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

This partially randomized phase Ib/II trial studies the side effects and best dose of selinexor when given together with gemcitabine and nab-paclitaxel, and to see how well they work in treating patients with pancreatic cancer that has spread to other parts of the body (metastatic). Drugs used in chemotherapy, such as selinexor, gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Primary Objectives:

1. Phase I: To determine the recommended phase 2 dose (RP2D) of gemcitabine, nabpaclitaxel and selinexor for untreated metastatic pancreatic cancer \[COMPLETED\]
2. Phase I: To determine the safety profile of gemcitabine, nab-paclitaxel and selinexor \[COMPLETED\]
3. 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:

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

Eligibility Criteria:
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