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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ursodiol, combination chemotherapy, bevacizumab)<br>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. | Biological: bevacizumab<br>* 5mg/kg IV day 1 and 15 of each 28 day course of treatment<br>Drug: FOLFOX regimen<br>* Leucovorin, 5-FU and Oxaliplatin<br>Drug: fluorouracil<br>* 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<br>Drug: leucovorin calcium<br>* 400 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.<br>Drug: oxaliplatin<br>* 85 mg/m2 IV infusion over 2 hours on days 1 and 15 of a 28 day course of treatment.<br>Drug: ursodiol<br>* 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.<br>Genetic: RNA analysis<br>* Analysis on discard tissues<br>Genetic: gene expression analysis<br>* Determined in normal and malignant tissues in patients who undergo surgical resection after treatment on this trial<br>Genetic: polymerase chain reaction<br>* Analysis on discard tissues<br>Genetic: western blotting<br>* 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<br>Other: immunohistochemistry staining method<br>* Performed on tumor blocks from the primary and the metastases from the patients on study<br>Other: laboratory biomarker analysis<br>* 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<br>Other: pharmacological study<br>* 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.<br>Procedure: positron emission tomography (PET)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Survival |  | 2 years after treatment | 
| Time to failure |  | 2 years after treatment | 
| Pharmacokinetics of ursodiol |  | 8 days after start of treatment during course 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV colon cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer, adenocarcinoma of the colon, adenocarcinoma of the rectum