Trial Information

Phase I Study of Ursodeoxycholic Acid (Ursodiol)in Combination With 5-Fluorouracil, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Metastatic 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.