (R140 or R172);
2. Eastern Cooperative Oncology Group (ECOG) performance status;
3. Prior intensive therapy for AML (yes versus no);
4. Prior refractory (yes versus no);
5. Prior stem cell transplants for AML (yes versus no; if yes, type);
6. Prior systemic anti-cancer therapies for AML;
7. Time (days) from last prior HSCT, calculated from starting date of the last prior HSCT to 
randomization date (≤100 days; > 100 days to ≤365 days; > 365 days);
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
27
8. Bone marrow blasts (%) and category (< 20%; 20% to < 30%;30% to < 50%; ≥50%) 
from the screening bone marrow aspirate sample (local, central) and bone marrow biopsy 
sample (local, central);
9. Peripheral blood blast (%) (local, central);
10. Cytogenetic Risk Status (better-risk, intermediate-risk, poor-risk, failure, normal, not 
done) (local);
11. Select Chromosomal Abnormalities at Baseline;
12. Co-occurring mutations (FLT3-ITD, NPM, TET2, IDH1) if data is available;
13. Baseline values of the following lab parameters: Hemoglobin (< 80 g/L , ≥80 g/L), 
platelet count (< 50 x10^9/L, ≥50 x10^9/L), absolute neutrophil count (ANC) (< 0.5 
x10^9/L, 0.5 to < 1 x10^9/L, ≥1.0 x10^9/L), white blood cells (WBC) (<15 x10^9/L, 15 
to < 30 x10^9/L, ≥30 x10^9/L), creatinine clearance (< 45 mL/min, 45 to < 60 mL/min, 
≥60 mL/min);
14. Number of transfusions and number of units transfused of red blood cell (RBC) and 
platelets within 56 days prior to randomization, and baseline transfusion dependence for 
both RBC and platelets.
15. Left Ventricular Ejection Fraction (LVEF) from Echocardiogram and Multigated 
Acquisition (MUGA)
16. Prior lines of AML Treatment and category (0 lines, 1lines, 2 lines, 3 lines, 4 lines, >4
lines), Prior refractory status, and prior relapse status
17. Best response to Prior lines of AML Treatment, split by Low-Intensity AML Therapy and 
Intensive Chemotherapy for First line, Second Line, Third Lines, Fourth Line, and Last 
line of prior AML treatment
8.2.2.
AML Diagnosis History
1. WHO Classification
2. AML initial diagnosis: primary (i.e., de novo) or secondary (MDS progression or 
myeloproliferative neoplasms (MPN), or therapy-related) according to WHO 
classification. If AML is secondary, number and percentage of subjects who has an 
antecedent hematologic disorder will be summarized, and type of disorder will be
tabulated too;
3. IPSS Classification for subjects with Higher Risk MDS
4. Time (month) from the initial diagnosis of AML, calculated from time of initial diagnosis 
to randomization date.
8.3.
Medical History and Concomitant Disease
The medical and surgical history, as well as concomitant disease will be summarized by the 
Medical Dictionary for Regulatory Activities (MedDRA) latest version by system organ class 
(SOC) and preferred term (PT) for the ITT population and safety population. Active concomitant 
disease will be summarized in separate tables.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
28
8.4.
Prior/Concomitant/Follow-up Medications/Procedures/Therapies
Prior medications/procedures/transfusions are defined as medications/procedures/transfusions
that were started prior to start of study treatment (start of study treatment refers to randomization 
date for BSC only group and first dose of study drug for other treatment groups) or have start 
dates missing.  If start date is missing and end date is before start of study treatment medication 
will be classed as prior only.
Concomitant medications/procedures/transfusions are defined as non-study 
medications/procedures/transfusions that are started on or after the start of study treatment but
before the end of the study treatment period or started before the start of the study treatment and 
ended or remain ongoing during the study treatment. For non-BSC groups, the end of the study 
treatment period is defined as the earlier date of last dose of study drug + 28 days and date of death.
For BSC groups, the end of the study treatment period is defined as the earlier date of 
discontinuation from the treatment period and date of death.
Medication/procedure/transfusion with missing start date but end date on or after start of the 
study treatment (randomization date for BSC only group) and before the end of the study 
treatment period or with both missing start date and end date is also considered as concomitant
medication/procedure/transfusion.
Follow-up medications/transfusions are defined as non-study medications/transfusions that are 
started after the date of the end of the study treatment period. All non-study medications and 
therapies will be coded by Anatomical Therapeutic Chemical (ATC) code and PT using the 
World Health Organization Drug Dictionary latest version. All procedures and surgeries will be 
coded by the Medical Dictionary for Regulatory Activities (MedDRA) latest version by system 
organ class (SOC) and preferred term (PT).
8.4.1.
Prior/Concomitant/Follow-up Medications 
All prior, concomitant and follow-up medications will be summarized in frequency tabulations 
(subject counts and percentages) and by World Health Organization ATC first level and PT. 
Listings will also be provided for general medications and concomitant QT prolonging 
medications. All tables described in this section will be produced on safety population. 
8.4.2.
Prior/Concomitant/Follow-up Procedures
All prior, concomitant and follow-up procedures will be summarized in frequency tabulations 
(subject counts and percentages) and by SOC and PT. Listings will also be provided for general 
medications/procedures and concomitant QT prolonging medications. All tables described in this 
section will be produced on safety population.
8.4.3.
Prior/Follow-up Anti-Cancer Therapies 
This section includes both AML therapies and non- AML therapies. AML therapies include 
surgery, radiation, systemic or any other therapy for the subject’s AML disease, particularly 
intensive AML chemotherapies as induction/re-induction/salvage chemotherapies, consolidation 
or maintenance therapies, HSCT, low-intensity AML therapies such as azacitidine, decitabine or 
LDAC, or other medications considered supportive care for AML, regardless of discontinuation 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
29
date of treatment. Non-AML therapies may consist of the same therapies like AML therapies but 
for other hematologic or non-hematologic malignancies.  
All tables described in this section will be produced on both ITT and safety population. 
Prior and follow-up therapies will be summarized separately in tables.
8.4.3.1.
Anti-Cancer Procedures/Surgeries  
A listing will be provided for procedure/surgery including indication and date of 
procedures/surgeries. All prior, concomitant and follow-up procedures will be summarized in 
frequency tabulations (subject counts and percentages) and by SOC and PT.
8.4.3.2.
Radiations  
The number and percentage of subjects who had any prior/follow-up radiation therapy will be 
presented by treatment group for the safety and ITT populations. Summaries will include total 
frequency of subjects receiving any prior/follow-up radiation therapy, as well as the frequency by 
type of radiation therapy received (i.e., external beam, radio-immuno therapy, brachytherapy, 
etc.) will be presented by treatment group and overall. For subjects with radiation therapy, 
treatment site, type of radiation therapy, location of external beam, start/stop date, dose, number 
of fraction, intent of therapy, and settings of therapy will be presented in a listing.
8.4.3.3.
Systemic Anti-Cancer Medication for AML 
The number and percentage of subjects with any prior/follow-up systemic anti-cancer medication
for AML will be presented by treatment group and overall for ITT and safety populations. A 
similar summary will also be presented for medication for AML or Higher Risk MDS. A 
summary of the Follow-up AML therapies, and their associated responses will also be presented.  
For subjects with systemic anti-cancer therapy for AML, detailed information will be presented 
in a listing.
8.4.3.4.
Systemic Anti-Cancer Medication Other than AML   
The number and percentage of subjects with any prior/follow-up systemic anti-cancer therapy for 
diseases other than AML will be presented by treatment group and overall for ITT and safety 
populations. For subjects with systemic anti-cancer therapy, detailed information will be 
presented in a listing.
8.4.3.5.
Stem Cell Transplants for AML  
The number and percentage of subjects with any prior/follow-up stem cell transplants for AML 
will be presented by treatment group and overall for ITT and safety populations. For subjects 
with stem cell transplants, type, date of procedure, intent of therapy, and disease status at the 
time of HSCT will be presented in a listing.
8.4.4.
Prior/Concomitant/Follow-up Transfusions
The number of subjects receiving any transfusion product, and the number of subjects receiving 
any transfusion of particular type (red blood cells, whole blood, platelets, plasma, other) will be 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
30
summarized by treatment groups. Prior /concomitant/follow-up transfusions will be summarized 
in separate tables for the safety population.
The number of subjects who are RBC transfusion dependent versus independent at baseline, the 
median transfusion burden at baseline, the changes from dependence to independence, 
independence remaining independent achieved at least 56 days RBC transfusion independence 
during treatment period together with the time to transfusion independence and duration of 
transfusion independence will be summarized by treatment groups. 
The number of subjects who are platelet transfusion dependent versus independent at baseline, 
the median transfusion burden at baseline, the changes from dependence to independence, 
independence remaining independent achieved at least 56 days platelet transfusion independence 
during treatment period together with the time to transfusion independence and duration of 
transfusion independence will be summarized by treatment groups. 
Transfusion type, number of units, reasons for taking transfusion, and dates of transfusions will 
be listed. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
31
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
All analyses of treatment exposure will be conducted using the safety population. Only exposure 
to the AG-221, azacitidine, LDAC, and IDAC will be included in the treatment exposure 
summaries. Treatment exposure is not applicable to the BSC only treatment group. Duration of 
treatment and number of cycles will be calculated for all treatment groups, including the BSC 
only group.
Descriptive statistics for duration of treatment exposure, duration of treatment, average 
prescribed daily dose, average calculated daily dose, average daily dose, cumulative dose, dose 
intensity and relative dose intensity, will be presented by treatment groups. Individual subject 
listings will be provided to support the tables.
9.1.
Duration of Treatment Exposure and Duration of Treatment
Duration of treatment exposure and duration of treatment will be summarized by treatment 
group. 
Duration of treatment exposure (days) is defined as: Treatment end date – treatment start date + 
28 days. The treatment start date is the date of the first dose of study drug, and the treatment end 
date is the last dose date. If death date or data cut-off is earlier than 28 days after treatment end 
date, duration of treatment exposure is defined as: the earlier of death date and data cut-off –
treatment start date + 1. Duration of treatment exposure will be summarized by treatment group 
of AG-221, azacitidine, LDAC, and IDAC. For BSC only group, duration of treatment exposure 
is the same as duration of treatment defined below. 
For AG-221, azacitidine, LDAC, and IDAC groups, duration of treatment (days) is defined as:
Treatment end date – treatment start date + 1. For subjects who are still on treatment at a data 
cut-off date, treatment end date will be the earlier date of data cut-off and the last dose date. 
For BSC only group, duration of treatment is defined as the period from date of randomization 
through the date of discontinuation from the treatment period, date of death, or clinical data cut-
off date, whichever is earliest (calculated as the earliest of death, clinical data cut-off, or 
discontinuation date – randomization date + 1). Duration of treatment will be summarized for all 
treatment groups including the BSC only group.
See Section 5 for cycle length and cycle number calculations. Average cycle length (days), 
average number of days dosed per cycle, and number of treatment cycles will be summarized by 
treatment group. Average cycle length and average number of days dosed per cycle will not be 
summarized for BSC only group. The number of days dosed per cycle is defined as the number 
of days with a non–missing dosing date within that cycle. For average cycle length and average 
number of days dosed per cycle, a single average value will be computed for each subject first 
and then the descriptive statistics will be computed for each treatment group. Additionally, the
count and percent of subjects by number of cycles of treatment will be provided for each 
treatment group.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
32
Person-years of exposure will be calculated as duration of treatment exposure (days)/365.25 for 
all treatment groups except BSC only group. Person-years of exposure will be calculated as 
duration of treatment (days)/365.25 for the BSC only group.
9.2.
Cumulative Dose 
Cumulative dose will be calculated for AG-221, azacitidine, LDAC, and IDAC treatment groups.  
Cumulative dose is defined as the sum of all doses taken across the treatment period in mg.
Cumulative dose for AG-221 and LDAC = Sum of (administered dose of each visit in mg); 
Cumulative dose for IDAC = Sum of (administered dose in g/m2 of each visit).
Cumulative dose for azacitidine = Sum of (administered dose in mg/m2 of each visit).
The dosage will be counted as zero for days when the study drug is not taken.
9.3.
Dose Intensity 
Dose intensity during the treatment is defined as the cumulative dose divided by the duration of 
treatment. Dose intensity will be calculated in the following way:  
Dose intensity for AG-221 and LDAC = [cumulative dose in mg]/[duration of treatment];
Dose intensity for IDAC = [cumulative dose in g/m2]/[duration of treatment].
Dose intensity for azacitidine = [cumulative dose in mg/m2]/[duration of treatment].
9.4.
Relative Dose Intensity
Relative dose intensity is the dose intensity divided by the planned dose intensity. 
For AG-221, the planned dose intensity is based on the assigned dose each time.
For LDAC, subjects randomized to LDAC treatment option will receive cytarabine 20 mg SC 
BID for the first 10 days of each every 28-day treatment cycle. Therefore, the planned dose 
intensity is 14.3 mg/day throughout the study;
For azacitidine, subjects in this group will receive 75 mg/m2/day for 7 days of each 28-day 
treatment cycle, so the planned dose intensity is 18.75 mg/m2/day;
For IDAC, subjects randomized to IDAC treatment option will receive cytarabine 0.5 to 1.5 g/m2
IV for the first 3 to 6 days of each 28-day treatment cycle. The dosing schedule is flexible with 
each site, so for calculation purpose, prior to the final analysis, the planned dose intensity for one 
specific cycle will be calculated in the following way:
Planned dose intensity = [dose administered (g/m2) x actual duration (Days)]/28, which equals to 
X.X g/m2/day.
Relative dose intensity for all four drugs mentioned above will be categorized into < 75%, 75% 
to < 90%, and > 90%, and frequency counts will be provided by treatment group.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
33
9.5.
Average Daily Dose
Average daily dose during treatment is defined as the cumulative dose divided by number of 
days dosed. A single average value will be computed for each subject, overall and within each 
cycle, and then the descriptive statistics will be computed for each treatment group. Average 
daily dose will be summarized for the prescribed daily dose (mg/day for AG221 and LDAC; 
g/m2/day for IDAC; and mg/m2/day for azacitidine), and the total daily dose.
9.6.
Dose Modification
This part does not apply to BSC only group. 
The number of subjects who have at least one dose modification, number of dose modifications
per subject, and reasons for dose modifications will be summarized by treatment group. Details 
of dose adjustments will be provided in a by subject listing.
According to protocol, under specific circumstances, AG-221 dose may increase for augmenting 
treatment responses. Number of subjects who undergo dose escalation, number of subjects who 
have dose modification after dose escalation will be summarized. Reasons for dose modifications 
after dose escalations will also be summarized. 
9.7.
Compliance
Overall and by cycle study medication compliance, which is measured by relative dose intensity 
(see Section 9.4 for details), will be summarised by treatment. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
34
10.
EFFICACY ANALYSIS
All efficacy analysis will be performed on the ITT population unless otherwise specified. Key 
efficacy analyses will also be performed on the mITT population as supportive evidence and to 
assess the robustness of the efficacy findings. Subjects will be analyzed according to randomized 
treatment group. Statistical comparisons will be made between AG-221 and CCR overall and by 
pre-selected CCR therapy whenever applicable. 
All statistical tests will be two-sided at the significance level of 0.05, and the corresponding two-
sided p-values and two-sided 95% confidence interval (CI) for intended point estimates will be 
reported, unless specified otherwise.
10.1.
Multiplicity 
In order to perform hypothesis testing on multiple endpoints while controlling the overall Type I 
error rate, a closed, sequential testing approach is proposed to test endpoints in a pre-specified 
order. The primary efficacy endpoint of OS will be tested first at a two-sided significance level 
of 0.05. If superiority of AG-221 is demonstrated in OS, then the first key secondary endpoints 
of overall response rate (ORR) will be tested next. The second key secondary endpoint of the
event-free survival (EFS) will be tested only if the test results for both OS and ORR are 
significant each at a two-sided 0.05 significance level. The interim superiority analysis adopts 
Lan-DeMets version of the O’Brien-Fleming alpha spending function to control the overall Type 
I error rate.  The alpha spending completed in the interim analysis is further detailed in Section 
12.2 of this document. The multiplicity strategy is applied to hypothesis tests between AG-221 
and CCR overall group only.
10.2.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint of OS is defined as the time between randomization and death 
from any cause. Subjects who are alive or whose death status is unknown will be censored at the 
last date known alive on or before data cutoff date. The OS period in months is calculated as (the 
earlier of death date/the last date known alive and cutoff date – date of randomization + 
1)/30.4375. For subjects who were known to be alive and in the study at data cut-off (were not 
lost to follow-up, and had not withdrawn consent), the last known-to-be-alive date is set to be the 
data cut-off date. 
The analysis of the primary endpoint will be based on the ITT population. Subjects will be 
analyzed as they were randomized, regardless of the actual treatment received. The survival 
distribution of OS will be estimated using Kaplan-Meier (KM) method. The 25th percentile, 
median and 75th percentile of OS including two-sided 95% CI for each treatment arm will be 
provided, and their differences with 95% CIs between two arms will be calculated using Kosorok’s 
method. KM curves will be provided by treatment arm in figures. 
A stratified log-rank test will provide the pivotal p-value for the comparison of the two survival
curves of AG-221 vs. CCR arm overall. Hazard ratio and its two-sided 95% CI will be estimated 
from a stratified Cox proportional hazards regression model. The stratification factors are:
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
35

Prior intensive therapy for AML: yes versus no 

Primary refractory: yes versus no  

Prior allogeneic HSCT for AML: yes versus no
They are assessed by investigators and captured both in the IVRS system at the time of screening
phase and in the CRF. In case the site made a stratification error at the time of 
screening/randomization, stratification errors are corrected in the CRF. Stratified analysis will 
use stratification factors taken from the CRF. If data does not converge in the stratified analysis 
due to small sample size in stratum or if there are less than 40 subjects in a stratum, the 
stratification factor leads to least subjects will be dropped from the model.
Reasons for censoring (e.g., lost to follow-up, withdrew consent, alive at data cut-off, 
Discontinuation due to other reasons) will be summarized (n, percent) for the OS endpoint. 
An unstratified log-rank analysis and Cox regression will be considered as supporting analyses.
Stratified analyses based on IVRS stratification factors will be included as a sensitivity analysis.
The analyses on the primary endpoint will be repeated for AG-221 versus BSC Only, Azacitidine 
+ BSC, LDAC + BSC, IDAC + BSC individually by pre-selected CCR therapy.
In addition, sensitivity analyses will be done in the following ways:
1. Analysis of OS using mITT population;  
2. Censoring subjects at the time of transplantation after study treatments; 
3. Censoring subjects at the start date of any subsequent AML therapy;
4. Censoring subjects at the start date of any subsequent therapy for diseases other than 
AML excluding the use of hydroxyurea;
5. Censoring subjects for subsequent treatment of AG-221 after initial CCRs;
6. Inverse Probability of Censoring Weighted (IPCW) method censoring subjects at off-
protocol AG-221;
7. IPCW method censoring subjects at any subsequent AML therapies if applicable;
8. Rank Preserving Structural Failure Time (RPSFT) model adjusting the confounding 
effect of off-protocol AG-221 if applicable;
9. Regression based imputation method adjusting subsequent AML therapies if applicable.
At the final analysis, the assumption of proportional hazards will be tested using a time-
dependent Cox model with categorical variables for survival time (e.g., 0 – 3 months, 3 – 6 
months, 6 – 9 months, etc.) and with following covariates:

