Vorinostat, Fluorouracil, and Leucovorin Calcium in Treating Patients With Metastatic Colorectal Cancer That Has Not Responded to Previous Treatment

Inclusion * Patients must have histologically or cytologically confirmed colorectal adenocarcinoma that is metastatic and which has failed standard treatment or for which no standard treatment is available * Patients should have fluoropyrimidine-refractory disease; radiographic evidence of progression within 4 weeks from the last dose of a fluoropyrimidine-based regimen (at least 6 weeks of fluoropyrimidine-based treatment) * Patients should have received and progressed on (or proved to be intolerant to) oxaliplatin and irinotecan; progression within 6 months from oxaliplatin-based therapy or irinotecan-based therapy is acceptable for eligibility * Patients with KRAS wild-type or unknown KRAS status tumors should have progressed on or within 6 months from last cetuximab or panitumumab-based therapy; no prior cetuximab therapy is required for KRAS mutant tumors * ECOG performance status =\< 2 * Life expectancy \>= 12 weeks * Ability to understand and the willingness to sign a written informed consent document * Ability to swallow pills * Absolute neutrophil count \>= 1,500/uL * Platelets \>= 100,000/uL * Total bilirubin =\< institutional upper limit of normal * AST(SGOT)/ALT(SGPT) =\< 3 x institutional upper limit of normal in the absence of metastatic disease to the liver and =\< 5 x institutional upper limit of normal in the setting of metastatic disease to the liver * Creatinine =\< 1.5 x institutional upper limit of normal * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation * Males undergoing study treatment should also agree to adequate measures of contraception (partner contraception and use of condoms or abstinence, or vasectomy) Exclusion * Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from significant adverse events due to agents administered more than 3 weeks earlier * Patients may not be receiving any other investigational agents * Patients with known brain metastases should be excluded from this clinical trial * History of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in study * Greater than Grade 2 neuropathy as defined by CTCAE version 3.0 * 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 * Baseline EKG with QTc prolongation that is grade 2 or higher by CTCAE version 3.0 * Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat * Patients should not have taken valproic acid or other histone deacetylase inhibitors, for at least 4 weeks prior to enrollment * Patients with known HIV infection or known active viral hepatitis * Prior treatment with vorinostat * Other non-study medications known to increase the QTc interval