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Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Recurrent or Progressive Glioblastoma

2014-07-23 21:09:05 | BioPortfolio

Summary

This phase II clinical trial is studying how well RO4929097 works in treating patients with recurrent or progressive glioblastoma. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Description

PRIMARY OBJECTIVES:

I. 6-month progression-free survival (PFS6) (Group A) II. Efficiency of neurosphere generation after pretreatment with RO4929097. (Group B)

SECONDARY OBJECTIVES:

I. Radiographic response rate. (Group A) II. Toxicities associated with this regimen. (Group A) III. Overall survival. (Group A) IV. Expression levels of Notch pathway components and downstream targets. (Group B) V. Tumor propagation. An extension of lifespan by 50% in tumor bearing mice (mice bearing fresh tumor tissue). (Group B) VI. Patient event-free survival in correlation with expression levels of Notch pathway components and downstream targets.

VII. 6-month progression-free survival (PFS6). VIII. Toxicities associated with this regimen. IX. Overall survival.

OUTLINE: Patients are assigned to 1 of 2 treatment groups.

Group A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3, 8-10, 15-17, and 22-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group B (surgical resection indicated): Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days -6 to -1. Patients undergo surgical resection on day 0. Within 30 days after surgical resection, patients receive gamma-secretase inhibitor RO4929097 as in group A.

After completion of study treatment, patients are followed up every 2 months.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Adult Giant Cell Glioblastoma

Intervention

gamma-secretase/Notch signalling pathway inhibitor RO4929097, therapeutic conventional surgery, pharmacological study, laboratory biomarker analysis

Location

Adult Brain Tumor Consortium
Baltimore
Maryland
United States
21231-1000

Status

Active, not recruiting

Source

National Cancer Institute (NCI)

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-23T21:09:05-0400

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PubMed Articles [15150 Associated PubMed Articles listed on BioPortfolio]

Notch signalling induces epithelial‑mesenchymal transition to promote metastasis in oral squamous cell carcinoma.

The activation of Notch signalling induces epithelial‑mesenchymal transition (EMT), but this signalling pathway and its association with EMT in the context of cell motility in oral squamous cell car...

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Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibito...

Endocytic Trafficking of the Notch Receptor.

The endosomal pathway plays an important role in several aspects of Notch signalling ranging from ligand-dependent to independent activation and also degradation of the Notch receptor. Here, we will f...

Notch signaling regulates the responses of lipopolysaccharide-stimulated macrophages in the presence of immune complexes.

Macrophages exhibit diverse effector phenotypes depending on the stimuli and their microenvironment. Classically activated macrophages are primed with interferon (IFN)γ and stimulated with pathogen-a...

Medical and Biotech [MESH] Definitions

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.

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. PSEN1 mutations cause early-onset ALZHEIMER DISEASE type 3 that may occur as early as 30 years of age in humans.

A disintegrin and metalloproteinase domain-containing protein that cleaves the membrane-bound precursor of TUMOR NECROSIS FACTOR-ALPHA to its mature form. It cleaves several other CELL SURFACE PROTEINS, including INTERLEUKIN-1 RECEPTOR TYPE II; TRANSFORMING GROWTH FACTOR ALPHA; L-SELECTIN; MUCIN-1; and AMYLOID BETA-PROTEIN PRECURSOR. It can also function as an activator of the Notch signaling pathway by mediating the cleavage of NOTCH RECEPTORS.

Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.

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