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

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of Selinexor (KPT‐330) in combination with
decitabine in patients with acute myeloid leukemia (AML).

II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting
toxicity (DLT) of this combination.

III. To determine the Recommended Phase 2 Dose (RP2D) of this combination.

SECONDARY OBJECTIVES:

I. To determine the overall response rate (ORR). II. To determine the rate and duration of
complete remission (CR) +/- hematological recovery of KPT‐330 plus decitabine in AML.

III. To conduct pharmacodynamic studies by measuring the effect of this chemotherapy
combination on the kinome, micronome and epigenome.

OUTLINE: This is a dose-escalation study of selinexor.

INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and
Selinexor orally (PO) on days 11, 13, 18, 20, 25 and 27. Treatment repeats every 31 days for
up to 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive decitabine IV over 1 hour on days 1-5 and Selinexor PO on days
6, 8, 13, 15, 20 and 22. Courses repeat every 31 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Patients with relapsed or refractory AML

- Newly diagnosed elderly AML patients (> 60 years) unfit for intensive chemotherapy
with cytarabine and anthracyclines are also eligible to this trial given that no
clinically beneficial therapy exists for these patients

- Patients with secondary AML or therapy related disease (t‐AML) are eligible; patients
who received decitabine or 5‐azacytidine as prior treatment for myelodysplastic
syndrome (MDS) or AML remain eligible; however, none of these agents is permitted
within 6 months of study entry

- 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

- 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 < 2.0 mg/d

- Glomerular filtration rate (GFR) > 50 mL/min

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

- 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

- Human immunodeficiency virus (HIV) infection without history of acquired immune
deficiency syndrome (AIDS) and sufficiently high cluster of differentiation (CD)4
cells (> 400/mm^3) and low HIV viral loads (< 30,000 copies/ml plasma) not requiring
anti‐HIV therapy are eligible

- Patients must have recovered from the toxicity of prior therapy to less than grade 2

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

- Patients with history of allergic reactions attributed to compounds of similar
chemical or biologic composition to decitabine that are not easily managed

- Major surgery within 2 weeks before day 1

- Uncontrolled active infection requiring parenteral antibiotics, antivirals, or
antifungals within one week prior to first dose

- Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C
virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)

- 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‐human chorionic gonadotropin (beta‐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 are excluded

- Patients with renal failure (GFR < 50 mL/min) are excluded

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