Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of selinexor in combination with mitoxantrone
hydrochloride, etoposide, cytarabine (MEC) or oral etoposide (respective cohorts are
independent of each other) in patients with relapsed or refractory acute myeloid leukemia
(AML).

II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting
toxicities (DLT) of these combinations.

III. To determine the recommended phase 2 dose (RP2D) of these combinations.

SECONDARY OBJECTIVES:

I. To determine the rate and duration of complete remission (CR) ± hematologic recovery of
selinexor plus MEC therapy in AML.

II. To determine the overall response rate (ORR). III. To define the rate of complete
remission (CR + CR with incomplete blood count recovery [CRi]) rate by the end of induction
therapy.

IV. Determine the disease-free survival for patients who reached CR/CRi within 1 year.

TERTIARY OBJECTIVES:

I. To conduct pharmacodynamic studies by measuring the effect of these chemotherapy
combinations on the inhibition of exportin 1 (XPO1).

II. To conduct pharmacokinetic sampling of selinexor and etoposide at limited time points to
assess drug metabolism, peak plasma levels and area under curve (AUC).

OUTLINE: This is a dose-escalation study of selinexor. Patients are assigned to 1 of 2
cohorts.

COHORT A (PATIENTS FIT FOR INTENSIVE THERAPY, AGE < 60): Patients receive mitoxantrone
hydrochloride intravenously (IV), etoposide IV, and cytarabine IV once daily (QD) on days 1-6
and selinexor orally (PO) on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course
(28 days). Further treatment is based on disease response. Patients achieving CR/CRi are
evaluated for stem cell transplant; patients who do not proceed to transplant may receive
selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.

COHORT B (PATIENTS UNFIT FOR INTENSIVE THERAPY, AGE ≥ 60): Patients receive etoposide PO QD
on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28
days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients
not achieving response after 4 courses discontinue treatment; patients achieving response may
receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue
selinexor as monotherapy at the discretion of the principal investigator.

After completion of study treatment, patients are followed up for at least 30 days.

Inclusion Criteria:

- Patients with relapsed or refractory AML; Cohort A patients must be < 60 years of age
and have failed at least one prior induction regimen for AML; Cohort B patients must
be ≥ 60 years of age, unfit for intensive therapy (physician opinion), and have failed
an induction regimen for AML. The maximum number of prior lines of induction for both
cohorts is 3

- Patients with secondary AML or therapy related disease (t-AML) are eligible

- If the patient has co-morbid medical illness, life expectancy attributed to this must
be greater than 6 months

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

- Total bilirubin < 2.0 mg/dL, except when patient is known to have Gilbert's Syndrome,
the total bilirubin can be ≤3.0 mg/dL.

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional upper limit of normal

- Creatinine (Cr) clearance > 50 mL/min by Modification of Diet in Renal Disease (MDRD)
calculation

- New York Heart Association (NYHA) congestive heart failure (CHF) class II or better

- Cardiac ejection fraction >= 50%

- Female patients of child-bearing potential must agree to use dual methods of
contraception and have a negative serum pregnancy test at screening, and male patients
must use an effective barrier method of contraception if sexually active with a female
of child-bearing potential; acceptable methods of contraception are condoms with
contraceptive foam, oral, implantable or injectable contraceptives, contraceptive
patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is
surgically sterilized or post-menopausal; for both male and female patients, effective
methods of contraception must be used throughout the study and for three months
following the last dose

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study

- Patients receiving any other investigational agents or patients that have received
other investigational agents within 14 days of enrollment

- Patients with active central nervous system (CNS) malignancy; asymptomatic small
lesions are not considered active; treated lesions may be considered inactive if they
are stable for at least 3 months; patients with malignant cells in their cerebrospinal
fluid (CSF) without CNS symptoms may be included

- Major surgery within 2 weeks before day 1

- Uncontrolled active infection; patients with infection requiring parenteral
antibiotics are eligible if the infection is controlled

- Patients with significantly diseased or obstructed gastrointestinal tract or
uncontrolled vomiting or diarrhea

- History of seizures, movement disorders or cerebrovascular accident within the past 3
years prior to cycle 1 day 1

- Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased
visual acuity

- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure (New York Heart Association [NYHA) class III or IV), unstable
angina pectoris, myocardial infarction within 6 months prior to enrollment, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities; prior to study entry, any
electrocardiogram (ECG) abnormality at screening has to be documented by the
investigator as not medically relevant

- Patients with serious medical or psychiatric illness likely to interfere with
participation in this clinical study

- Pregnant women or women who are breastfeeding are excluded from this study;
confirmation that the subject is not pregnant must be established by a negative serum
beta (β)-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during
screening; pregnancy testing is not required for post-menopausal or surgically
sterilized women

- Patients with advanced malignant solid tumors

- Patients whom, in the opinion of the investigators, are significantly below their
ideal body weight

- Patients who are not able to swallow capsules or tablets