Treatment

Prior intensive therapy for AML (yes, no) from CRF;

Prior refractory (yes, no) from CRF;

Prior stem cell transplants for AML (yes, no) from CRF;
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
36
If the model does not converge due to small sample size, the covariate leads to least subjects will 
be dropped from the model.  If a stratification factor covariate has less than 40 subjects in one of 
its levels across treatment groups, then this factor will not be used in stratified analysis;
A statistically significant estimation of any of these survival time categories indicates that the 
proportional hazard assumption is violated. A figure of smoothed hazard function over time will
give an instinct idea of hazard trend over time.
If proportional hazard assumption is violated, the following sensitivity analyses will be 
conducted using ITT population: 
1. Restricted mean survival time will be calculated between AG-221 and CCR arms;
2. Piecewise cox regression will provide hazard estimates for every 3 months;
3. Piecewise cox regression will provide hazard estimates for every 6 months;
4. In the presence of non-proportional and early OS separation, a generalized Wilcoxon test 
will be utilized to compare survival curves.
A number of subgroups analyses will also be carried out.  For details see Section 10.4.
Additionally, the primary endpoint will be repeated for a dose level group analysis of AG-221 
subjects who had at least one dose > 100mg during the study versus those who received only 
dose ≤100mg.
10.3.
Analyses of Secondary Efficacy Endpoints
The time-to-event secondary efficacy variables will be analyzed similarly to the primary efficacy 
variable with and without stratification when appropriate. KM methods will be used to estimate 
time-to-event curves, and hazard ratio and its two-sided 95% confidence interval (CI) will be 
estimated from Cox proportional hazards regression model, unless otherwise specified. Counts 
and percentages will be used to describe categorical secondary variables. 
All secondary efficacy endpoints will be analyzed based on ITT population and key efficacy
analysis will be performed on the mITT population as supportive evidence and to assess the 
robustness of the efficacy findings. Subjects will be analyzed according to randomized treatment 
group. 
Throughout, summaries of Complete Remission will include both CR and CRc responses, and 
will be displayed as CR. CRc will be summarized separately once, and otherwise will be
displayed in combined categories as CR.
10.3.1.
Key Secondary Endpoints
The key secondary efficacy endpoints include ORR and EFS assessed by an Independent 
Response Assessment Committee (IRAC) and by local investigators based on modified 
International Working Group (IWG) AML response criteria. Details of the procedure used to 
proceed IRAC assessed IWG and CR/CRh responses, and the IRAC assessed HI response can be 
found in the separate IRAC Charter.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
37
10.3.1.1.
Overall Response Rate
Overall response rate (ORR) is defined as the rate of Best Response in CR + CRi + CRp + partial
remission (PR) + morphologic leukemia-free state (MLFS) according to modified IWG AML
response criteria.
The ORR will be summarized by treatment group and be compared between arms by the 
Cochran-Mantel-Haenszel (CMH) test with stratification factors:

Prior intensive therapy for AML: yes versus no 

Primary refractory: yes versus no  

Prior allogeneic HSCT for AML: yes versus no
If a stratification factor covariate has less than 40 subjects in one of its levels across treatment 
groups, then this factor will not be used in stratified analysis. This analysis based on IRAC 
assessment in the ITT population will be used as the main analysis of ORR.
As sensitivity analyses, a CMH test with the above strata will be performed in the mITT 
population. In addition, a Fisher’s exact test without stratification factors will be performed in
both ITT and mITT population. An Odds Ratio and its 95% C.I. of responders versus non-
responders between treatment arms will also be calculated. This analysis will be repeated for the 
local assessment of response as a supportive analysis of ORR.
Additionally, overall response rate will be repeated for a Dose group analysis of AG-221 
subjects who had at least one dose > 100mg during the study versus those who received only 
dose ≤100mg.
10.3.1.2.
Event-Free Survival
Event-free survival (EFS) is defined as the period from the date of randomization to the date of 
documented morphologic relapse (hereafter referred as relapse) after CR/CRi/CRp, PD
according to modified IWG AML response criteria or death from any cause, whichever occurs 
first. Subjects who are alive without any of these events will be censored at the date of their last
valid response assessment. Subjects who do not have post-randomization response assessment
will be censored at date of randomization.
If a subject begins a new anti-cancer therapy prior to documented disease progression (or death), 
the subject will be censored at the date of last assessment before starting the new anti-cancer
therapy. Subjects with two or more consecutive missing response assessments prior to 
documented progression (or death) will be censored at the last date of response assessment 
before the missing assessments.
Analysis of EFS will be similar to the analysis of OS. The stratified log-rank test based on the 
ITT population will be considered the primary analysis for EFS, with unstratified analyses and 
the analyses based on mITT populations considered supportive analyses. The analysis based on 
local assessment of response will be conducted as a supportive analysis of EFS.
Additionally, EFS will be repeated for a Dose group analysis of AG-221 subjects who had at 
least one dose > 100mg during the study versus those who received only dose ≤100mg.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
38
Table 4:
Censoring Rules for EFS
Value of Event-free Survival 
Date (ADT)
Censored 
(Y,N) 
Derivation
ADT = min(death date, 
relapse date, progression
date) 
N
If a subject died, relapsed, or had disease
progression by independent review, and the 
subject has less than two consecutive missing 
response assessments prior to a visit documented 
death, relapse, or progression which is before any 
subsequent anti-cancer therapies
ADT = the last event-free 
assessment date before
missing assessments/ 
randomization date
Y
If a subject died, relapsed, or had disease 
progression by independent review, and the 
subject has two or more consecutive missing 
response assessments prior to a visit documented 
death, relapse, or progression
ADT = the last assessment
date/randomization date 
Y
If a subject did not die, or did not have relapse or 
progression, and did not receive any subsequent 
anti-cancer therapies.
If there was no post-randomization response
assessment, then ADT = the randomization date.
ADT = the last assessment 
date on or prior to start of 
subsequent anti-cancer 
therapies/randomization date
Y
If a subject did not die, or did not have relapse or 
progression on or prior to start of subsequent 
anti-cancer therapies. 
If there was no post-randomization response
assessment on or prior to subsequent therapies, 
then ADT = the randomization date.
ADT = the last assessment 
date on or prior to start of 
subsequent anti-cancer 
therapies/randomization date
Y
If a subject died, relapsed, or had disease 
progression by independent review after receiving 
subsequent anti-cancer therapies.
If there was no post-randomization response 
assessment on or prior to subsequent therapies, 
then ADT = the randomization date.
ADT = analysis date; N = no; Y = yes.
Note: Event-free response refers to a response that was neither morphologic relapse, 
progressive disease (PD) nor death.
Sensitivity analyses for EFS will be done with the following censoring rules:
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
39

Subjects with two or more consecutive missing response assessments prior to an 
event date (death, relapse or disease progression) will not be censored at the last date 
of last response assessment before the missing assessment; 

Subjects with subsequent anti-cancer therapies or with two or more consecutive 
missing assessments prior to an event date will not be censored;

Subjects with subsequent transplantation after treatment will not be censored;

Subjects with off-protocol AG221 prior to an event will not be censored;

