A Phase 1/2, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation
Phase: PHASE1
Conditions: Hematologic Neoplasms
Sponsor: Celgene

EDMS Doc. Number: 22238790 - 20010369
1.
TITLE PAGE
Clinical Study Protocol AG221-C-001
A
 Phase 1/2, Multicenter
, Open-Label, Dose-Escalation and Expansion, Safety, 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of 
Orally Administered AG-221in Subjects with
Advanced Hematologic Malignancies with an IDH2 Mutation
Study Sponsor:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
Phone: 1-877-501-7738
In Collaboration with:
Agios Pharmaceuticals
88 Sidney Street
Cambridge, MA 02139-4169
Responsible Medical 
Officers:
Ira Gupta, MD–Lead Medical Monitor
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Primary Study Medical 
Monitor
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Document Version (Date):
Revised:
Version 1.0 (3 June 2013) Final
Amendment 1, Protocol Version 2.0 (18 July 2013) Final
Amendment 2, Protocol Version 3.0 France Only (23September2013) Final
Amendment 3, Protocol Version 4.0 (16 April 2014) Final
Amendment 4, Protocol Version 5.0 (02 February 2015) Final
Amendment 5, Protocol Version 6.0(18May 2015)Final
Amendment 6, Protocol Version 7.0 (14Oct2015) Final
Amendment 7, Protocol Version 8.0 (17Oct2017) Final

EDMS Doc. Number: 22238790 - 20010369
This study will be conducted according to the protocol and in compliance with Good Clinical Practice, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory requirements.
CONFIDENTIALITY NOTE:
The information contained in this document is confidential and proprietary to Celgene Corporation. 
Any distributio
n, copying, or disclosure is strictly prohibited unless such disclosure is required by federal 
regulations or state law. Persons to whom the information is disclosed must know that it is confidential and that it 
may not be further disclosed by them.

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Celgene Corporation
INVESTIGATOR’S AGREEMENT
I understand that all documentation provided to me by Celgene or its designated representative(s) 
concerning this study that has not been published previously will be kept in strict confidence. 
This documentation includes the study protocol, Investigator’sBrochure, case report forms, and 
other scientific data.
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). No changes will be 
made to the study protocol without the prior written approval of Celgene or its designated 
representative(s) and the IRB/IEC, except where necessary to eliminate an immediate hazard to 
the subject.
I have read, understood, and agree to conduct this study as outlined in the protocol and in 
accordance with the guidelines and all applicable government regulations.
Investigator Name (printed)
Investigator Signature
Date
Investigational site or name of institution and location (printed)

EDMS Doc. Number: 22238790 - 20010369
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Celgene Corporation
2.
SYNOPSIS
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
Title of Study: 
A Phase 1/2, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, 
Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-221 in Subjects with 
Advanced Hematologic Malignancies with an IDH2 Mutation
Study Center(s):
Up to 25 study centers will participate in this study, including enrollment into expansion arms.
Phase of Development: 1/2
Phase 1(Dose Escalation and Part 1 Expansion) Objectives:
Primary
To assess the safety and tolerability of treatment with AG-221 administered continuously as a 
single agent dosed orally on Days 1 to 28 of a 28-day cycle in subjects with advanced 
hematologic malignancies. 
To determine amaximum tolerated dose (MTD)or a maximum administered dose (MAD)and/or 
the recommended Phase 2 dose (RP2D) of AG-221 in subjects with advanced hematologic 
malignancies.
Secondary
To describe the dose-limiting toxicities (DLTs) of AG-221 in subjects with advanced hematologic 
malignancies.
To characterize the pharmacokinetics (PK) of AG-221 and its metabolite in subjects with 
advanced hematologic malignancies.
To characterize the PK/pharmacodynamic (PD) relationship of AG-221 and 2-hydroxygluturate 
(2-HG).
To characterize the clinical activity associated with AG-221 in subjects with advanced 
hematologic malignancies.
Exploratory

 

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate

l 
r.

 
Phase2(previously Part 2 Expansion) Objectives:
Primary
To assess the efficacy of AG-221 as treatment for subjects with relapsed or refractory AML with 
an IDH2 mutation.
Secondary
To further evaluate the safety profile of AG-221 in subjects with relapsed or refractory AML with 
an IDH2 mutation.
To characterize the pharmacokinetics (PK) of AG-221 and its metabolite in subjects with relapsed 
or refractory AML with an IDH2 mutation.
To characterize the PK/pharmacodynamic (PD) relationship of AG-221 and 2-hydroxygluturate 
(2-HG).
Exploratory

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
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or 
Methodology:
Study AG221-C-001 is a Phase 1/2, multicenter, open-label, 3-part(Phase 1 dose escalation, Phase 1 
Part 1 Expansion, and Phase 2),safety, PK/PD, and clinical activity evaluation of orally administered 
AG-221 in subjects with advancedhematologic malignancies withan IDH2 mutation. 
In the Phase 1portion, the study includes a dose escalation phase to determine MTD/MADand/or the 
RP2D and an expansion phase(Part 1 Expansion)to further evaluate the safety, tolerability and 
clinical activity of AG-221 in select populations.   The Phase 2portion (previously Part 2 Expansion) 
will further inform on the efficacy, safety, tolerability and clinical activity of AG-221 in subjects with 
refractory or relapsed AML with an IDH2 mutation.

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Celgene Corporation
Name of Sponsor/Company:
n
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o 
be followed until death, withdrawal of consent, or the end of the studyas perSection11.2.
Number of subjects (planned):
Approximately a minimum of 291subjects in total is planned to be enrolled in the study (i.e., in the 
doseescalation, Part 1 Expansion, and Phase 2 portion of the trial). 
Assuming that identification of the MTD/MADrequires the evaluation of 13dose levels/schedulesof 
AG-221 with up to 5subjects per dose level, with the exception that the MTD/MADrequires 6 
subjects, then 66subjects will be enrolled during the dose escalation part of the study. Additional 
subjects may be needed for cohort expansion during dose escalation, for the replacement of subjects
who are not evaluable for PK/PD, safety, or clinical activity, or for evaluation of alternative dosing 
regimens other than the planned escalation scheme or the MTD/MAD, to optimize the RP2D and 
regimen(s).As of April 2015, 5 dose levels (ranging from 30 mg to 150 mg) have been evaluated in 
the BID schedule and 8 dose levels (ranging from 50 mg to 650 mg)havebeenevaluated in the QD 
schedule.  
Four cohorts of a minimum of25additional subjects in specific hematologic malignancy subsets 
(total a minimum of 100 subjects) will be enrolled in Part 1 Expansion of the study.
The Phase 2 portion of the trialwill enroll approximately 125 subjects with relapsed or refractory 
AMLwith an IDH2 mutation. Additional subjects may be needed for the replacement of subjects who 
are not evaluable for PK/PD, safety, and/or clinical activity, or for evaluation of alternative dosing 
regimens.The final total sample size may be adjusted according to the observed toxicity rate, and 
number of subjects enrolled for expanded evaluation.
Diagnosis and main criteria for inclusion:
Inclusion criteria
Subjects must meet all of the following criteria to be enrolled in the study:
1. Subject must be ≥18 years of age.
2. Subjects must have advanced hematologic malignancy including:
Phase 1/ Dose escalation:
- Diagnosis of AML according to World Health Organization (WHO) criteria (Appendix
15.1);
o Disease refractory or relapsed(defined as the reappearance of > 5% blasts in the 
bone marrow, seeTable7andTable 8).

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
o Untreated AML,≥60 years of age and are not candidates for standard therapy due 
to age, performance status, and/or adverserisk factors, according to the treating 
physician and with approval of the Medical Monitor;
- Diagnosis of MDS according to WHO classification (Appendix15.2)with refractory 
anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the
Revised International Prognostic Scoring System (IPSS-R)(Appendix15.3)(Greenberg, 
et al. 2012)that isrecurrent or refractory, or the subject is intolerant to established 
therapy known to provide clinical benefit for their condition (i.e., subjects must not be 
candidates for regimens known to provide clinical benefit), according to the treating 
physician and with approval of the Medical Monitor.(Subjects with other relapsed and/or 
primary refractory hematologic cancers, for example CMML, who fulfill the 
inclusion/excluding criteria may be considered on a case-by case basis, with approvalof 
the Medical Monitor.)
Phase 1/ Part1Expansion:
- Arm 1: Relapsed or refractory AML (Table7andTable 8) and age ≥60 years, or any 
subject with AML regardless of age who has relapsed following a BMT.
- Arm 2: Relapsed or refractory AML(Table7andTable 8)and age <60 years, excluding 
subjects with AML who have relapsed following a BMT.
- Arm 3: Untreated AML and age ≥60 years that decline standard of care chemotherapy.
- Arm 4: IDH2-mutated advanced hematologic malignancies noteligible for Arms 1 to 3.
Phase 2:
- Diagnosis of AML according to World Health Organization (WHO)criteria (Appendix 
15.1) and disease relapsed or refractory as defined by (Table7andTable 8):
o Subjects who relapse after allogeneic transplantation;
o Subjects in second or later relapse;
o Subjects who are refractory to initial induction or re-inductiontreatment;
o Subjects who relapsewithin 1 year of initial treatment, excluding patients with 
favorable-risk status according to NCCN Guidelines (NCCN 2015). Favorable-
risk cytogenetics: inv(16), t(16;16), t(8;21), t(15;17).
3. Subjects musthave documented IDH2 gene-mutated disease:

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
For subjects in the dose escalation phaseand Part 1 Expansion,IDH2 mutation may be 
based on local evaluation. (Centralized testing will be performed retrospectively).
4. For subjects in the Phase 2 portion of the trial, central testing of IDH2 mutationin samples of 
bone marrow aspirate and/orperipheral blood, is required during screening to confirm 
eligibility. Subjects must be amenable to serial bone marrow sampling, peripheral blood 
sampling, and urine samplingduring the study.
The diagnosis and evaluation of AML or MDS will be made by bone marrow aspiration 
and biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the diagnosis may be made 
from the core biopsy.
Screening bone marrow aspirate andperipheral blood samples are required for all 
subjects.  A bone marrow biopsy must be collected if adequate aspirate is not attainable 
unless: 
o A bone marrow aspirate and biopsy was performed as part of the standard of care 
within 28 days prior to the start of the study treatment; and
o Slides of bone marrow aspirate, biopsyand stained peripheral blood smear are 
available for bothlocal and central pathology reviewers; 
5. Subjects must be able to understand and willing to sign an informed consent. A legally 
authorized representative may consent on behalf of a subject who is otherwise unable to 
provide informed consent, if acceptable to, and approved by, the site and/or site’s Institutional 
Review Board (IRB)/Independent Ethic Committee (IEC). 
6. Subjects must have ECOG PS of 0 to 2(Appendix15.5).
7. Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed.) Subjects with a 
baseline platelet count of <20,000/µL due to underlying malignancy are eligible with Medical 
Monitor approval.
8. Subjects must have adequate hepatic function as evidenced by:
- Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to 
Gilbert’s disease, a gene mutation in UGT1A1, or leukemic organ involvement, 
following approval by the Medical Monitor;
- Aspartate aminotransferase(AST), alanine aminotransferase (ALT),and alkaline 
phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement.
9. Subjects must have adequate renal function as evidenced by:
- Serum creatinine ≤2.0×ULN

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
OR
- Creatinine clearance 40 mL/min based on the Cockroft-Gault glomerular filtration rate 
(GFR) estimation:
(140Age)(weight in kg)(0.85 if female)/72serum creatinine
10.Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, 
radiotherapy,or other therapy intended for the treatment of cancer. (Subjects with residual 
Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual alopecia, are allowed 
with approval of the Medical Monitor.)
11.Female subjects with reproductive potential must agree to undergo medically supervised 
pregnancy test prior to starting study drug. The first pregnancy test will be performed at 
screening (within 7 days prior to first study drug administration), and on the day of the first 
study drug administration and confirmed negative prior to dosing and Day 1 before dosing all 
subsequent cycles.
12.Female subjects with reproductive potential musthave a negative serum pregnancy test 
within 7 days prior to the start of therapy. Subjects with reproductive potential are defined as 
sexually mature women who have not undergone a hysterectomy, bilateral oophorectomy or 
tubal occlusion or who have not been naturally postmenopausal (i.e., who have not 
menstruated at all) for at least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). Females of reproductive potential as well as fertile men 
and their partners who are female of reproductive potential must agree to abstain from sexual 
intercourse or to use two highly effective forms of contraception from the time of giving 
informed consent, during the study and for 120 days (females and males) following the last 
dose of AG-221. A highly effective form of contraception is defined as hormonal oral 
contraceptives, injectables, patches, intrauterine devices, double-barrier method (e.g., 
synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel),or male 
partner sterilization.
13.Able to adhere to the study visit schedule (ie, clinic visits at the study sites are mandatory, 
unless noted otherwise for particular study visits) and other protocol requirements
Exclusion criteria
Subjects who meet any of the following criteria will not be enrolled in the study:
1. Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of 
the first dose of AG-221, or subjects 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 steroids post HSCT and/or topical steroids for ongoing skin GVHD is 
permitted with Medical Monitor approval.) 

EDMS Doc. Number: 22238790 - 20010369
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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
2. Subjects who received systemic anticancer therapyor radiotherapy <14 days prior to their 
first day of study drug administration. (Hydroxyurea is allowed prior to enrollment and after 
the start of AG-221 for the control of peripheral leukemic blasts in subjects with leukocytosis 
(white blood cell [WBC] counts >30,000/μL).
3. Subjects who received a small molecule investigational agent <14 days prior to their first day 
of study drug administration. In addition, the first dose of AG-221 should not occur before a 
period ≥5 half-lives of the investigational agent has elapsed.
4. Subjects taking the following sensitive cytochrome P450 (CYP)substrate medications that 
have a narrow therapeutic range are excluded from the study unless they can be transferred to 
other medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, 
phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and 
tizanidine (CYP1A2). 
5. Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) 
transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the study 
unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
6. Subjects for whom potentially curative anticancer therapy is available.
7. Subjects who are pregnant or lactating.
8. Subjects with an active severe infection that required anti-infective therapy or with an 
unexplained fever >38.5°C during screening visits or on their first day of study drug 
administration (at the discretion of the Investigator, subjects with tumor fever may be 
enrolled).
9. Subjects with known hypersensitivity to any of the components of AG-221.
10.Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure 
or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan 
obtained within approximately 28 days of C1D1.
11.Subjects with a history of myocardial infarction within the last 6 months of screening.
12.Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or 
diastolic BP >100mmHg) at screening are excluded. Subjects requiring 2 or more 
medications to control hypertension are eligible with Medical Monitor approval.
13.Subjects with known unstable or uncontrolled angina pectoris.
14.Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
15.Subjects with QTcF (QT corrected based on Fridericia’s equation) interval ≥450 msec or 
other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart 
failure, hypokalemia, family history of long QT interval syndrome) at screening. Subjects 
with bundle branch block and a prolonged QTc interval should be reviewed by the Medical 
Monitor for potential inclusion.
16.Subjects taking medications that are known to prolong the QT interval (see Section9.12.3)
unless they can be transferred to other medications within ≥5 half-lives prior to dosing.
17.Subjects withknown infection with human immunodeficiency virus (HIV) or active 
hepatitisB or C.
18.Subjects with any other medicalor psychological condition, deemed by the Investigator to be 
likely to interfere with a subject’s ability to sign informed consent, cooperate, or participate in 
the study.
19.Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that 
limit the ingestion or gastrointestinal absorption of drugs administered orally.
20.Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or 
known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical 
suspicion of CNS involvement by leukemia during screening.
21.Subjects with immediately life-threatening, severe complications of leukemia such as 
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular 
coagulation.
22.In Phase 2 portion of the trialonly, subjects who have previously received treatment with an 
inhibitor of IDH2.
Investigational product, dosage and mode of administration:
AG-221 (AG-221 mesylate) will be provided as 5, 10, 25, 50, 100, 150 and 200 mg free-base
equivalent strength tablets to be administered orally.
Phase 1/Dose Escalation
The first 3 subjects in each cohortin the dose escalation portion of the studyand the first 15 subjects 
in eacharm of Part 1 Expansion will receive a single dose of study drug on Day -3; their next dose of 
study drug will be administered on C1D1 at which time subjects will start daily dosing on Days 1 to 
28 in 28-day cycles. Starting with C1D1, dosing is continuous; there are no inter-cycle rest periods. 
Subjects who are not required to undergo the Day -3 PK/PD assessments will initiate daily dosing 
with AG-221 on C1D1.
The dose of AG-221 administered to a subject will be dependent upon which dose cohort is open for 
enrollment when the subject qualifies for the study. The starting dose of AG-221 to be administered 

EDMS Doc. Number: 22238790 - 20010369
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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
to the first cohort of subjects is 30 mg administered orally twice a day,andthe maximum 
administered doseof AG-221 to be administered is 650 mg administered orally oncea day.
Phase 1/Part 1 Expansionand Phase 2
The starting dose of AG-221 recommended for evaluation is 100mg QD.  This is based on the safety, 
PK, pharmacodynamics and clinical activity of AG-221 observed to date in AG221-C-
001.Evaluation of pharmacodynamic response demonstrated sustained reduction in 2-HG plasma 
levels by Day 1 of Cycle 2 and up to 98% inhibition in most subjects with R140Q mutation at all 
doses.Increasing dose is associated with higher exposure and inhibition of 2-HG in subjects with 
R172K mutation. Importantly, preliminary efficacy data of the 44 subjects treated at 100 mg QD has 
shown an overall response rate of 36.4%. Thus a dose of 100 mg should adequately achieve inhibition 
of 2-HG in subjects with either R140Q or R172K mutation.Moreover, the safety profile at 100 mg, 
including ≥ Grade 3, is consistent with that of lower doses.
Intra-subject dose escalation is possible as per criteria in Section 9.7.2.1.
Duration of treatment: 
Subjects may continue treatment with AG-221 until disease progression or development of 
unacceptable toxicity. Subjects who experience disease progression per the applicable response 
criteria who are, in the opinion of the Investigator, benefiting from treatment may be allowed to 
continue on study drug with approval of the Medical Monitor.
End of Study:
The End of Studyis defined as either the date of the last visit of the last subject to complete the study, 
3 years after the first doseof the last subject enrolled into Phase 2, or the date of receipt of the last 
data point from the last subject that is required for primaryand secondary analysis, as pre-specified in 
the protocol, whichever isthe later date.
Reference therapy, dosage and mode of administration: 
Not applicable
Criteria for evaluation:
y:
 
s; 
S.
3.
:
e 
I-
 
Clinical Activity:

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
Serial blood and bone marrow sampling to determine response to treatment based on modified IWG 
response criteria (Table7throughTable10) or other appropriate response criteria based on the 
malignancy under study.
Statistical methods:
Overallresponse rate (ORR), the primary efficacy endpoint, is defined as the rate of responders 
including complete remission (CR), CR with incomplete platelet recovery (CRp), marrow CR (mCR) 
(morphologic leukemia-free state [MLFS] for subjects with AML), CR with incomplete hematologic 
recovery (CRi), and partial remission (PR). Other measures ofclinical activity including complete 
remission rate (CRR), duration of remission/response, event-free survival, overall survival, and time 
to remission/response will be summarized.
For Phase 1 Dose Escalation/Part 1 Expansion, the efficacy analysis of responserates as assessed by 
the site Investigators using modified International Working Group ( IWG) response criteria (Table7
throughTable10)will be conducted in Full Analysis Set for each dose level, expansion arm, and 
overall if appropriate. The analysis of Part 1 expansion arms may also include subjects from the dose-
escalation phase who received the same dose/regimen as subjects in the expansion arms and who 
meet the eligibility criteria of individual arms. 
For Phase 2 portion of the trial, the primary efficacy analysis of AG-221 will be determined by the 
Investigatorsbased on modified International Working Group (IWG) response criteria (Table7and
Table 8).  Response will also be assessed retrospectively by an Independent Response Adjudication 
Committee (IRAC)using the Full Analysis Set(FAS).Key supportive analyses will be based on 
independent centralreview of response in FAS.
An observed ORR of at least 33.6% in Phase 2 portion of the trial(at least 42 responses in 125 
subjects) will result in an exact binomial 95% CI with a lower bound greater than 25%, which is 
clinically meaningful in this setting and exceeds the ORR expected with available therapies (Roboz, 
et al. 2014). This will be considered as evidence of clinically significant activity of AG-221.
Tabulations will be produced for disposition, demographic and baseline disease characteristics, safety, 
PK, PD, and clinical activity parametersand will be presented by study phase, dose level, disease, and 
overall if appropriate. Categorical variables will be summarized by frequency distributions (number 
and percentages of subjects) and continuous variables will be summarized by descriptive statistics 
(mean, standard deviation, median, minimum, and maximum). 
) 
t-
st 
y-
 
Descriptive statistics will be provided forclinical laboratory, ECG interval, LVEF, and vital signs 
data, presented as both actual values and changes from baseline relative to each on-study evaluation 
and to the last evaluation on study. Shift analyses will be conducted for laboratory parameters and 
ECOG PS.

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Celgene Corporation
Name of Sponsor/Company:
Celgene Corporation
Name of Investigational Product:
AG-221
Name of Active Ingredient:
AG-221 mesylate
Descriptive statistics will be used to summarize PK parameters for each dose group and, where 
appropriate, for the entire population. The potential relationshipbetween plasma levels of AG-221 
and plasma, urine, and bone marrow 2-HG (and/or α-KG) levels will be explored with descriptive and 
graphical methods.
All time to event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 95% 
CIs will be provided where appropriate. Estimates of the median and other quantiles, as well as 
individual time points (e.g. 3-month, 6-month, and 12-month rates) will be produced. Other measures 
of clinical activity will be evaluated for subjects in Phase 2 portion of the trial, including summaries 
of transfusion requirements and infection rates.
The study data will be analyzed and reported based on all subjects’ data from the dose escalation and 
expansion phases up to the time when all subjects have completed at least 6 cycles of treatment 
regardless of dose interruption or discontinuedstudy drug earlier, or when the follow up is deemed 
adequate for the assessment of duration of response, whichever is the later date. Any additional data 
for subjects continuing to receive study treatment or in follow up for HSCT or survival past the data
cutoff date for the clinical study report (CSR) will be reported in a final descriptiveupdate at the end 
of study.

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Celgene Corporation
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES
TABLE OF CONTENTS
1.
TITLE PAGE...........................................................................................................1
2.
SYNOPSIS...............................................................................................................4
3.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES..............20
4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................26
5.
INTRODUCTION..................................................................................................30
5.1.
Cellular Metabolism and Cancer.............................................................................30
5.1.1.
The Role of Isocitrate Dehydrogenase....................................................................30
5.1.2.
IDH Mutations in Cancer........................................................................................32
5.1.2.1.
IDH Mutations in Hematologic Cancers.................................................................32
5.2.
AG-221..................................................................................................................33
5.2.1.
Overview................................................................................................................33
5.2.2.
Summaryof Nonclinical Information......................................................................33
5.2.2.1.
Biochemical and Cellular Pharmacology.................................................................33
5.2.2.2.
Absorption, Distribution, Metabolism, and Excretion..............................................37
5.2.2.3.
Pharmacokinetic Drug Interactions.........................................................................38
5.2.2.4.
Human PK and Efficacious Dose Projection...........................................................38
5.2.2.5.
Safety Pharmacology and Toxicology.....................................................................39
5.2.3.
Emerging Clinical Data..........................................................................................41
5.3.
Study Rationale......................................................................................................42
6.
TRIAL OBJECTIVES ANDENDPOINTS............................................................44
6.1.
Primary Objectives.................................................................................................44
6.2.
Secondary Objectives.............................................................................................44
6.3.
Exploratory Objectives...........................................................................................44
6.4.
Study Measures and Endpoints...............................................................................45
6.4.1.
Safety Measures and Endpoints..............................................................................45
6.4.2.
Pharmacokinetic and Pharmacodynamic Measures and Endpoints..........................45
6.4.3.
Clinical Activity Measures and Endpoints..............................................................46
6.4.3.1.
Phase 1 (Dose Escalation and Part 1 Expansion).....................................................46
6.4.3.2.
Phase 2...................................................................................................................46

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6.4.4.
Exploratory Endpoints............................................................................................46
7.
INVESTIGATIONAL PLAN.................................................................................47
7.1.
Overall Study Design..............................................................................................47
7.1.1.
Overview of the Phase 1/Dose Escalation Phase.....................................................47
7.1.2.
Overview of the Phase 1/Part 1 Expansion..............................................................51
7.1.3.
Overview of Phase 2...............................................................................................52
7.1.4.
General Conduct.....................................................................................................53
7.2.
Justification of the Study Design.............................................................................56
7.3.
Rationale for the Dose Selected..............................................................................57
7.3.1.
Phase 1 Dose Escalation.........................................................................................57
7.3.2.
Phase 1 Expansion and Phase 2...............................................................................57
7.4.
Criteria for Study Termination................................................................................58
8.  
STUDY POPULATION.........................................................................................59
8.1.
Number of Subjects................................................................................................59
8.2.
Inclusion Criteria....................................................................................................59
8.3.
Exclusion Criteria...................................................................................................62
8.4.
Subject Identification and Registration....................................................................64
8.5.
Subject Withdrawal Criteria and Replacement of Subjects......................................64
9.
STUDY TREATMENT..........................................................................................66
9.1.
Description of Study Drug......................................................................................66
9.2.
Study Drug Packaging and Labeling.......................................................................66
9.3.
Study Drug Storage................................................................................................66
9.4.
Method of Assigning Subjects to Treatment............................................................66
9.5.
Clinical Supplies.....................................................................................................67
9.6.
Study Drug Preparation and Administration............................................................67
9.7.
Criteria for Dose Escalation, Dose Modification, or Discontinuation of Study 
Drug.......................................................................................................................68
9.7.1.
Dose Escalation Procedures....................................................................................68
9.7.1.1.
Dose-limiting Toxicity............................................................................................69
9.7.2.
Intra-subject Dose Modification Criteria.................................................................70
9.7.2.1.
Dose Escalation Criteria.........................................................................................70
9.7.2.2.
Dose Reduction Criteria..........................................................................................70
9.7.3.
Dose Discontinuation Criteria.................................................................................71

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9.8.
Guidelines for Important Events.............................................................................71
9.8.1.
Guidelines for Management of QT Prolongation.....................................................71
9.8.2.
IDH Differentiation Syndrome................................................................................72
9.8.3.
Leukocytosis..........................................................................................................73
9.8.4.
Gastrointestinal Disorders (Diarrhea, Nausea, Vomiting, Decreased 
Appetite, and Alterations in Taste)..........................................................................73
9.8.5.
Tumor Lysis Syndrome..........................................................................................73
9.8.6.
Increased blood bilirubin........................................................................................73
9.9.
Duration of Subject Participation............................................................................73
9.9.1.
Treatment Duration.................................................................................................73
9.9.2.
End of Study...........................................................................................................74
9.10.
Treatment Compliance............................................................................................74
9.11.
Study Drug Accountability.....................................................................................74
9.12.
Prior and Concomitant Medications and Treatments...............................................75
9.12.1.
Prior Medications and Procedures...........................................................................75
9.12.2.
Concomitant Medications and Procedure................................................................75
9.12.3.
Prohibited Concomitant Therapy............................................................................75
9.12.4.
Restricted Concomitant Therapy.............................................................................76
9.12.5.
Allowed Concomitant Therapy...............................................................................76
10.
STUDY ASSESSMENTS.......................................................................................78
10.1.
Schedule of Events.................................................................................................78
10.2.
Informed Consent...................................................................................................91
10.3.
Information to be Collected on Screen Failures.......................................................91
10.4.
Demographic Data and Medical, Surgical, and Medication History.........................91
10.5.
Gene Mutation Analysis.........................................................................................91
10.6.
Safety Assessments.................................................................................................92
10.6.1.
Physical Examination and ECOG Performance Status............................................92
10.6.2.
Vital Signs..............................................................................................................92
10.6.3.
Electrocardiogram and Assessment of Left Ventricular Ejection Fraction...............92
10.6.4.
Safety Laboratory Assessments...............................................................................93
10.6.5.
Adverse Events.......................................................................................................94
10.7.
Bone Marrow Samples and Peripheral Blood Leukemic Blast Cells........................94
10.8.
Clinical Activity Assessments.................................................................................97

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10.8.1.
Phase 1 (Dose Escalation and Part 1 Expansion).....................................................97
10.8.2.
Phase 2...................................................................................................................97
10.8.3.
Assessment of Response Criteria............................................................................98
10.9.
Pharmacokinetic Assessments...............................................................................104
10.9.1.
Blood Sample Collection and Pharmacokinetic Measurements During Dose 
Escalation.............................................................................................................104
10.9.2.
Urine Collection...................................................................................................105
10.10.
Pharmacodynamic Assessments............................................................................106
10.10.1.
Blood Samples......................................................................................................106
10.10.2.
Urine Samples......................................................................................................106
10.11.
Evaluation of Cholesterol and 4β-OH-Cholesterol................................................106
10.12.
Sample Processing, Storage, and Shipment...........................................................107
11.
ADVERSE EVENTS............................................................................................108
11.1.
Definition of Adverse Events................................................................................108
11.1.1.
Adverse Event (AE)..............................................................................................108
11.1.2.
Suspected Adverse Reaction.................................................................................108
11.1.3.
Unexpected Adverse Event...................................................................................108
11.1.4.
Serious Adverse Event..........................................................................................108
11.2.
Procedures for Reporting Adverse Events and Serious Adverse Events.................109
11.3.
Pregnancy Reporting............................................................................................111
12.  
STATISTICAL METHODS.................................................................................113
12.1.
Sample Size Estimation........................................................................................113
12.2.
Populations for Analysis.......................................................................................114
12.3.
Procedures for Handling Missing, Unused, and Spurious Data..............................115
12.4.
Interim Analyses...................................................................................................115
12.5.
Statistical Methodology........................................................................................115
12.5.1.
General Methods..................................................................................................115
12.5.2.
Disposition...........................................................................................................116
12.5.3.
Baseline Evaluations.............................................................................................116
12.5.4.
Exposure and Safety Analyses..............................................................................116
12.5.5.
Pharmacokinetic Analyses....................................................................................117
12.5.6.
Pharmacodynamic Analyses.................................................................................117
12.5.7.
Clinical Activity Analyses....................................................................................117

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12.5.8.
Exploratory Analyses............................................................................................119
12.6.
Procedures for Reporting Deviations to Protocol-defined Statistical Analysis 
Plan......................................................................................................................119
13.
ADMINISTRATIVE REQUIREMENTS.............................................................120
13.1.
Good Clinical Practice..........................................................................................120
13.2.
Ethical Considerations..........................................................................................120
13.3.
Subject Information and Informed Consent...........................................................120
13.4.
Subject Confidentiality.........................................................................................120
13.5.
Protocol Compliance............................................................................................121
13.6.
Data Management.................................................................................................121
13.7.
Source Document/Case Report Form Completion.................................................121
13.8.
Direct Access to Source Data................................................................................122
13.9.
Record Retention..................................................................................................122
13.10.
Liability and Insurance.........................................................................................122
13.11.
Publication of Study Findings and Use of Information..........................................122
14.
LIST OF REFERENCES......................................................................................124
15.  
APPENDICES......................................................................................................127
15.1.
World Health Organization Classification of Acute Myeloid Leukemia................127
15.2.
Myelodysplastic Syndromes World Health Organization Classification 
System..................................................................................................................128
15.3.
International Prognostic Scoring System Score for Myelodysplastic 
Syndromes............................................................................................................130
15.4.
Risk Status Based on Validated Cytogenetics and Molecular Abnormalities.........131
15.5.
Eastern Cooperative Oncology Group Performance Status Scoring.......................132
15.6.
New York Heart Association Classification..........................................................133
15.7.
National Cancer Institute Common Terminology Criteria for Adverse Events.......134
15.8.
Declaration of Helsinki.........................................................................................134
15.9.
CYP Sensitive Substrates......................................................................................139
15.10.
Transporter Sensitive Substrates...........................................................................140
15.11.
Monitoring of Liver Function...............................................................................141
LIST OF TABLES
Table1:
Planned Dose Escalation Scheme............................................................................51
Table2:
Schedule of Assessments: Phase 1(Dose Escalation and Part 1 Expansion).............80

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Table3:
Schedule of Assessments: Phase 2..........................................................................84
Table4:
Pharmacokinetic and Pharmacodynamic Sampling and Electrocardiogram 
Schedule for the Phase 1 Dose Escalation and Part 1 Expansion.............................88
Table 5:
Pharmacokinetic and Pharmacodynamic Sampling and Electrocardiogram 
Schedule for Phase 2...............................................................................................90
Table 6:
Disease Assessment and Treatment after 1
stEvidence of Disease Progression.........99
Table7:
Proposed Modified International Working Group Response Criteria for 
Acute Myeloid Leukemia.....................................................................................100
Table 8:
Criteria for Stable Disease and Progressive Disease for Acute Myelogenous 
Leukemia..............................................................................................................102
Table9:
Proposed Modified International Working Group Response Criteria for 
Altering Natural History of MDS..........................................................................103
Table10: Proposed Modified International Working Group Response Criteria for 
Hematologic Improvement...................................................................................104
LIST OF FIGURES
Figure1: The Citric AcidCycle.............................................................................................30
Figure2: IDH2 Mutation Estimates in Hematologic and Solid Tumors, 2012........................31
Figure3: Impact of IDH Mutations on Cell Metabolism........................................................34
Figure4: Intracellular Levels of 2-HG in TF-1/IDH2 (R140Q) Mutant Cells After 
7Days of Treatment with Control (DMSO) or Increasing Levels of AG-221..........35
Figure5: AG-221 and Tumor 2-HG Concentration Profiles Following a Single Oral 
Dose of 25 or 50 mg/kg AG-221 in a Mouse Xenograft Tumor Model....................37
Figure 6: Study Diagram........................................................................................................47
Figure7: Dose Escalation Scheme.........................................................................................48
Figure8: Probability of Dose Escalation for the 3+3 Design................................................113

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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OFTERMS
Abbreviation or Specialist Term
Explanation
2-HG
2-hydroxyglutarate
α-KG
Alpha-ketoglutarate
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AML
Acute myelogenous leukemia
aPPT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC0-12hr
Area under the concentration-time curve from 0 to 12 hours
BCRP
Breast cancer resistance protein
BMT
Bone marrow transplant
BP
Blood pressure
BUN
Blood urea nitrogen
C1D1
Cycle 1, Day 1
CEAS
Central efficacy analysis set
CI
Confidence interval
CIMP
Cytosine-guanine dinucleotide island methylator phenotype
CLp
Total body clearance
Cmax
Maximum concentration
CMML
Chronic myelomonocytic leukemia
CNS
Central nervous system
CpG
Cytosine-phosphodiesterase-guanine
CR
Complete remission
CRi
Complete remission with incomplete hematologic recovery
CRp
Complete remission with incomplete platelet recovery
CRR
Complete remission rate
CV
Cardiovascular
CYP
Cytochrome
DLT
Dose limiting toxicity
DMSO
Dimethylsulfoxide
DNA
Deoxyribonucleic acid

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Abbreviation or Specialist Term
Explanation
DOCR
Duration of complete remission
DOR
Duration of response
EAS
Efficacy analysis set
EAUC90(0-12hr)
Estimated area under the AG-221 concentration × time curve from 
0 to 12 hours that results in sustained 90% tumor inhibition
EAUC97(0-12hr)
Estimated area under the AG-221 concentration × time curve from 
0 to 12 hours that results in sustained 97% tumor inhibition
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic Data Capture
EFS
Event-free survival
EOT
End of Treatment
F
Projected human oral bioavailability
FAS
Full analysis set
FLT3/ITD
FMS-like tyrosine kinase 3/internal tandem duplication
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GLP
Good Laboratory Practice
GM-CSF
Granulocyte-macrophage colony-stimulating factor
GVHD
Graft versus Host Disease
hCG
Human chorionic gonadotropin
hERG
Human ether à-go-go
HIV
Human immunodeficiency virus
HNSTD
Highest non-severely toxic dose
HSCT
Hematopoietic stem cell transplant
IC
50
Inhibitory concentration, 50%
IC
90
Inhibitory concentration, 90%
ICH
International Conference on Harmonization
ICSH
International Council for Standardization in Hematology
IDH, IDH1, IDH2
Isocitrate dehydrogenase protein, 1, 2
IEC
Independent Ethics Committee

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Abbreviation or Specialist Term
Explanation
IND
Investigational New Drug
INR
International normalized ratio
IPSS-R
Revised International Prognostic Scoring System
IRB
Institutional Review Board
IRAC
Independent Response Adjudication Committee
IWG
International Working Group
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MAD
Maximum AdministeredDose
mCR
Marrow complete remission
MDS
Myelodysplastic syndrome
MPN
Myeloproliferative neoplasms
MPD
Myeloproliferative disorders
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NPM1
Nucleophosmin 1
NYHA
New York Heart Association
ORR
Overallresponse rate
OS
Overall survival
PAS
Pharmacokinetic analysis set
PD
Pharmacodynamic
P-gp
P-glycoprotein
PK
Pharmacokinetic
PR
Partial remission
PS
Performance status
PT
Prothrombin time
RAEB, RAEB-1, RAEB-2
Refractory anemia with excess blasts, 1, 2
RBC
Red blood cell (count)
RP2D
Recommended Phase 2 dose
QTc
Heart-rate corrected QT interval

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Abbreviation or Specialist Term
Explanation
QTcF
Heart-rate corrected QT interval, Fridericia’s correction
SAE
Serious adverse event
sAML
Secondary AML
SAP
StatisticalAnalysis Plan
SAS
Safety analysis set
SOP(s)
Standard Operating Procedure(s)
TEAE
Treatment-emergent adverse event
Tmax
Time to maximum concentration
TTCR
Time to complete remission
TTR
Time to remission
UGT1A1
UDP (uridine diphosphate)-glucuronosyltransferase 1 family, 
polypeptide A1
ULN
Upper limit of normal
Vss
Volume of distribution at steady state
WBC
White blood cell (count)
WHO
World Health Organization

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
al 
al 
or 
e. 

a.

.

4 
).
e:

th 
of 
d 
s.

al 
al 
or 
6.4.
Study Measures and Endpoints
6.4.1.
Safety Measures and Endpoints
Safety will be evaluated by:
Monitoring of adverse events (AEs), including determination of DLTs, serious adverse 
events (SAEs), and AEs leading to discontinuation. The severity of AEs will be assessed by 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), version 4.03.
Monitoring of safety laboratory parameters, physical examination findings, vital signs, 
12-lead ECGs, evaluation of left ventricular ejection fraction (LVEF), and Eastern 
Cooperative Oncology Group (ECOG) performance status (PS).
6.4.2.  
Pharmacokinetic and Pharmacodynamic Measures and Endpoints
The PK and PD profile of AG-221 will be evaluated by:
Serial blood sampling at specified time points for determination of plasma concentration-
time profiles and PK parameters ofAG-221 and its metabolite AGI-16903.
Urine sampling at specified time points for determination of concentrations of AG-221 and 
its metabolite AGI-16903 (dose escalation and Part 1 Expansion subjects only).
Blood, bone marrow, and urine sampling at specified time points for determination of 2-HG 
levels to characterize the PD effects of AG-221.

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6.4.3.
Clinical Activity Measures and Endpoints
6.4.3.1.
Phase 1 (Dose Escalation and Part 1 Expansion)
Clinical activity of AG-221 will be evaluated by:
Serial blood and bone marrowsampling to determine response to treatment based on 
modified International Working Group (IWG) Response Criteria in AML (Cheson, et al. 
2003)and in MDS (Cheson, etal. 2006)or other appropriate response criteria for the 
malignancy under study. Response for all subjects will be assessed by the site Investigators.
6.4.3.2.
Phase 2
Eligibility, treatment decisions, and response to treatmentwill be determined by the Investigators
based on modified International Working Group (IWG) response criteria (Table7andTable 8).  
Response will be also be assessed retrospectively by an Independent Response Adjudication 
Committee (IRAC).  
Other measures of clinical activity will be evaluated for subjects in this phase, including 
summaries of hematological recovery, including changes in platelets, hemoglobin,
neutrophils, transfusion requirements,and infection rates.
6.4.4.
Exploratory Endpoints

c 
.
 

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7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design
This is a Phase 1/2, multicenter, open-label, 3-part (Phase 1 dose escalation, Phase 1 Part 1 
Expansion, and Phase 2), safety, PK/PD, and clinical activity evaluation of orally administered 
AG-221 in subjects with advanced hematologic malignancies thatharbor an IDH2 mutation. The 
study includes a dose escalation phase to determine MTD /MAD and/or RP2D,an expansion 
phase (Part 1) to further evaluate the safety, tolerability, and clinical activity of AG-221, and a 
Phase 2 to assessthe clinical efficacy of AG-221 at the RP2Dand to further evaluate safety in 
subjects with refractoryand relapsed AML carrying an IDH2 mutation. 
Figure 6:
Study Diagram
Note: Part 1 Expansion and Phase 2 at 100mg QD will proceed in parallel and as soon as this dose is declared safe 
during the dose escalation portion of the study.
7.1.1.
Overview of the Phase 1/Dose Escalation Phase
A schematic of the dose escalation scheme is provided in Figure7. The dose escalation phase 
will utilize a standard “3 + 3” design. During the dose escalation phase, consented eligible 
subjects will be enrolled into sequential cohorts of increasing doses of AG-221. Each dose cohort 
will plan to enroll a minimum of 3subjects. The first 3 subjects in each cohort enrolled in the 
dose escalation phase will initially receive a single dose of AG-221 on Day -3 (i.e., 3 days prior 
to the start of daily dosing) to evaluate concentrations of AG-221, its metabolite AGI-16903, 2-
HG and α-KGlevels; safety also will be assessed. Daily dosing will begin on Cycle 1, Day 1 

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(C1D1). The initial dosing regimen was twice daily (approximately every 12 hours). Based on 
the emerging data, a once daily dosing schedule also has been implemented. Alternative dosing 
schedules (e.g., loading dose followed by once daily dosing) may continue to be explored in the 
dose escalation and expansion phases as agreed upon by the Clinical Study Team. If there are 
multiple subjects in the screening process at the time the third subject within a cohort begins 
treatment, up to 2 additional subjects may be enrolled, for a maximum of 5subjects per cohort, 
with approval of the Medical Monitor. For these additional subjects, the Day-3 PK/PD 
assessments are optional following discussion with the Medical Monitor.
Figure7:
Dose Escalation Scheme
*If only 3 subjects were enrolled at the MTD level, an additional 3 subjects will beenrolled to confirm that <2 of 6 subjects 
experiences a DLT at this dose.
Note: CST = Clinical Study Team; DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Candidates for the dose-escalation phase of the study are adult subjects, 18 years of age or older, 
with:
- Diagnosis of AML according to WHO criteria (Appendix 15.1);
o Disease refractory or relapsed(defined as the reappearance of >5% blasts in 
the bone marrow, seeTable7andTable 8)or
o Untreated AML, ≥60 years of age and not candidates for standard therapy due 
to age, performance status, and/or adverse risk factors, according to the 
treating physician and with approval of the Medical Monitor; 
- Diagnosisof Myelodysplastic syndrome with refractory anemia with excess blasts 
(subtype RAEB-1 or RAEB-2), or considered high-risk by the Revised International 
Enroll 
3subjects
No subjecthas a 
DLT
After CST
review, enroll 
next dose level
1 subjecthas a 
DLT
Enroll 3 
additional 
subjects
No additional 
subjecthas a 
DLT
1 additional 
subjecthas a 
DLT
After CST
review, enroll 
next dose level
Previous dose 
level MTD*; 
begin enrollment 
in expansion 
cohorts
2 subjects
have a DLT
Previous dose 
level MTD*; 
begin enrollment 
in expansion 
cohorts
Current Dose 
Level:
If:
Then:
If:
Then:

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Prognostic Scoring System (IPSS-R) (Appendix 15.3)(Greenberg, et al. 2012),that is 
recurrent or refractory, or the subject is intolerant to established therapy known to 
provide clinical benefit for their condition (i.e., subjects must not be candidates for 
regimens known to provide clinical benefit), according to the treating physician and 
with approval of the Medical Monitor.Subjects with other relapsed and/or primary 
refractory hematologic cancers, for example chronic myelomonocytic leukemia 
(CMML), who fulfill the inclusion/exclusion criteriamay be considered on a case-by 
case basis, with approval of the Medical Monitor.
Confirmation of the primary malignancy is required. Subjects in the dose escalation phase are 
required to have IDH2 gene-mutated disease, documented by local site testing. Retrospective 
gene mutation analysis will be conducted at a central laboratory to support contemporaneous 
companiondiagnostic development. 
The safety of dosing will be evaluated by the Clinical Study Team, which is comprised of the 
Sponsor designee (Responsible Medical Officer), Study Medical Monitor, and Investigators. The 
Clinical Study Team will review the emerging safety data from each cohort to determine if dose 
escalation will occur. If, after the third subject completes the 28-day DLT evaluation period (i.e., 
Cycle 1), no DLTs are observed (see Section9.7.1.1), the study will proceed with dose escalation 
to the next cohort following a review by the Clinical Study Team. If 1 of 3 subjects experiences a 
DLT during the first cycle, 3 additional subjects willbe enrolled in that cohort. If none of the 
additional 3 subjects experience a DLT, dose escalation may
 continue to the next cohort 
following review by the Clinical Study Team. If 2 or more subjects in a cohort experience DLTs 
during the first cycle, dose escalation will be halted and the next lower dose level will be 
declared the MTD. If the MTD cohort included only 3subjects, an additional 3 subjects will be 
enrolled at that dose level to confirm that <2 of 6 subjects experience a DLT at that dose. 
Alternatively, a dose level intermediate between the non-tolerated dose level and the previously 
tolerated dose level may be explored and declared the MTD if <2 out of 6 subjects experience a 
DLT at that dose.
Note that if a given cohort initially enrolled 4 or5 subjects (i.e., if there were multiple subjects in 
the screening process at the time the third subject within a cohort began treatment), the same 
rules for dose escalation apply. If 1 of the 4 (or 5 subjects) experiences a DLT, the cohort will be 
expanded to include a total of 6 subjects; dose escalation will occur if only 1 of 6 subjects 
experiences a DLT and will be halted if 2 or more subjects experiences a DLT.
Toxicity severity will be graded according to the NCI CTCAE Version 4.03. A DLT is defined
as outlined below:
Non-hematologic:
All clinically significant non-hematologic toxicities CTCAE ≥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× upper limit of normal (ULN) may be 
considered a DLT.

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Hematologic:
Prolonged myelosuppression, defined as persistence of ≥Grade 3 neutropenia or 
thrombocytopenia (by NCI CTCAE, version 4.03, leukemia-specific criteria, i.e., marrow 
cellularity <5% on Day 28 or later from the start of study drug without evidence of leukemia) 
at least 42 days after the initiation of Cycle 1 therapy. Leukemia-specific grading should be 
used for cytopenias (based on percentage decrease from baseline: 50 to 75% = Grade 3, 
>75% = Grade 4).
Due to frequent co-morbidities and concurrent medications in the population under study, 
attribution of AEs to a particular drug is challenging. Therefore, all AEs that cannot clearly be 
determined to be unrelated to AG-221 will be considered relevant to determining DLTs and will 
be reviewed by the Clinical Study Team.
The Clinical Study Team also will review any other emergent toxicities that are not explicitly 
defined by the DLT criteria to determine if any warrant a DLTdesignation.
Increases in the dose of AG-221 for each cohort will be guided by an accelerated titration design, 
where the dose will be doubled (100% increase) from one cohort to the next until CTCAE Grade 
2 or greater AG-221-related toxicity is observed in any subject within the cohort. Following 
evaluation of the event(s) by the Clinical Study Team, subsequent increases in dose will be 50% 
or less until the MTD is determined. The absolute percent increase in the dose will be determined 
by the Clinical Study Team predicated on the type and severity of any toxicity seen in the prior 
dose cohorts (but will never exceed 100%). The MTD is the highest dose that causes DLTs in <2 
of 6 subjects.
To optimize the number of subjects treatedat a potentially clinically relevant dose, intra-subject 
dose escalation will be permitted with approval of the Medical Monitor (see Section9.7.2).
Regularly scheduled teleconferences will serve as a forum for review of safety and other relevant 
data by the Clinical Study Team. Decisions to escalate the dose will be documented along with a 
summary of the information supporting the decision.
The planned study drug doses for the dose escalation phase are summarized in Table1.The 
starting dose for this study is 30mg administered approximately every 12 hours, based on the 
results of GLP dose range-finding studies (see Section5.2.2.5). Based on evaluation of the 
safety, tolerability, and PK/PD data of the previous dose levels, it may
 also be decided that 
escalation will take place at an intermediate dose level not specified in the tables below.The 
maximum administered doseof AG-221 to be administered in this portion of the trial is 650 mg 
administered orally oncea day.  Enrollment in the dose escalation phase of this trial is complete,
and no additional subjects will be enrolled.

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Table1:
Planned Dose Escalation Scheme
BID Schedule AG-221 Dose
(mg)
QD Schedule AG-221 Dose
(mg)
301
Not evaluated
50
50
75
75
100
100
150
150
Not evaluated 
200
Not evaluated
300
Not evaluated
450
Not evaluated
650
1Starting Dose 
The results of a completed Phase 1 food-effect study in healthy volunteers (AG221-C-002) 
indicate a mild or moderate food effect on AG-221 plasma PK at 100 mg single dose. The 90% 
CIs (confidence intervals) of LSM (least-squares means) for PK parameters under fed versus 
fasted conditions were above the 80.00-125.00% range for Cmax, and AUC. There was an 
approximately 50% increase in AUC and a 64% increase in Cmax when AG-221 was 
administered under fed conditions compared with fasted conditions. Based on this, the effect of 
food and fasting on AG-221 exposure isbeing further evaluated in the dose escalation portion of 
this study. Specifically, AG-221 dosing without food restrictions will be conducted in 4 subjects 
at doses of 200 and 300 mg for 15 days of treatment (through C1D15) with the final formulation. 
Depending on these results, subjects in the Phase 2 portion of the trial may be dosed without 
food restriction.
7.1.2.
Overview of the Phase 1/Part 1 Expansion
Adose of 100 mg QD has been selected for initial evaluation in Part1 Expansion(see Section 
7.3.2.).  Different dosing regimens may be explored within the expansion phase of the study if 
warranted based on the emerging clinical safety, PK, PD and clinical activity data. During the 
expansion phase, safety, PK/PD, and preliminary clinical activity data will be reviewed by the 
Clinical Study Team every 8 weeks.
Part 1 Expansion phase will enroll approximately a minimum of 100 subjects divided into 4 non-
randomized arms of approximately a minimum of 25 subjects per arm with IDH2-mutated 
hematologic malignancies as follows:

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Arm 1: Relapsed or refractory AML (Table7andTable 8) and age ≥60 years, or any subject 
with AML regardless of age who has relapsed following a BMT.
Arm 2: Relapsed or refractory AML(Table7andTable 8) and age <60 years, excluding 
subjects with AML who have relapsed following a BMT.
Arm 3: Untreated AML and age ≥60 yearsthat decline standard of care chemotherapy.
Arm 4: IDH2-mutated advanced hematologic malignancies not eligible for Arms 1 to 3.
As in the dose escalation phase, subjects in Part 1 Expansion are required to have IDH2 gene-
mutated disease documented by local site testing with retrospective gene mutation analysis 
conducted at the central laboratory.
7.1.3.
Overview of Phase 2
Based on continued ongoing demonstration of safety and clinical activity in the dose escalation 
portion of the study, the Phase 2 portion of the trialwill further establish the clinical activity and 
safety profile of AG-221 in subjects with relapsedor refractory AML that harbor an IDH2 
mutation . 
The Phase 2 portion of the trialwill enroll approximately 125 subjects with IDH2-mutated 
relapsed or refractory AML defined as follows(Table7andTable 8):
Subjects who relapse after allogeneic transplantation
Subjects in second or later relapse
Subjects who are refractory to initialinduction or re-induction treatment
Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-risk 
status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: inv(16),
t(16;16), t(8;21), t(15;17)The Phase 2portion of the trial will be used to confirm the safety and 
clinical activity of AG-221 and to explore the relationship with PK/PD and IDH2 mutations for 
the treatment of subjects with relapsed or refractory AML that harbor an IDH2 mutation. 
The starting dose of AG-221 recommended for evaluation for the Phase 2 portion of the trial is 
100mg QD.  This is based on the safety, PK, pharmacodynamics and clinical activity of AG-221 
observed to date in AG221-C-001.Evaluation of pharmacodynamic response demonstrated 
sustained reduction in 2-HG plasma levels by Day 1 of Cycle 2 and up to 98% inhibition in most 
subjects with R140Q mutation at all doses.Increasing dose is associated with higher exposure 
and inhibition of 2-HG in subjects with R172K mutation. Importantly, preliminaryefficacy data 
of the 44 subjects treated at 100 mg QD has shown an overall response rate of 36.4%. Thus a 
dose of 100 mg should adequately achieve inhibition of 2-HG in subjects with either R140Q or 
R172K mutation. Moreover, the safety profile at 100 mg,including ≥ Grade 3, is consistent with 
that of lower doses.
Subjects in the Phase 2 portion of the trialare required to have IDH2-mutation testedcentrally
in samples of bone marrow aspirate and/orperipheral blood, and confirmed positive in bone 
marrow aspirate and/orperipheral bloodduring screeningprior to study treatment. 
The purpose of this phase is to provide an assessment of its antitumor activity in subjects with 
AML and characterize the safety and tolerability profile.

