Brief Summary: This pilot phase I trial studies the side effects and best dose of CPI-613 when given together with fluorouracil in treating patients with colorectal cancer that has spread to other parts of the body and cannot be removed by surgery. CPI-613 may kill tumor cells by turning off their mitochondria. Mitochondria are used by tumor cells to produce energy and are the building blocks needed to make more tumor cells. By shutting off these mitochondria, CPI-613 deprives the tumor cells of energy and other supplies that they need to survive and grow in the body. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CPI-613 with fluorouracil may kill more tumor cells.

Detailed Description: PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis\[benzylthio\]octanoic acid), when used in combination with 5-FU (fluorouracil), in patients with non-resectable metastatic colorectal cancer who have failed FOLFOX (leucovorin calcium, fluorouracil and oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and, if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, then a epidermal growth factor receptor (EGFR) inhibitor-based regimen. SECONDARY OBJECTIVES: I. To assess the pharmacokinetic (PK), safety and efficacy of various doses of CPI-613, when used in combination with 5-FU, in patients with non-resectable metastatic colorectal cancer. OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid. Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4 and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 2 months for 3 years.