Subjects with any anti-cancer therapies (including AML therapy, any therapy for 
diseases other than AML excluding hydroxyurea) prior to an event date will not be 
censored.
Other sensitivity rules may be added when data is applicable.
10.3.2.
Other Secondary Endpoints
The other secondary endpoints include duration of response, time to response, rates of overall 
remission, CR, complete remission rate and HI rates assessed by an IRAC and by local 
investigators according to modified IWG AML response criteria and IWG myelodysplastic
syndromes (MDS) HI criteria, treatment mortality at 30- and 60-day, one-year survival, rate of 
HSCT and time to treatment failure. CR/CRh rate, duration of CR/CRh, and time to CR/CRh 
assessed by IRAC only and using a sponsor derived assessment will also be presented.
10.3.2.1.
Duration of Response
Duration of response is defined as time from first documented CR/CRi/CRp/PR/MLFS to 
documented morphologic relapse, PD, or death due to any cause, whichever occurs first. 
Subjects without morphologic relapse, PD, or death due to any cause will be censored at the date 
of the last valid response assessment. 
The duration of response will be analyzed using the KM method. The 25th percentile, median and 
75th percentile time (including two-sided 95% CI) will be summarized for each treatment arm. 
Only subjects with documented CR/CRi/CRp/PR/MLFS response as determined by the IRAC 
will be included in the analysis. Investigator assessed results will be summarized as a supportive 
analysis.
10.3.2.2.
Time to Response
Time to response is defined as time from randomization to first documented 
CR/CRi/CRp/PR/MLFS. 
Time to response will be summarized with descriptive statistics in subjects with documented 
CR/CRi/CRp/PR/MLFS response as determined by the IRAC. Number of subjects who attain 
first response in a given cycle will also be summarized. Investigator assessed results will be 
summarized as a supportive analysis.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
40
10.3.2.3.
Time to Best Response
Time to best response is defined as time from randomization to the documented best response of 
CR/CRi/CRp/PR/MLFS. 
Time to best response will be summarized with descriptive statistics in subjects with documented 
CR/CRi/CRp/PR/MLFS response as determined by the IRAC. Number of subjects who attain 
best response in a given cycle will also be summarized. Investigator assessed results will be 
summarized as a supportive analysis.
10.3.2.4.
Treatment Mortality at 30- and 60-Day
Treatment mortality at 30- and 60-day is defined as rate of death from any cause within 30 or 
60 days of initiation of study treatment.
Number and percentage of deaths at 30- and 60-day will be summarized for each treatment arm. 
Treatment mortality at 30- and 60-Day will also be evaluated by KM estimate for both AG-221 
and CCR treatment groups. 
10.3.2.5.
One-Year Survival
One-year survival is defined as the probability of survival at 1 year from randomization.
One-year survival will be evaluated by KM estimate with 95%CI for each treatment arm. 
Difference between the two treatment groups and corresponding two-sided 95% CI will also be 
displayed. The CI for the difference in the 1-year survival probabilities will be derived using 
Greenwood's variance estimate.
10.3.2.6.
Overall Remission Rate
Overall remission rate is defined as rate of CR + CRi + CRp according to modified IWG AML 
response criteria per IRAC.
Number and percentage of subjects with overall remission will be summarized by treatment 
groups. Comparisons between AG-221 and CCR will be analyzed by Fisher’s exact test. 
Investigator assessed results will be summarized as a supportive analysis
10.3.2.7.
Complete Remission Rate
Complete remission rate is defined as rate of CR according to modified IWG AML response 
criteria per IRAC.
Number and percentage of subjects with complete remission will be summarized by treatment 
groups. Comparisons between AG-221 and CCR will be analyzed by Fisher’s exact test. 
Investigator assessed results will be summarized as a supportive analysis
10.3.2.8.
Hematologic Improvement Rate
Hematologic improvement rate is defined as rate of neutrophil response (hematologic 
improvement neutrophil response [HI-N]) + platelet response (hematologic improvement platelet 
response [HI-P]) + erythroid response (hematologic improvement erythroid response [HI-E]) 
according to IWG MDS HI criteria (Section 15.6).
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
41
Number and percentage of subjects with hematologic improvement will be summarized by 
treatment groups. Comparisons between AG-221 and CCR will be analyzed by Fisher’s exact 
test. 
Subjects who achieved post-baseline 56-day RBC transfusion independence, i.e., without RBC 
transfusion for at least 56 consecutive days post baseline during treatment exposure period, will 
be summarized by baseline RBC transfusion dependence status (Yes vs. No), within each 
category of best response (e.g., CR, CRi/CRp, PR/MLFS, SD, PD, etc.) and overall. Subjects 
with at least one transfusion during the baseline period (defined as within 56 days before the first 
dose date) are considered transfusion dependent at baseline. Time to transfusion independence
will be summarized for the subject’s first transfusion independence, and duration of the 
independence will be summarized using the transfusion independence with the longest duration
experienced by a subject. 
The post-baseline 56-day Platelet transfusion independence will be analyzed similarly.
10.3.2.9.
Rate of HSCT
Rate of HSCT is defined as rate of bridge-to-HSCT through study treatment. This analysis is for
the subjects who proceeded to a subsequent HSCT immediately after discontinuation of the study 
drugs. Subjects who received systemic anti-cancer page for AML after discontinuation of the 
study drugs and later underwent a subsequent HSCT are not included.
Number and percentage of subjects with HSCT will be summarized by treatment groups. 
Comparisons between AG-221 and CCR will be analyzed by Fisher’s exact test. In addition, 
Numbers and percentages of subjects who with HSCT after reaching CR/CRi/CRp or without 
CR/CRi/CRp will be summarized.
10.3.2.10. Time to Treatment Failure
Time to treatment failure is defined as time from randomization to discontinuation of study 
treatment due to any cause. For BSC subjects, the duration is from randomization to the date of 
treatment discontinuation or the last visit date if still ongoing. For subjects received treatment 
other than BSC, the duration is from randomization to the last dose date or day before start of 
non-BSC treatment whichever occurs first; subjects who have completed the study treatment or 
are still active will be censored at last dose date.
The time to treatment failure will be analyzed using the KM method. The 25th percentile, median 
and 75th percentile time (including two-sided 95% CI) will be summarized for each treatment 
arm; the associated HR with two-sided 95% CI will be estimated using Cox proportional hazard 
models with and without stratification factors. A stratified and an unstratified log-rank tests will 
provide the pivotal p-value for the comparison between AG-221 and CCR arm.
10.3.2.11. CR/CRh Rate
CR/CRh rate is the rate of CR or CRh where CRh is defined as partial hematologic recovery that 
achieves all criteria of CR except ANC and platelet criteria.  For CRh, those criteria are:

ANC > 0.5 x 109/L; and
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
42

Platelet > 50 x 109/L
Number and percentage of subjects with CR/CRh will be summarized by treatment groups. 
Comparisons between AG-221 and CCR will be analyzed by Fisher’s exact test. 
CR/CRh assessed by IRAC only and using a sponsor derived assessment.
10.3.2.12. Duration of CR/CRh
Duration of CR/CRh is defined as time from first documented CR or CRh to documented 
morphologic relapse, PD, or death due to any cause, whichever occurs first. Subjects without 
morphologic relapse, PD, or death due to any cause will be censored at the date of the last 
response assessment. 
The duration of CR/CRh will be analyzed using the KM method. The 25th percentile, median and 
75th percentile time (including two-sided 95% CI) will be summarized for each treatment arm. 
Only subjects with CR/CRh response will be included and will be summarized for both IRAC 
and sponsor assessed responses. 
10.3.2.13. Time to CR/CRh
Time to CR/CRh is defined as time from randomization to first documented CR/CRh. 
Time to CR/CRh will be summarized with descriptive statistics in subjects with documented 
CR/CRh as determined by IRAC and sponsor assessment. It will also be summarized by cycle.
10.4.
Subgroup Analysis
Appropriate subgroup analyses for primary and key secondary efficacy endpoints (ORR and 
EFS) by the following subgroups:
1. Age groups (≥60 years and <70 years, ≥70 years and <80 years, ≥80 years);
2. Gender (male and Female);
3. Region (North America, South America, Europe, Asia, Australia; US, non-US); 
4. Race;
5. Prior systemic anti-cancer therapies for AML (2nd versus 3rd lines);
6. Baseline cytogenetic risk status (better-risk, intermediate-risk, poor-risk, failure);
7. IDH2 gene mutate type (R140 vs. R172);
8. AML initial diagnosis (primary or secondary);
9. WHO classification of AML;
10. ECOG performance status at baseline (Grade 0, 1, 2, 3);
11. Prior intensive therapy for AML (yes versus no) (IVRS and CRF source);
12. Primary refractory (yes versus no) (IVRS and CRF source);
13. Prior allogeneic HSCT for AML (yes versus no) (IVRS and CRF source);
14. ELN risk classification
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
43
15. Non-Protocol Definition Primary Refractory, defined as having at least 2 lines prior AML 
or Higher MDS treatment and never attained CR, Cri, or CRP ( yes versus no).
A forest plot will be provided based on the HRs for each subgroup. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
44
11.
SAFETY ANALYSIS
All analyses of safety data will be conducted using the safety population unless otherwise 
specified. Safety summaries based on the safety population will be provided by treatment and 
pre-specified CCR option (Overall, BSC only, Azacitidine + BSC, LDAC + BSC, IDAC + BSC). 
Dosing summaries will be carried out for each study drug separately.
For summaries of safety data, the treatment period is defined as follows: 
• AG-221, azacitidine, LDAC and IDAC AZA: date of first dose through date of last dose + 28 
days, or until the EOT visit, whichever is longer; 
• BSC only: date of randomization through date of treatment discontinuation. 
11.1.
Adverse Events
Adverse events will be analyzed in terms of treatment-emergent adverse events (TEAEs) which 
are defined as any AEs that begin or worsen on or after the start of study drug through 28 days 
after the last study treatment or until the EOT visit, whichever is longer, as well as those serious 
adverse events (SAEs) made known to the Investigator at any time thereafter that are suspected 
of being related to investigational product. All AEs will be coded using the Medical Dictionary 
for Regulatory Affairs® (MedDRA) version 22.0. The severity will be graded by the study 
personnel based on NCI National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03.
A treatment-related TEAE is defined as TEAE that is suspected by the Investigator to be related 
to study treatment. 
If a subject experiences the same AE more than once with different toxicity grade, then the event 
with the highest grade will be tabulated in “by grade” tables. If a subject experiences multiple
AEs under the same preferred term (system organ class), then the subject will be counted only 
once for that preferred term (system organ class). 
Summarizations of TEAEs per person-year of exposure are carried out in exposure-adjusted 
event rate, which is defined as number of events occurred in treatment exposure duration.
The number of subjects with at least one TEAE will be summarized. The incidence of TEAEs 
will be summarized by alphabetic order of SOC and descending order of PT for AG-221 group.
Tables summarizing the incidence of TEAEs will be generated for each of the following:

