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

Study Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
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

Detailed 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
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
Study Start Date :	March 4, 2009
Estimated Primary Completion Date :	September 2019
Estimated Study Completion Date :	September 2019

Arms and Interventions

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Arm

Intervention/treatment

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.

Biological: bevacizumab; 5mg/kg IV day 1 and 15 of each 28 day course of treatment; Drug: FOLFOX regimen; Leucovorin, 5-FU and Oxaliplatin; Drug: 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; Drug: 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 tissues; Genetic: gene expression analysis; Determined in normal and malignant tissues in patients who undergo surgical resection after treatment on this trial; Genetic: polymerase chain reaction; Analysis on discard tissues; Genetic: 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; Other: 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; Other: 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.

Outcome Measures

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Primary Outcome Measures :

1. Maximum-tolerated dose of ursodiol [ Time Frame: 28 days from the start of treatment ]
2. Toxicities as assessed by NCI CTCAE 3.0 [ Time Frame: 28 days after the last cycle of treatment ]
3. Survival [ Time Frame: 2 years after treatment ]
4. Time to failure [ Time Frame: 2 years after treatment ]
5. Pharmacokinetics of ursodiol [ Time Frame: 8 days after start of treatment during course 1 ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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Locations

United States, California
City of Hope Medical Center
Duarte, California, United States, 91010-3000

Sponsors and Collaborators

City of Hope Medical Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Lily L. Lai, MD	City of Hope Medical Center

More Information

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Responsible Party:	City of Hope Medical Center
ClinicalTrials.gov Identifier:	NCT00873275 History of Changes
Other Study ID Numbers:	08005; P30CA033572 ( U.S. NIH Grant/Contract ); CHNMC-08005; CDR0000637521 ( Registry Identifier: NCI PDQ ); NCI-2010-00926 ( Registry Identifier: NCI CTRP )
First Posted:	April 1, 2009
Last Update Posted:	August 9, 2018
Last Verified:	August 2018

Keywords provided by City of Hope Medical Center:

stage IV colon cancer; stage IV rectal cancer; recurrent colon cancer	recurrent rectal cancer; adenocarcinoma of the colon; adenocarcinoma of the rectum

Additional relevant MeSH terms:

Ursodeoxycholic Acid; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Bevacizumab; Oxaliplatin; Fluorouracil	Leucovorin; Levoleucovorin; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Antidotes; Protective Agents