Enasidenib and Azacitidine in Treating Patients With Recurrent or Refractory Acute Myeloid Leukemia and IDH2 Gene Mutation

PRIMARY OBJECTIVES:

I. To determine the clinical activity of enasidenib mesylate (AG221, IDHIFA) in combination
with azacitidine (AZA) for patients with relapsed/refractory acute myeloid leukemia is
measured by overall response rate (ORR).

SECONDARY OBJECTIVES:

I. To determine duration of response, event-free survival (EFS), and overall survival (OS).

II. To determine the safety of enasidenib in combination with azacitidine in patients with
relapsed/refractory acute myeloid leukemia (AML).

EXPLORATORY OBJECTIVES:

I. To evaluate occurrence of minimal residual disease (MRD) negative status by IDH2 mutation
analysis and flow cytometry.

II. To investigate possible relationships between baseline protein and gene expression
signatures and mutation profile and clinical response to the combination.

III. To evaluate the incidence and characteristics of IDH-inhibitor related differentiation
syndrome (IDH-DS) with combination therapy.

OUTLINE:

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30 minutes on
days 1-7 and enasidenib mesylate orally (PO) once daily (QD) beginning on day 1. Courses
repeat every 4-6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3-6
months for up to 5 years.

Inclusion Criteria:

- Patients with AML or biphenotypic or bilineage leukemia (including a myeloid
component) who have failed prior therapy. Patients with isolated extramedullary AML
are eligible. The World Health Organization (WHO) classification will be used for AML

- Elderly (> 60 years old) patients with newly diagnosed AML not eligible for intensive
chemotherapy are also eligible

- AML patients with prior history of myelodysplastic syndrome (MDS) or chronic
myelomonocytic leukemia (CMML) regardless of prior therapy received, are eligible at
the time of diagnosis of AML

- Subjects must have documented IDH2 gene mutation

- Eastern Cooperative Oncology Group (ECOG) performance status =< 3

- Adequate renal function including creatinine < 2 unless related to the disease

- Total bilirubin < 2 x upper limit of normal (ULN) unless increase is due to Gilbert's
disease or leukemic involvement

- Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN
unless considered due to leukemic involvement

- Provision of written informed consent

- Oral hydroxyurea and/or cytarabine (up to 2 g/m2) for patients with rapidly
proliferative disease is allowed before the start of study therapy, as needed, for
clinical benefit and after discussion with the principal investigator (PI). Concurrent
therapy for central nervous system (CNS) prophylaxis or continuation of therapy for
controlled CNS disease is permitted

- Females must be surgically or biologically sterile or postmenopausal (amenorrheic for
at least 12 months) or if of childbearing potential, must have a negative serum or
urine pregnancy test within 72 hours before the start of the treatment

- Women of childbearing potential must agree to use an adequate method of contraception
during the study and until 3 months after the last treatment. Males must be surgically
or biologically sterile or agree to use an adequate method of contraception during the
study until 3 months after the last treatment

Exclusion Criteria:

- Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia
(French-American-British [FAB] class M3-AML)

- Active and uncontrolled comorbidities including active uncontrolled infection,
uncontrolled hypertension despite adequate medical therapy, active and uncontrolled
congestive heart failure New York Heart Association (NYHA) class III/IV, clinically
significant and uncontrolled arrhythmia as judged by the treating physician

- Any other medical, psychological, or social condition that may interfere with study
participation or compliance, or compromise patient safety in the opinion of the
investigator

- Pregnant or breastfeeding