Phase I Study of Ursodeoxycholic Acid (Ursodiol)in Combination With 5-Fluorouracil, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Metastatic Colorectal Cancer
18 Years
N/A
Both
Colorectal Cancer
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.
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
Type of Study:
Interventional
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:
Yes
Principal Investigator
Lily L. Lai, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
City of Hope Medical Center
Authority:
United States: Institutional Review Board
Study ID:
08005
NCT ID:
NCT00873275
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
Name | Location |
|---|---|
| City of Hope Medical Center | Duarte, California 91010 |
