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RATIONALE: GDC-0449 and RO4929097 may slow the growth of tumor cells and may be an effective treatment for advanced breast cancer.
- To determine the safety and tolerability of Hedgehog antagonist GDC-0449 in combination with gamma-secretase inhibitor RO4929097 in women with advanced breast cancer.
- To determine the dose-limiting toxicity and maximum tolerated dose and/or recommended phase II dose of this regimen in these patients.
- To determine the pharmacokinetics and pharmacogenetics of Hedgehog antagonist GDC-0449 and gamma-secretase inhibitor RO4929097 when administered alone and in combination.
- To attempt to evaluate select pharmacodynamic stem cell differentiation biomarkers in the Hedgehog and Notch signaling pathways (e.g., Gli1/2/3, Ptch1/2, Hes1, Hip1, Hey1, Notch4, Jagged1, Numb, Bmi-1, CD44/CD24, ALDH) and the percentage of breast cancer stem cells in serial breast tumor biopsies before and after Hedgehog antagonist GDC-0449 or gamma-secretase inhibitor RO4929097 when administered alone and after 1 course of treatment when administered in combination.
- To determine tumor response in patients with measurable disease as assessed by RECIST criteria.
OUTLINE: This is a multicenter study.
Patients receive oral gamma-secretase inhibitor RO4929097 on day 1 OR on days -2, -1, and 1 and oral Hedgehog antagonist GDC-0449 on days 8-21 of course 1. Beginning in course 2, patients receive oral gamma-secretase inhibitor RO4929097 on days 1-3 and 8-10 and oral Hedgehog antagonist GDC-0449 on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Blood, tumor tissue, and hair samples are collected periodically for pharmacokinetic, pharmacodynamic, pharmacogenomic, and other correlative biomarker studies.
After completion of study treatment, patients are followed up for 30 days.
Masking: Open Label, Primary Purpose: Treatment
Hedgehog antagonist GDC-0449, gamma-secretase inhibitor RO4929097, laboratory biomarker analysis, pharmacogenomic studies, pharmacological study
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
Published on BioPortfolio: 2014-08-27T03:15:48-0400
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