An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation

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

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

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

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

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

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

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

1. Subject is ≥ 60 years of age at the time of signing the ICF

2. Subject has primary (ie, de novo) or secondary (progression of MDS or
myeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHO
classification (Appendix B)

3. Subject has received second- or third-line of AML therapy (see Appendix G for the
definition of prior AML line; note that, for subjects having AML secondary to prior
higher risk [Intermediate-2 or High risk according to the International Prognostic
Scoring System] MDS treated with a hypomethylating agent [eg, azacitidine or
decitabine], the hypomethylating therapy can be counted as a line if there is disease
progression to AML during or shortly [eg, within 60 days] after the hypomethylating
therapy.)

4. Subject has the following disease status:

1. Refractory to or relapsed after second- or third-line of intensive therapy for
AML (eg, the "7 + 3" regimen):

at least 5% leukemic blasts in bone marrow (the minimum number of treatment
cycles of the intensive therapy is per the investigator's discretion); or

2. Refractory to or relapsed after second- or third-line low-intensity AML therapy
(eg, LDAC, azacitidine or decitabine):

at least 5% leukemic blasts in bone marrow after at least 2 treatment cycles

5. Subject is eligible for and willing to receive the pre-selected CCR treatment option,
according to the investigator's assessment (Note: Subjects with degenerative and toxic
encephalopathies, especially after the use of methotrexate or treatment with ionizing
radiation, should not receive cytarabine.)

6. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
(Appendix D)

7. Subject has IDH2 gene mutations tested centrally (using the "investigational use
only"PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate and
peripheral blood, and confirmed positive in bone marrow aspirate and/or peripheral
blood. (Note: in the event that the central laboratory result is delayed and precludes
acute clinical management of a subject who has confirmed IDH2 gene mutation by local
evaluation, the subject may be eligible for randomization with approval by the Medical
Monitor.)

8. Subject has adequate organ function defined as:

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)
and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3
x upper limit of normal (ULN), unless considered due to leukemic organ
involvement, following review by the Medical Monitor; and

- Serum total bilirubin ≤ 1.5 x ULN, unless considered due to Gilbert's syndrome
(eg, a gene mutation in UGT1A1) or leukemic organ involvement, following review
by the Medical Monitor; and

- Creatinine clearance > 30 mL/min based on the Modification of Diet in Renal
Disease (MDRD) glomerular filtration rate (GFR):

GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 if
female) × (1.212 if African American)

9. Females of childbearing potential (FCBP)* may participate, providing they meet the
following conditions:

- Agree to practice true abstinence from sexual intercourse or to use highly
effective contraceptive methods (eg, combined [containing estrogen and
progestogen] or progestogen-only associated with inhibition of ovulation, oral,
injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateral
tubal occlusion; intra-uterine device; intrauterine hormone-releasing system; or
male partner sterilization [note that vasectomized partner is a highly effective
birth control method provided that partner is the sole sexual partner of the FCBP
trial participant and that the vasectomized partner has received medical
assessment of the surgical success]) at screening and throughout the study, and
for 4 months following the last study treatment (6 months following the last dose
of cytarabine); and

- Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancy
test (sensitivity of at least 25 mIU/mL) at screening; and

- Have a negative serum or urine (investigator's discretion under local
regulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72
hours prior to the start of study treatment in the Treatment Phase (note that the
screening serum pregnancy test can be used as the test prior to the start of
study treatment in the Treatment Phase if it is performed within the 72-hour
timeframe).

10. Male subjects must agree to practice true abstinence from sexual intercourse or to the
use of highly effective contraceptive methods (as described above) with non-pregnant
female partners of childbearing potential at screening and throughout the course of
the study, and should avoid conception with their partners during the course of the
study and for 4 months following the last study treatment (6 months following the last
dose of cytarabine; 6 months following the last dose of azacitidine in Canada)

11. Subject must understand and voluntarily sign an ICF prior to any study-related
assessments/procedures being conducted

12. Subject is willing and able to adhere to the study visit schedule and other protocol
requirements

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

1. Subject is suspected or proven to have acute promyelocytic leukemia based on
morphology, immunophenotype, molecular assay, or karyotype

2. Subject has AML secondary to chronic myelogenous leukemia

3. Subject has received a targeted agent against an IDH2 mutation

4. Subject has received systemic anticancer therapy or radiotherapy < 14 days prior to
the start of study treatment. Note that hydroxyurea is allowed prior to the start of
study treatment for the control of leukocytosis (however, hydroxyurea should not be
given within 72 hours prior to and after administration of azacitidine).

5. Subject has received non-cytotoxic or investigational agents < 14 days or 5
half-lives, whichever is longer, prior to the start of study treatment

6. Subject has undergone HSCT within 60 days prior to the start of study treatment, or on
immunosuppressive therapy post HSCT at the time of screening, or with clinically
significant graft-versus-host disease (GVHD). The use of a stable dose of oral steroid
post-HSCT and/or topical steroids for ongoing skin GVHD is permitted.

7. Subject has persistent, clinically significant non-hematologic toxicities from prior
therapies

8. Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening.

9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other treatment)

10. Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation

11. Subject has significant active cardiac disease within 6 months prior to the start of
study treatment, including New York Heart Association (NYHA) class III or IV
congestive heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke;
or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan obtained within 28 days prior to the start of
study treatment

12. Subject has prior history of malignancy, other than MDS, MPN or AML, unless the
subject has been free of the disease for ≥ 1 year prior to the start of study
treatment.

However, subjects with the following history/concurrent conditions are allowed:

- Basal or squamous cell carcinoma of the skin

- Carcinoma in situ of the cervix

- Carcinoma in situ of the breast

- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
node, metastasis clinical staging system)

13. Subject is known seropositive or active infection with human immunodeficiency virus
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

14. Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally

15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 100 mmHg)

16. Subject is a pregnant or lactating female

17. Subject has known or suspected to have hypersensitivity to any of the components of
study treatment

18. Subject is taking those medications (listed in Section 8.2) that are known to prolong
QT interval unless the subject can be transferred to other medications at least 5
half-lives prior to the start of study treatment

19. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or other
factors that increase the risk of QT prolongation or arrhythmic events (eg, heart
failure, hypokalemia, family history of long QT interval syndrome) at screening

20. Subject is taking the following sensitive CYP substrate medications that have a narrow
therapeutic range are excluded from the study unless the subject can be transferred to
other medications at least 5 half-lives prior to the start of study treatment:
paclitaxel and docetaxel (CYP2C8), phenytoin (CYP2C9), S-mephenytoin (CYP2C19),
thioridazine (CYP2D6), theophylline, and tizanidine (CYP1A2)

21. Subject is taking the breast cancer resistance protein (BCRP) transporter-sensitive
substrate rosuvastatin should be excluded from the study unless the subject can be
transferred to other medications at least 5 half-lives prior to the start of study
treatment

22. Subject has any significant medical condition, laboratory abnormality, or psychiatric
illness that would prevent the subject from participating in the study

23. Subject has any condition including the presence of laboratory abnormalities, which
places the subject at unacceptable risk if he/she were to participate in the study

24. Subject has any condition that confounds the ability to interpret data from the study