MEK Inhibitor MEK162 in Combination With Leucovorin Calcium, Fluorouracil, and Oxaliplatin in Treating Patients With Advanced Metastatic Colorectal Cancer

Inclusion Criteria:

* Patients with pathologically confirmed colon or rectal cancer who have received and progressed or failed following a fluoropyrimidine, irinotecan, and oxaliplatin based chemotherapy regimens will be eligible for this study; patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild type tumor should have progressed or failed following cetuximab or panitumumab based chemotherapy; prior bevacizumab or regorafenib exposure is not mandated on this study as some patients are deemed poor candidates for anti-angiogenesis therapy and never receive these agents
* Patients should have measurable disease defined as a minimum of one tumor measuring \>= 10 mm on computed tomography (CT) scans
* Signed written informed consent
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
* Hemoglobin (Hgb) \>= 9 g/dL without transfusions
* Platelets (PLT) \>= 100 x 10\^9/L without transfusions
* Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =\< 2.5 × upper limit of normal (ULN); patient with liver metastases =\< 5 ×ULN
* Total bilirubin =\< ULN
* Creatinine =\< 1.5 mg/dL
* Left ventricular ejection fraction (LVEF) \>= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
* Corrected QT (QTc) interval =\< 480 ms
* Able to take oral medications
* Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up)
* Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) performed locally within 72 hrs prior to first dose
* Eastern Cooperative Oncology Group (ECOG) performance status =\< 1

Exclusion Criteria:

* 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)
* Patients who have had chemotherapy, biologic, targeted, or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from grade 2 and above adverse events due to agents administered more than 4 weeks earlier (with the exception of alopecia or neuropathy)
* History of retinal degenerative disease
* History of Gilbert's syndrome
* Previous or concurrent malignancy with the following exceptions:

  * Adequately treated skin basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
  * In situ carcinoma of the cervix, treated curatively and without evidence of recurrence
  * A primary malignancy which has been completely resected and in complete remission for \>= 1 years
* Prior therapy with a MEK- inhibitor
* History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting \[CABG\], coronary angioplasty, or stenting) \< 6 months prior to screening
* Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: symptomatic chronic heart failure; evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities \< 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
* Uncontrolled arterial hypertension despite appropriate medical therapy (defined as systolic blood pressure \> 160 or diastolic blood pressure \> 100)
* Known positive serology for human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection
* Patients who have neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
* Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment; NB: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment
* Impairment of gastrointestinal function or gastrointestinal disease (e.g., active ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
* 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, social/ psychological issues, etc.
* Patients who have undergone major surgery =\< 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
* Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test
* Women of child-bearing potential unless they are using highly effective methods of contraception throughout the study and for 60 days after study drug discontinuation
* Sexually active males unless they use a condom during intercourse while taking the drug and for 60 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men
* 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
* Current grade 3 or higher neuropathy
* Use of other investigational drugs
* Known hypersensitivity to any components of the study drugs
* Prior intolerance to fluorouracil (5-FU) or oxaliplatin, excluding severe neuropathy that reversed to grade 2 or less