Enasidenib in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia With an IDH2 Gene Mutation

PRIMARY OBJECTIVES:

I. Evaluate the effect of IDH2 inhibition following conventional high dose salvage
chemotherapy with detectable IDH2 mutations on event free survival (EFS) in patients with
relapsed/refractory acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

I. Evaluate the effect of IDH2 inhibitor maintenance therapy following intensive salvage
therapy: i.e., rate of hematocrit (HCT), duration of maintenance therapy and overall survival
in patients with IDH2 mutant relapsed/refractory AML.

EXPLORATORY OBJECTIVES:

I. Evaluate the changes in IDH2 mutational variant allelic frequency and deoxyribonucleic
acid (DNA) methylation signature while on enasidenib therapy.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I: Patients receive enasidenib orally (PO) once daily (QD). Treatment repeats every 28
days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
Patients then undergo a hematopoietic cell transplantation (HCT) 7-14 days after treatment.
Within 30-100 days following the transplant, patients receive enasidenib QD. Treatment
repeats every 28 days for 24 cycles in the absence of disease progression or unacceptable
toxicity.

COHORT II: Patients receive enasidenib PO QD. Treatment repeats every 28 days in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 6 months and then yearly for
5 years.

Inclusion Criteria:

- Confirmed diagnosis of AML harboring a mutation in IDH2 relapsed or refractory to
first line cytarabine/anthracycline induction chemotherapy, failed to respond to or
relapsed following at least 2 cycles of hypomethylating agent (azacitidine,
decitabine, sgi-110)

- First relapse defined as untreated hematologic relapse (according to
International Working Group criteria) after one line of intensive regimen for AML
including at least one cytarabine containing induction block with a total dose no
less than 700 mg/m^2 per cycle and 3 days of an anthracycline that induced a
complete remission (CR)/complete remission with incomplete hematologic recovery
(CRi)/complete remission with incomplete platelet recovery (CRp). Subjects are
allowed to receive induction, consolidation, transplant and/or maintenance
therapy prior to achieving their first CR/CRi/CRp

- Refractory to induction therapy is defined as never achieving CR, CRi or CRp
(according to International Working Group criteria) after one line of intensive
regimen for AML (reinduction, consolidation and/or transplant allowed) including
at least one cytarabine containing induction block with a total dose no less than
700 mg/m^2 per cycle and 3 days of an anthracycline

- Subjects considered eligible for intensive chemotherapy

- Subjects had received a first salvage within the last 60 days (day 15 to 60 following
most recent cytarabine-based standard salvage number [#] 1 therapy) who achieved
either > 50% reduction in blast percentage from the pre-treatment bone marrow OR < 20%
cellularity with any blast percentage AND < 5% peripheral blood blasts

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2

- Normal total blood serum bilirubin with the exception of elevation due to Gilbert?s
disease (within 72 hours of enrollment)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.0 x upper
limit of normal (ULN) (within 72 hours of enrollment)

- Adequate renal function within 72 hours of enrollment, defined as blood creatinine =<
1.5 x ULN

- Women of childbearing potential must have a negative serum or urine pregnancy test
within 72 hours prior to enrollment and either commit to continued abstinence from
heterosexual intercourse or begin one acceptable method of birth control pills or
barrier contraception. Should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately

- Men must use a latex condom during any sexual contact with women of childbearing
potential

- Willing to adhere to protocol specific requirements

- Clinically significant toxic effects of prior therapy (except hydroxyurea) resolved to
grade =< 1 before the start of study

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Acute promyelocytic leukemia (APL)

- Subject has or is suspected of having central nervous system (CNS) leukemia.
Evaluation of cerebrospinal fluid is only required if CNS involvement by leukemia is
suspected during screening

- Clinically active or unstable graft-versus-host disease (GVHD) requiring treatment
that precludes administration of chemotherapy as defined in this protocol

- Prior anti-leukemia therapy within 5 x the half-life for other investigational agents
and consolidation chemotherapy within last 14 days

- Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e.,
control of white blood count [WBC]) are allowed but should be discontinued at
least 24 hours prior to enrollment. Other agents used strictly with palliative
intent might be allowed during this period after discussing with principal
investigator

- Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic
steatohepatitis, sclerosing cholangitis)

- Subject is known seropositive or active infection with human immunodeficiency virus
(HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

- Subject has active uncontrolled systemic fungal, bacterial, or viral infection
(defined as ongoing signs/symptoms related to the infection without improvement
despite appropriate antibiotics, antiviral therapy, and/or other treatment)

- Pregnant or nursing female participants

- Subjects of childbearing potential not willing to use adequate contraception

- Subject has significant active cardiac disease within 6 months prior to the start of
study treatment, including New York Heart Association (NYHA) class III or IV
congestive heart failure; acute coronary syndrome (ACS); and/or stroke; or left
ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan obtained within 28 days prior to the start of study treatment

- Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions
that in the opinion of the investigator may impair the participation in the study or
the evaluation of safety and/or efficacy

- Subject has immediately life-threatening, severe complications of leukemia such as
uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated
intravascular coagulation

- Subject is known to have dysphagia, short-gut syndrome, gastroparesis, or other
conditions that limit the ingestion or gastrointestinal absorption of drugs
administered orally

- Subjects has uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg or
diastolic BP > 90 mmHg)

- Subject has known (or suspected to have) hypersensitivity to any of the components of
study treatment

- Subject has corrected QT (QTc) interval (i.e., Fridericia?s correction [QTcF]) >= 450
ms 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

- Subject is taking the following sensitive CYP substrate medications that have a narrow
therapeutic range are excluded from the study unless the subject can be transferred to
other medications at least 5 half-lives prior to the start of study treatment:
phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline, and
tizanidine (CYP1A2)

- Subject who is taking the breast cancer resistance protein (BCRP)
transporter-sensitive substrate (i.e., rosuvastatin) should be excluded from the study
unless the subject can be transferred to other medications at least 5 half-lives prior
to the start of study treatment

- Subject has prior history of malignancy, other than myelodysplastic syndrome (MDS),
myeloproliferative neoplasm (MPN) or AML. However, subjects with the following
history/concurrent conditions are allowed:

- Basal or squamous cell carcinoma of the skin

- Carcinoma in situ of the cervix

- Carcinoma in situ of the breast

- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
node, metastasis clinical staging system)

- Concurrent participation in another therapeutic clinical trial

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug