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

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City of Hope

Status and phase

Active, not recruiting
Phase 1

Conditions

Colorectal Cancer

Treatments

Genetic: western blotting
Drug: oxaliplatin
Drug: ursodiol
Other: pharmacological study
Drug: leucovorin calcium
Drug: FOLFOX regimen
Procedure: positron emission tomography (PET)
Other: immunohistochemistry staining method
Genetic: polymerase chain reaction
Biological: bevacizumab
Genetic: RNA analysis
Drug: fluorouracil
Genetic: gene expression analysis
Other: laboratory biomarker 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:
Other: laboratory biomarker analysis
Genetic: gene expression analysis
Drug: fluorouracil
Genetic: RNA analysis
Biological: bevacizumab
Procedure: positron emission tomography (PET)
Other: immunohistochemistry staining method
Genetic: polymerase chain reaction
Drug: FOLFOX regimen
Drug: leucovorin calcium
Other: pharmacological study
Drug: ursodiol
Drug: oxaliplatin
Genetic: western blotting

Trial contacts and locations

1

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Data sourced from clinicaltrials.gov

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