Study of Orally Administered AG-221 in Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation Subjects With Advanced Solid Tumors, Including Glioma, and With Angioimmunoblastic T-cell Lymphoma, With an IDH2 Mutation

Inclusion Criteria:

- Subject must be ≥18 years of age

- Histologically or cytologically confirmed advanced solid tumor, including glioma, or
angioimmunoblastic T-cell lymphoma (AITL) that has recurred or progressed following
standard therapy, or that has not responded to standard therapy

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

- Documented IDH2 gene-mutated disease based on local site testing

- Measurable disease by RECIST v1.1 for subjects with solid tumors without glioma, by
modified RANO criteria for subjects with glioma, or by the revised IWG criteria for
subjects with AITL

- Subjects must have ECOG PS of 0 to 2

- Adequate bone marrow function (subjects other than those with AITL) as evidenced by:
absolute neutrophil count ≥1.0 ×109/L;hemoglobin >9 g/dL (Subjects may be transfused
red blood cells to this level.); platelets ≥50 × 109/L

- 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,
or disease involvement, following approval by the Medical Monitor; AST, ALT, ALP ≤2.5
× ULN, with the exception of subjects with bone metastases and/or suspected
disease-related liver or biliary involvement, where ALP must be ≤5 × ULN

- Adequate renal function as evidenced by: serum creatinine ≤2.0 × ULN; OR creatinine
clearance > 40 mL/min based on the Cockroft-Gault GFR estimation: (140 - Age) x
(weight in kg) x (0.85 if female)/72 x serum creatinine

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

- Previous allogeneic stem cell transplant is allowed only if subjects are >100 days
from stem cell transplant and do not have uncontrolled acute or chronic graft-vs-host
disease

Exclusion Criteria:

- Received systemic anticancer therapy or radiotherapy <21 days prior to their first day
of study drug administration

- Received an 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 taking the following sensitive cytochrome P450 (CYP) substrate medications
that have a narrow therapeutic range are excluded from the study unless they can be
transferred to other medications prior to enrolling: paclitaxel (CYP2C8), warfarin,
phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and
tizanidine (CYP1A2)

- Subjects taking the P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP)
transporter-sensitive substrates digoxin and rosuvastatin should be excluded from the
study, unless they can be transferred to other medications prior to enrolling. study
unless they can be transferred to other medications prior to enrolling

- Subjects for whom potentially curative anticancer therapy is available

- Pregnant or breastfeeding

- 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)

- Known hypersensitivity to any of the components of AG-221

- 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

- History of myocardial infarction within the last 6 months

- Subjects with uncontrolled hypertension (systolic blood pressure >180 mmHg or
diastolic blood pressure >100 mmHg) are excluded. Subjects requiring 2 or more
medications to control hypertension are eligible with Medical Monitor approval.

- Known unstable or uncontrolled angina pectoris

- Known history of severe and/or uncontrolled ventricular arrhythmias

- Heart-rate corrected QT (QTc) interval >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). Subjects with right 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

- Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C

- 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

- Known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the
ingestion or gastrointestinal absorption of drugs administered orally

- Subjects with brain metastases that are untreated, symptomatic, or require therapy to
control symptoms; or any radiation, surgery, or other therapy, including to control
symptoms, within 2 months of first dose. Subjects with glioma who are on a stable,
steroid-dosing regimen prior to screening MRI may be permitted to enroll with Medical
Monitor approval

- In subjects with AITL, evidence of meningeal or cerebral disease or a history of
progressive multifocal leukoencephalopathy

- Radiotherapy involving <25% of the hematopoietically active bone marrow within 21 days
preceding first dose of study treatment

- Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days
preceding first dose of study treatment