Phase 1/2 Study of Enasidenib (AG-221) in Adults With Advanced Hematologic Malignancies With an Isocitrate Dehydrogenase Isoform 2 (IDH2) Mutation

Inclusion Criteria

• Subject must be greater than or equal to 18 years of age.
• Subjects must have an advanced hematologic malignancy including:

Phase 1/ Dose escalation:

• Diagnosis of acute myelogenous leukemia (AML) according to World Health Organization (WHO) criteria;
• Disease refractory or relapsed (defined as the reappearance of > 5% blasts in the bone marrow).
• Untreated AML, greater than or equal to 60 years of age and are not candidates for standard therapy due to age, performance status, and/or adverse risk factors, according to the treating physician and with approval of the Medical Monitor;
• Diagnosis of Myelodysplastic syndrome (MDS) according to WHO classification with refractory anemia with excess blasts (RAEB-1 or RAEB-2), or considered high-risk by the Revised International Prognostic Scoring System (IPSS-R), that is recurrent or refractory, or the subject is intolerant to established therapy known to provide clinical benefit for their condition (i.e., subjects must not be candidates for regimens known to provide clinical benefit), according to the treating physician and with approval of the Medical Monitor.

Phase 1/Part 1 Expansion:

Arm 1: Relapsed or refractory AML and age greater than or equal to 60 years or any subject with AML regardless of age who has relapsed following a bone marrow transplant (BMT).

Arm 2: Relapsed or refractory AML and age 30,000/μL as well as prior to enrollment).

• Subjects who received a small molecule investigational agent 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).
• Subjects with 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 left ventricular ejection fraction (LVEF) 180 mmHg or diastolic BP > 100 mmHg) at screening are excluded. Subjects requiring 2 or more medications to control hypertension are eligible with Medical Monitor approval.
• Subjects with known unstable or uncontrolled angina pectoris.
• Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
• Subjects with heart-rate corrected QT (QTc) interval ≥ 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening.
• Subjects taking medications that are known to prolong the QT interval unless they can be transferred to other medications within ≥ 5 half-lives prior to dosing.
• Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
• 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.
• Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.
• Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia.
• Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
• In the Phase 2 portion of the trial only, subjects who have previously received treatment with an inhibitor of Isocitrate dehydrogenase ( IDH).