Clinical trial NCT00873275: Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer
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 type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Colorectal Cancer
Keywords: stage IV colon cancer
stage IV rectal cancer
recurrent colon cancer
recurrent rectal cancer
adenocarcinoma of the colon
adenocarcinoma of the rectum
Lead sponsor: City of Hope Medical Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-04-01
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Maximum-tolerated dose of ursodiol
timeFrame: 28 days from the start of treatment
measure: Toxicities as assessed by NCI CTCAE 3.0
timeFrame: 28 days after the last cycle of treatment
measure: Survival
timeFrame: 2 years after treatment
measure: Time to failure
timeFrame: 2 years after treatment
measure: Pharmacokinetics of ursodiol
timeFrame: 8 days after start of treatment during course 1
Secondary outcomes:
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
Study officials:
affiliation: City of Hope Medical Center
name: Lily L. Lai, MD
role: PRINCIPAL_INVESTIGATOR
References: