Inclusion Criteria:

• Subjects must be ≥ 18 years of age.
• Subjects must have an advanced hematologic malignancy including:
• Dose Escalation Phase
  • Relapsed and/or primary refractory AML as defined by WHO criteria; or
  • 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;
  • Myelodysplastic syndrome with refractory anemia with excess blasts (subtype RAEB-1 or RAEB-2), or considered high-risk by the IPSS-R (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 CMML, who fulfill the inclusion/excluding criteria may be considered on a case-by case basis, with approval of the Medical Monitor).
• Expansion Phase
  • Arm 1: R/R AML defined as:
    • Subjects who relapse after 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 subjects with favorable-risk status according to NCCN Guidelines, version 1.2015 (National Comprehensive Cancer Network 2015).
  • Arm 2: Untreated AML who are not candidates for standard therapy due to comorbid condition, performance status, and/or adverse risk factors, according to the Investigator and with approval of the Medical Monitor.
  • Arm 3: Other non-AML IDH1-mutated R/R advanced hematologic malignancies, where no standard of care treatment option is available. Such as:
    • Myelodysplastic syndrome that is recurrent or refractory after having failed hypomethylating agent(s) and with the approval of Medical Monitor;
    • Relapsed and/or primary refractory CMML with the approval of Medical Monitor;
    • Other non-AML IDH1-mutated R/R advanced hematologic malignancy, that have failed standard of care or no standard of care treatment option is available according to the Investigator and with the approval of the Medical Monitor.
  • Arm 4: Relapsed AML subjects not eligible for Arm 1 that have failed available standard of care or are unable to receive standard of care due to age, comorbid condition, performance status, and/or adverse risk factors, according to the Investigator and with approval of the Medical Monitor.
• MDS Substudy
  • MDS substudy: Subjects with R/R MDS, defined as meeting all of the following criteria:
    • Bone marrow blasts > 5% and/or transfusion dependence (receipt of ≥ 2 units of either packed red blood cells or platelets within the 8 weeks prior to Cycle 1 Day 1).
  • MDS that is:
    • relapsed or refractory to intensive induction chemotherapy and/or stem cell transplantation; or
    • relapsed or refractory to hypomethylating agents or that has progressed after initiation of azacitidine or decitabine.
  • Refractory disease is defined as the absence of CR, mCR, PR, or hematologic improvement after at least 4 cycles of azacitidine or decitabine.
  • Subjects must have documented IDH1 R132 gene-mutated disease:
    • For subjects in the dose escalation phase, IDH1 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively);
    • For subjects in the expansion phase and MDS substudy, central testing of IDH1 genemutated disease is required during screening to confirm eligibility.
  • Subjects must be amenable to serial bone marrow sampling, peripheral blood sampling, and urine sampling (dose escalation only) during 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.
  • Subject 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).
  • Subjects must have ECOG PS of 0 to 2.
  • 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.
  • Subjects must have adequate hepatic function as evidenced by:
    • Serum total bilirubin ≤ 1.5 × ULN, unless considered due to Gilbert’s disease or leukemic disease;
    • Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic disease.
  • Subjects must have 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) estimation:
      • (140 - Age) x (weight in kg) x (0.85 if female)/72 x serum creatinine.
  • 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),
  • 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.
  • 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 with partners who are female of reproductive potential must agree to abstain from sexual intercourse or to use 2 effective forms of contraception (including at least 1 barrier form) from the time of giving informed consent, during the study and for 90 days (both females and males) following the last dose of AG-120. Effective forms of contraception are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization. Co-administration of AG-120 may decrease the concentrations of hormonal contraceptives.

Exclusion Criteria:

• Subjects who previously received prior treatment with a mutant-specific IDH1 inhibitor and progressed on therapy.
• Subjects who have undergone HSCT within 60 days of the first dose of AG-120, 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.)
• Subjects who received systemic anticancer therapy or radiotherapy < 14 days prior to their first day of study drug administration. Hydroxyurea is allowed prior to enrollment and after the start of AG-120 for the control of peripheral leukemic blasts in subjects with leukocytosis (e,g,, white blood cell [WBC] counts > 30,000/μL).
• Subjects who received an investigational agent < 14 days prior to their first day of study drug administration. In addition, the first dose of AG-120 should not occur before a period ≥ 5 half-lives of the investigational agent has elapsed.
• Subjects taking sensitive CYP3A4 substrate medications with narrow therapeutic windows are excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing, or unless the medications can be properly monitored during the study. Subjects taking strong CYP3A4 inducers are excluded from the study unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing,
• Subjects for whom potentially curative anticancer therapy is available.
• Subjects who are pregnant or breast feeding.
• 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).
• Subjects with known hypersensitivity to any of the components of AG-120.
• 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.
• Subjects with a history of myocardial infarction within the last 6 months of screening.
• Subjects with known unstable or uncontrolled angina pectoris.
• Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
• Subjects with heart rate corrected QT interval (QTc) ≥ 450 msec or with 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.
• Subjects 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 or unless the medications can be properly monitored during the study
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
• 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.
• Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
• 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.
• Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
• Subjects with a known medical history of PML.
• MDS substudy only: Subjects with documented AML (≥ 20% bone marrow or peripheral blood blasts).
• MDS substudy only: Subjects who have received treatment with myeloid growth factors within 14 days prior to the screening bone marrow biopsy.