NCT00873275

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

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

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 11 (actual)
• Sponsor: City of Hope Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

RATIONALE: Drugs used in chemotherapy, such as ursodiol, oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Giving ursodiol together with leucovorin calcium, fluorouracil, oxaliplatin, and bevacizumab may be an effective treatment for colorectal cancer. PURPOSE: This phase I trial is studying the side effects and best dose of ursodiol when given together with combination chemotherapy and bevacizumab in treating patients with stage IV colorectal cancer.

Detailed description

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.

Conditions

• Colorectal Cancer

Interventions

Type	Name	Description
BIOLOGICAL	bevacizumab	5mg/kg IV day 1 and 15 of each 28 day course of treatment
DRUG	FOLFOX regimen	Leucovorin, 5-FU and Oxaliplatin
DRUG	fluorouracil	400 mg/m2 IV bolus immediately following leucovorin on days 1 and 15 of a 28 day course of treatment. Then 2.4 gm/m2 IV continuous infusion over 46 hours immediately following bolus dose on days 1 and 2 and 15 and 16 of a 28 day course of treatment
DRUG	leucovorin calcium	400 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.
DRUG	oxaliplatin	85 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.
DRUG	ursodiol	Dose escalation in cohorts (3 patients/cohort) from an initial dose of 125 mg PO BID through 625 mgs PO BID beginning on Day -6 from infusion of bevacizumab and FOLFOX continuing for the duration of the treatment.
GENETIC	RNA analysis	Analysis on discard tissues
GENETIC	gene expression analysis	Determined in normal and malignant tissues in patients who undergo surgical resection after treatment on this trial
GENETIC	polymerase chain reaction	Analysis on discard tissues
GENETIC	western blotting	Determined on blood collected at Day -6, Day 0 and Day 7 (1 week after the first cycle of chemotherapy) from treatment and at the end of treatment
OTHER	immunohistochemistry staining method	Performed on tumor blocks from the primary and the metastases from the patients on study
OTHER	laboratory biomarker analysis	Performed on blood collected at Day -6, Day 0 and Day 7 (1 week after the first cycle of chemotherapy) from treatment and at the end of treatment
OTHER	pharmacological study	Day 0, day 7 before treatment, 1/2 hour after the start of treatment, 1, 2, 3, 4, and 8 hours after the start of treatment.
PROCEDURE	positron emission tomography (PET)	Patients will undergo PET scan imaging as part of their original staging or at baseline. If the PET scan was more than 2 weeks prior to Day 0 from study treatment, there will be a PET scan at Day 0. In any case there will be a PET scan when the patient completes treatment.

Timeline

• Start date: 2009-03-11
• Primary completion: 2012-09-25
• Completion: 2025-02-26
• First posted: 2009-04-01
• Last updated: 2025-06-22

Locations

1 site across 1 country: United States