A Study of Selinexor in Combination With Daunorubicin and Cytarabine for Untreated AML

Induction Therapy - Dose escalation of selinexor with Daunorubicin and cytarabine at fixed
doses.

Consolidation Phase - Patients who are in complete remission (CR) or complete remission with
incomplete count recovery (CRi) by day ≤70 and have recovered from any previous non-
hematologic toxicity to baseline or grade ≤1 by day ≤70 following induction chemotherapy may
go on to receive consolidation therapy for up to 2 cycles. The consolidation treatment phase
will include up to two courses of therapy (28 day cycles) as follows:

Daunorubicin 45mg/m^2/day (days 1-2) Cytarabine 100mg/m^2/day (continuous infusion on days
1-5) Selinexor same dose as induction (days 1,3,8,10) unless dose limiting toxicity (DLT)
dictates a dose reduction. Selinexor will be given 2 hours prior to daunorubicin on day 1.

A second cycle of consolidation therapy using the same doses as above will be administered,
at the investigators discretion, between 28 and 42 days following initiation of the first
consolidation treatment, after peripheral blood counts have recovered to CR, CRi levels, and
after recovery from any non-hematologic toxicity to baseline or grade ≤1. Dose escalation of
Selinexor will not occur during the consolidation phase.

Maintenance Phase - Patients who remain in CR, CRi after up to 2 cycles of consolidation and
are not eligible for allogeneic stem cell transplant will be eligible for the maintenance
phase of treatment after recovery from any previous non-hematologic toxicity to baseline or
grade ≤1. Maintenance therapy will consist of:

Selinexor at the same dose as induction on days 1 and 8 of a 21 day cycle. They will continue
for a maximum of 12 months.

Expansion Phase - Once the MTD has been established, there will be an expansion phase to
enroll an additional 13 subjects at the MTD to better characterize the safety profile and
tolerability.

Inclusion Criteria:

- Potential participants must have newly diagnosed, previously untreated acute myeloid
leukemia (AML) (excluding M3); Must have adverse-risk AML defined as poor-risk
karyotype (complex, monosomal or other known poor risk cytogenetic abnormality),
poor-risk mutations/fusion genes or known history of antecedent hematologic disorder,
or treatment related AML, or be ≥60 years of age; Cytogenetics, FISH or mutational
analysis confirming adverse risk features must have been done within 90 days prior to
enrollment.

- May not have undergone any prior therapy for their AML other than hydroxyurea.
However, if patients had an antecedent myelodysplastic syndrome (MDS), prior treatment
with a hypomethylating agent or any other therapy (with the exception of allogeneic
stem cell transplant) used to treat their MDS is allowed.

- Age ≥18 years

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Life expectancy of greater than 2 months

- Must have normal organ function

- Able and willing to adhere to the study visit schedule and other protocol requirements

- Baseline left ventricular ejection fraction (LVEF) ≥ 50%

- Women of child-bearing potential must have a negative serum or urine pregnancy test
with a sensitivity of at least 50 milli-international units per milliliter (mIU)mL)
within 10 days and again within 24 hours prior to beginning study treatment.
Participants of childbearing potential must practice recommended contraception. Should
a woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately. Breastfeeding mothers must agree
to discontinue nursing if the mother is treated with selinexor.

- Ability to understand and the willingness to sign a written informed consent document

- Able to swallow capsules and have no evidence of GI tract abnormality that would alter
the absorption of oral medications

- Prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x upper limit of
normal (ULN)

Exclusion Criteria:

- May not be receiving any other investigational agents

- Documented central nervous system (CNS) involvement of AML

- AML with favorable risk cytogenetic abnormalities including t(15;17), t(8;21) or
inv(16)

- Potential participants who are in the blast phase of chronic myeloid leukemia

- Major surgery within 2 weeks of first dose of study drug; must have recovered from the
effects of any surgery performed greater than 2 weeks prior

- White blood cell (WBC) count ≥50,000 on hydroxyurea

- Predicted inability to tolerate standard induction chemotherapy with daunorubicin and
cytarabine

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- HIV-positive, receiving combination anti-retroviral therapy

- No other malignancies in addition to AML that are currently requiring treatment with
the exception of basal cell or squamous cell carcinoma of the skin, or carcinoma in
situ of the cervix or breast

- History of allogeneic stem cell transplant for MDS or any other antecedent hematologic
disorder.