Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer - Full Text View

Purpose

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	Intervention	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

Study Type:	Interventional
Study Design:	Intervention Model: Single Group Assignment Masking: 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

Resource links provided by NLM:

MedlinePlus related topics: Calcium Cancer Colorectal Cancer

Drug Information available for: Fluorouracil Ursodiol Calcium Gluconate Leucovorin calcium Oxaliplatin Ribonucleic acid Levoleucovorin Bevacizumab

U.S. FDA Resources

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:

Maximum-tolerated dose of ursodiol [ Time Frame: 28 days from the start of treatment ] [ Designated as safety issue: Yes ]
Toxicities as assessed by NCI CTCAE 3.0 [ Time Frame: 28 days after the last cycle of treatment ] [ Designated as safety issue: Yes ]
Survival [ Time Frame: 2 years after treatment ] [ Designated as safety issue: No ]
Time to failure [ Time Frame: 2 years after treatment ] [ Designated as safety issue: No ]
Pharmacokinetics of ursodiol [ Time Frame: 8 days after start of treatment during course 1 ] [ Designated as safety issue: No ]

Estimated Enrollment:	30
Study Start Date:	November 2008
Estimated Primary Completion Date:	September 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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.

Arms

Assigned Interventions

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.

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00873275

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

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	City of Hope Medical Center
ClinicalTrials.gov Identifier:	NCT00873275 History of Changes
Other Study ID Numbers:	08005, P30CA033572, CHNMC-08005, CDR0000637521, NCI-2010-00926
Study First Received:	March 31, 2009
Last Updated:	September 7, 2012
Health Authority:	United States: Institutional Review Board

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:

Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Fluorouracil
Oxaliplatin
Bevacizumab
Leucovorin

Levoleucovorin
Ursodeoxycholic Acid
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances

ClinicalTrials.gov processed this record on May 23, 2013