Study of Orally Administered AG-120 in Subjects With Advanced Solid Tumors, Including Glioma, With an IDH1 Mutation

Key Inclusion Criteria:

1. Dose Escalation

1. Subjects must have histologically or cytologically confirmed, IDH1 gene-mutated
advanced solid tumors, including glioma, that have recurred or progressed
following standard therapy, or that have not responded to standard therapy.

2. Subjects must have evaluable disease by RECIST v1.1 for subjects without glioma
or by RANO criteria for subjects with glioma.

2. Dose Expansion: Cholangiocarcinoma

1. Subjects must have histologically-confirmed diagnosis of IDH1 gene-mutated
cholangiocarcinoma Stage II, III, or IV (intra-hepatic, extra-hepatic and
perihilar) that is not eligible for curative resection, transplantation, or
ablative therapies. Tumors of mixed histology are not allowed.

2. Cholangiocarcinoma subjects must have progressed following gemcitabine-based
regimen.

3. Cholangiocarcinoma subjects must have radiographically measurable disease in at
least one site not previously treated with radiation, chemoembolization,
radioembolization, or other local ablative procedures; a new area of tumor
progression within or adjacent to a previously-treated lesion, if clearly
measurable by a radiologist, is acceptable.

3. Dose Expansion: Chondrosarcoma

a. Subjects must have IDH1 gene-mutated chondrosarcoma that is either locally advanced
or metastatic and not amenable to complete surgical excision.

4. Dose Expansion: Non-enhancing Glioma

1. Subjects must have progressive glioma that is solely non-enhancing on MRI.

2. Progression of glioma must have occurred over 12 months or less.

3. Subject must have available at least 3 prior full sets of scans (not including
screening), each separated by at least 2 months with less than or equal to 5 mm
slice thickness and up to 1 mm interslice gap on either 2D T2 weighted image, 3D
T2 weighted image, or FLAIR.

4. Subjects must not have had prior surgery (biopsy allowed) or radiation therapy
within 6 months of enrollment.

5. Dose Expansion: Solid Tumors Not Otherwise Eligible for the Cholangiocarcinoma,
Chondrosarcoma, or Non-enhancing Glioma Cohorts

1. IDH1 gene-mutated solid tumors refractory to conventional therapy or the subject
does not tolerate the conventional therapy

2. Subjects must have radiographically measurable disease in at least one site not
previously treated with radiation, chemoembolization, radioembolization, or other
local ablative procedures; a new area of tumor progression within or adjacent to
a previously-treated lesion, if clearly measurable by a radiologist, is
acceptable.

6. Subject must be ≥18 years of age.

7. Subjects must have documented IDH1 gene-mutated disease based on local test
evaluation. (Centralized testing will be performed retrospectively.)

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

9. 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).

10. Subjects must have ECOG PS of 0 to 1.

11. Subjects must have expected survival of ≥3 months.

12. Subjects must have adequate bone marrow function as evidenced by:

1. Absolute neutrophil count ≥1.5 ×109/L;

2. Hemoglobin >9 g/dL (Subjects are allowed to be transfused to this level)

3. Platelets ≥ 75 × 109/L.

13. Subjects must have adequate hepatic function as evidenced by:

1. Serum total bilirubin ≤1.5 × upper limit of normal (ULN), unless considered due
to Gilbert's disease or disease involvement following approval by the Medical
Monitor;

2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline
phosphatase (ALP) ≤2.5 × ULN. For subjects with bone metastases and/or suspected
disease-related liver or biliary involvement, ALP must be ≤5 × ULN.

14. Subjects must have adequate renal function as evidenced by:

a. Serum creatinine ≤2.0 × ULN OR b. Creatinine clearance >40 mL/min based on the
Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 - Age) x (weight in
kg) x (0.85 if female)/72 x serum creatinine

15. Subjects must be recovered from any clinically relevant toxic effects of any prior
surgery, radiotherapy, or other therapy intended for the treatment of cancer. (For
example, subjects with residual Grade 1 toxicity or stable Grade 2 peripheral
neuropathy due to prior chemotherapy are allowed with approval of the Medical
Monitor.)

16. 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. 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 and
their partners who are female of reproductive potential, must agree to abstain from
sexual intercourse or to use two highly effective forms of contraception from the time
of giving informed consent, during the study and for 90 days (females and males)
following the last dose of AG-120. A highly effective form of contraception is defined
as hormonal oral contraceptives, injectables, patches, intrauterine devices,
double-barrier method (e.g., synthetic condoms, diaphragm, or cervical cap with
spermicidal foam, cream, or gel), or male partner sterilization.

Exclusion Criteria:

1. Subjects who received systemic anticancer therapy or radiotherapy <21 days prior to
their first day of study drug administration.

2. 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.

3. Subjects taking the following sensitive cytochrome P450 (CYP) 3A4 substrate
medications are excluded from the study unless they can be transferred to other
medications prior to enrolling: alfentanil, aprepitant, budesonide, buspirone,
conivaptan, darifenacin, darunavir, dronedarone, eletriptan, eplerenone, felodipine,
indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam,
nisoldipine, quetiapine, saquinavir, sildenafil, simvastatin, tolvaptan, tipranavir,
triazolam, ticagrelor, vardenafil and/or the CYP2B6 substrates: bupropion, efavirenz.

4. Subjects taking the following P-glycoprotein (P-gp) transporter-sensitive substrate
medications are excluded from the study unless they can be transferred to other
medications prior to enrolling: aliskiren, ambrisentan, colchicine, dabigatran
etexilate, digoxin, fexofenadine, maraviroc, posaconazole, ranolazine, saxagliptin,
sitagliptin, talinolol, and tolvaptan.

5. Subjects for whom potentially curative anticancer therapy is available.

6. Subjects who are pregnant or breast feeding.

7. 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).

8. Subjects with known hypersensitivity to any of the components of AG-120.

9. Subjects with New York Heart Association (NYHA) Class III or IV congestive heart
failure or left ventricular ejection fraction (LVEF) <40% by echocardiogram (ECHO) or
multi-gated acquisition (MUGA) scan within approximately 28 days of C1D1.

10. Subjects with a history of myocardial infarction within the last 6 months.

11. Subjects with known unstable or uncontrolled angina pectoris.

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

13. Subjects with 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.

14. Subjects taking medications that are known to prolong the QT interval (see Section
9.11.3).

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

16. 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.

17. Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions
that limit the ingestion or gastrointestinal absorption of drugs administered orally.

18. Subjects with brain metastases that are untreated, symptomatic, or require therapy to
control symptoms; or any radiation, surgery, or other therapy, including those used to
control symptoms, within 2 months of first dose. Subjects with glioma who are on a
stable, steroid dosing regimen 5 days prior to the screening MRI may be permitted to
enroll with Medical Monitor approval.

19. Subjects with a history of Grade 4 astrocytoma.