Summary of TEAEs;

All TEAEs by SOC and PT;

All TEAEs by decreasing frequency of PT for AG-221;

All TEAEs per person-year of exposure, person-years of exposure is defined as (Sum 
of subjects’ overall treatment exposure (days) from first dose date (or randomization 
date for BSC only group) to the end of the TEAE period [c])/365.25;

TEAEs related to study treatment;

TEAEs by maximum severity;
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
45

TEAEs with CTCAE grade ≥3;

Related TEAEs with CTCAE grade ≥3;

TEAEs with CTCAE grade ≥3 per person-years exposure;

Related TEAEs with CTCAE grade ≥3 per person-years exposure;

All AEs resulting in death;

Serious TEAEs;

Serious TEAEs per person-years exposure;

All serious TEAEs by decreasing frequency of PT for AG-221;

Serious TEAEs related to study treatment;

Serious TEAEs related to study treatment per person-years exposure;

TEAEs leading to study drug withdrawal;

TEAEs leading to study drug withdrawal per person-years exposure;

TEAEs related to study drug and leading to study drug withdrawn;

TEAEs with leading to dose reduction;

TEAEs with leading to dose reduction per person-years exposure;

TEAEs related to study drug and leading to study drug dose reduction;

TEAEs leading to study drug dose interruption;

TEAEs leading to study drug dose interruption per person-years exposure;

TEAEs related to study drug and leading to study drug dose interruption;

TEAEs leading to study drug dose reduction and dose interruption;

TEAEs related to study drug and leading to dose reduction and study drug dose 
interruption;

TEAEs for the following baseline subgroups (provided when the number of subjects 
is sufficient): 

Gender (male and female); 

Age (≥60 years and <70 years, ≥70 years and <80 years, ≥80 years);

Region (North America, South America, Europe, Australia, Asia; US vs. Non-
US);

Baseline ECOG performance status (Grade 0, 1, 2);

Prior intensive therapy for AML (yes versus no) (IVRS and CRF source);

Primary refractory: yes versus no  

Prior allogeneic HSCT for AML (yes versus no) (IVRS and CRF source);
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
46

Baseline ANC value (≤0.5x109/L, 0.5<1x109/L, ≥1x109/L)

Baseline creatinine clearance value (<45, 45-<60, ≥60 mL/min);

Best clinical response (CR, PR, SD, PD) adjusted by person years on treatment.
In addition, the impact of dose escalation to AEs will be explored. Sensitivity analyses will be 
carried out for the following two tables:

All TEAEs by AG-221 ≤100 mg and AG-221 > 100 mg cohorts:
AEs which occurred in subjects which only received doses of AG-221 ≤100mg, and 
AEs which occurred prior to a dose switching to > 100 mg for subjects which had an 
escalated dose, or AEs which occurred following a reduction to <=100mg following 
an escalation are to be counted in ≤100 mg cohort.  Only AEs which occurred after a 
dose > 100 mg was administered and occurred within 28 days following this dose 
administration, and where there were no subsequent dose reductions between 
escalated dose date and AE start date will be counted in the > 100 mg cohort.

TEAEs with CTCAE grade ≥3 by AG-221≤100 mg and AG-221 > 100 mg cohorts.
Listings for the corresponding summary tables will be presented separately. Non-treatment-
emergent AEs will also be included in one of the listings. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
47
11.2.
Adverse Events of Special Interest
The following TEAEs of special interest will be summarized: 
1. QT prolongation; 
      Standardized MedDRA Query (SMQ) Torsade de pointes/QT prolongation.
2. IDH inhibitor associated Differentiation syndrome (IDH-DS);
a.
TEAE AE differentiation syndrome as reported by the investigators.
b.
Time to IDH-DS: Summary statistics including mean, standard deviation, median, 
minimum, maximum will be provided.
i. From start of treatment until an event of IDH-DS
ii. From onset until end date of an event of IDH-DS
c.
Signs and symptoms of PT IDH-DS (% of subject with specific symptom with 
denominator of N of subjects with completed CRF page for the differentiation 
syndrome). 

Symptoms of the IDH-DS (from the CRF AE page)

Treatment for IDH-DS: systemic steroids 

Mean duration of steroid treatment for the IDH-DS

Study drug interruption, discontinuation, dose adjustment due to IDH-DS
d.
Concurrency of the IDH-DS and tumor lysis syndrome PT.
3. Bilirubinemia and liver safety;
a.
SMQ Biliary system related investigations, signs and symptoms (narrow 
terms)
b.
SMQ Drug related hepatic disorders (broad terms).
c.
Time to onset and time to resolution
4. Hepatic Disorders;
5. Acute Renal Failure;
6. Pulmonary Events;
7. Peripheral Neuropathy
8. Hepatobiliary Disorders;
The following summaries will be provided for TEAEs of special interest: 

All TEAEs by PT;

Treatment related TEAEs by PT; 

Serious TEAEs by PT; 

Serious treatment related TEAEs by PT; 

TEAEs with CTCAE grade of Grade ≥3;
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
48

Treatment related TEAEs with CTCAE grade of Grade ≥3;

Time to first onset of TEAE; 
11.3.
Death
Cause of death will be collected in the CRF and will be summarized for all treated subjects with 
the following categories during on-treatment period and post-treatment period:

Death from malignant disease under study, or complication due to malignant disease 
under study

Death from adverse event (not otherwise specified)

Death from other cause

Death from unknown cause (not assessable or insufficient data)
A death listing will include deaths for all screened subjects during pre-treatment, on-treatment, 
and post-treatment period.
11.4.
Clinical Laboratory Evaluations
Clinical laboratory results will be summarized descriptively by treatment group, which will also 
include a display of change from baseline. Laboratory values outside of the normal ranges will 
be identified. Normal ranges will be used to determine the categories of High, Low, and Normal 
for laboratory tests that have no severity grade. 
Where multiple laboratory records exist for the same scheduled visit, the record closest to the
scheduled clinical visit date will be summarized. If a record exists on the same day of a 
scheduled visit date, this record will be selected.  If no such record exists then the closest record 
will be determined by first checking for a record with date one day before clinical record, then 
for a record one day after clinical record.  If neither of these exist then check two days before 
clinical record, and then two days after clinical record.  Follow a similar logic until a closest 
record can be found. If more than one record is selected using above process, then the record 
with sample type not equal to “U” will used. If a unique record still cannot be determined then an 
average of records fitting above criteria will be taken, and this will be used in summaries. 
Clinically significant hematologic and non-hematologic laboratory abnormalities that meet 
Grade 3 or Grade 4 criteria according to the NCI CTCAE 4.03 will be summarized. Where 
applicable, shift to high values will be presented separately from shift to low value (e.g.
leukocytosis and leukopenia). The worst grade during the treatment period will be summarized 
by treatment group and by cycle. Frequency distributions of CTC grade that shift from baseline 
to the worst grade during treatment period will be presented by treatment arm when data is 
applicable. Graphical display of select laboratory parameters over the course of the study will be 
provided where useful to assist in the interpretation of results.
Listings of all clinical laboratory data from central laboratory with abnormal flags will be 
provided by subjects and tests. Listings will also be provided for the local laboratory data. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
49
11.4.1.
Hematology
For specific haematological parameters (Hemoglobin, platelet counts, ANC, WBC, and RBC), 
the change from baseline to nadir value will be summarized by treatment group.
Shifts in CTCAE grades from baseline to worst grade will be summarized by treatment and by 
cycle.
11.4.2.
Serum Chemistry
For serum chemistry parameters, the change from baseline will be summarized by treatment 
group and study visit. Change in total, direct and indirect bilirubin by UGT1A1 mutation will be 
analyzed.
Shifts in CTC grades from baseline to worst grade will be summarized by treatment and by 
cycle.
The proportion of subjects with clinically significant post-baseline change in hepatic, renal 
function and electrolytes will be assessed based on the criteria presented below. 
Table 5
Serum Chemistry Changes of Interest
Laboratory Test
Parameters for any value and the last value
Alanine Aminotransferase (ALT)
CTCAE Grades ≥3
Aspartate Aminotransferase (AST)
CTCAE Grades ≥3
Total Bilirubin 
CTCAE Grades ≥3
Total Bilirubin ≥Grade 2 and ALT 
≥Grade 2
Composite of Total Bilirubin ≥Grade 2 and ALT ≥Grade 2
within 1 cycle of Total Bilirubin elevation 
Total Bilirubin ≥Grade 2 and AST 
≥Grade 2 
Composite of Total Bilirubin ≥Grade 2 and AST ≥Grade 2
within 1 cycle of Total Bilirubin elevation 
Potassium
Composite: 
Hypokalemia Grade ≥2 and >15% decrease from baseline
Hyperkalemia Grade ≥3 and >15% increase from baseline
Phosphorus
Composite: Hyperphosphatemia > ULN and >25% increase 
from baseline 
Calcium
Composite: Hypocalcemia Grade ≥3 and > 15 % decrease 
from baseline 
Magnesium
Composite: Hypomagnesemia Grade ≥2 and >25% 
decrease from baseline 
Uric Acid
Composite: Hyperuricemia >ULN and >25% increase from 
baseline 
11.4.3.
Urinalysis 
Urinalysis includes the following tests: specific gravity, glucose, ketones, blood, pH, and protein, 
and microscopic analysis. Since urinalysis will only be performed when clinically indicated after 
screening, the results will only be listed in a listing.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
50
11.4.4.
Coagulation
Coagulation includes the following tests: prothrombin time with international normalized ratio
and partial thromboplastin time. Since coagulation will only be performed when clinically 
indicated after screening, the results will only be listed in a listing.
11.4.5.
Fasting Lipid Panel 
Fasting lipid panel includes total cholesterol, low-density lipoprotein cholesterol (LDL-C), 
high-density lipoprotein cholesterol (HDL-C), and triglycerides. Lipid profiles will be described 
by concentration of the lipids at scheduled visits. The proportion of subjects with clinically 
meaningful post-baseline increase in lipids will be summarized based on criteria presented in 
Table 6 below.
Table 6:
Fasting Lipid Changes of Interest
Laboratory Test
Parameters for any value and the last value
LDL cholesterol 
>ULN and >10% increase from BL
LDL-C/HDL-C ratio
>3.5 and >10% increase from BL
11.4.6.
Cardiac Markers
Cardiac markers include creatine kinase and cardiac troponins I. Incidence of the test values 
above upper limit of normal will be summarized at scheduled visits.
11.4.7.
Females of Childbearing Potential 
Pregnancy incidences will be reported as adverse events and listed out at subject level. 
11.5.
Vital Sign Measurements
Evaluation of vital signs includes recording height (only at screening), weight, temperature, 
systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate, and respiratory rate at 
scheduled visits. 
Vital sign measurements will be listed for each subject and by scheduled visit. Descriptive 
statistics for vital signs (except height), both observed values and changes from baseline, will be 
summarized by treatment group. 
11.6.
Physical Examination
Abnormal physical examination findings will be captured as medical history (screening) and will 
be summarized as medical history or be captured as adverse events and will be summarized as 
adverse events.
11.7.
Electrocardiograms 
Electrocardiogram (ECG) parameters include heart rate, PR interval, QRS duration, RR interval, 
QT, QTc Fridericia value (QTcF) and QTc Bazett value (QTcB). QTcB is not recorded in the 
CRF page and will be calculated in the following way: QTcB=QT/sqrt (RR).
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
51
Recorded values and of ECG parameters and change from baseline values will be summarized at 
each time point by treatment group. 
In addition, at baseline and maximum post-baseline visits, the proportion of subjects having 
absolute QTcF and QTcB intervals of the following categories will be presented:

