Selinexor, Gemcitabine Hydrochloride, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of gemcitabine (gemcitabine
hydrochloride), nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) and
KPT-330 (selinexor) for untreated metastatic pancreatic cancer.

II. To determine the safety profile of gemcitabine, nab-paclitaxel and KPT-330. III. To test
whether gemcitabine, nab-paclitaxel and KPT-330 improves overall survival as compared to
historical controls comprising of patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. To determine objective response rate to combination of gemcitabine, nab-paclitaxel and
KPT-330 using Response Evaluation Criteria In Solid Tumors (RECIST) criteria.

II. To confirm safety of KPT-330 at the RP2D in combination with gemcitabine and
nab-paclitaxel in phase II arm of the study.

III. To determine progression free survival (PFS) in phase II cohort treated with
gemcitabine, nab-paclitaxel and KPT-330.

IV. To determine the influence of KP-330, gemcitabine and nab-paclitaxel on the nuclear
expression and localization of tumor suppressor gene proteins.

OUTLINE: This is a phase Ib, dose-escalation study of selinexor followed by phase II.

PHASE IB:

Patients receive gemcitabine hydrochloride intravenously (IV) and paclitaxel
albumin-stabilized nanoparticle formulation IV once weekly (Mondays) for 3 weeks. Patients
also receive selinexor orally (PO) twice weekly (Mondays and Wednesdays) for 4 weeks.
Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

PHASE II: The first 14 patients with liver metastases are randomized to 1 of 2 treatment
groups. Remaining patients are assigned to Group II.

GROUP I: Patients receive gemcitabine hydrochloride IV and paclitaxel albumin-stabilized
nanoparticle formulation IV as in Phase Ib. Beginning day 3 of course 1, patients also
receive selinexor PO twice weekly (Mondays and Wednesdays) for 4 weeks. Courses repeat every
4 weeks in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive gemcitabine hydrochloride, paclitaxel albumin-stabilized
nanoparticle formulation, and selinexor as in Phase Ib.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- Written informed consent in accordance with federal, local, and institutional
guidelines

- Patients with metastatic pancreatic adenocarcinoma not treated with chemotherapy for
metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Bilirubin < 2 times the upper limit of normal (ULN) (except patients with Gilbert's
syndrome who must have a total bilirubin of < 3 times ULN)

- Alanine aminotransferase (ALT) < 2.5 times ULN

- Serum creatinine =< 1.5 mg/dL

- Serum albumin >= 3.0 g/dL

- 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

- Patients with history of previously treated malignancies who have no evidence of
disease for last five years are allowed to participate

Exclusion Criteria:

- Patients who are pregnant or lactating

- Radiation, chemotherapy, or immunotherapy or any other anticancer therapy =< 3 weeks
prior to cycle 1 day 1; mitomycin C or radio-immunotherapy 6 weeks prior to cycle 1
day 1

- Major surgery within four weeks before cycle 1 day 1

- Unstable cardiovascular function:

- Symptomatic ischemia, or

- Uncontrolled clinically significant conduction abnormalities (e.g.: ventricular
tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular [AV]
block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch
block [RBBB] will not be excluded), or

- Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3,
or

- Myocardial infarction (MI) within 3 months of cycle 1 day 1 dose

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

- Known to be HIV seropositive who are on anti-HIV drugs because of the unknown
interactions between these drugs and the study agents

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

- Grade >= 2 peripheral neuropathy within 14 days prior to cycle 1 day 1

- History of seizures, movement disorders or cerebrovascular accident within the past 5
years prior to cycle 1 day 1

- Patients with muscular degeneration, uncontrolled glaucoma, or markedly decreased
visual acuity based on physician's assessment

- Serious psychiatric or medical conditions that could interfere with treatment

- Participation in an investigational anti-cancer study within 3 weeks prior to cycle 1
day 1

- Concurrent therapy with approved or investigational anticancer therapeutic

- Presence of clinically significant ascites