Overview

This trial is active, not recruiting.

Condition colorectal cancer
Treatments bevacizumab, folfox regimen, fluorouracil, leucovorin calcium, oxaliplatin, ursodiol, rna analysis, gene expression analysis, polymerase chain reaction, western blotting, immunohistochemistry staining method, laboratory biomarker analysis, pharmacological study, positron emission tomography (pet)
Phase phase 1
Target VEGF
Sponsor City of Hope Medical Center
Collaborator National Cancer Institute (NCI)
Start date March 2009
End date September 2017
Trial size 30 participants
Trial identifier NCT00873275, 08005, CDR0000637521, CHNMC-08005, NCI-2010-00926, P30CA033572

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
bevacizumab
5mg/kg IV day 1 and 15 of each 28 day course of treatment
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.
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
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.
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.

Primary Outcomes

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

Eligibility Criteria

Male or female participants at least 18 years old.

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

Additional Information

Official title Phase I Study of Ursodeoxycholic Acid (Ursodiol)in Combination With 5-Fluorouracil, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Metastatic Colorectal Cancer
Principal investigator Lily L. Lai, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in August 2016.
Information provided to ClinicalTrials.gov by City of Hope Medical Center.