Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer
NCT ID: NCT00873275
Last Updated: 2025-06-22
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE1
11 participants
INTERVENTIONAL
2009-03-11
2025-02-26
Brief Summary
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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.
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Detailed Description
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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
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Treatment (ursodiol, combination chemotherapy, 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.
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.
Interventions
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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.
Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
City of Hope Medical Center
OTHER
Responsible Party
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Principal Investigators
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Lily L. Lai, MD
Role: PRINCIPAL_INVESTIGATOR
City of Hope Medical Center
Locations
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City of Hope Medical Center
Duarte, California, United States
Countries
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Other Identifiers
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CHNMC-08005
Identifier Type: -
Identifier Source: secondary_id
CDR0000637521
Identifier Type: REGISTRY
Identifier Source: secondary_id
NCI-2010-00926
Identifier Type: REGISTRY
Identifier Source: secondary_id
08005
Identifier Type: -
Identifier Source: org_study_id
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