Azacitidine and Enasidenib in Treating Patients With IDH2-Mutant Myelodysplastic Syndrome

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 andrefractory anemia with excess blasts in transformation (RAEB-T) (acute myeloidleukemia [AML] with 20-30% blasts and multilineage dysplasia byFrench-American-British [FAB] criteria) by World Health Organization (WHO), andchronic myelomonocytic leukemia (CMML) are eligible

• Subjects must have an IDH2 gene mutation (IDH2-R140 or R172) as determined by locallaboratory result

• (Arm A only): Subject must be hypomethylating agent naive (i.e. prior azacitidine,decitabine, SGI-110 is exclusionary). Receipt of other MDS-directed therapy such aslenalidomide is allowed

• (Arm A only): Subjects with high-risk MDS (i.e. International Prostate Symptom Score [IPSS] intermediate-2 or high-risk; or revised [R]-IPSS high or very-high risk).Patients with intermediate-1 risk by IPSS or intermediate risk by R-IPSS withhigh-risk molecular features including TP53, ASXL1, EZH2, and/or RUNX1 mutations arealso eligible

• (Arm B only): Subject must be relapsed or refractory to prior hypomethylating agenttherapy, defined as prior receipt of 6 cycles of HMA therapy with failure to attaina response, or relapse after prior response to HMA therapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Serum bilirubin =< 2 x the upper limit of normal (ULN) (except for patients withGilbert's disease)

• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) =< 3 x thelaboratory ULN

• Serum creatinine =< 2 x the ULN

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

• Resolution of all clinically significant treatment-related, non-hematologicaltoxicities, except alopecia, from any previous cancer therapy to =< grade 1 prior tothe first dose of study treatment

• Female patients of childbearing potential must have a negative serum or urinepregnancy test within 7 days of the first dose of study drug and agree to use dualmethods of contraception during the study and for a minimum of 3 months followingthe last dose of study drug. Post-menopausal females (> 45 years old and withoutmenses for > 1 year) and surgically sterilized females are exempt from theserequirements. Male patients must use an effective barrier method of contraceptionduring the study and for a minimum of 3 months following the last dose of study drugif sexually active with a female of childbearing potential

Exclusion Criteria:

• Any prior or coexisting medical condition that in the investigator's judgment willsubstantially increase the risk associated with the subject's participation in thestudy

• Subject has received a prior targeted IDH2 inhibitor

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

• Active uncontrolled infection at study enrollment including known diagnosis of humanimmunodeficiency virus or chronic active hepatitis B or C infection

• Clinically significant gastrointestinal conditions or disorders that may interferewith study drug absorption, including prior gastrectomy

• Patients with known active central nervous system (CNS) disease, includingleptomeningeal involvement

• Impaired cardiac function, uncontrolled cardiac arrhythmia, or clinicallysignificant cardiac disease including the following: a) New York Heart Associationgrade III or IV congestive heart failure, b) myocardial infarction within the last 6months

• Subjects with a corrected QT (QTc) > 480 ms (QTc > 510 msec for subjects with abundle branch block at baseline

• Nursing or pregnant women

• Subjects with known hypersensitivity to study drugs or their excipients