| Eligibility |
Inclusion Criteria:
- Participants must =18 years of age
- Previously untreated AML (de novo or secondary) defined according to World Health
Organization (WHO) criteria, excluding acute promyelocytic leukemia (APL) [AML with
t(15;17)], with locally documented IDH1 and/or IDH2 gene mutation scheduled for
induction therapy followed by consolidation therapy. Participants with 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 are also eligible. Participants may have had
previous treatment for MDS or other AHD, including hypomethylating agents (HMAs),
provided it was = 14 days prior to study drug initiation
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 2
- 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
(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 participant 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 participants 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 participants with reproductive potential must have a negative serum pregnancy
test within 7 days prior to the start of the therapy. Participants 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 one highly effective form (for
participants receiving AG-221) or two highly effective forms (for participants
receiving AG-120) of contraception from the time of giving informed consent, during
the study, and for 2 months (for participants receiving AG-221) and for 4 months (for
participants receiving AG-120) following the last dose of AG-120 or AG-221 (females
and males). 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 prior to enrollment for the control
of peripheral leukemic blasts in participants with leukocytosis; hydroxyurea may be
allowed on study with study Sponsor approval
- 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 participants 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 participant has been
free of the disease for =1 year prior to the start of study treatment However,
participants 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 left
ventricular ejection fraction (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 milliseconds (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 participant's ability to give informed consent or participate in
the study
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