Phase 1 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation

• Safety/tolerability: incidence of adverse events [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
• Maximum Tolerated Dose/recommended Phase II dose [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]

• Dose Limiting Toxicities [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
• Pharmacokinetics [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
  Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include max concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.
• Clinical Activity according to the 2006 modified IWG criteria for MDS, MDS/myeloproliferative neoplasms (MPN) or AML [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
• Pharmacodynamics [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
  The potential relationship between levels of AG-221 and 2-HG levels will be explored with descriptive and graphical methods.

• Dose Limiting Toxicities [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: Yes ]
• Pharmacokinetics [ Time Frame: through Day 29 ] [ Designated as safety issue: Yes ]
  Descriptive statistics will be used to summarize PK parameters for each dose group and, where appropriate, for the entire population. Such parameters will include max concentration (Cmax), time to maximum concentration (Tmax), AUC, elimination half-life, and the fraction of drug excreted unchanged in the urine.
• Clinical Activity according to the 2006 modified IWG criteria for MDS, MDS/myeloproliferative neoplasms (MPN) or AML [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
• Pharmacodynamics [ Time Frame: up to 26 weeks, on average ] [ Designated as safety issue: No ]
  The potential relationship between levels of AG-221 and 2-HG levels will be explored with descriptive and graphical methods.

The purpose of this Phase 1, multi-center study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-221 in advanced hematologic malignancies that harbor an IDH2 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-221 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-221 to further evaluate the safety, tolerability, and clinical activity. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.

• Relapsed or Refractory AML Patients
• Untreated AML Patients Who Decline Standard of Care Chemotherapy
• Patients With Other IDH2-mutant Positive Hematologic Malignancies

Inclusion Criteria:

• Subject must be ≥18 years of age.
• Subjects must have documented IDH2 gene-mutated advanced hematologic malignancy based on local evaluation.
• Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
• Subjects must be able and willing to sign an informed consent.
• 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 Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement, and serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic organ involvement.
• Subjects must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN or creatinine clearance >40mL/min based on Cockroft-Gault glomerular filtration rate (GFR)
• Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
• 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 one who is biologically capable of becoming pregnant. Women of childbearing potential as well as fertile men and their partners must agree to abstain from sexual intercourse or to use an effective form of contraception during the study and for 90 days (females and males) following the last dose of AG-221.

Exclusion Criteria:

• Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-221, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of topical steroids for ongoing skin GVHD is permitted.)
• Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed for up to 28 days after the start of AG-221 for the control of peripheral leukemic blasts in subjects with white blood cell [WBC] counts >30,000/μL as well as prior to enrollment).
• Subjects who received a small molecule investigational agent <14 days prior to their first day of study drug administration. In addition, the first dose of AG-221 should not occur before a period ≥5 half-lives of the investigational agent has elapsed.
• Subjects who are pregnant or lactating.
• Subjects with an active severe infection 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 New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.
• Subjects with a history of myocardial infarction within the last 6 months.
• Subjects with uncontrolled hypertension (systolic blood pressure [BP] >180 mmHg or diastolic BP >100 mmHg) are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
• 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 (QTc) interval ≥450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
• Patients taking medications that are known to prolong the QT interval
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis C.
• 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.
• Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.