Trametinib and Hydroxychloroquine in Treating Patients With Pancreatic Cancer

Inclusion Criteria:

* Male or female subject aged ≥ 18 years.
* Subject with histologically confirmed metastatic or locally advanced, unresectable pancreatic carcinoma
* Subject is willing to provide a baseline biopsy.
* EXPANSION COHORT ONLY: Subject must have progressed during or after two standard of care lines of treatment or refused standard of care options.
* Subject must have computed tomography (CT) measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Subject must be able and willing to undergo disease assessment while on study and afterwards, if removed for reason other than progression
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
* Adequate organ function as defined as:

  * Hematologic:

    * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
    * Platelet count \>= 100 x 10\^9/L
    * Hemoglobin \>= 9 g/dL
  * Hepatic:

    * Total bilirubin level =\< 1.5 x the upper limit of normal (ULN) range
    * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =\< 3 x ULN. Patients with liver metastases will be allowed to enroll with AST and ALT levels =\< 5 x ULN
  * Renal:

    * Estimated creatinine clearance \>= 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
* Negative serum or urine pregnancy test at screening for women of childbearing potential
* Highly effective contraception for both male and female subjects throughout the study and for at least 4 months after last study treatment administration
* Recovery to baseline or =\< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
* Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

Exclusion Criteria:

* Subject who have received systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy within 2 weeks or within 5 half-lives of the investigational therapy prior to starting study treatment, whichever is shorter.
* Subject who have received radiotherapy within 2 weeks prior to the first dose of study treatment. Localized radiation therapy for the treatment of symptomatic bone metastasis is allowed during that timeframe
* Subjects who have undergone major surgery =\< 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
* Patients with multiple primary malignancies may be enrolled if non-pancreatic ductal adenocarcinoma (PDAC) tumor(s) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by treating investigator and do not require active treatment
* Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
* History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
* History of active major bleeding.
* Patients whom thromboembolic prophylaxis is medically contraindicated per the treating investigator's assessment.
* Current evidence of uncontrolled, significant intercurrent illness including, but not limited to, the following conditions:

  * Cardiovascular disorders:

    * Congestive heart failure New York Heart Association class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
    * Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 3 months before first dose. The presence of an asymptomatic portal vein thrombosis will not preclude study participation.
  * History of glucose-6-phosphate dehydrogenase (G6PD) deficiency
  * History of seizures
  * Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. Muscular activities, such as strenuous exercise, that can result in significant increases in plasma creatine kinase (CK) levels should be avoided while on study treatment
  * Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  * Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the principal investigator \[PI\] may impair absorption of study drugs)
  * Any other condition that would, in the Investigator?s judgment, contraindicate the patient?s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication.(patients may not receive drug through a feeding tube), social/ psychological issues, etc
* Screening corrected QT interval by Fridericia (QTcF) \> 500 msec
* Known human immunodeficiency virus (HIV), unless patient is on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Known chronic hepatitis B virus, unless hepatitis B virus (HBV) viral load is undetectable
* Known history of hepatitis C virus (HCV) infection, unless treated and cured; for patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
* Sexually active males who are not willing to use a condom during intercourse while taking the drug and for 4 months after stopping treatment. A condom is also required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid
* Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer institute \[NCI\] CTCAE v5.0 grade \>= 3)