Inclusion Criteria:

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

• - Subjects with a histologically confirmed diagnosis of MDS, including both MDS and refractory anemia with excess blasts (RAEB)-T (acute myeloid leukemia [AML] with 20-30% blasts and multilineage dysplasia by French-American-British [FAB] criteria) by World Health Organization (WHO) and chronic myelomonocytic leukemia (CMML) are eligible.

• - Subjects with high-risk MDS (i.e. International Prognostic Scoring System [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.

• - Subjects with prior hypomethylating agent therapy exposure may be eligible based on discussion with the principal investigator (PI) - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• - Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients with Gilbert's disease) - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3 x the laboratory ULN.

• - Creatinine clearance > 30 mL/min based on the Cockcroft-Gault equation.

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

• - 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.

• - 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:

• - 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.

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

• - Active uncontrolled infection at study enrollment including known diagnosis of human immunodeficiency virus or chronic active hepatitis B or C infection.

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

• - Patients with known active central nervous system (CNS) disease, including leptomeningeal involvement.

• - 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.

• - Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with a bundle branch block at baseline) - Nursing or pregnant women.

- Subjects with known hypersensitivity to study drugs or their excipients

PRIMARY OBJECTIVES:

• I. To determine the safety, tolerability and clinical activity of glutaminase inhibitor CB-839 (CB-839) in combination with azacitidine (AZA) for patients with advanced myelodysplastic syndrome (MDS).

SECONDARY OBJECTIVES:

• I. To explore the pharmacokinetics (PK) of CB-839 in combination with AZA.

• II. To explore the pharmacodynamics (PDn) of CB-839 in combination with AZA.

• III. To assess overall survival, event-free survival and duration of response of CB-839 in combination with AZA.

OUTLINE: Patients receive glutaminase inhibitor CB-839 orally (PO) twice daily (BID) on days 1-28 and azacitidine subcutaneously (SC) or intravenously (IV) over 10-40 minutes on days 1-7. After completion of study treatment, patients are followed up at 28 days.

Arms

Experimental: Treatment (glutaminase inhibitor CB-839, azacitidine)

Patients receive glutaminase inhibitor CB-839 PO BID on days 1-28 and azacitidine SC or IV over 10-40 minutes on days 1-7.

Interventions

Drug: - Azacitidine

Given IV or SC

Drug: - Glutaminase Inhibitor CB-839

Given PO