CPI-613 and Fluorouracil in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

Inclusion Criteria: * Histologically and cytologically confirmed metastatic colorectal adenocarcinoma (colon, rectal or colorectal cancer) that is not resectable * Have failed or have not tolerated FOLFOX, FOLFIRI and, if KRAS wild type, then a EGFR inhibitor-based regimen * Eastern Cooperative Oncology Group (ECOG) performance status being 0-2 * Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device \[IUD\], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation * Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists * At least 2 weeks must have elapsed from any prior surgery * Granulocyte count \>= 1500/mm\^3 * White blood cell (WBC) \>= 3500 cells/mm\^3 or \>= 3.5 bil/L * Platelet count \>= 100,000 cells/mm\^3 or \>= 100 bil/L * Absolute neutrophil count (ANC) \>= 1500 cells/mm\^3 or \>= 1.5 bil/L * Hemoglobin \>= 9 g/dL or \>= 90 g/L * Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 3 x upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x UNL (=\< 5 x UNL if liver metastases present) * Bilirubin =\< 1.5 x UNL * Serum creatinine =\< 1.5 mg/dL or 13 umol/L * International normalized ratio or INR must be =\< 1.5 unless on therapeutic blood thinners * No evidence of active infection and no serious infection within the past month * Mentally competent, ability to understand and willingness to sign the informed consent form * At least one measurable lesion as assessed by computed tomography (CT) scan using Response Evaluation Criteria in Solid Tumors (RECIST) criteria Exclusion Criteria: * Therapy with CPI-613 prior to participating in this trial * Known hypersensitivity to 5-FU injection, poor nutritional state, known dipyrimidine dehydrogenase deficiency, or taking sorivudine (such as Usevir, brovavir, etc.) * History of hypersensitivity to active or inactive excipients of any component of treatment * Previous radiotherapy for central nervous system metastases * Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication, within the past 2 weeks prior to initiation of treatment with study drugs * Serious medical illness that would potentially increase patients' risk for toxicity * Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease) * History of abdominal fistula or gastrointestinal perforation =\< 6 months prior to treatment with study drugs * Pregnant women, or women of child-bearing potential not using reliable means of contraception * Lactating females * Fertile men unwilling to practice contraceptive methods during the study period * Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients * Unwilling or unable to follow protocol requirements * Symptomatic heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction or symptomatic congestive heart failure * Patients with a history of myocardial infarction that is \< 3 months prior to registration * Evidence of active infection, or serious infection within the past month * Patients with known human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C * Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment; steroid use for management of refractory pain or for contrast induced allergy is allowed * Requirement for immediate palliative treatment of any kind including surgery * Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of the patient