≤450 ms

> 450 to ≤500 ms

> 500 ms 
At maximum post-baseline visits, the proportion of subjects who have an increase from baseline 
in QTcF and QTcB intervals of the following categories will be presented: 

≤30 ms

> 30 to ≤60 ms

> 60 ms 
The overall ECG interpretation will be summarized by presenting the shift from baseline to worst 
by treatment group and by cycle. The overall ECG interpretation will be displayed in cross–
tabulations for each treatment. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
52
12.
INTERIM ANALYSIS
12.1.
General Information
The interim analysis for superiority was performed when approximately 65% of the expected 
numbers of deaths (i.e., approximately 163 deaths) have been reported. The interim efficacy 
analysis was performed by an unblinded study team and the results will be kept strictly
confidential in order to maintain the integrity of the study. The interim analysis results were
provided to the DMC to review and give advice to the Sponsor regarding the study conduct. The 
analysis results were not disseminated among investigators and those directly involved with the 
study conduct. The analysis was shared with regulators as needed to support regulatory 
submissions. 
Data Monitoring Committee (DMC)
An external DMC was convened. The DMC included a group of physicians with experience in 
treating subjects with AML and a statistician, all of whom are not otherwise involved in the 
study conduct. The DMC members reviewed the efficacy and safety data from the interim 
analysis and recommended whether the trial should continue according to the protocol. During 
the course of the study, the DMC members will also periodically review the safety data to ensure 
the safety of the study subjects. The detailed roles and responsibilities of DMC can be found in 
the DMC charter.
Independent statistician who conducted the unblinded analyses  
 an independent CRO, was used to conduct unblinded statistical analyses. 
 unblinded 
statisticians/programmers received the unblinded randomization codes directly from the IVRS 
system, conducted the statistical analyses, and provided the unblinded summary results to the 
DMC members. Only DMC members and 
 statisticians/programmers who performed the 
unblinded analyses could access to the unblinded summary results.
12.2.
Statistical Approaches for Control of Alpha
The type I error rate was controlled at the overall two-sided 0.05 level by using an O’Brien-
Fleming monitoring boundary with a Lan-DeMets alpha spending function. The decision rules 
were as follows: 

65% of expected events
Stop for superiority if one-sided p-value ≤0.0055 (HR ≤0.6715)

100% of expected events 
Claim success if one-sided p-value ≤0.0233 (HR ≤0.7775)
The actual levels used depended on the actual number of events observed at the interims and the 
final analyses. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
53
At the time of the interim analysis, the death rate was evaluated relative to the study 
assumptions, and enrollment into the study may be increased to ensure that the required number 
of 250 deaths can be reached in a reasonable time period.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
54
13.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
Additional analysis of the Transfusion Independence of subjects will be conducted, which is not 
mentioned in the Protocol.  For details see Section 10.3.2.8 of this SAP.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
55
14.
REFERENCES
David L. DeMets, K. K. Gordon Lan. Lan-DeMets Alpha-Spending Function. John Wiley & 
Sons, Inc. 2008
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group for diagnosis, standardization of response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in Acute Myeloid 
Leukemia. J Clin Oncol. 2003 Dec; 21(24):4642-4649.  
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al.  
Clinical application and proposal for modification of the International Working Group (IWG) 
response criteria in myelodysplasia. Blood 2006; 108 (2):419-25.
Kosorok, MR. Two-sample quantile tests under general conditions. Biometrika 1999;86:909-
921.
Robins JM, Finkelstein DM. Correcting for noncompliance and dependent censoring in a AIDS 
clinical trial with inverse probability of censoring weighted (IPCW) log rank tests. Biometrics 
2000; 56:779-788.
Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models Commun. Statist.-Therory Meth. 1991; 20 (8): 2609-
2631.
Luo X, Li M, Wu C, Xu Q, Chen G, Dornseif BE, Renschler MF, Koch G. A proposed approach 
for analyzing post-study therapy effect in survival analysis. J Biopharmaceutical Statistics 2016; 
26 (4): 790-800
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
56
15.
APPENDICES 
15.1.
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in 
DDMMMYYYY format (i.e., the Date9. datetime format in SAS). Dates in the clinical database 
are classified into the categories of procedure dates, log dates, milestone dates, outcome dates, 
and special dates.

Procedure Dates are the dates on which given protocol-specified procedure are 
performed. They include the dates of laboratory testing, physical examinations, etc. 
They should be present whenever data for a protocol-specified procedure are present 
and should only be missing when a procedure are marked as NOT DONE in the 
database. Procedure dates will not be imputed.

Log Dates are dates recorded in CRF data logs. Specifically, they are the start and 
end dates for AE and concomitant medications/procedures. They should not be 
missing unless an event or medication is marked as ongoing in the database. 
Otherwise, incomplete log dates will be imputed according to the rules in Section 
15.2 (e.g., for duration or cycle assignment, etc.). However, in listings, log dates will 
be shown as recorded without imputation.

Milestone Dates are dates of protocol milestones such as randomization, study drug 
start date, study drug termination date, study closure date, etc. They should not be 
missing if the milestone occurs for a subject. They will not be imputed.

Outcome Dates are dates corresponding to study endpoints such as survival, 
progression, etc. In most cases they are derived either from a milestone (e.g., the 
survival date is derived from the death date), or a procedure date (e.g., the progression 
date is derived from the date of the hematology lab that was used to determine
progression). They may be subject to endpoint-specific censoring rules if the outcome 
did not occur but are not otherwise subject to imputation.

Special Dates cannot be classified in any of the above categories and they include the 
date of birth. They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
15.1.1.
Calculation Using Dates
Calculations using dates (e.g., subject’s age or relative day after the first dose of study drug) will 
adhere to the following conventions: 

Study days after the start day of study drug will be calculated as the difference 
between the date of interest and the first date of dosing of study drug (e.g., 
lenalidomide) plus 1 day. The generalized calculation algorithm for relative day is the 
following: 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
57
o
If TARGET DATE ≥DSTART then STUDY DAY = (TARGET DATE –
DSTART) + 1; 
o
Else use STUDY DAY = TARGET DATE – DSTART.
Note that Study Day 1 is the first day of treatment of study drug. Negative study days 
are reflective of observations obtained during the baseline/screening period. Note: 
Partial dates for the first study drug are not imputed in general. All effort should be 
made to avoid incomplete study drug start dates. Some analyses may exclude subjects 
without study drug start date. The SAP may be amended on a case-by-case basis, 
including guideline and suggestion such as imputing Day 1 by consent date of treated 
subject.

Age (expressed in days) is calculated: AGE = CONSENT – DATE of BIRTH + 1. In 
practice, age will be transformed to years by dividing the difference by 365.25 days, 
then truncating.

