Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation
Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation
The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics,
 pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that
 harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where
 cohorts of patients will receive ascending oral doses of AG-120 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-120 to further evaluate
 the safety, tolerability, and clinical activity of the recommended Phase II dose.
 Additionally, the study includes a substudy evaluating the safety and tolerability, clinical
 activity, pharmacokinetics, and pharmacodynamics of AG-120 in subjects with relapsed or
 refractory myelodysplastic syndrome with an IDH1 mutation. Anticipated time on study
 treatment is until disease progression or unacceptable toxicity occurs.
Key Inclusion Criteria:

 -  Subject must be ≥18 years of age.

 -  Subjects must have documented IDH1 R132 gene-mutated advanced hematologic malignancy
 based on local or central evaluation.

 -  Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling,
 and urine sampling during the study.

 -  Subjects must have ECOG PS of 0 to 2.

 -  Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed).

 -  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 disease and serum total bilirubin ≤1.5 x
 upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic
 disease

 -  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 and on the first day of study drug
 administration.

 Key Exclusion Criteria:

 -  Subjects who have undergone hematopoietic stem cell transplant (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 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 prior to
 enrollment and after the start of AG-120).

 -  Subjects who received an investigational agent <14 days prior to their first day of
 study drug administration.

 -  Subjects who are pregnant or breastfeeding.

 -  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 of
 screening.

 -  Subjects with a known unstable or uncontrolled angina pectoris.

 -  Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.

 -  Subjects with known unstable or uncontrolled angina pectoris.

 -  Subjects with heart-rate corrected QT (QTc) interval ≥450 ms or other factors that
 increase the risk of QT prolongation or arrhythmic events.

 -  Patients taking medications that are known to prolong the QT interval

 -  Subjects with known infection with human immunodeficiency virus (HIV) or active
 hepatitis B or C.

 -  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.