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7.1.4.
General Conduct
Thisis a multicenter study.  
Approximately minimum of 291 subjects in total is planned to be enrolled in the study (i.e., in 
the dose escalation, Part 1 Expansion, and Phase 2). 
Assumingthat identification of the MTD requires the evaluation of 13dose levels/schedulesof 
AG-221 with up to5subjects per dose level, with the exception of the MTD,which requires 6 
subjects, then 66subjects will be enrolled during the dose escalation part of the study. Additional 
subjects may be needed for cohort expansion during dose escalation, for the replacement of 
subjectswho are not evaluable for PK/PD, safety or clinical activity, or for evaluation of 
alternative dosing regimens other than the planned escalation scheme or the MTD, to optimize 
the RP2D and regimen(s).
As of April 2015, 5 dose levels (ranging from 30 mg to 150 mg) have beenevaluated in the BID 
schedule and 8 dose levels (ranging from 50 mg to 650 mg)havebeenevaluated in the QD 
schedule.  
Four cohorts of a minimum of25additional subjects in specific hematologic malignancy subsets 
(total of a minimum of100 subjects) will be enrolled in Part 1 Expansion and 1 cohort of 125 
subjects with relapsed or refractory AML will be enrolled in Phase 2. Additional subjects may be 
needed for the expansion phase for the replacement of subjects who are not evaluable for PK/PD, 
safety or clinical activity, or for evaluation of alternative dosing regimens.
The final total sample size may be adjusted according to the observed toxicity rate, and number 
of subjects enrolled for expanded evaluation.
Schedule of assessments for the study are provided inTable2throughTable 5.
Screening Procedures
Following informed consent, all subjects will undergo screening procedures within 28 days prior 
to C1D1 to determine eligibility. All subjects are required to have confirmation of positive 
IDH2-mutated disease from a bone marrow aspirate and peripheral blood(report collected as a 
source document). For subjects in the dose escalation phase andPart 1 Expansion, 
documentation can be based on local site testing with central laboratory testing performed 
retrospectively. 
Note: Subjects in the Phase 2 portion of the trialare required to have IDH2-mutation tested
centrallyin samples of bone marrow aspirate and/orperipheral blood, and confirmed positive in 
bone marrow aspirate and/orperipheral bloodduring screeningprior to study treatment. 
Additional screening procedures include collection of medical, surgical, and medication history; 
a buccal swab for germ-line mutation analysis; complete physical examination; vital signs; 
ECOG PS; 12-lead ECG; evaluation of LVEF; clinical laboratory assessments (hematology, 
chemistry, coagulation, and serum pregnancy test); bone marrow biopsy and/or aspirate; and 
blood for 2-HG, α-KG measurements, and determination of UGT1A1 mutation status. In 
addition, subjects in the dose escalation phase and Part 1 Expansion willhave urine obtained for 
2-HG and α-KG measurements and blood samples for cholesterol and 4β-OH-cholesterol levels 
during screening.

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Pharmacokinetic/Pharmacodynamic and ECG Assessments
Phase 1/Dose Escalation 
Three days prior to starting daily dosing of AG-221 (Day -3), the first 3 subjects in each cohort 
in the dose escalation phase and the first 15 subjects enrolled in each arm in Part 1 Expansion 
(unless approved by the Medical Monitor to omit the assessment) will receive a single dose of 
AG-221 in clinic and have serial blood and urine samples obtained for determination of 
blood/plasma and urine concentrations of AG-221, it’s metabolite AGI-16903, 2-HG, and α-KG. 
A full 72-hour PK/PD profile will be obtained: subjects will be required to remain at the study 
site for 10 hours on Day -3 and return on Days -2, -1, and 1 for 24-, 48-, and 72-hour samples, 
respectively. During the in-clinic period on Day -3, clinical observation and serial 12-lead ECGs 
and vital signs assessments will be conducted over an 8-hour period after the first dose. 
Daily treatment with AG-221 will begin on C1D1. Subjects in the dose escalation phase and Part 
1 Expansion who did not receive the Day-3 dose of AG-221 are to remain in clinic for 8 hours 
after the C1D1 dose for clinical observation,serial 12-lead ECGs, and vital signs assessments.
After 12 months, subjects in the dose Phase 1 dose escalationwill no longer undergoPK 
assessments,but bone marrow biopsy and/or aspirates as well as peripheral bloodsampleswill 
still be collected for evaluation of disease, including exploratory biomarkers.
Phase 1/Part 1 Expansion
Subjects in the dose escalation phase and Part 1 Expansion will undergo PK/PD assessments 
over a 10-hour period on C1D15, C2D1, and C4D1. Predose blood samples (trough) will be 
obtained on C1D1 (for subjects who did not undergo the Day -3 assessments), C1D8, C1D22, 
C2D15, C3D1, C3D15, C5D1, and Day 1 of all cycles thereafter for determination of AG-221, 
and 2-HG, and α-KG concentrations. These subjects will have urine collected for PK/PD 
evaluation at screening; prior to dosing on C1D15, C2D1 and Day 1 of all cycles through cycle 
12; and at the End of Treatment visit. Available bone marrow biopsy samples also will be 
assessed for 2-HG and α-KG levels.
After 12 months, subjects in the Phase 1 Part 1 Expansionwill no longer undergoPK 
assessments,but bone marrow biopsy and/or aspirates as well as peripheral bloodsampleswill 
still be collected for evaluation of disease, including exploratory biomarkers.
Phase 2
The Day -3 single dose and associated PK/PD assessments are not required for subjects enrolled 
in The Phase 2 portion of the trial; daily treatment with AG-221 will begin on C1D1. Subjects in 
The Phase 2 portion of the trialwill have more limited PK/PD assessments conducted and will 
undergo time-matched triplicate ECGs. Available bone marrow samples will be assessed for 2-
HG and α-KG levels.
For subjects in the Phase 2 portion of the trial, blood will be drawn for PK/PD assessment on 
Day1 of Cycles 1 and 2 atthe following time points: predose (within 30 minutes) and 2, 4, 6, 
and 8 hours (±10 minutes) post-dose. Additional blood samples for PK/PD assessments will be 
drawn predose (within 30 minutes) on Day 2of Cycle 1, Day 2 of Cycle 2, Day 1 of Cycle 3, and 
at the End of Treatment visit. 

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Time-matched 12-lead ECGs will be conducted in triplicate on Day 1 of Cycles 1 and 2 atthe 
following time points: predose (within 30 minutes) and 2, 4, and 6 hours post-dose (±15 
minutes); a triplicate ECG is also to beobtained at the End of Treatment visit. When the timing 
of a blood sample coincides with the timing of an ECG measurement, the ECG will be 
completed before the collection of the blood sample (within 10 minutes). Single 12-lead ECGs 
will also be conducted on Day 1 of every cycle beginning with Cycle 3 and at the Follow-up 
visit.
Other Safety Assessments
All subjects will undergo safety assessments during the treatment period to include physical 
examination, vital signs, ECOG PS, 12-lead ECGs, evaluation of LVEF, and clinical laboratory 
assessments (hematology, chemistry, coagulation, and pregnancy testing).
Clinical Activity Assessments
Phase 1 (Dose Escalation and Part 1 Expansion):
Subjects in the dose escalation phase and Part 1 Expansion will have the extent of their disease 
assessed, including bone marrow biopsies and/or aspirates, and peripheral blood, at screening, on 
C1D15, C2D1and C3D1, and every 28 days (peripheral blood only) or every 56 days (bone 
marrow biopsies and/or aspirates and peripheral blood) thereafter while on study drug treatment, 
independent of dose delays and/or dose interruptions, and/or at any time when progression of 
disease is suspected.
After at least 12 months, subjects in the dose escalation phase and Part 1 Expansionmayhave
the extent of their disease assessed, including bone marrow biopsy,aspirates or peripheral blood
based on their response to treatment. 
Response to treatment and treatment decisions in all subjects will be determined by the 
Investigators based on modified International Working Group (IWG) response criteria or other 
appropriate response criteria for the malignancy under study (Section10.8). 
Phase2:
For subjects enrolled in the Phase 2 portion of the trialextent of disease, including bone marrow 
biopsies and/or aspirates and peripheral blood, will be assessed at Screening, on C2D1, every 28 
days thereafter through 12 months, and every 56 days thereafter while on study drug treatment, 
independent of dose delays and/or dose interruptions, and/or at any time when progression of 
disease is suspected.
After at least 12 months, subjects in the Phase 2 portion of the trialmayhave the extent of their 
disease assessed, including bone marrow biopsy,aspirates or peripheral blood based on their 
response to treatment. 
Eligibility, treatment decisions, and response to treatmentwill be determined by the Investigators
based on modified International Working Group (IWG) response criteria (Table7andTable 8).  
Response will be also be assessed retrospectively by an Independent Response Adjudication 
Committee (IRAC).  

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End of Treatment and Follow-up
Subjects may continue treatment with AG-221 until disease progression or development of 
unacceptable toxicity. Subjects who experience disease progression per the applicable response 
criteria (Section10.8) who are, in the opinion of the Investigator, benefiting from treatment may 
be allowed to continue on study drug with approval of the Medical Monitor. 
All subjects are to undergo an end of treatment assessment (within approximately 5 days of the 
last dose of study drug); in addition, a follow-up safety assessment is to be scheduled 28 days 
after the last dose.Furthermore, all subjects will be followedmonthly for disease status, overall 
survival, and initiation of non-study anti-neoplastictherapy until death, withdrawal of consent, or 
the end of the study, whichever occurs first.
Subjects who achieve an adequate response to treatment with AG-221 and meet other criteria 
required to undergo HSCT may proceed to HSCT after discontinuation of study therapy.   Those 
subjects will be followed on study for outcome until disease relapse or end of study to support 
the overall clinical benefit of AG-221 in this setting. 
Subjects who relapse followingHSCT may be eligible to restart treatment with AG-221 with 
Medical Monitor approvaland at the discretion of the Investigator, if they have confirmed 
recurrent IDH2 mutant positive disease,  no cancer treatment was administered since the last 
dose of AG-221(with the exception of anti-neoplastic therapiesused in the course ofHSCT such 
as conditioning regimen or induction-type regimenand anti-GVHD prophylaxis [i.e.,
methotrexate]),the subject meets the safety parameters listed in the Inclusion/Exclusion criteria, 
and the trial is open.  Subjects will resume AG-221 therapy at the same dose and schedule at the 
time of discontinuationof study drug.
All subjects are to be followed for survival status follow up every 3 months until death, 
withdrawal of consent,or end of studyfor survival. Serious AEs considered related to study drug 
should continue to be followed until death, withdrawal of consent,or the end of the studyas per 
Section 11.2.
End of Study:
The End of Studyis defined as either the date of the last visit of the last subject to complete the 
study, 3 years after the first dose of the last subject enrolled into Phase2, or the date of receipt of 
the last data point from the last subject that is required for primaryand secondary analysis, as 
pre-specified in the protocol, whichever is the later date.
2.
n
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o 
3 
ch 
le 
g.
 
 

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s 
 
f 
7.4.
Criteria for Study Termination
This study may be prematurely terminated, if in the opinion of the Sponsor, there is sufficiently 
reasonable cause. In the event of such action, written notification documenting the reason for 
study termination will be provided to each Investigator.
Circumstances that may warrant termination include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to subjects.
Failure to enter subjects at an acceptable rate.
Insufficient adherence to protocol requirements.
Plans to modify, suspend, or discontinue the development of the study drug.
Other administrativereasons.
Should the study be closed prematurely, all study materials must be returned to the Sponsor or 
Sponsor’s designee. See Section8.5for specific requirements for subject termination from the 
study.

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8.
STUDY POPULATION
8.1.
Number of Subjects
Approximately minimum of 291 subjects in total is planned to be enrolled in the study (i.e., in 
the dose escalation,Part 1 Expansion, and Phase 2). Assuming that 50% of subjects will not meet 
inclusion and/or exclusion criteria, i.e., are screen failures, approximately a minimum of 582
subjects will need to be screened to enroll a minimum of 291. Reasons for screen failure will be 
captured, including tumor samples obtained at screening that are IDH2 wild-type on local 
testing; note that tumor samples from these subjects also should be submitted for central 
evaluation.
Assuming that identification of the MTD requires the evaluation of 13dose levels/schedulesof 
AG-221, and requires the evaluation of up to 5 subjects per dose level with the exception of the 
MTD which requires 6 subjects, then 66 subjects will be enrolled during the dose escalation part 
of the study. Additional subjects may be needed for cohortexpansion during dose escalation, for 
the replacement of subjects who are not evaluable for PK/PD, safety or clinical activity, or for 
evaluation of alternative dosing regimens other than the planned escalation scheme or the MTD, 
to optimize the RP2D and regimen(s).
As of April 2015, 5 dose levels (ranging from 30 mg to 150 mg) have been evaluated in the BID 
schedule and 8 dose levels (ranging from 50 mg to 650 mg)have beenevaluated in the QD 
schedule.  
Four cohorts of approximately a minimum of 25 additional subjects in specific hematologic 
malignancy subsets (see Section7.1.2) (total of approximately a minimum of 100 subjects) will 
be enrolled in Part 1 Expansion of the study and 1 cohort of 125 subjects with relapsed or 
refractory AML will be enrolled in the Phase 2 portion of the trial(see Section 7.1.3). Additional 
subjects may be needed for the replacement of subjects who are not evaluable for PK/PD, safety 
or clinical activity, or for evaluation of alternative dosing regimens.
The final total sample size may be adjusted according to the observed toxicity rate, and number 
of subjects enrolled for expanded evaluation.
8.2.
Inclusion Criteria
Subjects must meet all of the following criteria to be enrolled in the study:
1. Subject must be ≥18 years of age.
2. Subjects must have an advanced hematologic malignancy including:
Dose escalation:
Phase 1/ Dose escalation:
Diagnosis of AML according to World Health Organization (WHO) criteria 
(Appendix 15.1);
o Disease refractory or relapsed(defined as the reappearance of > 5% blasts in the 
bone marrow, seeTable7andTable 8).

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o Untreated AML, ≥60 years of age and are not candidates for standard therapy due 
to age, performance status, and/or adverse risk factors, according to the treating 
physician and with approval of the Medical Monitor; 
Diagnosis of MDS according to WHO classification (Appendix 15.2) with refractory 
anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by 
the IPSS-R (Appendix 15.3) (Greenberg, et al. 2012),that isrecurrent or refractory, 
or the subjectis intolerant to established therapy known to provide clinical benefit for 
their condition (i.e., subjects must not be candidates for regimens known to provide 
clinical benefit), according to the treating physician and with approval of the Medical 
Monitor.
(Subjects with other relapsed and/or primary refractory hematologic cancers, for 
example CMML, who fulfill the inclusion/excluding criteria may be considered on a 
case-by case basis, with approval of the Medical Monitor.)
Phase 1/Part 1 Expansion:
Arm 1:Relapsed or refractory AML (Table7andTable 8) and age ≥60 years, or any 
subject with AML regardless of age who has relapsed following a BMT.
Arm 2: Relapsed or refractory AML (Table7andTable 8) and age <60 years, 
excluding subjects with AML who have relapsed following a BMT.
Arm 3: Untreated AML and age ≥60 years that decline standardof care 
chemotherapy.
Arm 4: IDH2-mutated advanced hematologic malignancies not eligible for Arms 1 to 
3.
Phase 2:
Diagnosis of AML according to World Health Organization (WHO) criteria 
(Appendix 15.1) and disease relapsed or refractory as defined by(Table7andTable 
8):
Subjects who relapse after allogeneic transplantation;
Subjects in second or later relapse;
Subjects who are refractory to initial inductionor re-inductiontreatment;
3. Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-
risk status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: 
inv(16), +(16;16), t(8;21), t(15;17).Subjects must have documented IDH2 gene-mutated 
disease:
For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may 
be based on local evaluation. (Centralized testing will be performed retrospectively.) 
For subjects in the Phase 2 portion of the trial, central testing of IDH2 mutationof 
bone marrow aspirate and/orperipheral blood,is required during screening to 
confirm eligibility.

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4. Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling, 
and urine sampling during the study.
The diagnosis and evaluation of AML or MDS will be made by bone marrow 
aspiration and/or biopsy. If an aspirate is unobtainable (i.e., a “dry tap”), the 
diagnosis may be made from the core biopsy.
Screening bone marrow aspirate andperipheral blood samples are required all 
subjects.  A bone marrow biopsy must be collected if adequate aspirate is not 
attainable unless: 
o A bone marrow aspirate and biopsy was performed as part of the standard 
of care within 28 days prior to the start of the study treatment; and 
o Slides of bone marrow aspirate, biopsyand stained peripheral blood smear 
are available for bothlocal and central pathology reviewers; and 
o A bone marrow aspirate sample acquired within 28days prior to the start 
of study treatment has been sent for cytogenetic analysis. 
5. Subjects must be able to understand and willing to sign an informed consent. A legally 
authorized representative may consent on behalf of a subject who is otherwise unableto 
provide informed consent, if acceptable to and approved by the site and/or site’s 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
6. Subjects must have ECOG PS of 0 to 2 (Appendix15.5).
7. Platelet count ≥20,000/µL (transfusions to achieve this level are allowed). Subjects with a 
baseline platelet count of <20,000/µL due to underlying malignancy are eligible with 
Medical Monitor approval.
8. Subjects must have adequate hepatic function as evidenced by:
Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due to 
Gilbert’s disease, a gene mutation in UGT1A1, or leukemic organ involvement, 
following approval by the Medical Monitor;
AST, ALT and ALP ≤3.0 × ULN, unless considered due to leukemic organ 
involvement.
9. Subjects must have adequate renal function as evidenced by:
Serum creatinine ≤2.0×ULN
OR
Creatinine clearance 40 mL/min based on the Cockroft-Gault glomerular filtration 
rate (GFR) estimation:
(140Age)(weight in kg)(0.85 if female)/72serum creatinine
10.Subjects must be recovered from any clinically relevant toxic effects of any prior surgery
, 
radiotherapy,or other therapy intended for the treatment of cancer.(Subjects with 
residual Grade 1 toxicity, for example Grade 1 peripheral neuropathy or residual 
alopecia, are allowed with approval of the Medical Monitor.)

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11.Female subjects of child-bearing potential must agree to undergo medically supervised 
pregnancy test prior to starting study drug. The first pregnancy test will be performed at 
screening (within 7 days prior to first study drug administration), and on the day of the 
first study drug administration and confirmed negative prior to dosing and Day 1 before 
dosing all subsequent cycles.
12.Female subjects with reproductive potential must have a negative serum pregnancy test 
within 7 days prior to the start of therapy. Subjects with reproductive potential are 
defined as sexually mature women who have not undergone a hysterectomy, bilateral 
oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., 
who have not menstruated at all) for at least 24 consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive months). Females of reproductive potential as 
well as fertile men and their partners who are female of reproductive potential must agree 
to abstain from sexual intercourse or to use two highly effective forms of contraception 
from the time of giving informed consent, during the study and for 120days (females and 
males) following the last dose of AG-221. A highly effective form of contraception is 
defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, 
double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with 
spermicidal foam, cream, or gel), or male partner sterilization.
13.Able to adhere to the study visit schedule (ie, clinic visits at the study sites are 
mandatory, unless noted otherwise for particular study visits) and other protocol 
requirements
8.3.
Exclusion Criteria
Subjects who meet any of the following criteria will not be enrolled in the study:
1. Subjects who have undergone a hematopoietic stem cell transplant(HSCT) within 
60days of the first dose of AG-221, or subjects 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 steroids post HSCT and/or topical steroids for 
ongoing skin GVHD is permitted with Medical Monitor approval.) 
2. Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their 
first day of study drug administration. (Hydroxyurea is allowed prior to enrollmentand 
after the start of AG-221 for the control of peripheral leukemic blasts in subjects with 
leukocytosis (white blood cell [WBC] counts >30,000/μL).
3. Subjects who received a small molecule investigational agent <14 days prior to their first 
day of study drug administration.In addition, the first dose of AG-221 should not occur 
before a period ≥5 half-lives of the investigational agent has elapsed.
4. Subjects taking the following sensitive CYP substrate medications that have a narrow 
therapeutic range are excluded from the study unless they can be transferred to other 
medications within ≥5 half-lives prior to dosing: paclitaxel (CYP2C8) warfarin, 
phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline 
and tizanidine (CYP1A2). 

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5. Subjects taking the P-gp and BCRP transporter-sensitive substrates digoxin and 
rosuvastatin should be excluded from the study unless they can be transferred to other 
medications within ≥5 half-livesprior to dosing.
6. Subjects for whom potentially curative anticancer therapy is available.
7. Subjects who are pregnant or lactating.
8. Subjects with an active severe infection that required anti-infective therapy or with an 
unexplained fever >38.5°C during screening visits or on their first day of study drug 
administration (at the discretion of the Investigator, subjects with tumor fever may be 
enrolled).
9. Subjects with known hypersensitivity to any of the components of AG-221.
10.Subjects with New York Heart Association (NYHA) Class III or IV congestive heart 
failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) 
scan obtained within approximately 28 days of C1D1.
11.Subjects with a history of myocardial infarction within the last 6 months of screening.
12.Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or 
diastolic BP >100mmHg) at screening are excluded. Subjects requiring 2 or more 
medications to control hypertension are eligible with Medical Monitor approval.
13.Subjects with known unstable or uncontrolled angina pectoris.
14.Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
15.Subjects with a QTcF(QT corrected based on Fridericia’s equation) interval ≥450 msec 
or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart 
failure, hypokalemia, family history of long QT interval syndrome) at screening. Subjects 
with bundle branch block and a prolonged QTc interval should be reviewed by the 
Medical Monitor for potential inclusion.
16.Subjects taking medications that are known to prolong the QT interval (see 
Section9.12.3unless they can be transferred to other medications within ≥5 half-lives
prior to dosing.
17.Subjects with known infection with human immunodeficiency virus (HIV) or active 
hepatitisB or C.
18.Subjects with any other medical or psychological condition, deemed by the Investigator 
to be likely to interfere with a subject’s ability to sign informed consent, cooperate, or 
participate in the study.
19.Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions 
that limit the ingestion or gastrointestinal absorption of drugs administered orally.
20.Subjects with clinical symptoms suggesting active central nervous system (CNS) 
leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if 
there is a clinical suspicion of CNS involvement by leukemia during screening.

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21.Subjects with immediately life-threatening, severe complications of leukemia such as 
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated 
intravascular coagulation.
22.In the Phase 2 portion of the trialonly, subjects who have previously received treatment 
with an inhibitor of IDH.
8.4.
Subject Identification and Registration
Subjects who are candidates for enrollment into the study will be evaluated for eligibility by the 
Investigator to ensure that the inclusion and exclusion criteria (see Sections8.2and 8.3, 
respectively) have been satisfied and that the subject is eligible for participation in this clinical 
study. The Medical Monitor will confirm eligibility for all subjects prior to receipt of the first 
dose of AG-221.
Trial personnel will have access to Interactive Response Technology (IRT, including an 
Interactive Web Response System [IWRS]) to allocate subjects, to assign treatment to subject, 
and to manage the distribution of clinical supplies. Investigator or designated site staff will be 
assigned password protected, coded identification numbers that give them authorization toaccess 
the IRT system to enroll subjects. 
8.5.
Subject Withdrawal Criteria and Replacement of Subjects
Subjects have the right to withdraw from the study at any time for any reason. 
Subjects may withdraw or be withdrawn from study treatment for any of the following reasons:
Withdrawal of consent
Experiences unacceptable toxicity
Any medical condition, which, in the opinion of the Investigators, would put the subject at 
risk for continuing treatment
Experiences disease progression (subjects who are, inthe opinion of the Investigator, 
benefiting from treatment may be allowed to continue on study drug with approval of the 
Medical Monitor)
Confirmed pregnancy (study therapy should be immediately interrupted based upon a 
positive urinary human chorionic gonadotropin (hCG), and permanently discontinued if 
confirmed by a serum β-hCG test) 
Development of an intercurrent medical condition that precludes further participation in the 
trial
The Investigator removes the subject from the trial in the best interests of the subject
Subject requires use of a prohibited concomitant medication (Section9.12.3)
Protocol violation: non-adherence to study drug regimen or protocol requirements
Lost to follow-up
Death

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Discontinuation from study treatment should be considered distinct from discontinuation from 
the study.  
Allsubjects discontinued from study treatment for any reason should undergo End of Treatment
(EOT) procedures, and will have a follow-up visit as described in Section10.1.  All subjects 
discontinued from study treatment for any reason will be followed further for disease status, 
overall survival, and initiation of non-study anti-neoplastic therapy until death, withdrawal of 
consent, or the end of the study, whichever occurs first.  Every attempt should be made to collect 
all data during the follow-up period unless subjects discontinue from the study.
Following discontinuation of study drug, all efforts will be made to complete and report the 
protocol-defined study observations as completely as possible and to determine the reason for 
withdrawal.
Once a subject has discontinued study drug (or for a subject in the expansion phase who 
underwent HSCT post-treatment and has subsequently relapsed and elects not to restart 
treatment), he or she will enter the follow-up phase for survival.
All subjects are to be followed for survival status follow up every 3 months until death, 
withdrawal of consent, or end of study for survival. 
In the event a subject is withdrawn from study drug or the follow-up phase of the study, the 
Medical Monitor must be informed. If there is a medical reason for withdrawal, the subject will 
remain under the supervision ofthe Investigator until satisfactory health has returned.
When a subject discontinues study drug or withdraws from the study, the primary reason(s) for 
discontinuation or withdrawal must be recorded in the appropriate section of the electronic case 
report form (eCRF) and all efforts will be made to complete and report final study observations 
as thoroughly as possible.
All AEs should be followed until resolution or for a period of 28 days from the last dose of study 
drug, whichever is shorter. If the subject withdrew from treatment because of an AE, every effort 
must be made to perform protocol-specified safety follow up procedures.
Serious AEs considered related to study drug should continue to be followed until death, 
withdrawal of consent, or the end of the studyas per Section11.
In addition, all pregnancies and suspected pregnancies (including a positive pregnancy test 
regardless of age or disease state) of a female subject or partner of a male subject occurring 
within 120days of the subject’s last dose of study drug, are considered immediately reportable 
events(Section 11.3). 
For the dose escalation phase, subjects who do not meet the minimum treatment and safety 
evaluation requirements for evaluation of DLT (Section9.7.1) and who do not experience DLT 
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If ≥2 subjects within a cohort experience a DLT, then the previous dose level will be 
declared the MTD. Alternatively, a dose level intermediate between the non-tolerated dose 
level and the previously tolerated dose level may be explored and declared the MTD if <2 out 
of 6 subjects experience a DLT at that dose.
Note that if a given cohort initially enrolled 4 or 5 subjects (i.e., if there were multiple subjects in 
the screening process at the time the third subject within a cohort began treatment), the same 
rules for dose escalation apply. If 1 of the 4 (or 5 subjects) experiences a DLT, the cohort will be 
expanded to include a total of 6 subjects; dose escalation will occur if only 1 of 6 subjects 
experiences a DLT and will be halted if 2 or more subjects experiences a DLT.
Increases in the dose of AG-221 for each dose cohort will be guided by an accelerated titration 
design, where the dose will initially be doubled (100% increase; see Table1) from one cohort to 
the next until NCI CTCAE Grade 2 or greater AG-221-related toxicity is observed in 1 subject 
within the cohort. Following evaluation of the event(s) by the Clinical Study Team, subsequent 
increases in dose will be 50% or less until the MTD is determined. The absolute percent increase 
in the dose will be determined by the Clinical Study Team predicated on the type and severity of 
any toxicity seen in the prior dose cohorts (but will never exceed 100%). Based on the emerging 
data, alternative dosing schedules may be explored as agreed upon by the Clinical Study Team.
The MTD is the highest dose that causes DLTs in <2 of 6 subjects.
If no DLTs are identified during the dose escalation phase, dose escalation may continue for 
2dose levels above the projected maximum clinically effective dose, as determined by an 
ongoing assessment of PK/PD and any observed clinical activity; this may occur in parallel with 
the expansion phase.
9.7.1.1.
Dose-limiting Toxicity
Dose-limiting toxicities will be evaluated during Cycle 1 of treatment. Toxicities will be graded 
and documented according to the NCI CTCAE, Version 4.03 (see Appendix15.7). A DLT is 
defined as outlined below:
Non-hematologic:
All clinically significant non-hematologic toxicities CTCAE ≥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× upper limit of normal (ULN) may be 
considered a DLT.
Hematologic:
Prolonged myelosuppression, defined as persistence of Grade ≥3 neutropenia or 
thrombocytopenia (by NCI CTCAE, version 4.03, leukemia-specific criteria, i.e., marrow 
cellularity <5% on Day 28 or later from the start of study drug without evidence of leukemia) 
at least 42 days after the initiation of Cycle 1 therapy. Leukemia-specific grading should be 
used for cytopenias (based on percentage decrease from baseline: 50 to 75% = Grade 3, 
>75% = Grade 4).
Due to frequent co-morbidities and concurrent medications in the population under study, 
attribution of AEs to a particular drug is challenging. Therefore, all AEs that cannot clearly be 

