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.

Inclusion criteria

• Patients with advanced, biopsy proven metastatic colorectal cancer
• Karnofsky Performance Status >= 80
• Prior therapy completed at least 3 weeks before protocol treatment initiation with recovery from any side-effects
• Serum albumin and prealbumin within normal limits
• Alanine aminotransferase (ALT) within 3 x upper limit of normal
• Alkaline phosphatase within 3 x upper limit of normal
• Serum bilirubin within normal limits
• Absolute neutrophil count >= 1500/ul
• Serum creatinine within 1.5 x upper limit of normal
• Ability to understand and sign an institutional review board (IRB) approved informed consent
• Ability to use appropriate contraception and no evidence of pregnancy in female patients of reproductive potential

Exclusion criteria

• Significant medical or psychiatric condition that would make treatment unsafe
• Use of systemic steroids use within 7 days from start of trial
• Nursing women
• Patients unable to comply with protocol related studies and follow up
• Weight loss of greater than 10% in the last 6 months