Selumetinib Sulfate in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer With KRAS G12R Mutations

Inclusion Criteria:

* Patients must have histologically confirmed locally advanced or metastatic pancreas cancer
* Patients must have received at least 6 months fluorouracil (5-FU)- or gemcitabine-based treatments for pancreas cancer (fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin \[FOLFIRINOX\], fluorouracil, leucovorin calcium and oxaliplatin \[FOLFOX\], 5-FU+ nal-IRI \[MM-398; nanoliposomal irinotecan\], or 5-FU \[including capecitabine\], gemcitabine-based gemcitabine plus abraxane, gemcitabine monotherapy among others)
* Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
* Patients must have Clinical Laboratory Improvement Act (CLIA) confirmed somatic Kirsten rat sarcoma (KRAS) G12R mutation as determined by sequence analysis of matched normal deoxyribonucleic acid (DNA) from any specimen obtained from the individual; patients must provide tumor sample for KRAS analysis or be willing to undergo mandatory screening biopsy
* Patients must not have had chemotherapy, molecular therapy with erlotinib, radiation therapy, or experimental biological or molecular therapy for at least 4 weeks prior to starting study medication; patients who received FOLFIRINOX must be 6 weeks from the last administration of therapy; patients must have recovered from any acute toxicity related to prior therapy or surgery, to a grade 1 or less unless specified
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 or Karnofsky \>= 70%
* Leukocytes \>= 3,000/mcL
* Absolute neutrophil count \>= 1,500/mcL
* Platelets \>= 75,000/mcL
* Hemoglobin (Hgb) \>= 9.0 g/dL
* Total bilirubin within normal institutional limits
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \< 3 x institutional upper limit of normal
* Creatinine =\< institutional upper limit of normal OR
* Creatinine clearance \> 60 mL/min/1.73 m\^2 by either Cockcroft-Gault formula or 24-hour urine collection analysis
* Patients must be willing to return to the clinic for follow-up visits
* Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 weeks after dosing with selumetinib sulfate (AZD6244) ceases; women of child-bearing potential must have a negative pregnancy test within 14 days prior to study treatment; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform her treating physician immediately; please note that the AZD6244 manufacturer recommends that adequate contraception for male patients should be used for 12 weeks post-last dose due to sperm life cycle; NOTE: breastfeeding should be discontinued if the mother is treated with selumetinib
* Ability to understand and the willingness to sign a written informed consent document or patients with Impaired Decision Making Capacity (IDMC) if they are represented by a Legally Authorized Representative (LAR)
* Patient must be able to reliably swallow oral medications

Exclusion Criteria:

* Patients who have received prior treatment with tyrosine kinase inhibitors (e.g. erlotinib), or anti-Epidermal growth factor receptor (EGFR) agents (e.g. cetuximab, panitumumab)
* Patients currently receiving any medication known to induce central serous chorioretinopathy which in the opinion of the principal investigator, would make the administration of study drug hazardous
* Patients with active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
* Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
* Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events
* Patients who are receiving any other investigational agents
* Patients with known brain metastases should be excluded from this clinical trial; no additional workup is needed to exclude brain metastases if the patient is asymptomatic or has no history of brain metastases
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to Selumetinib (AZD6244) or other agents used in study
* Previous Mitogen-activated protein kinase kinase (MEK), RAS, or Rapidly Accelerated Fibrosarcoma (RAF) inhibitor use
* Patients with the following cardiac conditions are excluded:

  * Uncontrolled hypertension (blood pressure \[BP\] of \>= 150/95 despite medical support/management)
  * Acute coronary syndrome within 6 months prior to starting treatment
  * Uncontrolled angina - Canadian Cardiovascular Society grade II-IV despite medical support/management
  * Heart failure New York Heart Association (NYHA) class II or above
  * Prior or current cardiomyopathy (within 6 months) including but not limited to the following:

    * Known hypertrophic cardiomyopathy
    * Known arrhythmogenic right ventricular cardiomyopathy
    * Abnormal ejection fraction (echocardiogram \[ECHO\]) =\< 53% (if a range is given then the upper value of the range will be used) or cardiac magnetic resonance imaging (MRI)
    * Previous moderate or severe impairment of left ventricular systolic function (left ventricular ejection fraction \[LVEF\] \< 45% on echocardiography or equivalent on multi-gated acquisition scan \[MUGA\]) even if full recovery has occurred; echocardiogram (Echo) and additional cardiac studies not indicated unless clinically symptomatic or patient has significant cardiac history
    * Severe valvular heart disease
    * Atrial fibrillation with a ventricular rate \> 100 beats per minute (bpm) on electrocardiogram (ECG) at rest
    * Fridericia's corrected QT interval (QTcF) \>= 450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) are excluded; the use of medication(s) that can prolong QTc interval is prohibited while treated on this study
* Patients with known ophthalmologic conditions, such as:

  * Current or past history of central serous retinopathy
  * Current or past history of retinal vein occlusion
  * Known intraocular pressure (IOP) \> 21 mmHg (or upper limit of normal \[ULN\] adjusted by age) or uncontrolled glaucoma (irrespective of IOP); patients with controlled glaucoma and increased IOP who do not have meaningful vision (light perception only or no light perception) may be eligible after discussion with the study chair
  * Subjects with any other significant abnormality on ophthalmic examination (performed by an ophthalmologist) should be discussed with the study chair for potential eligibility
  * Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor or strabismus) or long-standing orbito-temporal plexiform neurofibroma (PN) (such as visual loss, strabismus) will NOT be considered a significant abnormality for the purposes of the study
* Patients with refractory nausea and vomiting, chronic gastrointestinal (GI) diseases (e.g., inflammatory bowel disease) or significant bowel resection
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; HIV-positive patients not on antiviral therapy with undetectable viral loads and cluster of differentiation 4 (CD4) counts \> 300, and after confirmation of eligibility after discussing with the study chair are eligible