Preference is for using calculated age from clinical database. When not available, 
calculated age from CRF or IVRS may be used

Partial birth date: impute missing day as 15th of the month; impute missing month 
as July; set missing age for missing year

Intervals that are presented in weeks will be transformed from days to weeks by using 
(without truncation) the following conversion formula:
WEEKS = DAYS /7

Intervals that are presented in months will be transformed from days to months by 
using (without truncation) the following conversion formula:
MONTHS = DAYS /30.4375
15.1.2.
Calculation of Cycles 
In this study, subjects meeting inclusion/exclusion criteria will be randomized 1:1 via IVRS into 
1 of 2 treatment arms to receive either AG-221 or CCR (one of the four options). Dose 
modification is permitted according to the protocol. The start date of each cycle will be 
calculated as follows:
The start date of a new cycle is the scheduled interval start date since there is no prescribed 
treatment break. One cycle is considered as 28 days. All qualified cycles will be sorted as the 
calculated cycle. An algorithm will be implemented to ensure that there are no gaps between 
Cycle X end date and Cycle X+1 start date. Details of the applied algorithm can be found in the 
Analysis Dataset specifications for the study.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
58
15.2.
Date Imputation Guideline
15.2.1.
Impute Missing Start/Stop Dates for Adverse Events/ Prior or Concomitant 
Medications 
Partially missing AE start dates will be imputed in the Analysis Data Model (ADaM) dataset for 
AEs, but partially missing AE end dates will not be imputed in the same dataset. If the AE end 
date is complete with no missing year, month, or day, and the partially missing start date imputed 
by the rules below is after the AE end date, then the start date will be imputed by the AE end 
date.
Partially missing start/stop dates for prior/concomitant medications and partially missing start 
dates for prior/concomitant procedures will be imputed in the ADaM dataset for 
prior/concomitant medications/procedures. For prior/concomitant medications, if the stop date is 
complete with no missing year, month, or day, and the partially missing start date imputed by the 
rules below is after the stop date, then the start date will be imputed by the stop date.
Incomplete Start Date: If the stop date is not missing, and the imputed start date is after the 
stop date, the start date will be imputed by the stop date.
Missing day and month

If the year is the same as the year of the first dosing date, then the day and month of 
the first dosing date will be assigned to the missing fields.

If the year is prior to the year of first dosing date, then December 31 will be assigned 
to the missing fields.

If the year is after the year of first dosing, then January 1 will be assigned to the 
missing fields.
Missing day only 

If the month and year are the same as the year and month of first dosing date, then the 
first doing date will be assigned to the missing day.

If either the year of the partial date is before the year of the first dosing date or the 
years of the partial date and the first dosing date are the same but the month of partial 
date is before the month of the first dosing date, then the last day of the month will be 
assigned to the missing day.

If either the year of the partial date is after the year of the first dosing date or the 
years of the partial date and the first dose date are the same but the month of partial 
date is after the month of the first dosing date, then the first day of the month will be 
assigned to the missing day.

If the stop date is not missing, and the imputed start date is after the stop date, the 
start date will be imputed by the stop date. 
Missing day, month, and year
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
59

No imputation is needed, the corresponding AE will be included as TEAE if end date 
of AE is after the first dose date or the end date is also missing. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year of the last dosing date, 
then the day and month of the last dosing date will be assigned to the missing fields. 

If the year of the incomplete stop date is prior to the year of the last dosing date or 
prior to the year of the first dosing date, then December 31 will be assigned to the 
missing fields. 

If the year of the incomplete stop date is prior to the year of the last dosing date but 
is the same as the year of the first dosing date, then the first dosing date will be 
assigned to the missing date. 

If the year of the incomplete stop date is after the year of the last dosing date, then 
January 1 will be assigned to the missing fields.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year 
of the last dosing date, then the day of the last dosing date will be assigned to the 
missing day. 

If either the year of the partial date is not equal to the year of the last dosing date or 
the years of the partial date and the last dosing date are the same but the month of 
partial date is not equal to the month of the last dosing date, then the last day of the 
month will be assigned to the missing day. 
15.2.2.
Medical History
Partially missing medical history start dates will be imputed in the ADaM dataset for medical 
history. The 16th of the month will be used to impute a partially missing start date that has only 
the day missing, and July 1st will be used to impute a partially missing start date that has both the 
month and day missing.
15.3.
Independent Response Assessment Committee 
Response to treatment is assessed locally by the Investigators and centrally by an IRAC 
according to modified IWG AML response criteria through collection of hematology laboratory 
parameters, peripheral blood smear, bone marrow aspirates and/or biopsies, and cytogenetics. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
60
15.4.
Table of Events
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Days -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Informed Consent
c
IVRS Registration and Calls

d



Inclusion & Exclusion Criteria

e, f
Demographics

Initial AML Diagnosis

Prior AML Therapies

AML Disease Status
g
Central Testing of IDH2 Gene 
Mutations on BMA and PB
g
Medical History

Prior Medications and 
Procedures
h
Eligibility of CCR Options
i
EORTC QLQ-C30 and 
EQ-ED-5L




ECOG Performance Status





Physical Exam j





Vital Signs









Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
61
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Height

Body Weight





BSA Calculation k




ECHO / MUGA Scan l
m
As clinically indicated
12-Lead ECG l






Pregnancy Test (FCBP only) n
o
l, p
l
l
l
Urinalysis o

As clinically indicated
Coagulation Laboratory o

Hematology Laboratory o









q
Chemistry Laboratory o






UGT1A1 Gene Mutation Test o
(for Diagnosis of Gilbert’s 
syndrome; refer to Section 4.2)

Cardiac Markers o
f
r
Fasting Lipid Laboratory o
f
s
Adverse Event
Continuous starting after signing ICF until 28 days after the last study treatment or until the EOT visit, whichever is longer
Concomitant Medications and 
Procedures
Continuous until 28 days after the last study treatment or until the EOT visit, whichever is longer
Transfusions
u
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
62
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
BMA for Assessing Disease 
Status /Response to Treatment v
g
w
x
y
z
q
BMB dd
g
w
x
y
z
q
PB Smear
g
w
x
y
z
q
Cytogenetics Testing
g
w, ee
x, ee
y, ee
z, ee
q, ee
Response and HI
w
x
y
z
q
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
63
Events
Screening Phase
Treatment Phase a
Follow-up Phase a
Screening
28-day cycles
EOT b
Follow-up
Cycles 1 to 2
Cycles 3 to 4
Cycle 5 and 
beyond
Day -28 to -1
Day 1
Day 8
Day 15
Day 22
Day 1
Day 15
Day 1
Treatment Accountability ii
jj



IP Dispensation



Treatment Administration
See protocol Section 7.2 for details
Survival Follow-up
kk
Subsequent AML Therapies
kk
Abbreviations: AML = acute myeloid leukemia; β- hCG = β-subunit of human chorionic gonadotropin; BMA = bone marrow aspirate; BSA = body surface area; 
CCR = conventional care regimen; CR = morphologic complete remission; ECHO = echocardiogram; eCRF = electronic case report form; 
ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC= European Organization for Research and Treatment of Cancer; 
FCBP = female of childbearing potential; EOT = End of Treatment; HI = hematologic improvement; HRQoL = Health-related Quality of Life; 
HSCT = hematopoietic stem cell transplantation; ICF = informed consent form; IDH2 = isocitrate dehydrogenase isoform 2; IP = investigational product; 
IVRS = Interactive Voice Response System; IWG = International Working Group; MUGA = multi-gated acquisition; 
 