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determined to be unrelated to AG-221 will be considered relevant to determining DLTs and will 
be reviewed by the Clinical Study Team.
The Clinical Study Team also will review any other emergent toxicities that are not explicitly 
defined by the DLT criteria to determine if any warrant a DLT designation.
9.7.2.
Intra-subject Dose Modification Criteria
9.7.2.1.
Dose Escalation Criteria
Intra-subject dose escalation is permitted for all subjects following Medical Monitor approval.
Phase 1 Dose Escalation
Subjects who are receiving a lower dose of AG-221 than has been evaluated and determined to 
be safe (i.e., following safety review of that cohort there are <2 of 6 [or 0 of 3] subjects with 
DLTs) may be escalated to the higher safe dose pending review with the Medical Monitor. There 
is no limit to the number of times the dose of AG-221 may be increased for a given subject 
following Medical Monitor approval. 
Phase 1 Part 1 Expansion
Subjects may only be dose-escalated once from their starting dose for the following: 
suboptimal response after the first clinical response assessment or later
evidence of relapse on AG-221 after a response either in the peripheral blood or bone 
marrow
Phase 2 
The AG-221 dose for the subsequent treatment cycles that are given may be increasedfrom 
100mg QD to 200mg QD if the following occurs:
ANC < 0.5 x 109/L after being on AG-221 for the firstcycle 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 2cycles 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, Section9.7.2.2) isobserved and 
considered as possibly or probably related to AG-221 treatment.  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.
9.7.2.2.
Dose Reduction Criteria
All effort must be madeto dose study drugaccording to schedule without cycle delay, dose 
interruption and reduction.  Subjects will be monitored for hematologic toxicity and non-

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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. 
Dose reductions to a dose approved by the Medical Monitor and/or interruption of dosing may be 
allowed in the event of toxicities that are assessed as possibly or probably related to treatment 
with AG-221 following discussion with the Medical Monitor. If the time required for recovery 
from toxicity, i.e., return to at least baseline levels, is more than 28 days (1 cycle), a subject’s 
continuation in the study should be discussed with the Medical Monitor regarding the risks and 
benefits of continuation. The AG-221 can be dose reduced in multiples of 50 mg. For example, 
at a starting dose of 200 mg QD, dose reductions should occur to 150 mg QD then to 100 mg QD 
and then to 50 mg QD. Any subject who is unable to tolerate 50 mg QD of AG-221 should be 
discontinued from study treatment.
Escalation back to the starting dose and/or an intermediate dose maybe permitted with Medical 
Monitor approval.
Subjects who experience persistent Grade ≥3 toxicity that are assessed as possibly or probably 
related to treatment with AG-221 who are, in the opinion of the Investigator, benefiting from 
treatment may be allowed to continue on study drug with approval of the Medical Monitor. If the 
time required for recovery from toxicity, i.e., return to at least baseline levels, is more than 28 
days (1cycle), a subject’s continuation in the study should be discussed with the Medical 
Monitor regarding the risks and benefits of continuation.
9.7.3.
Dose Discontinuation Criteria
Dosing for an individual subject will be discontinued permanently for any DLT unless the 
subject is benefitting from study drug treatment per the Investigator and with approval of the 
Medical Monitor; a dose reduction may be considered (Section9.7.2). Other reasons for 
treatment termination are provided in Section8.5.
9.8.
Guidelines for ImportantEvents
The following are guidelines for the management of adverse events of special interest based on 
the non-clinical and clinical safety findings to date.
9.8.1.
Guidelines for Management of QT Prolongation
The discussion of the emergency management of torsade de pointes and its hemodynamic 
consequences is beyond the scope of this guideline.
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 prolongationand 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 adjustedas appropriate for medication 
with known QT prolonging effects.

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If no other cause is identifiedand the Investigator believes it is appropriate, 
particularly if QTc remains elevated (after above measures have been implemented, 
or as determined by the Investigator), investigational product may be interrupted, and 
an ECG should be rechecked in approximately 1 week after the QTc prolongation 
was first observed, or more frequently as clinically indicated.  
o If QTc hasrecovered or improved and the Investigatorbelieves it is safe to do 
so, 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.
o If Grade 2 (QTcF > 480 and ≤ 500 msec), the dose of AG-221 may be reduced 
to a dose approved by the medical monitor 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).
o If Grade 3 (QTcF > 500 msec), when QTc prolongation is first observed, 
hospitalization for continuous cardiac monitoring and evaluation by a 
cardiologist should both be done.  Dosing with AG-221 will be interrupted.  If 
QTc returns to within 30 ms 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.
o 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 hospital when QTc 
prolongation is first observed for continuous cardiac monitoring and be 
discharged only after review by a cardiologist.  Dosing with AG-221 should 
be permanently discontinued.
9.8.2.
IDH Differentiation Syndrome
Subjects treated with AG-221 may developsigns and symptoms of a IDH Differentiation 
Syndrome.  Signs and symptoms couldinclude fever, dyspnea, edema/weight gain, increased 
serum creatinine and, in some cases, clinicalfeatures consistent with the acute respiratory 
distress syndrome with associated pulmonary infiltrates, and pulmonary or pericardial effusions. 
Increases in white blood cell (WBC) count concurrent to Differentiation Syndromehas been 
observed, but by itself do not substantiate the syndrome. No single sign or symptom may be 
considered per se asdiagnostic of the syndrome.  
Corticosteroidsshould be promptly initiatedat a suggested dose 10 mg of dexamethasone IV 
every 12 hours until resolution of IDH Differentiation Syndrome, after which the dose can be 
progressively reduced in the next few days or weeks.

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Further information on diagnosis and treatment of IDH Differentiation Syndrome can be found 
in the supplemental guidance document.
9.8.3.
Leukocytosis
Initiation of treatment with the differentiating agents may lead to rapid WBC expansion not 
associated with infectious process and not manifesting with the signs and symptoms of IDH 
Differentiation Syndrome discussed above. 
In subjects with elevated WBC, prompt initiation of hydroxyurea is suggested, as per standard 
local practices (eg, dose of 2 to 3 g PO twice or 3times dailyfor WBC > 30 x 10
9/L).  In case of 
severe leukocytosis (WBC >100 x 10
9/L), useof leukapheresismay be appropriate.  Subject 
should be regularly monitored for changes in WBC count and for new signs and symptoms of 
infection or IDH Differentiation Syndrome.
9.8.4.
Gastrointestinal Disorders(Diarrhea, Nausea, Vomiting, Decreased Appetite, 
and Alterations inTaste)
Monitoring and timely management of gastrointestinal events, as appropriate, is critical in 
avoiding malnourishment and dehydration.
9.8.5.
Tumor Lysis Syndrome
Tumor Lysis Syndrome can causesabnormalities in your blood such as higher than normal levels 
of potassium andphosphorus or low levels of calcium with elevation of uric acid levels 
(hyperuricaemia)and may affect kidneyfunction. Monitoring electrolytesand kidney function is 
advised and subjects may need to be treated with additional fluids or other medications, as 
appropriate. 
9.8.6.
Increased blood bilirubin
AG-221 slows breakdown of bilirubin, causing blood bilirubin increased.  Liver enzyme 
monitoring may be instituted.  Elevated blood bilirubin may also cause skinyellowing.
9.9.
Duration of Subject Participation
9.9.1.
Treatment Duration
Subjects may continue treatment with AG-221 until disease progression, development of 
unacceptable toxicity or confirmed pregnancy. Subjects who experience disease progression per 
the applicable response criteria (Section10.8) who are, in the opinion ofthe Investigator, 
benefiting from treatment may be allowed to continue on study drug with approval of the 
Medical Monitor.
All subjects are to undergo an end of treatment assessment (within approximately 5 days of the 
last dose of study drug); in addition, a follow-up safety assessment is to be scheduled 28 days 
after the last dose. 
All subjects are to be followed for survival status follow up every 3 months until death, 
withdrawal of consent,or end of studyfor survival.

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Subjects who achieve an adequate response to treatment with AG-221 and meet other criteria 
required to undergo HSCT may proceed to HSCT after discontinuation of study therapy.   Those 
subjects will be followed on study for outcome until relapse or end of study to support the 
overall clinical benefit of AG-221 in this setting. 
Subjects who relapsed after HSCT may be eligible to restart treatment with AG-221 with 
Medical Monitor approval and at the discretion of the Investigator, if they have confirmed 
recurrent IDH2 mutant positive disease, no cancer treatment was administered since the last dose 
of AG-221(with the exception of anti-neoplastic therapies used in the course of HSCT such as 
conditioning regimen or induction-type regimen and anti-GVHD prophylaxis [i.e.,
methotrexate]),the subject meets the safety parameters listed in the Inclusion/Exclusion criteria, 
and the trial is open.  Subjects will resume AG-221 therapy at the same dose and schedule at the 
time of discontinuationof study drug.
All subjects, including subjects who relapse following HSCT and elect not to restart treatment, 
will be contacted monthly thereafter for assessment of survival status and anti-neoplastic
therapies since discontinuation of study drug until death or end of study.
9.9.2.
Endof Study
The End of Study is defined as either the date of the last visit of the last subject to complete the 
study, 3 years after the first dose of the last subject enrolled into Phase 2, or the date of receipt of 
the last data point from the last subject that is required for primary and secondary analysis, as 
pre-specified in the protocol, whichever isthe later date.
9.10.
Treatment Compliance
Subjects will be dispensed the appropriate number of Sponsor-packaged, labeled bottle(s) for 28 
days of dosing on Day 1 of each cycle; alternatively, subjects may be dispensed the appropriate 
number of bottle(s) neededuntil the next study visit. The subject will be asked to return all 
bottles and unused tablets (or empty bottles) on Day 1 of each cycle or at their next study visit 
for assessment of compliance with the dosing regimenand at EOT visit.
9.11. 
Study Drug Accountability
Accountability for the study drug at the study site is the responsibility of the Investigator. The 
Investigatorwill ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigatormay choose to assign drug accountability responsibilities to a 
pharmacist or other appropriate individual.
The Investigator or delegate will maintain accurate drug accountability records indicating the 
drug’s delivery date to the site, inventory at the site, use by each subject, and return to Celgene 
or its designee (or disposal of the drug, if approved by Celgene). These records will adequately 
document that the subjects were provided the doses as specified in the protocol and should 
reconcile all studydrug received from Celgene. Accountability records will include dates, 
quantities, batch/serial numbers, expiration dates (if applicable), and subject numbers. The 
Investigator(s) or designee(s) will verify the accuracy of the information on the form and access 
the IRT system to register the study medication received at the site.

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The Sponsor or its designee will review drug accountability at the site on an ongoing basis 
during monitoring visits.
Study drug must not be used for any purpose other than the present study. Study drug which has 
been dispensed to a subject and returned unused must not be re-dispensed to a different subject.
Subjects will receive instructions for home administration of AG-221 along with a diary to 
record the date and time of each dose, as well as the number and strength (mg) of tablets taken.
All unused and used study drug will be retained at the site until they are inventoried by the study 
monitor. All used, unused or expired study drug will be returned to Celgene or its designee or if 
authorized, disposed of at the study site per the site’s Standard Operating Procedures (SOPs) and 
documented. All material containing AG-221 will be treated and disposed of as hazardous waste 
in accordance with governing regulations.
9.12.
Prior and Concomitant Medications and Treatments
1.
s
of 
he 
d.
its 
e 
y.
2.
y 
ys 
4.
te 
il 
y.  
 
 
 

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10.
STUDY ASSESSMENTS
10.1.
Schedule of Events
Table2and Table3provide the schedulesof assessments for subjects enrolled in Phase 1and for 
subjects enrolled in the Phase 2 portion of the trial, respectively.Table4and Table 5provide the 
Pharmacokinetic and Pharmacodynamic Sampling and Electrocardiogram Schedule for subjects 
enrolled in Phase 1and for subjects enrolled in Phase 2, respectively.
After obtaining written informed consent, subjects will undergo screening evaluations. The 
screening visit is to be conducted within 28 days prior to C1D1. For subjects who receive a 
single dose of study drug on Day -3, all screening procedures should be complete prior to first 
study drug administration. Subjects are to attend study center visits as outlined in the schedules 
of assessments (Table2and Table3). A detailed description of study assessments follows the 
tables.
For subjects in the Phase 2 portion of the trial,central testing of IDH2 mutation is required 
during screening to confirm eligibility and should be performed before all other assessments to 
diminish the number of invasive tests on subjects for whom eligibility maynot be confirmed. 
All study center visits will be conducted on an outpatient basis. Whenever possible, the study 
visit should occur on the scheduled visit day; a ±2-day window is allowed to accommodate 
subjects’ schedules. The first 3 subjects in each cohort enrolled in the dose escalation phase of 
the study and the first 15 subjects in each arm of Part 1 Expansion (unless approved by the 
Medical Monitor to omit the assessment) will initially receive a single dose of AG-221 on 
Day -3. Following the Day -3dose, subjects are required to remain at the study center for 
10hours for serial blood and urine samples and clinical observations and assessments; subjects 
are to return to the clinic on Days -2, -1 and 1 for 24-, 48-and 72-hour PK/PD assessments, 
respectively. The Day -3 dose and PK/PD assessments are not required for subjects in the Phase 
2 portion of the trial.
Following the C1D1 dose of study treatment, subjects in the dose escalation phase and Part 1 
Expansion who did not receive the Day -3 dose of AG-221 are required to remain at the study 
center for 8 hours for clinical observation and assessments. 
Subjects in the dose escalation and Part 1 Expansion are to remain at the study center for 10 
hours following the C1D15, C2D1 and C4D1 doses for PK/PD assessments. In addition, these 
subjects are required to receive their first daily dose of study drug in clinic in order to obtain 
predose (trough) samples on C1D1 (for subjects who did not undergo the Day -3 PK/PD 
assessments), C1D8, C1D22, C2D15, C3D1, C3D15, C5D1, and Day 1 of all cycles thereafter 
for determination of AG-221 and 2-HG concentrations.
After 12 months, subjects in the Phase 1 dose escalationwill no longer undergoPK assessments,
but bone marrow biopsy and/or aspirates as well asperipheral bloodsampleswill still be 
collected for evaluation of disease, including exploratory biomarkers.
Subjects in the Phase 2 portion of the trialare to remain at the study center for at least 8 hours 
following the C1D1 and C2D1 doses for PK/PD and triplicate ECG assessments andare required 
to receive their first daily dose of study drug in clinic on C1D2, C2D2and C3D1 in order to 
obtain predose (trough) samples.

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An End of Treatment (EOT) visit will be conducted as soon as possible after discontinuing study 
treatment (within 5 days of last dose of study drug); in addition, subjects are to attend a Follow-
up visit 28 days after the last dose of study drug for final assessments.
All subjects are to be followed for survival status follow up every 3 months until death, 
withdrawal of consent,or end of studyfor survival. Serious AEs considered related to study drug 
should continue to be followed until death, withdrawal of consent, or the end of the studyas per 
Section11.2.
Subjects who discontinue from study treatment and undergo HSCT will enter HSCT follow-up 
and are to be evaluated on study until relapse or end of study.Subjects who relapsed after HSCT 
may be eligible to restart treatment with AG-221 with Medical Monitor approval and at the 
discretion of the Investigator, if they have confirmed recurrent IDH2 mutant positive disease,  no 
cancer treatment was administered since the last dose of AG-221(with the exception of anti-
neoplastic therapies used in the course ofHSCT such as conditioning regimen or induction-type 
regimenand anti-GVHD prophylaxis [i.e.,methotrexate]),the subject meets the safety 
parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume 
AG-221 therapy at the same dose and schedule at the time of discontinuation.  These subjects 
will ‘re-enter’ the study at Cycle 3 and have assessments conducted per that visit and beyond.  

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Table2:
Schedule of Assessments: Phase 1(Dose Escalation and Part 1 Expansion)
Visit/Cycle:
Scrn
Day
-3
1,2
Cycle 1
Cycle 2
Cycle 3
4–
Cycle 12
Cycle 13
31
and 
beyond
EOT
3
Safety 
Follow-
upVisit
Follow-
up 
HSCT
4
Survival 
Follow-
up
5
Study Day:
D -28
D12
D8
D152
D22
D12
D15
D12
D15
D1
28days 
post 
Discon.
Every 
28 Days 
Every 
28 Days 
Informed Consent
X
Review Entry Criteria
X
Demographics
X
Medical and Surgical 
History
X
Medication History
X
Complete Physical Exam
X
X
Limited Physical Exam
X  
X  X  
X
X
X
X
Height
6and Weight
X  
X  
X
X
X
X
X  
X
ECOG PS
X  
X  
X
X
X
X
X  
X  
X
Vital Signs
7
X
X
X
X
X
Serial Vital Signs7,8
X  
X
Single 12-lead ECG
9
Please refer toTable4
Serial single 12-lead ECG
9
ECHO/MUGA for LVEF
X
X
10
X10
Gene Mutation Analysis
11
X
UGT1A1 Gene Testing
X
Laboratory Evaluations:
Hematology
12
X  
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
X
X
13
Serum Chemistry
14
X  
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
X
Coagulation Studies
15
X  
X  
X
X
X
X
X  
X
Fasting Lipid Panel
16
X
X16
X  
X
Pregnancy Test
17
X  
X  
X
X
X
X  
X
Bone Marrow Biopsy and 
Aspirate
18,19
X
X
X
X
X  
X
X13

EDMS Doc. Number: 22238790 - 20010369
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Visit/Cycle:
Scrn
Day
-3
1,2
Cycle 1
Cycle 2
Cycle 3
4–
Cycle 12
Cycle 13
31
and 
beyond
EOT
3
Safety 
Follow-
upVisit
Follow-
up 
HSCT
4
Survival 
Follow-
up
5
Study Day:
D -28
D12
D8
D152
D22
D12
D15
D12
D15
D1
28days 
post 
Discon.
Every 
28 Days 
Every 
28 Days 
Peripheral blood for 
IDH2-mutated 
cells/leukemic blasts, 
plasma, and neutrophils
19
X
X
X
X
X  
X
X13
Evaluate Extent of Disease 
and Response to 
Treatment19,20
X
X
X
X  
X21
X
X13
Transfusion Assessment22
X
X
X
X
X  
X21
X
X13
Single-dose Study Drug 
Administration23,24
X
Study Drug 
Administration24
X  X  
X  
X  
X  
X  
X  
X  
X32
Compliance Assessment25
X
X
X  
X
PK/PD Assessments26
Please refer to Table4
Blood Sampling26
Urine Sampling
26
Adverse Events
X  
X  
X  X  
X  
X  
X  
X  
X  
X  
X33
X  
X27
Concomitant Medications 
/ Procedures
X  
X  
X  X  
X  
X  
X  
X  
X  
X  
X33
X  
X
Study Completion28
X
Survival Status29
X  
X  
X
New Anti-neoplastic 
Therapy30
X  
X  
X
D = Day,Discon=discontinuation,EOT= End of Treatment, ECG = electrocardiogram, ECHO = echocardiography, ECOG = Eastern Cooperative Oncology 
Group, IWG = International Working Group, LVEF = left ventricular ejection fraction, MUGA = multiple gated acquisition, PD = pharmacodynamic, PK = 
pharmacokinetic, PS = performance status, Scrn = screening
Note: All cycles are 28 days in duration, there are no rest periods between cycles.
Note: Whenever possible, the study visit should occur on the scheduled visit day; a ±2-day window is allowed to accommodate subjects’ schedules.

EDMS Doc. Number: 22238790 - 20010369
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1.Procedures listed on Day -3 are for the first 3 subjects enrolled in each cohort during the dose escalation phase of the study and for the first 15 subjects 
enrolled within each of the 4 arms of Part 1 Expansion unless approved by the Medical Monitor to omit the assessment.
2.Subjects are to remain in the clinic for 8 or 10 hours after the first (daily) dose of study drug administration (Day -3 [10 hours] or C1D1 [8 hours] as 
applicable) for observation, serial 12-lead ECGs, serial vital signs (Day -3 or C1D1), and for PK/PD assessments (Day -3, C1D15, C2D1, and C4D1).
3.Assessments to be conducted on the last day of study treatment (within 5 days of last dose of study drug).
4.All subjects who undergo HSCT following discontinuation of AG-221 are to be followed after the last dose untilrelapse, start of new anti-neoplastic
treatment,or end of study. Subjectswho relapse and have recurrent IDH2-mutant positive disease may be eligible to restart treatment with AG-221 with 
Medical Monitor approval; these subjects will ‘re-enter’ the studyat Cycle 3 assessments. Subjects who relapse and elect not to restart treatment will enter 
the survival follow-up phase.
5.Subject should be followed (either with in-person visit or contacted by phone)every 28 days to assess for survival status.All subjects are to be followed 
for survival status follow up every 3 months until death, withdrawal of consent,or end of studyfor survival. 
6.Height is to be obtained only at the screening assessment.
7.Systolic and diastolic blood pressure (BP), heart rate, respiratory rate, and temperature. Assessments should be conducted while the subject is seated or 
supine.
8.Serial vital signs are to be conducted predose and 30 ± 10 minutes and 2, 4, 6 and 8 hours (± 15 minutes) post dose followingthe morning administration 
of study drug (prior to performing serial ECG assessments).
9.Refer to Table4for complete ECG assessment schedule, including timing of serial samples.
10.Procedure is to be conducted on C3D1 and Day 1 every other cycle thereafter (e.g., C5D1, C7D1, etc), at the End of Treatment visit and at the Follow-up 
visit. The same procedure to evaluate LVEF should be conducted throughout the study.
11.Gene mutation analysisfor confirmation of IDH2-mutated disease from a bone marrow sample will be conducted on all subjects. For subjects in the dose 
escalation phase and Part 1 Expansion, the confirmation will be based on the local site’s testing platform with central laboratory testing performed 
retrospectively. A separate tumor (blood and/or bone marrow) sample will be required for central laboratory biomarker analysis (see Section10.5). A 
buccal swab for germ-line mutation analysis will be obtained at screening.
12.Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count with differential, platelet count, and blastcount.
13.If performed, the results and/or samples of hematological assessments, bone marrow biopsies and/or aspirates, peripheral blood for molecular and 
functional studies of blasts and neutrophils, and evaluation of the extent of disease and response to treatment will be collected and assessed as part of the 
study for subjects who undergo HSCT after discontinuation of AG-221. These subjects will be followed at least monthly for assessment of disease 
response until relapse of end of study.
14.Sodium, potassium, chloride, calcium, magnesium, phosphorus, carbon dioxide (CO
2), bicarbonate (HCO
3), albumin, total protein, glucose, blood urea 
nitrogen (BUN), creatinine, uric acid, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, direct bilirubin, and indirect bilirubin. In addition,creatine kinase, cardiac troponin, amylase, and lipase are to be 
obtained at screening, Day -3 (for subjects undergoing 72-hour PK/PD profile), on Day 1 of each treatment cycle, and at the End of Treatment visit.
15.Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR).
16.Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides. To be conducted at screening, 
every 6 cycleson treatment, and at the End of Treatment visit.
17.A serum pregnancy test will be performed at screening (within 7 days prior to first study drug administration) and at the EOT.  Aurine pregnancy test 
must be conducted on the day of first study drug administration and confirmed negative prior dosing (Day -3 for subjects undergoing 72-hour PK/PD 
profile or on C1D1) and Day 1 of all subsequent cycles.

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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18.Bone marrow aspirates and core sampling should be performed according to standard of care and analyzed at the local site’s laboratory in accordance with 
the International Council for Standardization in Hematology (ICSH) Guidelines (Lee, et al. 2008)(see Section10.7). Analyses should include cytogenetics 
and flow cytometry according to institutional standards and results should be recorded in the eCRFs. 
19.Assessment to be conducted on C1D15, C2D1and C3D1; following C3D1assessment, evaluation of disease response, including bone marrow assessment, 
will be conducted every 56 days during treatment through at least the Month 12 (see Section10.8.1)whileperipheral blood for plasma and IDH2-mutated 
cells, including leukemic blasts and neutrophils, will be conducted every 28 days during treatment through at least Month 12 (see Section10.8.1), 
independent of dose delays and/or dose interruptions, and/or at any time when progression of disease is suspected.  After at least 12 months, subjects may
have the extent of their disease assessed, including bone marrow biopsy,aspirates or peripheral blood based on their response to treatment.
20.Subjects will have the extent of their disease assessed based on modified IWG criteria or other appropriate response criteria for the malignancy under 
study (see Section10.8).
21.Response to treatment is to be assessed at this visit if the subject discontinues treatment for reasons other than disease progression.
22.Subjects are also to be evaluated for RBC and platelet transfusions (dates and units administered) and associated hemoglobin levels and/or platelet counts 
at each response assessmentand as clinically indicated.
23.72-hour PK/PD assessments will be conducted for the first 3 subjects enrolled in each cohort during the dose escalation phase and the first 15 subjects 
enrolled in each arm in the expansion phase (unless approved by the Medical Monitor to omit the assessment) following a single dose of AG 221 
administered on Day -3; these procedures are optional (based on Medical Monitor evaluation) for any additional subjects enrolled in a cohort during the 
dose escalation and Part1 Expansion. All screening assessments must be completed prior to single dose administration on Day -3.
24.The morning doses onDay -3, C1D1, C1D8, C1D15, C1D22, C2D15, C3D15, and Day 1 of all cycles after cycle 1 (C2D1, C3D1, etc.) are to occur in 
clinic to accommodate full PK/PD sampling (Day -3, C1D15, C2D1, and C4D1) and to allow for predose assessments (C1D1 [for subjects who did not 
undergo the Day -3 assessments], C1D8, C1D22, C2D15, C3D1, C3D15, C5D1 and Day 1 of all cycles thereafter) (see Table4)
25.Treatment compliance is to be assessed based on return of unused drug as well as subject diaries.
26.Refer to Table4for complete serial PK/PD sampling schedule. See Section10.11for details on sampling for plasma cholesterol and 4β-OH-cholesterol 
levels, and Section10.10for details for urine and blood sampling for 2-HG and α-KG.
27.Any serious adverse events (SAEs) that are assessed by the Investigator as possibly or probably related to study treatment that occur >28 days post-
treatment also are to be reported.
28.Subjects who do not go to HSCT are considered to have completed the study at the time of the Day +28 follow-up assessment; subjects who undergo 
HSCT after discontinuation of AG-221 remain on study until relapse, start of a new medication, or end of study
. All subjects enter the survival follow-up 
phase after study completion.
29.After the safety follow-up assessments, or for subjects who relapse after HSCT and elect not to restart treatment, subjects are to be followedevery 28 days 
to assess survival status until death or end of study.After 12 month of survivalstatus follow up, subjects are to be followed every 3 months until death or 
end of study.
30.All new anti-neoplastic therapies administered after the last dose of AG-221 are to be captured for all subjects through end of study.
31.Starting at Cycle 13,all assessments may be reduced to every 3 cyclesunless otherwise indicated.
32.Starting at Cycle 13, 3 Cyclesof AG-221 should be dispensed.
33.Adverse events and concomitant medication must still be captured every 28 days. On cycle Day 1 (every (28 days) when assessments are not performed
documented phone contact is acceptable.

