CB-839 + Azacitidine for Treatment of Myelodysplastic Syndrome (MDS)

Study Drug Administration:

Every study cycle is 28 days.

- You will take CB-839 by mouth 2 times per day while you are on study. You should take
each dose with food, and about 12 hours apart.

- You will receive azacitidine by vein over about 10-40 minutes, or as an injection under
the skin about 1 hour after taking CB-839 on Days 1-7 of every cycle. If needed, you may
receive azacitidine at your local doctor's office.

It is important that you tell the study doctor about any drugs you are taking during the
study. This includes prescription drugs, over-the-counter drugs, natural or herbal medicines,
alternative medicines, and vitamins.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the End-of-Study visit.

Study Visits:

You may visit your regular home doctor for any study visits in which PD or PK testing is not
taking place. However, you will need to come to MD Anderson on Day 1 of each cycle in order
to get your supply of CB-839.

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests and pharmacokinetic (PK)
testing before the dose of CB-839. PK testing measures the amount of study drug in the
body at different time points.

- Blood (about 8 teaspoons) will be drawn for biomarker testing, including genetic
biomarkers. Biomarkers are found in the blood/tissue and may be related to your reaction
to the study drug.

- You will have two EKGs within 2-4 hours after the dose.

On Days 8, 15, and 22 of Cycle 1:

- You will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine testing.

On Day 1 of Cycles 2 and 3, and Day 15 of Cycle 1, blood (about 1 tablespoon) will be drawn
for PK testing before the dose. You should not take the morning dose of CB-839 at home before
the clinic visits.

On Day 1 of Cycle 2 and beyond:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine and biomarker testing, including
genetic biomarkers.

You will have a bone marrow biopsy and aspirate for biomarker and pharmacodynamic (PD)
testing and to check the status of the disease on Day 1 of Cycles 1,2,4,6 and every 3 cycles
after that. PD testing measures how the level of study drug in your body may affect the
disease.

End-of-Study Visit:

Within 28 days of the last dose of the study drugs:

- You will have a physical exam.

- Blood (about 2 tablespoons) will be drawn for routine tests.

- You will have an EKG.

- You will have a bone marrow biopsy and aspirate for biomarker and PD testing. You may
also have blood (about 2 tablespoons) drawn for this sample instead.

- If you can become pregnant, blood (about 1 tablespoon) or urine will be collected for a
pregnancy test.

Inclusion Criteria:

1. Signed, informed consent must be obtained prior to any study specific procedures.

2. 2. Subjects must be >/= 18 years of age at the time of informed consent

3. Subjects with a histologically confirmed diagnosis of MDS, including both MDS and
RAEB-T (AML with 20-30% blasts and multilineage dysplasia by FAB criteria) by World
Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible.

4. Subjects with high-risk MDS (i.e. IPSS Intermediate-2 or high-risk; or R-IPSS high or
very-high risk). Patients with Intermediate-1 risk by IPSS or Intermediate risk by
R-IPSS and with IDH1 or IDH2, or high-risk molecular features including TP53, ASXL1,
EZH2, and/or RUNX1 mutations are also eligible.

5. Subjects with prior hypomethylating agent therapy exposure may be eligible based on
discussion with the PI.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.

7. Adequate liver function, as evidenced by a serum bilirubin patients with Gilbert's disease) and ALT or AST
8. Adequate renal function including creatinine clearance > 30 mL/min based on the
Cockcroft-Gault equation.

9. Able to understand and voluntarily sign a written informed consent, and willing and
able to comply with protocol requirements

10. Resolution of all treatment-related, non-hematological toxicities, except alopecia,
from any previous cancer therapy to < Grade 1 prior to the first dose of study
treatment

11. Female patients of childbearing potential must have a negative serum or urine
pregnancy test within 3 days of the first dose of study drug and agree to use dual
methods of contraception during the study and for a minimum of 3 months following the
last dose of study drug. Post-menopausal females (>/= 45 years old and without menses
for >/= 1 year) and surgically sterilized females are exempt from these requirements.
Male patients must use an effective barrier method of contraception during the study
and for a minimum of 3 months following the last dose of study drug if sexually active
with a female of childbearing potential.

Exclusion Criteria:

1. Any prior or coexisting medical condition that in the investigator's judgment will
substantially increase the risk associated with the subject's participation in the
study.

2. Psychiatric disorders or altered mental status precluding understanding of the
informed consent process and/or completion of the necessary study procedures

3. Active uncontrolled infection at study enrollment including known diagnosis of human
immunodeficiency virus or chronic active Hepatitis B or C infection.

4. Clinically significant gastrointestinal conditions or disorders that may interfere
with study drug absorption, including prior gastrectomy.

5. Patients with known active CNS disease, including leptomeningeal involvement.

6. Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinically significant
cardiac disease including the following: a) New York Heart Association Grade III or IV
congestive heart failure, b) myocardial infarction within the last 6 months

7. Subjects with a QTc > 480 ms (QTc > 510 msec for subjects with a bundle branch block
at baseline).

8. Nursing or pregnant women.

9. Subjects with known hypersensitivity to study drugs or their excipients.