Ursodiol, Combination Chemotherapy, and Bevacizumab in Treating Patients With Stage IV Colorectal Cancer
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Colorectal Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 8/11/2018 |
| Start Date: | March 4, 2009 |
| End Date: | September 2019 |
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.
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.
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.
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.
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
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