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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Table3:
Schedule of Assessments: Phase 2
Visit/Cycle:
Scrn
Cycle 1
Cycle 2
Cycle 3
4–
Cycle 12
Cycle 13
and 
beyond
29
EOT
1
Follow-
up
Follow
-up 
HSCT
2
Survival 
Follow-
up
3
Study Day:
D -28
D1
4
D2  D8
D15 D22
D14
D2
D15
D1
D15
D1
28Days 
post 
Discon
Every 
28 
Days 
Every 28 
Days
Informed Consent
X
Review Entry Criteria
X
Demographics
X
Medical and Surgical History
X
Medication History
5
X
Complete Physical Exam
X
X
Limited Physical Exam
X
X  
X
X
X
X
Height
6and Weight
X  
X
X
X
X
X  
X
ECOG PS
X  
X
X
X
X
X  
X  
X  
X
Vital Signs
7
X
X
X
X
X
X
Serial Vital Sign7,8
X
Single 12-lead ECG
9
Please refer to Table 5
Serial Triplicate 12-lead 
ECGs9
ECHO/MUGA for LVEF
X
X
10
X
Gene Mutation Analysis
11
X
UGT1A1 Gene Testing
X
Laboratory Evaluations:
Hematology
12
X  
X
X  
X  
X  
X  
X  X  
X  
X  
X
X
13
Serum Chemistry
14
X  
X
X  
X  
X  
X  
X  X  
X  
X  
X
X
Coagulation Studies
15
X  
X
X
X
X
X  
X
X
Pregnancy Test
16
X  
X
X
X
X  
X
Bone Marrow Biopsy and 
Aspirate
17,18
X
X
X
X  
X
X13

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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Confidential
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Visit/Cycle:
Scrn
Cycle 1
Cycle 2
Cycle 3
4–
Cycle 12
Cycle 13
and 
beyond
29
EOT
1
Follow-
up
Follow
-up 
HSCT
2
Survival 
Follow-
up
3
Study Day:
D -28
D1
4
D2  D8
D15 D22
D14
D2
D15
D1
D15
D1
28Days 
post 
Discon
Every 
28 
Days 
Every 28 
Days
Peripheral blood for molecular 
and functional studies of 
plasma, blasts and 
neutrophils18
X
X
X
X  
X
X13
Evaluate Extent of Disease and 
Response to Treatment18,19
X
X
X  
X20
X13
Transfusion Assessment21
X
X
X
X  
X20
X13
Study Drug Administration22
X  
X  
X  
X  
X  
X  X  X  X  
X  
X30
Compliance Assessment23
X
X
X  
X
PK/PD Assessment24
Please refer to Table 5
Adverse Events
X  
X  
X  
X  
X  
X  
X  X  X  X  
X  
X31
X  
X25
Concomitant Medications / 
Procedures
X  
X  
X  
X  
X  
X  
X  X  X  X  
X  
X31
X  
X  
X
Study Completion26
X  
X  
X
Survival Status27
X  
X  
X
New Anti-neoplastic Therapy
28
X  
X
D = Day, Discon=discontinuation, EOT=Endo of Treatment, ECG = electrocardiogram, ECHO = echocardiography, ECOG = Eastern Cooperative Oncology 
Group, HSCT = hematopoietic stem cell transplant, IWG = International Working Group, LVEF = left ventricular ejection fraction, MUGA = multiple gated 
acquisition, PD = pharmacodynamic, PK = pharmacokinetic, PS = performance status, Scrn = screening
Note: All cycles are 28 days in duration, there are no rest periods between cycles.
Note: Whenever possible, the study visit should occur on the scheduled visit day; a ±2-day window is allowed to accommodate subjects’ schedules.
1.Assessments to be conducted on the last day of study treatment (within 5 days of last dose of study drug).
2.All subjects who undergo HSCT following discontinuation of AG-221 are to be followed after the last dose until relapse or end of study. Subjectswho 
relapse and have recurrent IDH2-mutant positive disease may be eligible to restart treatment with AG-221 with Medical Monitor approval; these subjects 
will ‘re-enter’ the study at Cycle 3 assessments. Subjects who relapse and elect not to restart treatment willenter the survival follow-up phase.
3.Subject should be followed (either with In-person visit or contacted by phone) every 28 days to assess for survival status.All subjects are to be followed 
for survival status follow up every 3 months until death, withdrawal of consent,or end of studyfor survival.
4.Subjects are to remain in the clinic for at least 8 hours after the C1D1 and C2D1 doses for clinical observation, serial triplicate ECGs, serial vital signs 
(C1D1 only) and PK/PD assessments.

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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Confidential
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5.To include information on red blood cell (RBC) and platelet transfusions (dates and units administered) and associated hemoglobin levelsand/or platelet 
counts for the 8-week period prior to C1D1.
6.Height is to be obtained only at the screening assessment.
7.Systolic and diastolic blood pressure (BP), heart rate, respiratory rate, and temperature. Assessments should be conducted while the subject is seated or 
supine.
8.Serial vital signs are to be conducted predose and 30 ± 10 minutes and 2, 4, 6 and 8 hours (± 15 minutes)post dose following the morning administration 
of study drug (prior to performing serial ECG assessments).
9.Refer to Table 5for complete ECG assessment schedule, including timing of serial samples in Cycles 1 and 2.
10.Procedure is to be conducted on C3D1 and Day 1 every other cycle thereafter (e.g., C5D1, C7D1, etc), at the End of Treatment visit and at the Follow-up 
visit. The same procedure to evaluateLVEF should be conducted throughout the study.
11.Gene mutation analysis for confirmation of IDH2-mutated disease from a bone marrow sample for subjects in Phase 2will be based on central laboratory 
testing performed prior to treatment. A separate tumor (blood and/or bone marrow) sample will be required for central laboratory biomarker analysis (see 
Section10.5). A buccal swab for germ-line mutation analysis will be obtained at screening.
12.Hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell (WBC) count with differential, platelet count, and blastcount.
13.If performed, the results and/or samples of hematological assessments, bone marrow biopsies,aspirates, peripheral blood for molecular and functional 
studies of blasts and neutrophils, and evaluation of the extent of disease and response to treatment will be collected and assessed as part of the study for 
subjects who undergo HSCT after discontinuation of AG-221. These subjects will be followed at least monthly for assessment of disease response until 
relapse or end of study.
14.Sodium, potassium, chloride, calcium, magnesium, phosphorus, carbon dioxide (CO2), bicarbonate (HCO
3), albumin, total protein, glucose, blood urea 
nitrogen (BUN), creatinine, uric acid, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, direct bilirubin, and indirect bilirubin. In addition,creatine kinase, cardiac troponin, amylase, and lipase are to be 
obtained at screening, on Day 1 of each treatment cycle, and at the End of Treatment visit.
15.Prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR)
16.A serum pregnancy test will be performed at screening (within 7 days prior to first study drug administration) and at the EOT.  Aurine pregnancy test 
must be conducted on the day of first study drug administration and confirmed negative prior dosing (Day -3 for subjects undergoing 72-hour PK/PD 
profile or on C1D1) and Day 1 of all subsequent cycles.
17.Bone marrow aspirates and core sampling should be performedand analyzed at the local site’s laboratory in accordance with the International Council for 
Standardization in Hematology (ICSH) Guidelines (Lee, et al. 2008)(see Section10.7). Investigator assessment of cytogenetic risk group at baseline and 
results of the bone marrow assessments performed for the evaluation of clinical activity will be collected for an independentreview during Phase 2of the 
study. Analyses should include cytogenetics and flow cytometry according to institutional standards and results should be recorded in the eCRFs. Studies 
should be conducted on peripheral blood samples if bone marrow aspirate is not available (e.g., a “dry” tap).
18.Evaluation of disease response, including bone marrow and peripheral blood for plasma and IDH2-mutated cells to be conducted on C2D1, every 28 days 
during treatment through at least Month12 (see Section10.8.1).  Evaluation should be independent of dose delays and/or dose interruptions, and/or at 
any time when progression of disease is suspected. After at least 12 months, subjects in the Phase 2 portion of the trial, mayhave the extent of their 
disease assessed, including bone marrow biopsy,aspirates or peripheral blood based on their response to treatment.
19.Subjects will have the extent of their disease assessed based on modified IWG criteria or other appropriate response criteria for the malignancy under 
study (see Section10.8). 
20.Response to treatment is to be assessed at this visit if the subject discontinues treatment for reasons other than disease progression.
21.Subjects are also to be evaluated for RBC and platelet transfusions (dates and units administered) and associated hemoglobin levels and/or platelet counts 
at each response assessmentand as clinically indicated.

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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Confidential
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Celgene Corporation
22.The daily doseon C1D1, C1D2, C2D1, C2D2and C3D1 are to occur in clinic to accommodate PK/PD sampling (C1D1 and C2D1) or to allow for 
predose assessments (C1D2, C2D2and C3D1).
23.Treatment compliance is to be assessed based on return of unused drug as well as subject diaries.
24.Refer to Table 5for completeserial PK/PD sampling schedule and to Section10.10for details for blood sampling for 2-HG and α-KG.
25.Any serious adverse events (SAEs) that are assessed by the Investigator as possibly or probably related to study treatment that occur >28 days post-
treatment also are to be reported.
26.Subjects who do not go to HSCT are considered to have completed the study at the time of the Day +28 follow-up assessment; subjects who undergo 
HSCT after discontinuation of AG-221 remain on study until relapse (or end of study). All subjects enter the survival follow-up phase after study 
completion.
27.After the safety follow-up assessments, or for subjects who relapse after HSCT and elect not to restart treatment, subjects are to be contacted every28 
days to assess survival status until death or end of study.All subjects are to be followed for survival status follow up every 3 months until death or end of 
study.
28. All new anti-neoplastic therapies administered after the last dose of AG-221 are to be capturedfor all subjects through end of study.
29. Starting at Cycle 13,all assessments may be reduced to every 3 cyclesunless otherwise indicated.
30. Starting at Cycle 13, 3 Cyclesof AG-221 should be dispensed.
31.
Adverse events and concomitant medication must still be captured every 28 days. On cycle Day 1 (every (28 days) when assessments are not performed 
documented phone contact is acceptable.

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
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Confidential
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Table4:
Pharmacokinetic and Pharmacodynamic Sampling and Electrocardiogram Schedule for the Phase 1 Dose 
Escalation and Part 1 Expansion
Visit/Cycle:
Scrn
D -3
1
,
2
Cycle 1
Cycle 2
Cycle 3
Cycle 4–
Cycle 12
EOT
F/U
Study Day:
D
-28
D1
3
D8
D15  
D22
D1
D15
D1
D15
D1
D
+28
Assessment
Blood/ 
Urine/
ECG
Blood
Urine
ECG
Blood/ 
Urine
ECG
Blood
ECG
Blood
Urine
ECG
Blood
ECG
Blood
Urine
ECG
Blood
ECG
Blood
Urine
ECG
Blood
Blood
Urine
ECG
Blood
Urine
ECG
ECG
Predose
4
X
5
X 
X 
X  X  X X  
X X  
X  
X X  
X  
X X  
X  
X  X
Post-dose
Anytime
X
X  
X
X  
X
X
X X X X 
X
0.5 hr
X
6
X6
X6
X6
X6
X6,
7
1 hr
X6
X6
X6
X6,7
2 hr
X6
X
8
X8
X6
X6
X6,7
3 hr
X6
X6
X6
X6,7
4 hr
X6
X8
X8
X6
X6
X6,7
6 hr
X6
X8
X8
X6
X6
X6,7
8 hr
X6
X8
X8
X6
X6
X6,7
10 hr
X6
X
X6
X6
X6,7
24 hr
X
9
X
48 hr
X9
X
72 hr
X9
X
Footnotes continue on next page 

EDMS Doc. Number: 22238790 - 20010369
AG221-C-001 Amendment 7, Protocol Version 8.0
17Oct 2017
Confidential
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Celgene Corporation
D = day; ECG = electrocardiogram, EOT = end of treatment, F/U = follow-upand follow-up post HSCT, Scrn = screening
Notes: For all days with predose samples, subjects should be instructed to take their dose of AG-221 in clinic. All 12-lead ECGs are to be conducted after 3 minutes of 
recumbency. A 12-lead single ECG should also be obtained as clinically indicated. Serial ECGs (Day -3 or C1D1) should be obtained following vital signs assessments. A subset 
of samples collected for pharmacokinetic (PK) also will be used to assess cholesterol and 4β-OH-cholesterol levels (Section10.11).
1  Day -3 assessments, including 72-hour PK/PD and serial 12-lead ECGs will be conducted for the first 3 subjects enrolled in each cohort during the dose escalation phase and the 
first 15 subjects in each arm of Part 1 Expansion following a single dose of AG-221administered on Day -3; these procedures are optional (based on Medical Monitor 
evaluation) for any additional subjects enrolled in these cohorts. All screening assessments must be completed prior to single dose administration on Day -3. 
2Five urine collections will be obtained during the 72-hour PK/PD sampling time: predose (at least 20 mL) and at the 10-, 24-, 48-and 72-hour blood draws (±1 hour).
3Only for subjects who did not undergo the Day -3 assessments. Additional urine samples are required during the treatment period for PD assessment (2-hydroxyglutarate [2 HG] 
and α-ketoglutarate [α-KG]).
4To be obtained within 30 minutes before dose; can be done at any time during screening.
5Screening blood sample for analysis of 2-HG and α-KG only.
6To be obtained within ±10 minutes of specified time.
7Assessments to be conducted on C4D1 only
8To be obtained within ±15 minutes of specified time.
9To be obtained within ±1 hour of specified time.

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Table 5:  
Pharmacokinetic and Pharmacodynamic Sampling and Electrocardiogram Schedule for Phase 2
Visit/Cycle: Screening
Cycle 1
Cycle 2
Cycle 3
EOT
F/U
Study Day:
D -28
D1
D2
D1
D2  
D1
D+28
Assessment
Blood
1
/ 
Single 
ECG
Blood
Triplicate 
ECG
2
Blood  Blood
Triplicate 
ECG2
Blood
Blood
Single 
ECG
Blood
Triplicate 
ECG2
Single 
ECG
Predose
3
X
X
X
X
X
X
X
X
4
X
Post-dose
2 hr 
X
5
X
6
X5
X6
4 hr
X5
X6
X5
X6
6 hr 
X5
X6
X5
X6
8 hr
X5
X5
Anytime
X
X  
X
D = day; ECG = electrocardiogram, EOT = end of treatment, F/U = follow-upand follow-up post HSCT 
Notes: PK refers to blood sample only. For all days with predose samples, subjects should be instructed to take their dose of AG-221 in clinic. All 12-lead ECGs are to be 
conducted after 3 minutes of recumbency. A 12-lead single ECG should also be obtained as clinically indicated.
1Screening blood sample for analysis of 2-hydroxyglutarate (2-HG) and α-ketoglutarate (α-KG) only.
212-lead triplicate ECGs, done approximately 2 minutes apart, are to be obtained at Day 1 of Cycles 1 and 2 and at EOT. ECGs should be done before pharmacokinetic (PK) 
sampling on these days.
3To be obtained within 30 minutes before dose. Can be done at any time during screening.
4Required on C3D1 only; not subsequent cycles.
5To be obtained within ±10 minutes of specified time. When the timing of a blood sample coincides with the timing of an ECG measurement, the ECG will be completed before 
the collection of the blood sample (within 10 minutes).
6ECG to be obtained within ±15 minutes of specified time.

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10.2.
Informed Consent
A complete description of the study is to be presented to each potential subject and a signed and 
dated informed consent is to be obtained before any study specificprocedures are performed.
10.3.
Information to be Collected on Screen 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).
10.4.
Demographic Data and Medical, Surgical, and Medication History
Subject demographic data, including gender, date of birth, age, race, and ethnicity, will be 
obtained during screening. A complete medical and surgical history, including the type of 
underlying malignancy and thedate of confirmation of the histologic diagnosis of the underlying 
malignancy(including reports of bone marrow aspirate and/or biopsy, peripheral blood smear, 
cytogenetics and other tests if pertinent), will be obtained during screening.
The medical history is to include all relevant prior medical history as well as all current medical 
conditions.
Prior therapies includesurgery, radiation, systemic or any other therapy for the subject’s 
underlying malignancy, particularly induction/re-induction/salvagechemotherapies, 
consolidationor maintenancetherapies, HSCT, low-intensity AML therapiessuch as azacitidine, 
decitabine or low dose cytarabine (LDAC), or othermedications 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 marrowaspirate and/or biopsy, peripheral 
blood smear, cytogenetics, hematology and othertests if pertinent.
Forsubjects in the Phase 2 portion of the trial, red blood cell and platelet transfusion history, 
including dates of the transfusion and units administered, as well as the associated hemoglobin 
levels and/or platelet counts, must be captured for the 8-week period prior to C1D1.
10.5.
Gene Mutation Analysis
For subjects in the dose escalation phase and Expansion Part 1, analysis of cells for IDH2 gene 
mutated disease, is to be evaluated at screening (if not evaluated previously) by the site’s local 
laboratory to determine subject eligibility for the study (report collected as a source document). 
For subjects enrolled inthe Phase 2 portion of the trial, analysis of cells for IDH2-gene mutated 
disease will be evaluated at screening by a central laboratory to determine subject eligibility for 
the study.
Screening bone marrow aspirate andperipheral bloodsamples are required all subjects.In 
addition:

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A buccal swab for germ-line mutation analysis also will be obtained at screening in all 
subjects.
A pre-treatment tumor sample (from blood and bone marrow) will be required for all 
screened subjects for central laboratory biomarker analysis.
A blood sample is to be obtained at screening for determination of UGT1A1 mutation 
status.
10.6.
Safety Assessments
10.6.1.
Physical Examinationand ECOG Performance Status
A complete physical examination, including assessment of weight, will be obtained at screening 
and at the End of Treatment visit. A limited physical examination will be completed on Day -3 
(for subjects undergoing 72-hour PK/PDprofile), on Days 1, 8 and 15 of Cycle 1, and on Day1 
of each treatment cycle through at least Cycle 12, and every 3 cyclesthereafter. Height will be 
obtained at the screening visit.
Determination of ECOG PS will be performed at screening, on Day -3 (for subjects undergoing 
72-hour PK/PD profile), on Days 1 and 15 of Cycle 1, on Day1 of each treatment cycle through 
at least Cycle 12, and every 3 cyclesthereafter, at the End of Treatment visit, and at the Follow-
up visit. See Appendix 15.5for ECOG PS scoring.
10.6.2.
Vital Signs
Vital signs, including systolic and diastolic BP, heart rate, respiratory
 rate, and temperature, will 
be obtained at screening, on Day 15 of Cycle 1, on Day 1 of every treatment cycle through at 
least Cycle 12, and every 3 cyclesthereafter,and at the End of Treatment visit. Assessments 
should be conducted while the subject is seated or supine.
Additionally, serial vital signs are to be obtained following the first dose of study treatment (i.e., 
on Day -3 for subjects undergoing the 72-hour PK/PD profile or on C1D1 for subjects who do 
not attend the Day -3 assessment) at the following times: predose, and 30 ± 10 minutes and 2, 4,
6, and 8 hours (± 15 minutes) post dose following the morning administration of study drug. 
Note that subjects should be instructed to take their dose of AG-221 in clinic on these days.
10.6.3.
Electrocardiogram and Assessment of Left Ventricular Ejection Fraction
See Table4and Table 5for the schedule ofECG assessments.
For subjects in the dose escalation phase and Part 1 Expansion, a single 12-lead ECG is to be 
obtained at screening, on Days 8, 15, and 22 of Cycle 1, on Days1 and 15 of Cycle 2, on Day 1 
of each treatment cycle thereafterthrough at least Cycle 12, at the End of Treatment visit, and at 
the Follow-up visit. A single 12-lead ECG should also be obtained as clinically indicated.
Additionally, serial single 12-lead ECGs are to be obtained in subjects in the dose escalation 
phase and Part 1 Expansion following the first dose of study treatment (i.e., on Day -3 for 
subjects undergoing the 72-hour PK/PD profile or on C1D1 for subjects who do not attend the 
Day -3 assessment) at the following times: predose, and 30 ± 10 minutes and 2, 4, 6, and 8hours 
(± 15 minutes) post dose following the morning administration of study drug. Serial single ECGs 

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should be obtained following vital signs assessments. Note that subjects should be instructed to 
take their dose of AG-221 in clinic on these days.
For subjects in The Phase 2 portion of the trial, triplicate 12-lead ECGs, obtained approximately 
2minutes apart, are to be obtained predose and 2, 4, and 6 hours (15 minutes) post-dose on 
Day 1 of Cycles 1 and 2; a triplicate ECG is also to be obtained at the End of Treatment visit. 
When the timing of a blood sample for PK/PD coincides with the timing of an ECG 
measurement, the ECG will be completed before the collection of the blood sample (within 10 
minutes). Note that subjects should be instructed to take their dose of AG-221 in clinic on these 
days. Single 12-lead ECGs are to be obtained in these subjects at screening, anytime post-dose 
on Day 1 of all cycles beginning with Cycle 3through at least Cycle 12, and at the Follow-up 
visit. A single 12-lead ECGshould also be obtained as clinically indicated.
All single and triplicate 12-lead ECGs should be obtained following 3 minutes of recumbency.
All subjects are to have LVEF determined by ECHO or MUGA within 28 days of C1D1; repeat 
assessments are to be conducted on C3D1, Day 1 of every other treatment cycle thereafter (e.g., 
C5D1, D7D1, etc)through at least Cycle 12, at the End of Treatment visit, and at the Follow-up 
visit. The same procedure to evaluate LVEF should be conducted throughout the study.
10.6.4.
Safety Laboratory Assessments
Clinical laboratory evaluations are to be performed by the site’s local laboratory. Prior to starting 
the study, the Investigator will provide to the Sponsor (or its designee) copies of all laboratory 
certifications and normal ranges for all laboratory parameters to be performed by that laboratory.
Clinical laboratory evaluations are to be conducted according to the schedule of assessments 
(Table2and Table3). In addition, all clinically significant laboratory abnormalities noted on 
testing will be followed by repeat testing and further investigated according to the judgment of 
the Investigator.
The following safety laboratory parameters are to be evaluated by the Investigator:
Hematology:
hematocrit, hemoglobin, red blood cell (RBC) count, white blood cell 
(WBC) count with differential, platelet count, blast count
Chemistry:
sodium, potassium, chloride, calcium, magnesium, phosphorus, CO
2, 
bicarbonate (HCO3), albumin, total protein, glucose, blood urea nitrogen 
(BUN), creatinine, uric acid, lactate dehydrogenase (LDH), ALP, AST, 
ALT, total bilirubin, direct bilirubin, indirect bilirubin
Serum Studies:
creatine kinase, cardiac troponin, amylase, and lipase
Coagulation Studies:prothrombin time (PT), activated partial thromboplastin time (aPTT), 
international normalized ratio (INR)
Fasting Lipid Panel:total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-
density lipoprotein cholesterol (HDL-C), triglycerides
Blood for hematology and serum chemistries is to be obtained at screening, Day -3 (for subjects 
undergoing 72-hour PK/PD profile), Days 1, 8, 15, and 22 of Cycle 1, on Days 1 and 15 of each 
treatment cycle through at least Cycle 12, and every 3 cyclesthereafter, and at the End of 
Treatment(EOT) visit. For subjects who undergo HSCT following discontinuation of AG-221, 

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all hematological assessments (e.g., complete blood count) that are performed are to be reported 
on the eCRF until relapse or end of study.
Blood for creatine kinase, cardiac troponin, amylase, and lipase is to be obtained at screening, 
Day -3 (for subjects undergoing 72-hour PK/PD profile), on Day 1 of each treatment cycle
through at least Cycle 12, and every 3 cyclesthereafter, and at the End of Treatment visit.
Blood for coagulation studies is to be obtained at screening, Day -3 (for subjectsundergoing 72-
hour PK/PD profile), Days 1 and 15 of Cycle 1, Day1 of each treatment cycle through at least 
Cycle 12, and every 3 cyclesthereafter, and at the End of Treatment visit.
Blood for the fasting lipid panel is to be obtained at screening, every6 cyclesthereafter on 
treatmentthrough at least Cycle 12, and every 3 cyclesthereafter, and at the End of Treatment 
visit.
Pregnancy Test:
All women of child-bearing potential must have a negative pregnancy test 
to be eligible. A serum pregnancy test will be performed at screening 
(within 7 days prior to first study drug administration); a urine pregnancy 
test must be conducted and confirmed negative on the first day of study 
drug administration before dosing (Day -3 for subjects undergoing 72-
hour PK/PD profile or on C1D1) and on Day 1 of each cycle through at 
least Cycle 12, and every 3 cyclesthereafter,and at the EOT visit.
10.6.5.
Adverse Events
 
 
 
8 
.
10.7.
Bone Marrow Samples and Peripheral Blood Leukemic Blast Cells
Screening bone marrow aspirate andperipheral bloodsamples are required all subjects.  A bone 
marrow biopsy must be collected if adequate aspirate is not attainable unless:  
A bone marrow aspirate and biopsy was performed as part of the standard of care within 
28 days prior to the start of the study treatment; and
Slides of bone marrow aspirate, biopsyand stained peripheral blood smear are available 
for bothlocal and central pathology reviewers; and

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A bone marrow aspirate sample acquired within 28 days prior to the start of study 
treatment has been sent for cytogenetic analysis. 
For subjects in the dose escalation phase and Part 1 Expansion, bone marrow biopsies and/or 
aspirates are to be obtained at screening, C1D15, C2D1, C3D1, every 56 days through at least 
Month 12independent of dose delays and/or interruptions, at any time when progression of 
disease is suspected, and at the End of Treatment visit.
Starting at Cycle13, at a minimum,subjectsin remission will require a BMA/BMB when blood 
counts suggest possible relapseor progressionof diseaseunless the local standard of care (SOC) 
required more frequent bone marrow samples. For those subjects,not in remission, it is 
reasonable to perform a bone marrow aspiration/biopsy every 1 to 2 months to assess for 
response.
Notethat the Cycle 1 Day 15 bone marrow evaluation should not be used to determine study 
treatment continuation status in any subject.
For subjects in the Phase 2 portion of the trial, bone marrow aspirates and peripheral blood are to 
be obtained at screening, C2D1, every 28 days thereafter through at least Cycle12 independent 
of dose delays and/or interruptions, at any
 time when progression of disease is suspected, and at 
the End of Treatment(EOT)visit. For those subjects who undergo HSCT following 
discontinuation of AG-221, results of any bone marrow biopsiesand/or aspirates that are 
performed are to be reported on the eCRF until relapse or end of study.
Starting at Cycle13, at minimum,a subject inremission will require a BMA/BMB when blood 
counts suggest possible relapse or progressionof diseaseunless the local standard of care (SOC) 
required more frequent bone marrow samples. For those patients,not in remission, it is 
reasonable to perform a bone marrow aspiration/biopsy every 1 to 2 months to assess for 
response.
Results of the bone marrow assessmentsperformed for the evaluation of clinical activity will be 
collected for evaluation retrospectively by an IRAC for subjects in the Phase 2 portion of the trial
of the study.
Bone marrow aspirates and core sampling should be performed according to standard of care and 
analyzed at the local site’s laboratory in accordance with the International Council for 
Standardization in Hematology (ICSH) Guidelines (Lee, et al. 2008).
The diagnosis and evaluation of AML or MDS can be made by bone marrow aspiration when a 
core sample is unobtainable and/or is not a part of the standard of care. A bone marrow biopsy is 
required in case of dry tap or failure (mainly dilution) with the aspiration.
Bone marrow core biopsies and aspirates are to be evaluated for morphology, flow cytometry, 
and for karyotype to assess potential clinical activity (see Section10.8).
Samples of the bone marrow and peripheral blood blast cells and neutrophils also will be 
evaluated at central laboratories for 2-HG and α-KGlevels, gene expression profiles, histone and 
DNA methylation patterns, and metabolomic profiling. 
Peripheral blood for the evaluation of plasma and IDH2-mutated cells, including leukemic blasts 
and neutrophils, (see Section10.5) is to be obtained at screening, C1D15 (dose escalation and
Part 1 Expansion only)C2D1, every 28 days through Month 12,and every 3 cyclesthereafter 

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independent of dose delays and/or interruptions, at any time when progression of disease is 
suspected, and at the EOTvisit. For those subjects who undergo HSCT following 
discontinuation of AG-221, any peripheral blood evaluations that are conducted should be 
assessed for plasma and IDH2-mutated cells, including leukemic blasts and neutrophils until 
relapse or end of study. 
Cell counts and flow cytometry will be used to assess the state of differentiation of blast cells 
collected from bone marrow and peripheral blood. Side scatter also will be analyzed to determine 
the complexity of the blast cells in response to AG-221.
Instructions for the processing, storage, and shipment of samples for central analysis will be 
provided in a separate study manual.

