Study of Orally Administered AG-881 in Patients With Advanced Hematologic Malignancies With an IDH1 and/or IDH2 Mutation

The first portion of the study is a dose escalation phase where cohorts of patients will
receive ascending oral doses of AG-881 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
patients will receive AG-881 to further evaluate the safety, tolerability, and clinical
activity of the recommended Phase II dose. Anticipated time on study treatment is until
disease progression or unacceptable toxicity occurs or the patient is removed at the
discretion of the investigator.

Inclusion Criteria:

Patients must be ≥18 years of age

Patients must have documented IDH1 and/or IDH2 gene-mutated disease

Patients must have an advanced hematologic malignancy with an IDH1 and/or IDH2 mutation

Patient must be able to understand and willing to sign an informed consent

Patients must have ECOG PS of 0 to 2

Patients must have adequate hepatic function as evidenced by serum total bilirubin ≤1.5
upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic
involvement

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase
(ALP) ≤3.0 × ULN, unless considered due to involvement by the neoplasm under consideration
for treatment

Patients must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN or
Creatinine clearance 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
estimation

Patients must be recovered from any clinically relevant toxic effects of any prior surgery,
radiotherapy, or other therapy intended for the treatment of cancer

Female patients with reproductive potential must have a negative serum pregnancy test
within 7 days prior to the start of therapy. Patients 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)

Exclusion Criteria:

Patients who have undergone HSCT within 60 days

Patients who received systemic anticancer therapy or radiotherapy <14 days prior to their
first day of study drug administration

Patients who received an investigational agent <14 days prior

Patients who are pregnant or breast feeding

Patients with an active severe infection who require 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, patients with tumor fever may be
enrolled)

Patients 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

Patients with a history of myocardial infarction within the last 6 months

Patients with known unstable or uncontrolled angina pectoris

Patients with a known history of severe and/or uncontrolled ventricular arrhythmias

Patients with QTc interval ≥450 msec or with other factors that increase the risk of QT
prolongation or arrhythmic events

Patients taking medications that are known to prolong the QT interval

Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B
or C

Patients 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

Patients with immediately life-threatening, severe complications of hematologic
malignancies such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or
disseminated intravascular coagulation