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

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

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: 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)

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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lily L. Lai, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2009
• Primary Completion (Actual): September 25, 2012
• Study Completion (Actual): February 26, 2025

Study Registration Dates

• First Submitted: March 31, 2009
• First Submitted That Met QC Criteria: March 31, 2009
• First Posted (Estimated): April 1, 2009

Study Record Updates

• Last Update Posted (Actual): June 22, 2025
• Last Update Submitted That Met QC Criteria: June 18, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Calcium-Regulating Hormones and Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Antimetabolites, Antineoplastic; Antimetabolites; Micronutrients; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antidotes; Vitamin B Complex; Vitamins; Cholagogues and Choleretics; Oxaliplatin; Bevacizumab; Calcium; Fluorouracil; Leucovorin; Levoleucovorin; Ursodeoxycholic Acid
• 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)