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

City of Hope

Status and phase

Active, not recruiting

Phase 1

Conditions

Colorectal Cancer

Treatments

Drug: oxaliplatin

Genetic: gene expression analysis

Drug: fluorouracil

Drug: ursodiol

Drug: FOLFOX regimen

Procedure: positron emission tomography (PET)

Drug: leucovorin calcium

Other: pharmacological study

Genetic: polymerase chain reaction

Genetic: western blotting

Biological: bevacizumab

Other: laboratory biomarker analysis

Other: immunohistochemistry staining method

Genetic: RNA analysis

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00873275

CDR0000637521 (Registry Identifier)

08005

P30CA033572 (U.S. NIH Grant/Contract)

CHNMC-08005

NCI-2010-00926 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

11 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

Non-Randomized

Interventional model

Single Group Assignment

Masking

None (Open label)

11 participants in 1 patient group

Treatment (ursodiol, combination chemotherapy, bevacizumab)

Experimental group

Description:

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.

Treatment: