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

Phase 1
18 Years
Open (Enrolling)
Colorectal Cancer

Thank you

Trial Information

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



- 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.


- 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

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum-tolerated dose of ursodiol

Outcome Time Frame:

28 days from the start of treatment

Safety Issue:


Principal Investigator

Lily L. Lai, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Institutional Review Board

Study ID:




Start Date:

November 2008

Completion Date:

Related Keywords:

  • Colorectal Cancer
  • stage IV colon cancer
  • stage IV rectal cancer
  • recurrent colon cancer
  • recurrent rectal cancer
  • adenocarcinoma of the colon
  • adenocarcinoma of the rectum
  • Colorectal Neoplasms



City of Hope Medical Center Duarte, California  91010