Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer
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.
|Colorectal Cancer||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)||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Phase I Study of Ursodeoxycholic Acid (Ursodiol)in Combination With 5-Fluorouracil, Leucovorin, Oxaliplatin and Bevacizumab in Patients With Metastatic Colorectal Cancer|
- 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 ]
|Actual Study Start Date:||March 4, 2009|
|Estimated Study Completion Date:||September 2018|
|Estimated Primary Completion Date:||September 2018 (Final data collection date for primary outcome measure)|
Experimental: 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.
5mg/kg IV day 1 and 15 of each 28 day course of treatmentDrug: FOLFOX regimen
Leucovorin, 5-FU and OxaliplatinDrug: 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 treatmentDrug: 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 tissuesGenetic: gene expression analysis
Determined in normal and malignant tissues in patients who undergo surgical resection after treatment on this trialGenetic: polymerase chain reaction
Analysis on discard tissuesGenetic: 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 treatmentOther: immunohistochemistry staining method
Performed on tumor blocks from the primary and the metastases from the patients on studyOther: 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 treatmentOther: 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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00873275
|United States, California|
|City of Hope Medical Center|
|Duarte, California, United States, 91010-3000|
|Principal Investigator:||Lily L. Lai, MD||City of Hope Medical Center|