Gemcitabine, Nab-paclitaxel and KPT-330 in Advanced Pancreatic Cancer

Primary Objectives:

• Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nabpaclitaxel and selinexor for untreated metastatic pancreatic cancer [COMPLETED]
• Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel and selinexor [COMPLETED]
• Phase II: To test whether the combination of gemcitabine and selinexor improves the median overall survival of patients with metastatic pancreatic cancer who have failed frontline non-gemcitabine containing regimens beyond 5.6 months (median overall survival of patient receiving gemcitabine only based on historical data.

Secondary Objectives:

• To determine objective response rate to the combination of gemcitabine and selinexor using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
• To assess safety of selinexor in combination with gemcitabine in phase II portion of the study
• To determine progression free survival (PFS) in patients treated with gemcitabine and selinexor
• To determine the influence of selinexor and gemcitabine on the nuclear expression and localization of tumor suppressor gene proteins.

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