Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation

Inclusion Criteria:

- Subjects must ≥18 years of age

- Previously untreated AML (de novo or secondary) defined according to World Health
Organization (WHO) criteria, excluding APL [AML with t(15;17)], with locally
documented IDH1 and/or IDH2 gene mutation scheduled for induction therapy followed by
consolidation therapy. Secondary AML is defined as AML arising after myelodysplastic
syndromes (MDSs) or other antecedent hematologic disorders (AHDs) or AML arising after
exposure to genotoxic injury including radiation and/or chemotherapy. Subjects may
have had previous treatment for MDS or other AHD, including hypomethylating agents
(HMAs), provided that the last dose of administration is ≥ 14 days prior to study drug
initiation

- ECOG PS score of 0 to 2

- Adequate hepatic function as evidenced by: serum total bilirubin ≤1.5 × ULN unless
considered due to Gilbert's disease, a gene mutation in UGT1A1 (only for patients who
will be receiving AG-221), or leukemic involvement following approval by the study
Sponsor; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and
alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic involvement
following approval by the study Sponsor

- Adequate renal function as evidenced by serum creatinine ≤2.0 × ULN or creatinine
clearance 40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)

- Agree to serial blood and bone marrow sampling

- Meet any criteria necessary for the safe and proper use of the induction and
consolidation agents involved in this trial

- Able to understand and willing to sign an informed consent form. 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's Institutional Review
Board (IRB)/Independent Ethics Committee (IEC).

- Female subjects with reproductive potential must agree to undergo a 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). A
pregnancy test should also be performed on the day of the first study drug
administration and confirmed negative prior to dosing as well as before dosing on Day
1 of all subsequent cycles

- Female subjects with reproductive potential must have a negative serum pregnancy test
within 7 days prior to the start of the 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 for at
least 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 4 months (females and males)
following the last dose of AG-120 or 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

Exclusion Criteria:

- Prior chemotherapy for AML. Hydroxyurea is allowed for the control of peripheral
leukemic blasts in subjects with leukocytosis

- Taking medications with narrow therapeutic windows, unless they can be transferred to
other medications prior to enrolling or unless the medications can be properly
monitored during the study

- Taking known strong cytochrome P450 (CYP) 3A4 inducers, unless they can be transferred
to other medications prior to enrolling. For subjects taking AG-120, systemic
administration of a moderate or strong CYP3A4 inhibitor requires careful monitoring of
the heart rate-corrected QT interval (QTc) using Fridericia's formula (QTcF)

- Taking P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) or OATP1B1/1B3
transporter-sensitive substrate medications unless they can be transferred to
alternative medications within ≥5 half-lives prior to administration of AG-221, or
unless the medications can be adequately monitored during the study. There are no
restrictions regarding the co-administration of such medications with AG-120.

- Pregnant or breastfeeding

- Uncontrolled active infection or uncontrolled invasive fungal infection (positive
blood or tissue culture). An infection controlled with an approved or closely
monitored antibiotic/antifungal treatment is allowed

- Prior history of malignancy, other than MDS 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

- 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; myocardial infarction, unstable angina and/or stroke; or LVEF <40% by
echocardiogram (ECHO), or by other methods according to institutional practice,
obtained within 28 days prior to the start of study treatment

- QTc interval using Fridericia's formula (QTcF) ≥450 msec or other factors that
increase the risk of QT interval prolongation or arrhythmic events (e.g., heart
failure, hypokalemia, family history of long QT interval syndrome). Bundle branch
block and prolonged QTc are permitted with approval of the study Sponsor

- Taking medications that are known to prolong the QT interval unless they can be
transferred to other medications within ≥5 half-lives prior to dosing (If equivalent
medication is not available QTc will be closely monitored)

- Known infection caused by human immunodeficiency virus (HIV) or active hepatitis B or
C

- Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the
ingestion or gastrointestinal absorption of orally administered drugs

- Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known
CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is required
only if there is a clinical suspicion of CNS involvement by leukemia during screening.

- Immediate life-threatening, severe complications of leukemia such as uncontrolled
bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular
coagulation

- Any other medical or psychological condition deemed by the Investigator to be likely
to interfere with a subject's ability to give informed consent or participate in the
study