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10.8.
Clinical Activity Assessments
The clinical activity of AG-221 will be evaluated by assessing response to treatment according to 
the 2003 revised IWG criteria for AML (Cheson, et al. 2003)or the 2006 modified IWG criteria 
for MDS (Cheson, et al. 2006)(see also Section10.7). 
10.8.1.
Phase 1 (Dose Escalation and Part 1 Expansion)
For subjects in Arm 4 of Part 1 Expansion with other IDH2-positive hematologic malignancies, 
e.g., multiple myeloma (MM), essential thrombocythemia (ET) or polycythemia vera (PCV), or 
myelofibrosis (MF), other appropriate response criteria for the malignancy should be used [i.e., 
the International Myeloma Working Group criteria for subjects with MM (Durie, et al. 2006)or 
the revised response criteria for ET/PCV (Barosi, et al. 2013)or MF (Tefferi, et al. 2013)].
Disease response to treatment will be assessed through the evaluation of bone marrow biopsies 
and/or aspirates, along with complete blood counts and examination of peripheral blood films. 
Eligibility and treatment decisions in all subjects will be determined by the Investigators based 
on IWG response criteria or other appropriate response criteria for the malignancy under study 
(Section10.8). 
Subjects in the dose escalation phase and Part 1 Expansion will have the extent of their disease 
assessed and recorded at screening, on C1D15, C2D1, C3D1, and every 56 days while on study 
drug treatmentthrough at least Month 12, independent of dose-delays and/or dose interruptions, 
and/or at any time when progression of disease is suspected. An assessment also will be 
conducted at the End of Treatment visit for subjects who discontinue the study due to reasons 
other than disease progression.
Starting at Cycle13, subjects in the dose escalation phase and Part 1 Expansion in remission may
have the extent of their disease assessedevery 3 cycles(via bone marrow biopsy,aspirates or 
peripheral blood) unless the local standard of care (SOC) requiresmore frequent extent of 
diseaseassessments.For those subjects not in remission, it is reasonable to have the extent of 
their disease assessedevery 1to 2 months to assess for response.
10.8.2.
Phase 2 
In the Phase 2portion of the trial, eligibility, treatment decisions, and response to treatmentwill 
be determined by the Investigatorsbased on modified International Working Group (IWG) 
response criteria (Table7andTable 8).  Response will be also be assessed retrospectively by an 
Independent Response Adjudication Committee (IRAC).  Subjects in the Phase 2 portion of the 
trialwill have the extent of their disease assessed and recorded at screening, on C2D1, every 28 
days thereafter through at least Cycle12while on study drug treatment, independent of dose-
delays and/or dose interruptions, and/or at any time when progression of disease is suspected. An 
assessment also will be conducted at the End of Treatment visit for subjects who discontinue the 
study due to reasons other than disease progression. For those subjects who undergo HSCT 
following discontinuation of AG-221, disease response assessments are to be conducted at least 
monthly until relapse or end of study.
Starting at Cycle13, subjects in Phase 2in remission mayhave the extent of their disease 
assessedevery 3 cycles(via bone marrow biopsy,aspirates or peripheral blood) unless the local 
standard of care (SOC) requires more frequent extent of disease assessments. For those subjects 

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not in remission, it is reasonable to have the extent of their disease assessedevery 1to 2 months 
to assess for response.
Subjects in the Phase 2 portion of the trialwill also be evaluated for RBC and platelet transfusion 
requirements, including dates of the transfusion and units administered, as well as the associated 
hemoglobin levels and/or platelet counts, at each disease response assessment.
10.8.3.
Assessment of Response Criteria
Evidence supports that cancer-associated IDH mutations block normal cellular differentiation 
and promote tumorigenesisvia the abnormal production of 2-HG, a potential oncometabolite 
(Figure3).  AG-221 may produce antitumor effects by reversing the differentiation block 
induced by the IDH2 mutations and promoting appropriate cellular differentiation.   
The response pattern seen with such mechanism of action may extend beyond the typical time 
course of responses seen with cytotoxic agents, and can generate a clinical response after an 
initial increase in the number of immature monocytes or blast cells, and increase in cellularity in 
the bone marrow, onset of cytopenia after initial rise in platelets, or appearance of 
differentiation-like syndrome. 
Standard assessment criteria developed based on the experience from the cytotoxic 
chemotherapeutic agents may not provide a complete and accurate response assessment for this 
novel class of IDH2 inhibitors.  Therefore,in the setting where a subject’s assessment shows 
signs similar to progression within the first 2 cycles, caution should be exercised in discontinuing 
study drug, and a discussion with the Medical Monitor is required, especially in situations where 
the subject’s clinical condition is stable as supported by, but limited to, absence of signs and 
symptoms of rapid deterioration indicating disease progressionand/or general condition is stable 
or improving.
Notethat for subjects enrolled in the Phase 1 portion of the trial, the C1D15 bone marrow 
evaluation should not be used to determine study treatment continuation status in any subject.
Subjects who experience progression of disease (PD) per the applicable response criteriashould 
have assessment of the disease repeated 28 days later in order to confirm PD with option of 
continuing treatment as described above while awaiting for confirmation.  If repeat evaluation 
confirms PD, subjects will discontinue study treatment and proceed to the survival follow-up 
phase (see Table 6for general guidance). 

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Table 6:
Disease Assessment and Treatment after 1stEvidence of Disease Progression
Clinically Stable
Clinically Unstable
Disease Assessment1,2
Treatment
Disease Assessment1, 2
Treatment
1st evidence 
of PDor 
signs of 
differentiation 
like syndrome 
Repeat assessment 28 
days after first sign of 
progression for
confirmation
Continue study 
treatment at the 
Investigator’s 
discretion while 
awaitingfor 
confirmatory 
assessment 
Repeat assessment 28 
days after first sign of 
progression for
confirmationif possible 
May discontinue study 
treatment at 
Investigator’s 
discretion while 
awaiting for 
confirmatory 
assessment
If repeat 
evaluation 
shows SD, 
PR, or CR
Continue regularly 
scheduled assessment 
as per schedule of 
event 
Continue study 
treatment 
Continue regularly 
scheduled assessment 
as per schedule of event 
Continue study 
treatment 
If repeat 
evaluation 
confirms PD
No additional 
assessmentrequired
Discontinue study 
treatment 
No additional 
assessment required
Discontinue study 
treatment 
1Subjects in the dose escalation phase and Part 1 Expansion will have the extent of their disease assessed and 
recorded at screening, on Days C1D15, C2D1,and C3D1, every 56 days thereafter while on study drug treatment, 
independent of dose-delays and/or dose interruptions, and/or at any time when progression of disease is suspected.
2Subjects in the Phase 2 portion of the trialwill have the extent of their disease assessed and recorded at screening, on 
C2D1, every 28 days thereafter through 12 months and then every 56 days while on study drug treatment, 
independent of dose-delays and/or dose interruptions, and/or at any time when progression of disease is suspected.
Notethat subjects with stable or progressive disease may continue to receive study treatment 
with AG-221 at the discretion of the Investigator and with Medical Monitor approval.
The following criteria outlined in Table7, Table 8, Table9and Table10will be used to assess 
response to treatment for subjects with AML (Table7and/or Table 8) and MDS (Table9and 
Table10). For subjects with other IDH2-positive hematologic malignancies other appropriate 
response criteria for the malignancy should be used.

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Table7:
Proposed ModifiedInternational Working Group Response Criteria for 
Acute Myeloid Leukemia
Category
Definition
Complete remission (CR)*
Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence 
of extramedullary disease; absolute neutrophil count >1.0 x 10
9/L 
(1000/µL); platelet count >100 x 10
9/L (100,000/µL); independence of red 
cell transfusions
CR with incomplete platelet 
recovery (CRp)
All CR criteria except for residual thrombocytopenia (platelet counts <100 
x 10
9/L [100,000/µL])
CR with incomplete recovery (CRi)• All CR criteria except for residual neutropenia (absolute neutrophil count 
<1.0 x 109/L [1000/µL])
Cytogenetic CR (CRc)◊
Reversion to a normal karyotype at the time of morphologic CR (or CRi) 
in cases with an abnormal karyotype at the time of diagnosis; based on the 
evaluation of 20 metaphase cells from bone marrow
Molecular CR (CRm)§
No standard definition; depends on molecular target
Morphologic leukemia-free stateΔ
Bone marrow blasts <5 percent; absence of blasts with Auer rods; absence
of extramedullary disease; no hematologic recovery required
Partial remission (PR)
Relevant in the setting of phase I and II clinical trials only; all 
hematologic criteria of CR; decrease of bone marrow blast percentage to 5 
to 25 percent; and decrease of pretreatment bone marrow blast percentage 
by at least 50 percent
Treatment failure
Resistant disease (RD)
Failure to achieve CR or CRi (general practice; Phase 2/3 trials), or failure 
to achieve CR, CRi or PR (Phase 1 trials); only includes patients surviving 
≥7 days following completion of initial treatment, with evidence of 
persistent leukemia by blood and/or bone marrow examination
Death in aplasia
Deaths occurring ≥7 days following completion of initial treatment while 
cytopenic; with an aplasticor hypoplastic bone marrow obtained within 7 
days of death, without evidence of persistent leukemia
Death from indeterminate cause
Deaths occurring before completion of therapy, or <7 days following its 
completion; or deaths occurring ≥7 days following completion of initial 
therapy with no blasts in the blood, but no bone marrow examination 
available
Relapse(defined only for subjects 
who have previously attained CR, 
Cri, CRp or MLFS)¥
Bone marrow blasts ≥5 percent; or reappearance of blasts in the blood; or 
development of extramedullary disease
Source: (Cheson, et al. 2003)
Footnotes on next page

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* All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an aspirate with spicules; if ambiguous, 
consider repeat exam after 5 to 7 days; flow cytometric evaluation may help to distinguish between persistent leukemia and regenerating normal 
marrow; a marrow biopsy should be performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required.
• The criterion ofCRi is of value in protocols using intensified induction or double induction strategies, in which hematologic recovery is not 
awaited, but intensive therapy will be continued. In such protocols, CR may even not be achieved in the course of the entire treatment plan. In 
these instances, the overall remission rate should include CR and CRi patients. Some patients may not achieve complete hematologic recovery 
upon longer observation times.
Δ This category may be useful in the clinical development of novel agents within phase I clinical trials, in which a transient morphologic 
leukemia-free state may be achieved at the time of early response assessment.
(Footnotes continued on next page)
◊ Four studies showed that failure to convert to a normal karyotype at the time of CR predicts inferior outcome.
§ As an example, in core-binding factor AML low-level polymerase chain reaction-positivity can be detected in patients even in long-term 
remission. Normalizing to 104 copies of ABL1 in accordance with standardized criteria, transcript levels below 10 to12 copies appear to be 
predictive for long-term remission.
¥ -. A repeat marrow should be performed to confirm relapse with 2 consecutive assessments separated by at least 1 month.  Appearance of new 
dysplastic changes should be closely monitored for emerging relapse. In a patient who has been recently treated, dysplasia or a transient 
increase in blasts may reflect a chemotherapy effect and recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse 
from therapy-related MDS/AML.

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Table 8:
Criteria for Stable Disease and Progressive Disease for Acute Myelogenous 
Leukemia
Category
Response criteria
Stable disease
Failure to achieve a response and not meeting the criteria for disease progression
Disease progression
(defined only for 
subjects who have 
previously attained PR 
or SD)
Progression should be confirmed by 2 consecutive assessments separated by at least 1 
month.
Development of new biopsy-confirmed extramedullary disease since last disease 
evaluation
The date of progressive disease is defined as the first date of progression.
Progression is defined as the following:
For patients with 5 to 67% bone marrow blastsat nadir:
- a >50% increase in bone marrow blast count percentage from the nadir and that 
is ≥20%.
For patients with ≥67% bone marrow blastsat nadir:
- a doubling of the nadir absolute peripheral blood blast count and the final 
absolute peripheral blood blast count is >10 x 10
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Table9:  
Proposed Modified International Working Group Response Criteria for 
Altering Natural History of MDS
Category
Response criteria (Responses must last at least 4 weeks)
Complete remission
Bone marrow: ≤5% myeloblasts with normal maturation of all cell lines*
Persistent dysplasia will be noted*†
Peripheral blood‡
Hgb ≥11 g/dL
Platelets ≥100 × 109/L
Neutrophils ≥1.0 × 109/L†
Blasts = 0%
Partial remission
All CR criteria if abnormal before treatment except:
Bone marrow blasts decreased by ≥50% over pretreatment but still >5%
Cellularity and morphology not relevant
Marrow CR†
Bone marrow: ≤5% myeloblasts and decrease by ≥50% over pretreatment†
Peripheral blood: if HI responses, they will be noted in addition to marrow CR†
Stable disease
Failure to achieve at least PR, but no evidence of progression for >8 wks
Failure
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a more 
advanced MDS FAB subtype than pretreatment
Relapse after CR or PR At least 1 of the following:
Return to pretreatment bone marrow blast percentage
Decrement of ≥50% from maximum remission/response levels in granulocytes or 
platelets
Reduction in Hgb concentration by ≥1.5 g/dL or transfusion dependence
Cytogenetic response
Complete: Disappearance of the chromosomal abnormality without appearance of new 
ones
Partial: At least 50% reduction of the chromosomal abnormality
Disease progression
For patients with:
Less than 5% blasts: ≥50% increase in blasts to >5% blasts
5%-10% blasts: ≥50% increase to >10% blasts
10%-20% blasts: ≥50% increase to >20% blasts
20%-30% blasts: ≥50% increase to >30% blasts
Any of the following:
At least 50% decrement from maximum remission/response in granulocytes or 
platelets
Reduction in Hgb by ≥2 g/dL
Transfusion dependence
Source: (Cheson, et al. 2006)
AML = acute myeloid leukemia; CR = complete remission; DFS = disease-free survival; FAB = French-American-British; Hgb = 
hemoglobin; HI = hematologic improvement; MDS = myelodysplastic syndromes; PFS = progression-free survival; PR = partial remission.
Note: Deletions to International Working Group (IWG) response criteria are not shown.
Note: To convert hemoglobin from g/L to g/dL, divide g/L by 10.
*Dysplastic changes should consider the normal range of dysplastic changes (modification).
†Modification to IWG response criteria (Cheson, et al. 2003)
‡In some circumstances, protocol therapy may require the initiation of further treatment (e.g., consolidation, maintenance) before the 4-week 
period. Such subjects can be included in the response category into which they fit at the time the therapy is started. Transient cytopenias 
during repeated chemotherapy courses should not be considered as interrupting durability of response, as long as they recover to the 
improved counts of the previous course.

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Table10:
Proposed Modified International Working Group Response Criteria for 
Hematologic Improvement
Hematologic improvement*
Response criteria (Responses must last at least 8 weeks)†
Erythroid response 
(pretreatment, < 11 g/dL)
Hgb increase by ≥1.5 g/dL
Relevant reduction of units of RBC transfusions by an absolute number of at 
least 4 RBC transfusions/8 wk compared with the pretreatment transfusion 
number in the previous 8 wk. Only RBC transfusions given for a Hgb of ≤9.0 
g/dL pretreatment will count in the RBC transfusion response evaluation†
Platelet response 
(pretreatment, < 100 × 10
9/L)
Absolute increase of ≥30 × 109/L for patients starting with >20 × 10
9/L platelets
Increase from <20 × 10
9/L to >20 × 10
9/L and by at least 100%†
Neutrophil response 
(pretreatment, < 1.0 × 10
9/L)
At least 100% increase and an absolute increase >0.5 × 109/L†
Progression or relapse after 
HI‡
At least 1 of the following:
At least 50% decrement from maximum response levels in granulocytes or 
platelets
Reduction in Hgb by > 1.5 g/dL
Transfusion dependence
Source: (Cheson, et al. 2006)
Hgb = hemoglobin; HI = hematologic improvement; RBC = red blood cell.
Note: Deletions to the International Working Group (IWG) response criteria are not shown.
Note: To convert hemoglobin from g/L to g/dL, divide g/L by 10.
* Pretreatment counts averages of at least 2 measurements (not influenced by transfusions) ≥1 week apart (modification).
†Modification to IWG response criteria (Cheson, et al. 2003)
‡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.
10.9.
Pharmacokinetic Assessments
10.9.1.
BloodSample CollectionandPharmacokinetic Measurements During Dose 
Escalation
Serial blood samples will be drawn before and after dosing with AG-221 in order to determine 
circulating plasma concentrations of AG-221 (and, if technically feasible, the metabolite of AG-
221, AGI-16903). The blood samples will also be used for the determination of 2-HG and α-KG, 
for evaluation of cholesterol,and 4β-OH-cholesterol levels (see Section10.10.1and 
Section10.11).
For the first3 subjects enrolled in a cohort during the dose escalation phaseand the first 15 
subjects enrolled in each arm of Part 1 Expansion (unless approved by the Medical Monitor to 
omit the assessment), a single dose of AG-221 will be administered on Day -3 (i.e., 3 days prior 
to their scheduled C1D1 dose). Blood samples will be drawn prior to the single-dose 
administration of AG-221 (within 30 minutes) and at the following time points after 
administration: 30 (±10) minutes and 1, 2, 3, 4, 6, 8, and 10 hours, (±10 minutes), and 24, 48, 
and 72 hours (±1 hour). After 72 hours of blood sample collection, subjects will begin oral daily 
dosing of AG-221 (i.e., C1D1). The PK/PD profile from Day -3 through Day 1 is optional for 
additional subjects enrolled in the dose escalation phase (i.e., for any subjects beyond the 3 initial 

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subjects enrolled in a cohort) and may be required for subjects beyond the initial 15 enrolled in 
each of the expansion arms based on Medical Monitor decision.
All subjects in the dose escalationphase and Part 1 Expansion will undergo 10-hour PK/PD 
sampling on C1D15, C2D1,andC4D1. For this profile, one blood sample will be drawn 
immediately prior to (within 30 minutes) that day’s first dose of AG-221 (i.e., dosing with AG-
221 will occur at the clinical site); subsequent blood samples will be drawn at the following time 
points after dosing: 30 minutes, and 1, 2, 3, 4, 6, 8, and 10 hours (±10 minutes). 
Predose blood samples (trough) will be obtained for subjects in the dose escalation phase and 
Part 1 Expansion on C1D1 (for those subjects who did not undergo the Day -3 sampling), C1D8, 
C1D22, C2D15, C3D1, C3D15, C5D1 and Day 1 of all cycles through cycle 12for 
determination of AG-221 concentrations, as well as 2-HG and α-KG concentrations (see 
Section10.10.1). Additionally, blood sampleswill be drawn at the End of Treatment Visit
(EOT).
For subjects in the Phase 2 portion of the trial, blood samples for PK assessment will be drawn
on C1D1 predose (within 30 minutes)and post-dose at the following time points: 2, 4, 6, and 8 
hours (±10 minutes); and on C2D1predose (within 30 minutes)and post-dose at the following 
time points: 2, 4, 6,and 8 hours (±10 minutes).  Additional blood samples for PK/PD 
assessments will be drawn on C1D2, C2D2, and C3D1predose (within30 minutes).  In addition, 
blood samples for PK/PD assessments will also be drawnat the EOT visit. 
When the timing of a blood sample coincides with the timing of an ECG measurement, the ECG 
will be completed before the collection of the blood sample (within 10minutes).The timing of 
blood samples drawn for AG-221 concentration determination may be changed if the emerging 
data indicates that an alteration in the sampling scheme is needed to better characterize AG-221’s 
PK profile.
See alsoTable4and Table 5for the schedule of PK/PD assessments.
10.9.2.
Urine Collection
For the first 3 subjects enrolled in a cohort during the dose escalation phase and the first 15 
subjects enrolled in each arm of Part 1 Expansion (unless approved by the Medical Monitor to 
omit the assessment), urine will be collected on Day -3 prior to and over the first 72 hours 
following a single dose of AG-221 to provide a preliminary estimate of the extent to which AG-
221 (and, if technically feasible, the potential metabolite of AG-221, AGI-16903) is eliminated 
unchanged in the urine. Samples also will be analyzed for 2-HG and α-KG concentrations and 
for urinary creatinine concentration(see Section10.10.2).Urine samples are not required for 
subjects enrolled in the Phase 2 portion of the trial.
Five urine collections will be obtained during this 72-hour period. An initial urine collection will 
be obtained prior to AG-221 dosing (at least 20 mL). Subsequent collections will be obtained at 
the time of the 10-, 24-, 48-and 72-hour blood draws (±1 hour). Additionally, a urine collection 
(at least 20mL) will occur at the End of Treatment Visit.
The serial urine sampling from Day -3 through Day 1 is optional for additional subjects enrolled 
in the dose escalation phase (i.e., for any subjects beyond the 3 initial subjects enrolled in a
cohort) and for subjects beyond the initial 15 enrolled in each of the Part 1 Expansion arms. For 

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subjects in the dose escalation phase and Part 1 Expansion who do not have the Day -3 through 
Day1 serial urine sampling, a predose urine sample is requiredon C1D1. 
Urine samples are not required for subjects enrolled in the Phase 2 portion of the trial.
The volume of each collection will be measured and recorded and sent to a central laboratory for 
determination of the urinary AG-221 concentration.
10.10.
Pharmacodynamic Assessments
10.10.1. Blood Samples
Serial blood samples will be drawn before and after dosing with AG-221 in order to determine 
circulating concentrations of 2-HG and α-KG. Samples collected for PK assessments also will be 
used to assess 2-HG and α-KG levels (see Section10.9.1). In addition, subjects will have blood 
drawn for determination of 2-HG and α-KG levels at the screening assessment.
The timing of blood samples drawn for 2-HG and α-KG concentration determination may be 
changed if the emerging data indicate that an alteration in the sampling scheme is needed to 
better characterize the 2-HG and/or α-KG response to AG-221 treatment.
Bone marrow also will be assessed for 2-HG and α-KG levels, see Section10.7.
10.10.2. Urine Samples
Urine will be collected from subjects in the dose escalation phase and Part 1 Expansion phase
before and after dosing with AG-221 for the determination of concentrations of 2-HG and α-KG. 
Samples collected for PK assessments on Day -3 through Day 1 will also be used to assess 2-HG 
and α-KG levels (seeSection10.9.2).In addition, subjects will have urine sample collected for 
determination of 2-HG and α-KG levels at the screening assessmentand the End ofTreatment 
visit. 
In addition, for all subjects, a urine collection will occur prior to dosing on Day 15 of Cycle 1 and 
on Day 1 of Cycle 2 through at least Cycle 12, and every 3 cyclesthereafter. At least 20 mL of 
urine will be collected for each sample.
Urine samples are not required for subjects enrolled in the Phase2 portion of the trial.
The volume of each collection will be measured and recorded and sent to a central laboratory for 
determination of urinary 2-HG and α-KG concentration. An aliquot from each collection will be 
analyzed for urinary creatinine concentration.
10.11.
Evaluation of Cholesterol and 4β-OH-Cholesterol
For subjects in the dose escalation phase and Part 1 Expansion, serial blood samples will be 
drawn to obtain plasma cholesterol and 4β-OH-cholesterol levels as a potential CYP3A4 
induction marker. A subset of samples collected for PK assessments also will be used to assess 
cholesterol and 4β-OH-cholesterol levels (see Section10.9.1). Specifically, samples obtained at
screening and on Day -3 predose (within 30 minutes), and 24, 48, and 72 hours (±1 hour) will be 
assessed for cholesterol and 4β-OH-cholesterol levels. Samples collected predose on Days 1, 8, 
15 and 22 of Cycle 1, Days 1 and 15 of Cycles 2 and 3, and Day 1 of every cycle through at least 

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Cycle 12, and samples obtained at the End of Treatment visit also will be assessed for cholesterol 
and 4β-OH-cholesterol levels. 
Samples for plasma cholesterol and 4β-OH-cholesterol levels are not required for subjects 
enrolled in the Phase 2 portion of the trial.
10.12.
Sample Processing, Storage, and Shipment
Instructions for the processing, storage and shipment of all study samples for central analysis 
will be provided in a separate study manual.

