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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00873275
• Other study ID #: 08005
• Secondary ID: P30CA033572CHNMC
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: March 11, 2009
• Est. completion date: January 13, 2025

Study information

• Verified date: November 2023
• Source: City of Hope Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 11
• Est. completion date: January 13, 2025
• Est. primary completion date: September 25, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• bevacizumab
5mg/kg IV day 1 and 15 of each 28 day course of treatment

Drug:
• FOLFOX regimen
Leucovorin, 5-FU and Oxaliplatin
• 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
• leucovorin calcium
400 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.
• oxaliplatin
85 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.
• 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
• gene expression analysis
Determined in normal and malignant tissues in patients who undergo surgical resection after treatment on this trial
• polymerase chain reaction
Analysis on discard tissues
• 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
• 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
• 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.

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California

Sponsors (2)

Lead Sponsor	Collaborator
City of Hope Medical Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum-tolerated dose of ursodiol		28 days from the start of treatment
Primary	Toxicities as assessed by NCI CTCAE 3.0		28 days after the last cycle of treatment
Primary	Survival		2 years after treatment
Primary	Time to failure		2 years after treatment
Primary	Pharmacokinetics of ursodiol		8 days after start of treatment during course 1