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

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 ormyeloproliferative neoplasms ([MPN], or therapy-related) AML according to WHOclassification (Appendix B)
3. Subject has received second- or third-line of AML therapy (see Appendix G for thedefinition of prior AML line; note that, for subjects having AML secondary to priorhigher risk [Intermediate-2 or High risk according to the International PrognosticScoring System] MDS treated with a hypomethylating agent [eg, azacitidine ordecitabine], the hypomethylating therapy can be counted as a line if there is diseaseprogression to AML during or shortly [eg, within 60 days] after the hypomethylatingtherapy.)
4. Subject has the following disease status:
5. Refractory to or relapsed after second- or third-line of intensive therapy forAML (eg, the "7 + 3" regimen): at least 5% leukemic blasts in bone marrow (the minimum number of treatmentcycles of the intensive therapy is per the investigator's discretion); or
6. 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
7. 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 toxicencephalopathies, especially after the use of methotrexate or treatment with ionizingradiation, should not receive cytarabine.)
8. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix D)
9. Subject has IDH2 gene mutations tested centrally (using the "investigational useonly"PCR assay, Abbott RealTime IDH2) in samples of bone marrow aspirate andperipheral blood, and confirmed positive in bone marrow aspirate and/or peripheralblood. (Note: in the event that the central laboratory result is delayed and precludesacute clinical management of a subject who has confirmed IDH2 gene mutation by localevaluation, the subject may be eligible for randomization with approval by the MedicalMonitor.)
10. Subject has adequate organ function defined as:

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤ 3x upper limit of normal (ULN), unless considered due to leukemic organinvolvement, 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 reviewby the Medical Monitor; and
• Creatinine clearance > 30 mL/min based on the Modification of Diet in RenalDisease (MDRD) glomerular filtration rate (GFR): GFR (mL/min/1.73 m2) = 175 × (serum creatinine)-1.154 × (Age)-0.203 × (0.742 iffemale) × (1.212 if African American)

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

• Agree to practice true abstinence from sexual intercourse or to use highlyeffective contraceptive methods (eg, combined [containing estrogen andprogestogen] or progestogen-only associated with inhibition of ovulation, oral,injectable, intravaginal, patch, or implantable hormonal contraceptive; bilateraltubal occlusion; intra-uterine device; intrauterine hormone-releasing system; ormale partner sterilization [note that vasectomized partner is a highly effectivebirth control method provided that partner is the sole sexual partner of the FCBPtrial participant and that the vasectomized partner has received medicalassessment of the surgical success]) at screening and throughout the study, andfor 4 months following the last study treatment (6 months following the last doseof cytarabine); and
• Have a negative serum β-subunit of human chorionic gonadotropin (β-hCG) pregnancytest (sensitivity of at least 25 mIU/mL) at screening; and
• Have a negative serum or urine (investigator's discretion under localregulations) β-hCG pregnancy test (sensitivity of at least 25 mIU/mL) within 72hours prior to the start of study treatment in the Treatment Phase (note that thescreening serum pregnancy test can be used as the test prior to the start ofstudy treatment in the Treatment Phase if it is performed within the 72-hourtimeframe).

10. Male subjects must agree to practice true abstinence from sexual intercourse or to theuse of highly effective contraceptive methods (as described above) with non-pregnantfemale partners of childbearing potential at screening and throughout the course ofthe study, and should avoid conception with their partners during the course of thestudy and for 4 months following the last study treatment (6 months following the lastdose 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-relatedassessments/procedures being conducted
12. Subject is willing and able to adhere to the study visit schedule and other protocolrequirements

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 onmorphology, 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 tothe start of study treatment. Note that hydroxyurea is allowed prior to the start ofstudy treatment for the control of leukocytosis (however, hydroxyurea should not begiven within 72 hours prior to and after administration of azacitidine).
5. Subject has received non-cytotoxic or investigational agents < 14 days or 5half-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 onimmunosuppressive therapy post HSCT at the time of screening, or with clinicallysignificant graft-versus-host disease (GVHD). The use of a stable dose of oral steroidpost-HSCT and/or topical steroids for ongoing skin GVHD is permitted.
7. Subject has persistent, clinically significant non-hematologic toxicities from priortherapies
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 issuspected during screening.
9. Subject has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvementdespite appropriate antibiotics, antiviral therapy, and/or other treatment)
10. Subject has immediately life-threatening, severe complications of leukemia such asuncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminatedintravascular coagulation
11. Subject has significant active cardiac disease within 6 months prior to the start ofstudy treatment, including New York Heart Association (NYHA) class III or IVcongestive heart failure (Appendix E); acute coronary syndrome (ACS); and/or stroke;or left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) ormulti-gated acquisition (MUGA) scan obtained within 28 days prior to the start ofstudy treatment
12. Subject has prior history of malignancy, other than MDS, MPN or AML, unless thesubject has been free of the disease for ≥ 1 year prior to the start of studytreatment. 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 otherconditions that limit the ingestion or gastrointestinal absorption of drugsadministered orally
15. Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg ordiastolic 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 ofstudy treatment
18. Subject is taking those medications (listed in Section 8.2) that are known to prolongQT interval unless the subject can be transferred to other medications at least 5half-lives prior to the start of study treatment
19. Subject has QTc interval (ie, Fridericia's correction [QTcF]) ≥ 450 ms or otherfactors that increase the risk of QT prolongation or arrhythmic events (eg, heartfailure, hypokalemia, family history of long QT interval syndrome) at screening
20. Subject is taking the following sensitive CYP substrate medications that have a narrowtherapeutic range are excluded from the study unless the subject can be transferred toother 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-sensitivesubstrate rosuvastatin should be excluded from the study unless the subject can betransferred to other medications at least 5 half-lives prior to the start of studytreatment
22. Subject has any significant medical condition, laboratory abnormality, or psychiatricillness that would prevent the subject from participating in the study
23. Subject has any condition including the presence of laboratory abnormalities, whichplaces 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