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12.
STATISTICAL METHODS
12.1.
Sample Size Estimation
Based on the planned dose escalation scheme (see Section9.7), it is estimated that approximately 
a minimum of 291 subjects may be enrolled in the study. 
Assuming that identification of the MTD/MADrequires the evaluation of 13dose 
levels/schedulesof AG-221 with up to 5 subjects per dose level, with the exception that the 
MTD requires 6 subjects, then 66 subjects will be enrolled during the dose escalation part of the 
study. Additional subjects may be needed for cohort expansion during dose escalation, for the 
replacement of subjects who are not evaluable for PK/PD, safety, or clinical activity, or for 
evaluation of alternative dosing regimens other than the planned escalation scheme or the MTD, 
to optimize the RP2D and regimen(s).As of April 2015, 5dose levels (ranging from 30 mg to 
150 mg) have been evaluated in the BID schedule and 8 dose levels (ranging from 50 mg to 650 
mg)have beenevaluated in the QD schedule.
Four cohorts of approximately a minimum of 25additional subjects in specific hematologic 
malignancy subsets (total a minimum of 100 subjects) will be enrolled in Part 1 Expansion of the 
study.  The Phase 2will enroll approximately 125 subjects with relapsed or refractory AML with 
an IDH2 mutation.
Figure8present the probability of escalation from a lower dose to the next higher dose, for a 
range of true rates of DLT, in the standard 3+3 dose-escalation design. For example, if the true 
DLT rate were 0.20 (20%), then the chance of dose escalation would be approximately 0.70 
(70%).
Figure8:
Probability of Dose Escalation for the 3+3 Design
To ensure acceptable toxicity at the MTD or other doses and regimensthat may be used in 
further studies, approximately 25 additional subjects will be accrued into each of 4 arms in Part 1 
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
0.1  
0.2  
0.3  
0.4  
0.5  
0.6
Probability of Dose Escalation
True Probability of DLT

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Expansion. Based on a sample size of 25 subjects within each arm, there is 93% probability of 
detecting 1 or more AEs with an underlying rate of 10%, and 72% probability of detecting 1 or 
more AEs with an underlying rate of 5%.
Phase 2:
An overallobjective response rate (ORR, see Section12.5.7) of at least 33.6% in 125 subjects (at 
least 42 responses in 125 subjects) will result in an exact binomial 95% CI with a lower bound 
greater than 25%, which is clinically meaningful in this setting and exceeds the ORR expected 
with available therapies (Roboz, et al. 2014). If 42 responses in 125 subjects are observed 
(33.6% observed ORR), the 95% CI will be (25.4%, 42.6%). This will be considered as evidence 
of clinically significant activity of AG-221.
Additional subjects may be needed for the replacement of subjects who are not evaluable for 
PK/PD, safety, and/or clinical activity, or for evaluation of alternative dosing regimens.
12.2.
Populations for Analysis
The following subject populations (i.e., analysis sets) will be evaluated and used for presentation 
of the data:
Full Analysis Set (FAS): All subjects who were enrolled and received at least one dose of 
study treatment. Subjects will be classified according to the assigned dose level and schedule. 
The FAS is the primary analysis population for efficacy and will be the default analysis set 
for all analyses, unless otherwise specified.
Dose Determining Set (DDS): All dose escalation subjects who either had a DLT during 
Cycle 1, or who completed at least 75% of their planned Cycle1 doses (21 out of 28 days) 
and were considered by the Clinical Study Team to have had sufficient safety data available 
to conclude that a DLT did not occur during Cycle 1.
Safety Analysis Set (SAS): All subjects who were enrolled and received at least one dose of 
study treatment. Subjects will be classified according to the treatment received, where 
treatment received is defined as the assigned dose level/schedule if it was received at least 
once, or the first dose level/schedule received if assigned treatment was never received. The 
SAS will be the primary set for the analysis of safety data.
Evaluable Analysis Sets
Evaluable Analysis Set (EAS): All subjects in the FAS for whom the baseline response 
assessment and at least one post baseline response assessment at Day 28 or later are 
available and evaluable. 
Central Evaluable Analysis Set (CEAS): All subjects in the FAS for whom the baseline 
response assessment and at least one post baseline response assessment at Day 28 or later 
are available and evaluable by central independent review. 
Results of the potential clinical activity of AG-221 will be primarily based on the FAS. 
Additional efficacy analyses will be produced for the EAS and CEAS.
Pharmacokinetic Analysis Set (PAS): All subjects who have at least one blood sample 
providing evaluable PK data for AG-221.

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12.3.
Procedures for Handling Missing, Unused, and Spurious Data
No imputation will be performed for missing data elements. 
When tabulating AE data, partial dates will be handled as follows. If the day of the month is 
missing, the onset day will be set to the first day of the month unless it is the same month and 
year as study treatment. In this case, in order to conservatively report the event as treatment 
emergent, the onset date will be assumed to be the date of treatment. If the onset day and month 
are both missing, the day and month will be assumed to be January1, unless the event occurred 
in the same year as the study treatment. In this case, the event onset will be coded to the day of 
treatment in order to conservatively report the event as treatment emergent. A missing onset date 
will be coded as the day of treatment.
For the purposes of reporting, subjects continuing to receive study drug will have time-to-event 
data (e.g., duration of response and EFS) censored at the date of last documented disease 
assessment prior to the data cutoff date. Further details of censoring rules will be documented in 
the statistical analysis plan.
Subjects who have disease progression and continue to receive treatment after progression will 
be considered as having documented progressive disease at the time of first progression and will 
be counted as progressive disease at that time in primary efficacy analyses. All response 
assessments occurring after documented progression will be listed and analyzed separately. 
Subjects who discontinue AG-221 treatment to receive HSCT will remain on study and will be 
followed until documented disease progression or end of study.
Subjects with a best overall response of ‘Unknown’ or ‘Not Evaluable’ will be considered non-
responders in estimating response ratesin theefficacy analysis.
12.4.
Interim Analyses
The data with the cutoffs of 15 Apr2016 and 14 Oct2016 were analyzed to descriptively 
estimate the efficacy and safety profile of AG-221 for the NDA submissionand 4-month safety 
update. These interim analyses were not intended to modify the study conduct. Interim safety 
reviews will be conducted by the Clinical Study Team following completion of each dosing 
cohort prior to dose escalation and enrollment in the next cohort and every 8 weeks during the 
expansion phase. Evaluation of PK and PD variables will also be conducted as needed to 
evaluate the potential relationship between levels of AG-221 and 2-HG (and/or α-KG) levels. 
Evaluation of other data, including baseline information and measures of clinical activity, may 
be undertaken to provide insight into the dosing regimen and plans for future studies. 
12.5.
Statistical Methodology
12.5.1.
General Methods
Tabulations will be produced for disposition, demographic and baseline disease characteristics, 
safety, PK, PD, and clinical activity parameters and will be presented by dose level, disease and 
overall. For analyses of safety and unless otherwise specified, subjects treated during the dose 
escalation phase will be pooled with those receiving the same dose and regimen during the 
expansion phase. For analyses of clinical activity, summaries will be produced separately for the 

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dose escalation, by each arm in Part 1 Expansion, and forthe Phase 2 portion of the study. 
Subjects from the dose escalation and Part 1 Expansion, who meet inclusion and exclusion 
criteria of Phase2, may be included in efficacy analyses if treated with the same dose and 
regimen.
Categorical variables will be summarized by frequencydistributions (number and percentages of 
subjects with 95% confidence interval, if applicable) and continuous variables will be 
summarized by descriptive statistics (mean, standard deviation, median, minimum, and 
maximum).
All data will be provided in by-subject listings.
The study data will be analyzed and reported based on all subjects’ data from the dose escalation 
and expansion phases up to the time when all subjects have completed at least 6 cycles of 
treatment regardless of dose interruptionor discontinued study drug earlier, or when the follow 
up is deemed adequate for the assessment of duration of response, whichever is the later date. 
Any additional data for subjects continuing to receive study treatment or in follow up for HSCT 
or survival past the data cutoff date for the clinical study report (CSR) will be reported in a final 
descriptiveupdate at theend of study.
12.5.2.
Disposition
A tabulation of the disposition of subjects will be presented, including the number enrolled, the 
number treated, and the reasons for study discontinuation will be reported. Entry criteria and 
protocol deviations will be listed.
12.5.3.
Baseline Evaluations
Demographic and baseline disease characteristics data summarization will be performed in order 
to descriptively assess the comparability of dose groups. Data to be tabulated will include sex, 
age, and race and ethnicity, as well as disease-specific information.
12.5.4.
Exposure and Safety Analyses
 
 
) 
 
 
 
l 
 

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on 
e 
ts 
S
t.
5.
s
n, 
K 
ch 
), 
be 
y.
6.
s
w 
.
 is not a mandatory analysis.α-KG levels may be analyzed on an exploratory 
basis.
12.5.7.
Clinical Activity Analyses
Response to treatment will be assessed by the site Investigator’s using modified IWG (see 
Section10.8).Additionally, for subjects in Phase 2, response will be assessed by independent 
central review.
Subjectswho discontinue AG-221 treatment to receive HSCT will remain on study and will be 
followed until documented disease progression or end of study.
For the dose-escalation phase, point estimates and 95% confidence intervals for response rates 
will be summarized for each dose level and overall; for Part1 Expansion, these will be 
summarized by expansion arm. The analysis of Part 1 Expansion arms may also include subjects 
from the dose-escalation phase who received the same dose/regimen as subjects in the expansion 
arms and who meet the eligibility criteria of individual arms. Response will be summarized by 
best objective response categories, complete remission rate (CRR), and overallresponse rate 
(ORR), including all responses of CR, CRp, mCR (morphologic leukemia-free state [MLFS]), 
CRi, and PR. Other measures of clinical activity, including duration ofcompleteremission, 
duration of response, EFS, overall survival, and time to remission/response will be summarized.
Statistical Considerations for Phase 2
Phase 2 is the pivotal part of this study.  The primary objective of Phase 2is to confirm the 
preliminary clinical activity observed in the dose escalation and Part1 Expansion in subjects 
with IDH2 mutated relapsed or refractory AML at the recommended dose/regimen for 
expansion.The primary analysis of the clinical activity of AG-221 will be based on 
Investigator’s response assessment (CRR, ORR, and duration of remission/response). The FAS 
will be used. Key supportiveanalyses will be based on independent central review of response in 
FAS. Additional analyses of efficacy will be conducted using the EAS/CEAS. Subjects from the 

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dose escalation and Expansion Part 1 who meet eligibility criteria for the Phase 2 portion of the 
trialmay be included as a supportive analysis of clinical activity if treatedwith the same dose 
and regimen.
An observed ORR of at least 33.6% (at least 42 responses in 125 subjects) will result in an exact 
binomial 95% CI with a lower bound greater than 25%, which is clinically meaningful in this 
setting and exceeds the ORR expected with available therapies (Roboz, et al. 2014). This will be 
considered as evidence of clinically significant activity of AG-221.
Endpoints
Overallresponse rate (ORR): ORR is defined as the rate of CR, CRp, mCR [MLFS], CRi, and 
PR.
Complete remission rate(CRR): CRR is defined as the rate of CR.
Duration of response (DOR):Among subjects who have a response of CR, CRp, mCR, CRi, or 
PR, DOR will be calculated as the date of the first occurrence of response to the date of 
documented disease relapse, progression or death, including subjects that discontinue AG-221 
treatment to receive bone marrow transplantation. Kaplan-Meier methods will be used to 
estimate DOR, and subjects without relapse, progression or death will be censored at the last 
response assessment date.
Duration of complete remission (DOCR):Among subjects who havea response of CR, DOCR 
will be calculated as the date of the first remission to the date of documented disease relapse or 
death, including subjects that discontinue AG-221 treatment to receive bone marrow 
transplantation. Kaplan-Meier methods will be usedto estimate DOCR, and subjects without 
relapse or death will be censored at the last response assessment date.
Time to response (TTR):Time to response will be assessed from the date of first dose to the date 
of first occurrence of response, which includes CR, CRp, mCR/MLFS, CRi, and PR. Subjects 
without a response will be censored at the date of last response assessment. 
Time to Best Response (TTBR): Time to best response will be assessed from the date of first 
dose to the date of first occurrence of best response. Subjects without a response will be censored 
at the date of last response assessment.
Time to complete remission (TTCR):Time to complete remission will be assessed from the date 
of first dose to the date of first remission (CR). Subjects without a remission will be censored at 
the date of last response assessment. 
Event-free survival (EFS):Event-free survival will be calculated from the date of first dose to the 
date of relapse, progression or death, whichever occurs first. Subjects without an EFS event will 
be censored at the last response assessment date. Kaplan-Meier methods will be used to estimate 
EFS, including subjects that discontinue AG-221 treatment to receive bone marrow 
transplantation. 
Overall survival (OS):Overall survival is defined as the time from first dose to the date of death. 
Subjects who are alive at the analysis cutoff date will be censored at the last contact date.
All subjects are to be followed for survival status follow up every 3 months until death, 
withdrawal of consent,or end of studyfor survival.

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56-Day transfusion independence rate: The rate of subjects who have been transfusion free for at 
least 56 consecutive days post baselineduring treatment exposure period.Sensitivity analyses 
will be conducted for all duration of response/remission, time to response/remission, and EFS 
endpoints in which subjects who go on to receive bone marrow transplantation will be censored 
at the time of transplantation. 
All time to event endpoints will be estimated using Kaplan-Meier methods. Point estimates and 
95% confidence intervals will be provided where appropriate. Estimates of the median and other 
quantiles, as well as individual time points (e.g.,3-month, 6-month, and 12-month rates) will be 
produced. Additional details of the censoring rules will be specified in the Statistical Analysis 
Plan. Other measures of clinical activity will be evaluated including summaries of transfusion 
requirements and infection rates. Descriptive statistics will be used.
12.5.8.
Exploratory Analyses
l 
 
12.6.
Procedures for Reporting Deviations to Protocol-defined Statistical 
Analysis Plan
All deviations from the protocol-defined statistical analysis plan will be provided in the final 
clinical study report.

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13.
ADMINISTRATIVE REQUIREMENTS
13.1.
Good Clinical Practice
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s). The 
Investigator will be thoroughly familiar with the appropriate use of the study drug asdescribed in 
the protocol and Investigators’ Brochure. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files should 
be established at the beginning of the study, maintained for the duration of the study, and 
retained according to the appropriate regulations.
13.2.
Ethical Considerations
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (Appendix15.8).
The Investigatormust obtain IRB/IECapproval for the investigationand must submit written 
documentation of the approval to the Sponsorbefore he or shecan enroll any subject into the 
study. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the subjects. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, Investigator’s Brochure, informed consent, 
advertisements (if applicable), written information given to the subjects (including diary cards), 
safety updates, annual progress reports, and any revisions to these documents will be provided to 
the IRB/IEC. The IRB/IEC is to be notified of any amendment to the protocol in accordance with 
local requirements. Progress reports and notifications of serious unexpected adverse drug 
reactions are to be provided to the IRB/IEC according to local regulations and guidelines.
13.3.
Subject Information and Informed Consent
The Investigator at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risk, and benefit of the study. Subjects 
must also be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided.
After the study has been fully explained, written informed consent will be obtained from either 
the subject or his/her guardian or legal representative prior to study participation. 
The subject’s signed and dated informed consent must be obtained before conducting anystudy-
related procedures. The Investigator must maintain the original, signed consent form. A copy of 
the signed form must be given to the subject.
The method of obtaining and documenting the informed consent and the contents of the consent 
will comply with ICH-GCP and all applicable regulatory requirement(s).
13.4.
Subject Confidentiality
In order to maintain subject privacy, all source documents/eCRFs, study drug accountability 
records, study reports and communications will identify the subject by initials and the assigned 

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subject number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor or its 
designee and regulatory authority(ies) access to the subject’s original medical records for 
verification of data gathered on the source documents/eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations.
13.5.
Protocol Compliance
The Investigator will conduct the study in compliance with the protocol. Modifications to the 
protocol should not be madewithout agreement of both the Investigator and the Sponsor. 
Changes to the protocol will require written IRB/IEC approval/favorable opinion prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
subjects. The IRB/IEC may provide, if applicable, where regulatory authority(ies) permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor or designee will submit all 
protocol modifications to the regulatory authority(ies) in accordance with the governing 
regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, theInvestigator will contact the Sponsor or Medical Monitor, if circumstances permit, 
to discuss the planned course of action. Any departures from the protocol must be fully 
documented in the source documents/eCRF.
13.6.
Data Management
All data for the subjects recruited for the trial will be entered onto the eCRFs via an Electronic 
Data Capture (EDC) system provided by the Sponsor or designee. Only authorized staff may 
enter data onto the eCRFs. If an entry error is made, the corrections to the eCRFs will be made
according to eCRF guidelines by an authorized member of the site staff.
Electronic case report forms will be checked for correctness against source document data by the 
Sponsor’s monitor. If any entries into the eCRF are incorrect or incomplete, the monitor will ask 
the Investigator or the study site staff to make appropriate corrections, and the corrected eCRF 
will again be reviewed for completeness and consistency. Any discrepancies will be noted in the 
eCRF system by means of electronic data queries. Authorized site staff will be asked to respond 
to all electronic queries according to the eCRF guidelines.
13.7.
Source Document/Case Report Form Completion
Source documents/eCRFs will be completed for each study subject. It is the Investigator’s 
responsibility toensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s source document/eCRF. The source document/eCRF should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, AEs 
and subject status.
The Investigator, or designated representative, should complete the source document/eCRF as 
soon as possible after information is collected, preferably on the same day that a study subject is 
seen for an examination, treatment, or any other study procedure. Any outstanding entries must 

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be completed immediately after the final examination. An explanation should be given for all 
missing data.
The Investigator must sign and date the Investigator’s Statement at the end of the source 
document/eCRF to endorse the recorded data. 
The Investigator will retain all completed source documents.
13.8.
Direct Access to Source Data
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) and will include on-site review of the 
source documents/eCRFs for completeness and clarity, cross-checking with source documents, 
and clarification of administrative matters will be performed. The review of medical records will 
be performed in a manner to ensure that subject confidentiality is maintained.
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, e-mail, and fax).
All unused study drug and other study materials should be destroyed or returned to the Sponsor 
or designee after the study has been completed, as directed by the Sponsor.
Regulatory authorities, the IEC/IRB, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, eCRFs, and other study documentation for 
an on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities.
13.9.
Record Retention
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified in writing if a custodial change occurs.
13.10.
Liability and Insurance
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liabilityfor injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
13.11.
Publication of Study Findings and Use of Information
All information regarding AG-221 supplied by the Sponsor or designee to the Investigator is 
privileged and confidential information. The Investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from the Sponsor. It 
is understood that there is an obligation to provide the Sponsor with complete data obtained 
during the study. The information obtained from the clinical study will be used towards the 

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development of AG-221 and a companion diagnosticdevice and may be disclosed to regulatory 
authority(ies), other Investigators, corporate partners, or consultants as required.

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15.
APPENDICES
15.1.
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, 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; 109-139.

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15.2.
Myelodysplastic Syndromes World Health Organization 
Classification System
Myelodysplastic Syndromes World Health Organization Classification System
Category
Definition
Peripheral Blood Smear 
Evaluation
Bone Marrow Evaluation
Refractory cytopenia with unilineage 
dysplasia (RCUD): (refractory anemia 
[RA]; refractory neutropenia [RN]; 
refractory thrombocytopenia [RT])
Unicytopenia or bicytopenia
a
No or rare blasts (< 1%)
b
Unilineage dysplasia: ≥ 10% of the cells 
in one myeloid lineage
< 5% blasts
< 15% of erythroid precursors are ringed 
sideroblasts
Refractory anemia with ringed 
sideroblasts (RARS)
Anemia
No blasts
≥ 15% of erythroid precursors are ringed 
sideroblasts
Erythroid dysplasia only
< 5% blasts
Refractory cytopenia with
Multilineage dysplasia (RCMD)
Cytopenia(s)
No or rare blasts (< 1%)b
No Auer rods
< 1x109/L monocytes
Dysplasia in ≥ 10% of the cells in
≥ 2 myeloid lineages (neutrophil and/or 
erythroid precursors and/or 
megakaryocytes)
< 5% blasts in marrow
No Auer rods
± 15% ringed sideroblasts
Refractory anemia with excess
blasts-1 (RAEB-1)
Cytopenia(s)
< 5% blastsb
No Auer rods
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
5%-9% blastsb
No Auer rods
Refractory anemia with excess
blasts-2 (RAEB-2)
Cytopenia(s)
5%-19% blasts
c
Auer rodsc
< 1x109/L monocytes
Unilineage or multilineage
dysplasia
10%-19% blastsc
Auer rods ±c
Myelodysplastic syndrome -
unclassified (MDS-U)
Cytopenias
< 1% blastsb
Unequivocal dysplasia in < 10% of cells 
in one or more myeloid lineages when 
accompanied by a cytogenetic 
abnormality considered as presumptive 
evidence for a diagnosis of MDS
d
<5% blasts
MDS associated with isolated
del(5q)
Anemia
Usually normal or increased platelet 
count
No or rare blasts (< 1%)
Normal to increased
megakaryocytes with
hypolobated nuclei
< 5% blasts
Isolated del(5q) cytogenetic
abnormality
No Auer rods
aBicytopenia may occasionally be observed.  Cases with pancytopenia should be classified as MDS-U.
bIf the marrow myeloblast percentage is < 5% but there are 2% to 4% myeloblasts in the blood, the diagnostic 
classification is RAEB-1.  Cases of RCUD and RCMD with 1% myeloblasts in the blood should be classified as 
MDS-U.

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Myelodysplastic Syndromes World Health Organization Classification System 
(Continued)
cCases with Auer rods and < 5% myeloblasts in the blood and less than 10% in the marrow should be classified as 
RAEB-2.  Although the finding of 5% to 19% blasts in the blood is, in itself, diagnostic of RAEB-2, cases of 
RAEB-2 may have 5% blasts in the blood if they have Auer rods or 10% to 19% blasts in the marrow or both.  
Similarly, cases of RAEB-2 may have < 10% blasts in the marrow but may be diagnosed by the other 2 findings, 
Auer rods + and/or 5% to 19% blasts in the blood.
dIncludes unbalanced abnormalities -7 or del(7q), -5 or del(5q), i(17q) or t(17p), -13 or del(13q), del(11q), del(12p) 
or t(12p), del(9q), idic(X)(q13), balanced abnormalities t(11;16)(q23;p13.3), t(3;21)(q26.2;q22.1), 
t(1;3)(p36.3;q21.1), t(2;11)(p21;q23), inv(3)(q21q26.2), and t(6;9)(p23;q34), and complex karyotype (3 or more 
chromosomal abnormalities) involving one of more of the listed abnormalities.
Sources: 
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 myeloid leukemia: rationale and 
important changes.  Blood 2009; 114(5):937-51.

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15.3.
International Prognostic Scoring System Score for Myelodysplastic 
Syndromes
Prognostic 
variable
0  
0.5  
1  
1.5  
2  
3  
4
Cytogenetics
1
Very Good
—3
Good
—3
Intermediate
Poor
Very Poor
BM blast, %
≤ 2
—3
> 2%-< 5%
—3
5%-10%
> 10%
—3
Hemoglobin
≥ 10
—3
8-< 10
< 8
—3
—3
—3
Platelets
≥ 100
50-< 100
< 50
—3
—3
—3
—3
ANC
≥ 0.8
< 0.8
—3
—3
—3
—3
—3
1Very good: −Y, del(11q); Good: Normal, del(5q), del(12p), del(20q), double including del(5q); Intermediate: del(7q), +8, +19, 
i(17q), any other single or double independent clones; Poor: −7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 
abnormalities; Very poor: Complex: > 3 abnormalities
2Not applicable.
Note-  Scores for risk groups are as follows: Very low: ≤ 1.5; Low: > 1.5-3; Intermediate:> 3-4.5; High: > 4.5-6; Very high: > 6
Sources: 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, et al. Revised international prognostic scoring system 
for myelodysplastic syndromes. Blood.2012;120(12):2454-65.

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15.4.
Risk Status Based on Validated Cytogenetics and Molecular 
Abnormalities
Risk Status
Cytogenetics Abnormalities
Molecular Abnormalities
Favorable-risk
Core binding factor: 
inv(16)
1, 2 or t(16;16)
1or t(8;21)
1
t(15;17)
Normal Cytogenetics:
NPM1 mutation in the absence of FLT3-
ITD orisolated biallelic CEBPA mutation
Intermediate-risk Normal cytogenetics
+8 alone 
t(9;11)
Other non-defined
inv(16), t(16;16),t(8;21): 
with c-KIT 3 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)
4
Normal Cytogenetics: 
with FLT3-ITD 
5 mutation
*The molecular abnormalities included in this table reflect those for which validated assays are available in   standardized 
commercial laboratories.
1Other cytogenetics abnormalities in addition to these finding do not alter risk status 
2Paschka P, 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
3Emerging data indicate that the presence of c-KIT mutations in patients with t(8;21) and to a lesser extent inv(16)  confers a 
higher risk of relapse.  
4Philadelphia+ AML t(9;22) consider managing as myeloid blast crisis in CML. These subjects are excluded from study entry. 
5FLT3-IDT mutations are considered to confer a significant poorer outcome in patients with normal karyotype.  There is 
controversy as to whether FLT#-TDK mutation carry an equal poor prognosis. 
Source: National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia 
Version 1.2015. National Comprehensive Cancer Network website. Available at 
https://www.nccn.org/store/login/login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf 
Accessed 20Apr2015.

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15.6.
New York Heart Association Classification
Class
Symptomatology
I
Nolimitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
II
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
III
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
IV
Unable to carry on any physical activity without discomfort. Symptoms at rest. If any 
physical activity is undertaken, discomfort is increased.
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

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15.7.
National Cancer Institute Common Terminology Criteria for 
Adverse Events
The NCI CTCAE, Version 4.03, can be accessed using the following link: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
15.8.
Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI:
Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects
Adopted by the 18
thWorld Medical Association (WMA) General Assembly, Helsinki, Finland, 
June 1964 and amended by the 29
thWMA General Assembly, Tokyo, Japan, October 1975, 35th
WMA General Assembly, Venice, Italy, October 1983, and the 41stWMA General Assembly, 
Hong Kong, September 1989, the 48thWMA General Assembly, Somerset West, Republic of 
South Africa, October 1996; 52ndWMA General Assembly, Edinburgh, Scotland, October 2000; 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added); 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added); and 
59th WMA General Assembly, Seoul, October 2008.
A.INTRODUCTION 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to beread as a whole and each of its constituent paragraphs 
should not be applied without consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human subjects to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of subjects, including 
those who are involved in medical research. The physician
's knowledge and conscience 
are dedicated to the fulfilment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, "The health 
of my subject will be my first consideration," and the International Code of Medical 
Ethics declares that, "A physician shall act in the subject
's bestinterest when providing 
medical care." 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. Populations that are underrepresented in medical research should be 
provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 

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7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
10.Physicians should consider the ethical,legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminateany of the protections for research subjects set 
forth in this Declaration. 
B.BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
11.It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12.Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
13.Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14.The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
Sponsors, institutional affiliations, other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjectswho are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
15.The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study
 begins. This committee must be 
independent of the researcher, the Sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 

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ongoing studies. The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the protocol may 
be made without consideration and approval by the committee. 
16.Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on subjects or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professional and never the 
research subjects, even though they have given consent. 
17.Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
18.Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison withforeseeable benefits to them and to other individuals 
or communities affected by the condition under investigation. 
19.Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20.Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
21.Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22.Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees.
23.Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24.In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study andthe discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject
's freely-given informed consent, 

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preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
25.For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
26.When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27.For apotential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended
to promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden. 
28.When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject
's dissent 
should be respected. 
29.Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious subjects, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
30.Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty
 to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published orotherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 

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C ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH 
COMBINED WITH MEDICAL CARE 
31.The physician may combine medical research with medical care only to the extent that 
the research is justified by its potential preventive, diagnostic or therapeutic value and if 
the physician has good reason to believe that participation in the research study will not 
adversely affect the health of the subjects who serve as research subjects. 
32.The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best current proven intervention, except in the following 
circumstances: 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of placebo is 
necessary to determine the efficacy or safety of an intervention and the subjects who receive 
placebo or no treatment will not be subject to any risk of serious or irreversible harm. 
Extreme care must be taken toavoid abuse of this option. 
33.At the conclusion of the study, subjects entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34.The physician must fully inform the subject which aspects of the care are related to the 
research. The refusal of a subject to participate in a study or the subject
's decision to 
withdraw from the study must never interfere with the subject-physician relationship. 
35.In the treatment of a subject, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
subject or alegally authorized representative, may use an unproven intervention if in the 
physician
's judgement it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available.

