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

Phase 1

Active, not recruiting

• Conditions: Colorectal Cancer
• Interventions: Biological: bevacizumab; Drug: FOLFOX regimen; Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Drug: ursodiol; Genetic: RNA analysis; Genetic: gene expression analysis; Genetic: polymerase chain reaction; Genetic: western blotting; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: positron emission tomography (PET)

• Registration Number: NCT00873275
• Lead Sponsor: City of Hope Medical Center

Brief 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.

Study Timeline

• Study Start: 2009-03-11
• Study First Submitted: 2009-03-31
• Study First Submitted QC: 2009-03-31
• Study First Posted: 2009-04-01
• Primary Completion: 2012-09-25
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-02
• Last Update Posted: 2024-12-04
• Study Completion: 2025-06-15

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 11

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (ursodiol, combination chemotherapy, bevacizumab)	leucovorin calcium	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	RNA analysis	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	western blotting	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	bevacizumab	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	FOLFOX regimen	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	positron emission tomography (PET)	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	polymerase chain reaction	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	immunohistochemistry staining method	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	laboratory biomarker analysis	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	pharmacological study	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	gene expression analysis	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	fluorouracil	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	oxaliplatin	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.
Treatment (ursodiol, combination chemotherapy, bevacizumab)	ursodiol	Patients receive oral ursodiol twice daily on days 1-28 (days -6 to 28 of course 1), leucovorin calcium 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.

Primary Outcome Measures

Name	Time	Method
Pharmacokinetics of ursodiol	8 days after start of treatment during course 1
Survival	2 years after treatment
Time to failure	2 years after treatment
Maximum-tolerated dose of ursodiol	28 days from the start of treatment
Toxicities as assessed by NCI CTCAE 3.0	28 days after the last cycle of treatment

Trial Locations

Locations (1)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States