PB = peripheral blood; SOC = standard of care; UGT1A1 = uridine diphosphate-glucuronosyltransferase 1 family, polypeptide A1.
a Study Treatment is to be initiated on Day 1 of each treatment cycle.  One treatment cycle (one month) is considered as 28 days (i.e., 4 weeks).  Unless noted 
otherwise, an administrative window of ± 3 days is permitted for all subsequent visits after the start of study treatment in the Treatment Phase.  Day 1 of 
Cycles 2 and beyond may be delayed from Day 28 of the prior cycle in order for subjects to recover from toxicity and meet criteria for initiating each treatment 
cycle (protocol Section 7.2).  The study visit window for EOT or monthly-scheduled survival follow-up is ± 7 days.  
b See protocol Section 6.2.3 for details.
c Including informed consent for mandatory genetic testing 
.
d The subject should start study treatment (i.e., Day 1 of Cycle 1) within 3 days after randomization.
e Subject should continue to be eligible for study entry prior to the start of study treatment on Day 1 of Cycle 1.
g See protocol Section 6.1 for details regarding collecting BMA, BMB, PBS and cytogenetics at screening for assessing AML disease status, collecting BMA and 
PB at screening for central testing IDH gene mutations
. 
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
64
h All prior medications (prescription and non-prescription) taken and treatment procedures received from the 4-week period (i.e., 28 days) prior to starting study 
treatment (including those prior to the start of study treatment on Day 1 of Cycle 1), and all prior anticancer therapies, regardless of discontinuation date of 
treatment.
i Documentation of CCR treatment option selected by the investigator must occur prior to randomization.
j Source documented only.
k The BSA calculation is per the Dubois & Dubois formula: BSA (m2) = weight (kg)0.425 x height (cm)0.725/139.2. Where applicable, the dose should be 
calculated on Day 1 of each treatment cycle.
l These assessments will be done locally.
m If an assessment has been performed within 28 days prior to the start of study treatment, it does not need to be repeated.
n Pregnancy test is required for all FCBPs (see protocol Section 4.2 for the definition).  Serum β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) will be 
performed centrally at screening.  For FCBP subjects, a local serum or urine (investigator’s discretion under local regulations) β- hCG pregnancy test 
(sensitivity of at least 25 mIU/mL) is to be done within 72 hours prior to study treatment administration on Day 1 of every treatment cycle in the Treatment 
Phase and at the EOT visit.  Negative results are required for study treatment administration.
o These assessments will be done centrally.
p A local serum or urine (investigator’s discretion under local regulations) pregnancy test (sensitivity of at least 25 mIU/mL) is to be done within 72 hours prior 
to the start of study treatment in the Treatment Phase for FCBP only (note that the screening central serum pregnancy test can be used as the test prior to the 
start of study treatment in the Treatment Phase if it is performed within the 72-hour timeframe).
q Whenever response/disease status is assessed in the Follow-up Phase (i.e., every 8 weeks [± 14 days]). See protocol Section 6.3 for details.
r Day 1 (± 14 days) of every 3rd cycle (e.g., Cycles 3, 6, 9, etc) or more frequently per standard institutional practice. Not necessary for the EOT visit if last 
performed within 14 days.
s Day 1 (± 28 days) of every 6th cycle (e.g., Cycles 6, 12, 18, etc) or more frequently per standard institutional practice. Not necessary for the EOT visit if last 
performed within 28 days.
u Including type, number of units, reasons and date of transfusions taken ≤8 weeks prior to the start of study treatment through 28 days after the last study 
treatment or until the EOT visit, whichever is longer. Thereafter, transfusions will continue to be collected until the next AML therapy after discontinuation 
from study treatment, death, lost to follow-up, withdrawal of consent for further data collection, or the End of Trial, whichever occurs first.  
v In addition to the frequency specified in the table, samples will also be collected if clinically indicated (e.g., confirmation of CR/CRi/CRp, morphologic relapse 
after CR/CRi/CRp or PD by a repeated bone marrow assessment at least 1 month later) or required for toxicity assessment.
w Within 7 days prior to Day 1 of Cycle 2.
x Within 7 days prior to Day 1 of Cycle 3.
y Within 7 days prior to Day 1 of Cycle 5 and Day 1 of every 2nd cycle thereafter (e.g., Cycles 7, 9, etc).
z Not necessary for the EOT visit if last performed within 28 days.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
65
dd A bone marrow biopsy can be collected in conjunction with an aspirate if it is standard institutional practice. A bone marrow biopsy must be collected if 
adequate aspirate is not attainable.
ee If the bone marrow aspirate is obtained for confirming CR/CRi/CRp, morphologic relapse after CR/CRi/CRp or PD, a sample of the bone marrow aspirate is to 
be sent to the local or central cytogenetics laboratory (for sites without local analysis capability) for standard metaphase preparation and analysis of a minimum 
of 20 metaphase cells. A bone marrow biopsy can be used for cytogenetics testing if adequate aspirate is not attainable (note that specific handling of the 
biopsy is required for cytogenetics testing).
ii Including diary cards, if utilized. See protocol Section 7.6 for details.
jj Cycle 2 only.
kk Every 4 weeks (± 7 days) for survival follow-up until death, lost to follow-up, withdrawal of consent for further data collection or the End of Trial, whichever 
occurs first.  Subsequent AML therapies should be collected at the same time schedule. See protocol Section 6.3 for details.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
66
15.5.
International Working Group Acute Myeloid Leukemia Response 
Criteria
Hematologic Response According to modified IWG Criteria for AML
Category
Definition
Morphologic Complete Remission (CR)
Defined as less than 5% blasts in a BM aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. There should be no blasts with 
Auer rods and absence of extramedullary disease.  Plus, all the following 
conditions should be met:

ANC ≥1 x 109/L (1,000/μL)

Platelet count ≥100 x 109/L (100,000/μL)

Independent of red cell transfusions for ≥1 week immediately before 
each response assessment
Morphologic Complete Remission with 
Incomplete Neutrophil Recovery (CRi) a
Defined as all criteria of morphologic CR except the following:

ANC < 1 x 109/L (1,000/μL)
Morphologic Complete Remission with 
Incomplete Platelet Recovery (CRp) a
Defined as all criteria of morphologic CR except the following:

Platelet count < 100 x 109/L (100,000/μL)
Morphologic Complete Remission with 
Partial Hematologic Recovery (CRh) a
Defined as all criteria of morphologic CR except the following:

ANC > 0.5 x 109/L (500/μL), and

Platelet count > 50 x 109/L (50,000/μL)
Morphologic Leukemia-free State (MLFS)
Defined as less than 5% blasts in a BM aspirate sample with marrow spicules 
and with a count of at least 200 nucleated cells. There should be no blasts with 
Auer rods and absence of extramedullary disease
Partial Remission (PR)
Defined as all hematologic criteria of morphologic CR with a > 50% decrease 
in the percentage of BM blasts to 5% to 25% (a blast count value of < 5% may 
also be considered a partial remission if Auer rods are present) b
Cytogenetic Complete Remission (CRc)
Defined as CR/CRi/CRp with a reversion to a normal karyotype in cases with 
an abnormal karyotype at baseline, based on evaluating ≥20 metaphase cells 
from BM
Morphologic Relapse after CR/CRi/CRp a
Defined as one of the following conditions:

Reappearance of ≥5% blasts in the BM not attributable to any other 
cause (e.g., BM regeneration after consolidation therapy); or 

Development of extramedullary disease
Not evaluable (NE) a
Defined as without a post-treatment response assessment
Stable Disease (SD) a
Defined as failure to meet any of the above criteria and not meeting the criteria 
of progressive disease (see below)
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
67
Progressive Disease (PD) a
Defined as one of the following conditions:

For subjects with 5 to 70% BM blasts at baseline: a > 50% increase of 
BM blast count percentage from baseline to ≥20%; or

For subjects with > 70% BM blasts at baseline: a doubling of 
absolute blast count in peripheral blood from baseline to ≥10 x 
109/L (10,000/μL); or

Development of new extramedullary disease since last response 
assessment
Progressive disease is to be confirmed by 2 consecutive response assessments 
separated by at least 1 month.  The date of progressive disease is defined as 
the first date that one of three conditions listed above was met.
AML = Acute Myeloid Leukemia; ANC= Absolute Neutrophil Count; BM= Bone Marrow; IWG= International Working Group.
a Modification to IWG response criteria. 
b If the pre-treatment bone marrow blast percentage was 50% to 100%, the percentage of blasts must decrease to a value between
5% and 25%; if the pre-treatment blast percentage was 20% to less than 49%, they must decrease by at least half to a value of 
more than 5%.
Notes:  Deletions to the IWG response criteria are not shown.  
Source: protocol Appendix F.
Approved
1.0
v


EDMS Doc. Number: 
AG-221 (CC-90007)
Statistical Analysis Plan. Protocol AG-221-AML-004
  Celgene Corporation
68
15.6.
Hematologic Improvement According to the International Working 
Group for Myelodysplastic Syndromes
Hematologic Improvement According to IWG Criteria
Hematologic improvement 
a
Response criteria (responses must last at least 8 week)
b
Erythroid Response (HI-E) 
(pre-treatment, < 11 g/dL) 

Hemoglobin increase by ≥1.5 g/dL

Relevant Reduction in units of RBC transfusions by an absolute number 
of at least 4 RBC transfusions/8 week compared with the pretreatment 
transfusion number in the previous 8 weeks
Note: Only RBC transfusions given for a hemoglobin of ≤9.0 g/dL on treatment 
will count in the RBC transfusion response evaluation b
Platelet Response (HI-P)
(pre-treatment, < 100 X 109/L) 

Absolute increase of ≥30 X 109/L for subjects starting with > 20 X 109/L 
platelets 

Increase from <= 20 X 109/L to > 20 X 109/L and by at least 100% b  
Neutrophil Response (HI-N)
(pre-treatment, < 1.0 X 109/L) 

At least 100% increase and an absolute increase > =0.5 X 109/Lb  
Progression or Relapse After 
HI 
c
At least 1 of the following:

At least 50% decrease from maximum response levels in granulocytes or 
platelets

Reduction in hemoglobin by ≥1.5 g/dL

Transfusion dependence
HI-E = hematologic improvement erythroid response; HI-N = hematologic improvement neutrophil response; HI-P = 
hematologic improvement platelet response; IWG = International Working Group; RBC = red blood cell.
Pre-treatment counts averages of at least 2 measurements (not influenced by transfusions, i.e., no RBC transfusions for 2 weeks 
and no platelet transfusions for 1 week) ≥1 week apart (modification).  
Modification to IWG (2000) response criteria.
c In the absence of another explanation, such as acute infection, repeated courses of chemotherapy (modification), 
gastrointestinal bleeding, hemolysis, and so forth.  It is recommended that the 2 kinds of erythroid and platelet responses be 
reported overall as well as by the individual response pattern. 
Note:  Deletions to the IWG response criteria are not shown.  To convert hemoglobin levels from grams per deciliter to grams per 
liter, multiply grams per deciliter by 10.  
Source:  Cheson, 2006.
Approved
1.0
v


EDMS Doc. Number: 
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Tuesday, 02 June 2020, 08:50 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
UserName: 
Title:  
Date: Tuesday, 02 June 2020, 02:35 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
UserName: 
Title:  
Date: Tuesday, 02 June 2020, 02:37 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
Approved
1.0
v