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15.9.
CYP Sensitive Substrates
From FDA DDI Website: Table7. Examples (1) of Sensitive In Vivo CYP Substrates and CYP
Substrates with Narrow Therapeutic Range (7/28/2011)
CYP 
Enzymes
Sensitive substrates (2)
Substrates withnarrow therapeutic range 
(3)
CYP1A2
Alosetron, caffeine,
Theophylline, tizanidine
duloxetine, melatonin, ramelteon,
tacrine, tizanidine
CYP2B6 (4) Bupropion, efavirenz
CYP2C8
Repaglinide(5)
Paclitaxel
CYP2C9
Celecoxib
Warfarin, phenytoin
CYP2C19
Lansoprazole, omeprazole, S-
mephenytoin
S-mephenytoin
CYP3A(6)
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,(7) cisapride,(7) 
cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, 
tacrolimus,terfenadine(7)
CYP2D6
Atomoxetine, desipramine, 
dextromethorphan, metoprolol, 
nebivolol, perphenazine, tolterodine, 
Venlafaxine
Thioridazine
(1) 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.
(2)Sensitive CYP substratesrefer to drugs whose plasma AUC values have been shown to increase 5-fold or 
higher when co-administered with a known CYP inhibitor.
(3) CYPsubstrates with narrow therapeutic rangerefers 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).
(4) 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.
(5) 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.
(6) 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.
(7) Withdrawn from the United States market because of safety reasons.

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15.10.
Transporter Sensitive Substrates
From the FDA DDI Website: Table13. Examples of In Vivo Substrates for Selected Transporters (1) 
(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,(2) 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
(1) 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.
(2) Selective for OATP1B3.

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15.11.
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 upincludes: 
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.

EDMS Doc. Number: 22238790 - 20010369
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 organizationselectronic signature policies and procedures.
UserName: Brownstein, Carrie (cbrownstein)
Title:  VP, Clin R&D Myeloid
Date: Tuesday, 17 October 2017, 05:33 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================

AG-221 
Summary of Changes AG221-C-001 
Celgene Corporation 
Confidential and Proprietary 
3 
AG221-C-001 Amendment 7.0 Final: 17 Oct 2017 
1. 
JUSTIFICATION FOR AMENDMENT 
Significant changes included in this amendment are summarized below: 
1. Update to the end of study definition 
Based on a regulatory request safety will be followed for 3 years from the first dose of 
the last subject enrolled into Phase 2.  
• “3 years after the first dose of the last subject enrolled into Phase 2” 
• “All subjects are to be followed for survival status follow up every 3 months until 
death, withdrawal of consent, or end of study for survival.” 
Revised Sections: 2, 7.1.4, 8.5, 9.9.2, 12.5.7 
2. To reduce the visit and assessment burden for ongoing study subjects including those on 
treatment and those in long term follow up. 
As global regulatory submission are ongoing and final data for primary efficacy analysis 
have been collected, the rigorous visit and assessment schedule has been modified. All 
subjects will be contacted monthly for the status of the subject and safety follow up and 
visits to the site will be quarterly, and efficacy assessments (including bone marrow 
biopsies, bone marrow aspirates, and peripheral blood) will be performed based on each 
individual subject response to study treatment. 
Revised Sections: 2, 7.1.4, 8.5, 9.6, 9.9.1, 10.1, Table 2 (Cycle 3-Cycle 12, Cycle 13 and 
beyond, Safety Follow-up visits, Footnotes; 5, 19, 29, 31, 32, 33), Table 3 (Cycle 3-Cycle 
12, Cycle 13 and beyond, Safety Follow-up visits, Footnotes; 3, 18, 27, 29, 30, 31), Table 
4 (Cycle 4-Cycle12), Table 5 (Cycle 3), 10.6.1, 10.6.2, 10.6.3, 10.6.4, 10.6.5, 10.7, 
10.8.1, 10.8.2, 10.9.1, 10.10.2, 10.11 
Minor changes included in this amendment are summarized below: 
• Updated contact details for the 
responsible medical officer’s medical monitor for the 
AG221-C-001 study. 
Revised Sections: Responsible Medical Officers and Medical Monitor Contact Information 
• While considered an exploratory objective and endpoint, α-KG levels have not been 
routinely tested as an ongoing analysis but still may be analyzed on an exploratory basis. 
Revised Sections: 12.5.6 
• Text has been updated to align the protocol and SAP in the following sections. 
o “The data with the cutoffs of 15 Apr 2016 and 14 Oct 2016 were analyzed to 
descriptively estimate the efficacy and safety profile of AG-221 for the NDA 
submission and 4-month safety update. These interim analyses were not intended 
to modify the study conduct.” 
o “The study data will be analyzed and reported based on all subjects’ data from the 
dose escalation and expansion phases up to the time when all subjects have 
completed at least 6 cycles of treatment regardless of dose interruption or 
discontinued study drug earlier, or when the follow up is deemed adequate for the 

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Summary of Changes AG221-C-001 
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Confidential and Proprietary 
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AG221-C-001 Amendment 7.0 Final: 17 Oct 2017 
assessment of duration of response, whichever is the later date. Any additional 
data for subjects continuing to receive study treatment or in follow up for HSCT 
or survival past the data cutoff date for the clinical study report (CSR) will be 
reported in a final descriptive update at the end of study.” 
Revised Sections: 2, 12.4, 12.5.1, 12.5.7 
• Safety and efficacy data have been updated to align the protocol with the IB and reflect 
management of the updated important events.  
Revised Sections: 5.2.2.5, 5.2.3, 9.8, 9.8.1, 9.8.2, 9.8.3, 9.8.4, 9.8.5, 9.8.6 
• Descriptions of drug strength and packaging have been clarified to reflect the current 
status of drug at the site. 
Revised Sections: 9.1, 9.2 
• Though not considered an “Important Event” (Section 9.8), guidance for the monitoring 
of liver function was added to the appendices. 
Revised Sections: 15.11 
 

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Summary of Changes AG221-C-001 
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Confidential and Proprietary 
4 
AG221-C-001 Amendment 6.0 Final: 14 Oct 2015 
1. 
JUSTIFICATION FOR AMENDMENT 
The justifications for the major changes included in Amendment 6 (Protocol Version 7.0, dated 
13 Oct 2015) relative to Amendment 5, Protocol Version 6.0 (dated 18 May 2015) are listed 
below and detailed in the pages that follow. 
This amendment to the protocol has been developed based on feedback received from the Food 
and Drug Administration regulatory authority.  The purpose of this amendment is to clarify, in 
the Phase 2 portion of the trial, the inclusion of patients with an unmet medical need defined as:  
• Diagnosis of AML according to World Health Organization criteria and disease relapsed 
or refractory as defined by: 
• Subjects who relapse after allogeneic transplantation;  
• Subjects in second or later relapse; 
• Subjects who are refractory to initial induction or reinduction treatment; 
• Subjects who relapse within 1 year of initial treatment, excluding patients with favorable-
risk status according to NCCN Guidelines (NCCN 2015). Favorable-risk cytogenetics: 
inv(16), +(16;16), t(8;21), t(15;17). 
Impacted sections are:  Section 2.0-Synopsis; Section 7.1-Figure 7; Section 7.1.3-
Overview of Phase 2; and Section 8.2-Inclusion Criteria-Inclusion Criterion #2 
In addition to the above mentioned modification, the following changes were implemented: 
• Clarification of the type of sample needed for central testing for IDH2 mutation.  Bone 
marrow biopsy was erroneously added to the previous version of the protocol.  For 
subjects in the Phase 2 portion of the trial, central testing of IDH2 mutation of bone 
marrow aspirate and peripheral blood is required during screening to confirm eligibility. 
Impacted sections are:  Section 2.0-Synopis; Section 7.1.3-Overview of Phase 2; 
Section 8.2-Inclusion Criteria-Inclusion Criterion #3; Section 10- Schedule of Event; 
and Section 10.7-Bone Marrow Samples and Peripheral Blood Leukemic Blast Cells  
• Added guidance for treatment of Differentiation-like Syndrome in cases in which subject 
is affected by infections requiring hospitalization, particularly those with pulmonary or 
pericardial manifestations, that do not respond to anti-infective treatments or worsen 
within the first 48 hours. 
Impacted section is: Section 9.8.2.- Differentiation-like Syndrome  
• Clarification of the criteria for intra-subject dose escalation and modification in patients 
enrolled in the Phase 2 portion of the trial. Language was modified to ensure consistency 
across protocols in the program. 
Impacted sections is: Section 9.7.2-Intra-Subject Dose Modification Criteria 
• Modification of language to increase the required duration of abstinence from sexual 
intercourse or use of two highly effective forms of contraception following the last dose 
of AG-221.  Duration was increased from 90 to 120 days post-AG-221.  

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Summary of Changes AG221-C-001 
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AG221-C-001 Amendment 6.0 Final: 14 Oct 2015 
Impacted sections are:  Section 2.0-Synopis ; Section 8.5-Subject Withdrawal 
Criteria and Replacement of Subjects; Section 8.2-Inclusion Criteria-Inclusion 
Criterion #12; and Section 11.3-Pregnancy Reporting 
• Removal of clinical data from ongoing trial to ensure consistency with  data included in 
the investigator brochure (IB). 
Impacted section is:  Section 5.2.3-Emerging Clinical Data  
Throughout the protocol 
The amendment also includes several other minor clarifications and corrections: 
• Clarification about requirement for RBC and platelets transfusions 
• Updates around role of medical monitor in decision regarding administration of 
concomitant medicines.  
• Clarification of PK sampling time points 
• Clarification of definition of Relapse (Table 9) 
• Clarification of definition of Disease Progression (Table 10) 
• Addition of NCCN 2015 reference 
Furthermore, the amendment includes typographical and formatting corrections and other minor 
editorial changes that did not affect the scope or conduct of the trial and that were carried out to 
improve readability.
 
 
 

AG-221 
Summary of Changes AG221-C-001 
Celgene Corporation 
Confidential and Proprietary 
4 
AG221-C-001 Amendment 5.0 Final: 18 May 2015 
1. 
JUSTIFICATION FOR AMENDMENT 
Significant changes included in this amendment are summarized below: 
Section 
Number 
Section Title(s) 
Description of Change(s) 
NA 
Title Page 
Study Sponsor 
Modified the study sponsor to Celgene Corporation, 
Summit, NJ. The study will be conducted in collaboration 
with Agios Pharmaceuticals, Cambridge, MA 
NA 
Title Page-Title  
Updated Title to reflect addition of Phase 2 (previously 
referred as Part 2 Expansion) 
NA 
Title Page 
Responsible Medical Officer 
Included Celgene Corporation  Responsible Medical 
Officer and Updated Agios Pharmaceuticals Responsible 
Medical Officer 
2.0 
Synopsis -Number of Subjects 
(planned)  
Updated Overall Sample Size to reflect current number of 
subjects enrolled in the study. 
7.1.4 
General Conduct 
8.1 
Number of Subjects 
12.1 
Sample Size Estimation 
5.2.3 
Emerging Clinical Data 
Update clinical data from ongoing trial  
2.0 
Synopsis -Number of Subjects 
(planned)  
Clarification of Primary Efficacy Population to include 
Full Analysis Set defined as  all subjects enrolled and 
received at least one dose of study treatment. 
12.2 
Populations for Analysis  
12.5.7 
Clinical Activity Analyses 
2.0 
Synopsis 
Clarification of Study Objectives and Endpoints to reflect 
difference in design of  the Phase 1 and Phase 2 portion of 
the study 
6.0  
Trial Objectives and Endpoints 
12.5.7 
Clinical Activity Analyses 
2.0 
Synopsis  
Clarification of Study Design and addition of Study 
Diagram (7.1. only) to reflect difference in design of  the 
Phase 1 and Phase 2 portion of the study. 
7.1 
Overall Study Design 
2.0 
Synopsis - Investigational product, 
dosage and mode of administration 
Clarified rationale for selection of 100 mg QD as starting 
dose for  Phase 1 Part 1 Expansion and Phase 2 . 
7.1.2 
Overview of Phase 1/Par 1 Expansion 
7.1.3 
Overview of Phase 2 
7.3.2 
Rationale for the Dose Selected 
2.0 
Synopsis  
Updated Eligibility Criterion #2 to provide additional 
clarification on the definition of the disease under 
evaluation in this study 
7.1.1 
Overview of the Dose Escalation Phase  
8.2 
Inclusion Criteria 
2.0 
Synopsis  
Addition of Inclusion Criterion #13 
8.2 
Inclusion Criteria 

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Summary of Changes AG221-C-001 
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AG221-C-001 Amendment 5.0 Final: 18 May 2015 
Section 
Number 
Section Title(s) 
Description of Change(s) 
2.0 
Synopsis  
Addition of Exclusion Criterion #22: Subjects who  have 
previously received treatment with an inhibitor of IDH 
8.3 
Exclusion Criteria 
8.4 
Subject Identification and Registration 
Addition of Interactive Response Technology  
8.5 
Subject Withdrawal Criteria and 
Replacement of Subjects 
Added language to clarify distinction between 
discontinuation from study treatment and discontinuation 
from the study.   
9.7.3 
Dose Discontinuation Criteria 
9.5  
Clinical Supply 
Clarification of Investigator responsibility regarding 
inventory of study treatment. 
9.7.2 
 
Intra-subject Dose Modification Criteria 
 
Clarification on Dose Modification Guidance to include 
guidance for dose escalation, dose reduction, and dose 
discontinuation. 
9.12.3 
Restricted Concomitant Therapy 
Clarification of co-administration of restricted concomitant 
therapy. 
2.0 
Synopsis  
Clarified Follow-up and Survival Follow-up Time points 
for all subjects. 
7.1.4 
General Conduct 
8.5 
Subject Withdrawal Criteria and 
Replacement of Subjects 
9.9.1  
Treatment Duration 
9.9.2 
End of Study 
10.1 
Schedule of Events 
10.8 
Clinical Activity Assessments 
10.1 
Schedule of Events 
Updated time points for Pregnancy Testing, and 
Transfusion Assessment 
10.1 
Schedule of Events 
Updated time points in Phase 2 to evaluate PK in the QD 
schedule. 
10.9 
Pharmacokinetic Assessments 
10.3 
Information  to be collected on 
Screening failures 
Added Celgene template language 
10.4 
Demographic Data and Medical, 
Surgical, and Medication History 
Clarification of data needed  
2.0 
Synopsis  
Modification of standard assessment criteria based on the 
response pattern seen with AG-221 mechanism of action  
10.8.3 
Assessments of Response Criteria 
15.1 
World Health Organization 
Classification of Acute Myeloid 
Leukemia 
Appendices added to improve clarity of the protocol. 
15.2 
Myelodysplastic Syndromes World 
Health Organization Classification 
System 
15.3 
International Prognostic Scoring System 
Score for Myelodysplastic Syndromes 

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Summary of Changes AG221-C-001 
Celgene Corporation 
Confidential and Proprietary 
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AG221-C-001 Amendment 5.0 Final: 18 May 2015 
Section 
Number 
Section Title(s) 
Description of Change(s) 
15.4 
Risk Status Based on Validated 
Cytogenetics and Molecular 
Abnormalities 
 
The amendment also includes typographical and formatting corrections, and other minor editorial 
changes, which did not affect the scope or conduct of the trial and that were carried out to 
improved readability of the protocol. 
 

AG221-C-001 Amendment 4, Protocol Version 5.0 
09 February 2015 
PROTOCOL AG221-C-001 
AMENDMENT 4 SUMMARY OF CHANGES 
A
 Phase 1, Multicenter
, Open-Label, Dose-Escalation and Expansion, Safety
, 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of  
Orally Administered AG-221 in Subjects with 
Advanced Hematologic Malignancies with an IDH2 Mutation 
The major changes included in Amendment 4 (Protocol Version 5.0, dated 02 February 2015) 
relative to Amendment 3, Protocol Version 4.0 (dated 16 April 2014) are itemized below and 
detailed in the pages that follow: 
 Added a Part 2 to the expansion phase of the study to include enrollment of an 
additional 125 subjects with relapsed or refractory acute myelogenous leukemia 
(AML), including detailed information on inclusion criteria and study procedures.  
Data from these subjects will be used to confirm the clinical activity, safety, and 
pharmacokinetic/pharmacodynamic (PK/PD) profile of AG-221 for the treatment of 
subjects with relapsed or refractory AML that harbor an isocitrate dehydrogenase-2 
(IDH2) mutation. 
 Subjects in this phase of the expansion are required to have central laboratory 
confirmation of IDH2-mutated disease prior to treatment with AG-221. 
 Subjects in Part 2 expansion will undergo more limited PK/PD evaluations than 
those in the dose escalation phase or Part 1 of the expansion phase and will have 
time-matched triplicate electrocardiograms (ECGs) performed, and are not 
required to have evaluations for plasma cholesterol and 4β-OH-cholesterol levels. 
 Disease response assessments, including bone marrow biopsy and peripheral 
blood, are to be conducted more frequently in subjects in Part 2 of the expansion 
phase (every 28 days after Day 57 rather than every 56 days) through Month 12 in 
this cohort.   
 Disease response information for subjects in Part 2 of the expansion phase will be 
evaluated by an Independent Review Committee (IRC). 
 Information on red blood cell and platelet transfusions will be captured for 
subjects in Part 2 of the expansion phase, including dates of the transfusion and 
units administered, as well as the associated hemoglobin levels, for the 8-week 
period prior to first dose of study drug and during the treatment period. 
 Based on the differences in the assessments to be conducted for subjects in Part 2 of 
the expansion phase, a new schedule of assessments was added for these subjects. 
 Based on the differences in PK/PD and ECG assessments across the cohorts, 2 new 
tables of PK/PD and ECG assessments were added to clarify assessments for subjects 
in the dose escalation phase and Part 1 of the expansion phase versus Part 2 of the 
expansion phase. 
 Statistical methodology was updated to include endpoints and statistical 
considerations for data from Part 2 of the expansion phase. 

AG221-C-001 Amendment 4, Protocol Version 5.0 
09 February 2015 
 Updated the number of subjects to be enrolled and study sites to be included based on 
the additional Part 2 expansion arm. 
 Modified the study sponsor to Celgene Corporation, Summit, NJ. The study will be 
conducted in collaboration with Agios Pharmaceuticals, Cambridge, MA. 
 Updated information on emerging clinical data from the trial, including safety, 
PK/PD and clinical activity data available from the first 73 subjects. 
 Added screening assessment to include an evaluation of uridine diphosphate-
glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) gene mutation. 
 Modified the definition of hematologic dose-limiting toxicity (DLT) to exclude 
≥Grade 1 blood bilirubin increases in subjects with a UGT1A1 mutation. In subjects 
with a UGT1A1 mutation, blood bilirubin increases of >5× upper limit of normal 
(ULN) may be considered a DLT. 
 Modified the exclusion criterion related to elevated bilirubin levels to allow for higher 
elevations in subjects with UGT1A1 mutation following approval by the Medical 
Monitor. 
 Added an evaluation of the effect of food on the PK of AG-221 for a subset of 
subjects in the dose escalation phase. 
 Provided for subjects who achieve an adequate response to treatment with AG-221 
who then proceed to hematopoietic stem cell transplant (HSCT) off treatment to be 
followed for outcome to support the overall clinical benefit of AG-221 in this setting.  
Subjects who subsequently relapse after HSCT may be eligible to restart treatment 
with AG-221 with Medical Monitor approval. 
 Modified requirements for clinical laboratory evaluations: 
 Removed the requirement for urinalysis for all subjects as to date there have been 
no safety findings related to urinalysis during dose escalation at doses up to 200 
mg/day. 
 Added a requirement for urine pregnancy tests on day 1 of each treatment cycle. 
 Added bicarbonate assessment to chemistry 
 Added a lipid panel to be conducted at screening, every 6 months on treatment 
and at end of treatment. 
 Clarified that response criteria other than the International Working Group (IWG) 
response criteria for AML or myelodysplastic syndrome (MDS) would be used for 
subjects with other hematologic malignancies enrolled in Part 1 expansion, Arm 3. 
 Added definitions for stable disease and progressive disease for subjects with AML as 
these specific response definitions are not included in the IWG response criteria. 
 Added an assessment of survival status monthly after completion of the Day +28 
followup visit and for the collection of new antineoplastic therapies after treatment 
with AG-221.  
 Removed the requirement that treatment with hydroxyurea be administered only 
during the first 28 days of treatment with AG-221. 
 Added additional tablet strengths of AG-221 (25, 100 and 150 mg). 

AG221-C-001 Amendment 4, Protocol Version 5.0 
09 February 2015 
 Added an allowance for subjects who experience disease progression per the 
applicable response criteria who are, in the opinion of the Investigator, benefiting 
from treatment, to be allowed to continue on study drug with approval of the Medical 
Monitor. 
 Added guidelines for the management of subjects who experience adverse events of 
special interest, including QT prolongation and differentiation-like syndrome. 
 Provided more detailed information on pregnancy reporting requirements and the 
specific use of contraceptives. 
In addition to the above, minor wording changes and clarifications were made that are not 
reflected in this document. 

AG221-C-001 Amendment 3, Protocol Version 4.0 
17 April 2014 
PROTOCOL AG221-C-001 
AMENDMENT 3 SUMMARY OF CHANGES 
A
 Phase 1, Multicenter
, Open-Label, Dose-Escalation, Safety
, 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of  
Orally Administered AG-221 in Subjects with 
Advanced Hematologic Malignancies with an IDH2 Mutation 
 
The major changes included in Amendment 3 (Protocol Version 4.0, dated 16 April 2014) 
relative to Amendment 1, Protocol Version 2.0 (dated 18 July 2013) are itemized below and 
detailed in the pages that follow: 
• Added information on emerging clinical data from the trial, including safety, PK/PD 
and clinical activity data available from the first 22 subjects. 
• Added information that a once daily dosing regimen has been explored based on the 
emerging PK/PD data. 
• Provided detailed information, including inclusion criteria, for the expansion cohorts.  
Four expansion arms are planned, with 25 subjects per arm, in specific hematologic 
malignancy subsets.   
• Updated the number of subjects and study sites to be enrolled based on the emerging 
data and the expansion cohorts. 
• Added evaluation of α-ketoglutarate as a potential biomarker and plasma cholesterol 
and 4β-OH-cholesterol levels as a potential cytochrome (CYP) 3A4 induction marker. 
• Added evaluation of PK/PD on Day -3 for initial 15 subjects in each expansion arm; 
unless omitted by Medical Monitor. 
• Included additional samples for PK/PD assessments. 
• Added specific AML response criteria (Cheson, 2003) for evaluation of clinical 
activity.  Modified peripheral blood sampling for evaluation of response to every 28 
days. 
• For the adequate renal function inclusion criterion, added the option of using 
creatinine clearance based on the Cockroft-Gault equation or serum creatinine. 
• Deleted the requirement for bone marrow biopsy when a core biopsy is unobtainable 
and/or is not part of the standard of care; bone marrow aspirates are required.  A bone 
marrow biopsy is required in case of dry tap or failure (mainly dilution) with the 
aspiration. 
• Deleted the exclusion criterion for subjects who had previously received study drug 
treatment under this protocol; clarified that subjects who had previously been treated 
and had undergone hematopoietic stem cell transplant with subsequent relapse could 
re-enter the study with Medical Monitor approval. 

AG221-C-001 Amendment 3, Protocol Version 4.0 
17 April 2014 
• Clarified the exclusion criterion for QTc interval for subjects with right bundle branch 
block. 
• Added an exclusion criterion for patients with active Hepatitis B. 
• Included information on the potential for phototoxicity with specific warnings to 
subjects regarding protection from sun exposure. 
• Included recommendation to avoid the use of antacids, H1 blockers, or proton pump 
inhibitors while taking AG-221. Given the solubility profile of AG-221, the exposure 
can be much lower for patients with elevated gastric pH. 
• Updated the statistical analysis plan to reflect the increased sample size for the 
expansion cohorts and to add detail on analysis of clinical activity. 
In addition to the above, minor administrative changes were made. 

AG221-C-001 Amendment 2, Protocol Version 3.0 (France only)   
23 September 2013 
PROTOCOL AG221-C-001 
AMENDMENT 2 (FRANCE) SUMMARY OF CHANGES 
A
 Phase 1, Multicenter
, Open-Label, Dose-Escalation, Safety
, 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of  
Orally Administered AG-221 in Subjects with 
Advanced Hematologic Malignancies with an IDH2 Mutation 
 
The major changes included in Amendment 2 (Protocol Version 3.0, dated 23 September 2013) 
relative to Amendment 1, Protocol Version 2.0 (dated 18 July 2013) are itemized below and 
detailed in the pages that follow: 
• Deleted the requirement for bone marrow biopsy when a core biopsy is unobtainable 
and/or is not part of the standard of care; bone marrow aspirates are required.  A bone 
marrow biopsy is required in case of dry tap or failure (mainly dilution) with the 
aspiration. 
• For the adequate renal function inclusion criterion, added the option of using 
creatinine clearance based on the Cockroft-Gault equation or serum creatinine. 
• Added an exclusion criterion for patients with active Hepatitis B. 
• Included information on the potential for phototoxicity with specific warnings to 
subjects regarding protection from sun exposure. 
In addition to the above, minor administrative changes were made; these are also detailed in the 
pages that follow. 

AG221-C-001 Amendment 1, Protocol Version 2.0 
18 July 2013 
Page 1 of 8 
 
PROTOCOL AG221-C-001 
AMENDMENT 1 SUMMARY OF CHANGES 
A
 Phase 1, Multicenter
, Open-Label, Dose-Escalation, Safety
, 
Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of  
Orally Administered AG-221 in Subjects with 
Advanced Hematologic Malignancies with an IDH2 Mutation 
 
The major changes included in Amendment 1 (Protocol Version 2.0, dated 18 July 2013) relative 
to the original protocol (dated 3 June 2013) are itemized below and detailed in the pages that 
follow: 
• Modified the inclusion criterion for subjects with myelodysplastic syndrome to 
indicate that patients must not be candidates for regimens known to provide clinical 
benefit. 
• Broadened the definition of non-hematologic toxicities to include any clinically 
significant events ≥Grade 3 in severity. 
• Clarified the text regarding dose escalation to indicate that escalation is never to 
exceed 100%. 
• Added assessments of creatinine kinase, cardiac troponin, amylase and lipase at 
screening, Day -3 (for subjects undergoing 72-hour PK/PD profile), on Day 1 of each 
treatment cycle, and at the End of Treatment visit. 
In addition to the above, minor administrative changes were made; these are also detailed in the 
pages that follow.