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GDC-0449 and RO4929097 in Treating Women With Advanced Breast Cancer

2014-08-27 03:15:48 | BioPortfolio

Summary

RATIONALE: GDC-0449 and RO4929097 may slow the growth of tumor cells and may be an effective treatment for advanced breast cancer.

PURPOSE: This phase I trial is studying the side effects and best dose of giving GDC-0449 together with RO4929097 in treating women with advanced breast cancer.

Description

OBJECTIVES:

Primary

- 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.

Secondary

- 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.

Study Design

Masking: Open Label, Primary Purpose: Treatment

Conditions

Breast Cancer

Intervention

Hedgehog antagonist GDC-0449, gamma-secretase inhibitor RO4929097, laboratory biomarker analysis, pharmacogenomic studies, pharmacological study

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore
Maryland
United States
21231-2410

Status

Recruiting

Source

National Cancer Institute (NCI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:15:48-0400

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Medical and Biotech [MESH] Definitions

An inhibitor of glutamate decarboxylase and an antagonist of GAMMA-AMINOBUTYRIC ACID. It is used to induce convulsions in experimental animals.

A frizzled-like, G-protein-coupled receptor that associates with PATCHED RECEPTORS to transduce signals from HEDGEHOG PROTEINS and initiate hedgehog signaling to ZINC FINGER PROTEIN GLI1. It may normally inhibit signaling in the absence of SONIC HEDGEHOG PROTEIN binding to PATCHED RECEPTOR-1.

A family of intercellular signaling proteins that play and important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action.

Integral membrane protein of Golgi and endoplasmic reticulum. Its homodimer is an essential component of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PROTEIN precursors. PSEN2 mutations cause ALZHEIMER DISEASE type 4.

Integral membrane proteins and essential components of the gamma-secretase complex that catalyzes the cleavage of membrane proteins such as NOTCH RECEPTORS and AMYLOID BETA-PROTEIN precursors. Mutations of presenilins lead to presenile ALZHEIMER DISEASE with onset before age 65 years.

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