Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer

OBJECTIVES: Primary * To determine the active dose and/or maximum tolerated dose of ursodiol when given in combination with fluorouracil, leucovorin calcium, oxaliplatin (FOLFOX regimen), and bevacizumab in patients with metastatic colorectal cancer. * To determine the pharmacokinetics of ursodiol when given with this regimen. Secondary * To determine the systemic metabolic effects of ursodiol activation of nuclear receptor farnesoid X receptor (FXR) in glucose and lipid metabolism. * To develop assays to detect ursodiol activation of FXR. * To identify and evaluate potential serum biomarkers of FXR activation. * To determine genes regulated by activation of FXR at target tissues. OUTLINE: This is a dose-escalation study of ursodiol. Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium intravenously (IV) over 2 hours on days 1 and 15, fluorouracil IV over 46 hours on days 1-2 and 15-16, and oxaliplatin IV over 2 hours and bevacizumab IV over 30-90 minutes on days 1 and 15. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Blood sample is collected periodically for pharmacokinetic studies. Samples are also analyzed for the role of nuclear receptor farnesoid X receptor (FXR) in glucose uptake and metabolism using PET scan imaging, an oral glucose tolerance test, and HbA1c levels; the effects of FXR activation on lipid metabolism; and a marker for response to FXR activation via western blot. Available formalin-fixed paraffin-embedded tumor tissue blocks are analyzed for FXR expressing via IHC; expression of known FXR target genes via RNA analysis and real-time PCR; and expression of genes involved in glucose metabolism.