Track topics on Twitter Track topics that are important to you
PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of gamma-secretase inhibitor RO4929097 in treating patients with metastatic or unresectable solid malignancies.
- To determine the safety profile of 6 different administration schedules of gamma-secretase inhibitor RO4929097 in patients with advanced solid malignancies.
- To determine pharmacokinetic (PK) parameters of gamma-secretase inhibitor RO4929097 administered using 6 different administration schedules.
- To assess the preliminary antitumor activity of gamma-secretase inhibitor RO4929097 in these patients.
- To assess the pharmacodynamic (PD) effects of gamma-secretase inhibitor RO4929097 on Notch signaling pathway in tumor and surrogate tissues, as well as soluble markers of angiogenesis in plasma, when administered using 6 different dosing schedules. (Exploratory)
- To evaluate the relationship between PK and PD effects in an attempt to define the optimal biological dosing schedule (OBDS) that can provide a sustained inhibition of Notch signaling pathway over time with a tolerable toxicity profile. (Exploratory)
- To correlate inhibition of Notch signaling pathway measured in tumor and surrogate tissues with preliminary antitumor activity and assess the potential clinical predictive value of OBDS as defined above. (Exploratory)
- To assess the effect of the various pharmacogenomic polymorphisms of the cytochrome P450 pathway on PK and PD parameters. (Exploratory)
OUTLINE: This is a multicenter, dose-escalation study. Patients are assigned to 1 of 6 dose schedules.
- Group A: Patients receive oral gamma-secretase inhibitor RO4929097 once daily on days 1-3 and 8-10.
- Group B: Patients receive oral RO4929097 once daily on days 1-7.
- Group C: Patients receive oral RO4929097 once daily on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21.
- Group D: Patients receive oral RO4929097 once daily on days 1, 8, and 15.
- Group E: Patients receive oral RO4929097 once daily on days 1, 4, 8, 11, 15, and 18.
- Group F: Patients receive oral RO4929097 once daily days 1-5, 8-12, and 15-19. Treatment in all groups repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.
Patients undergo tumor biopsies at baseline and between days 15 and 22 in the first course of treatment. Plasma samples are collected periodically for pharmacokinetic, pharmacodynamic, and pharmacogenomic analysis and to assess levels of adipsin and markers of angiogenesis.
After completion of study treatment, patients are followed up for 4 weeks.
Allocation: Non-Randomized, Masking: Open Label, Primary Purpose: Treatment
Unspecified Adult Solid Tumor, Protocol Specific
gamma-secretase inhibitor RO4929097, laboratory biomarker analysis, pharmacogenomic studies, pharmacological study
Not yet recruiting
National Cancer Institute (NCI)
Published on BioPortfolio: 2014-07-23T21:09:41-0400
RATIONALE: Gamma-secretase inhibitor RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hy...
RATIONALE: Gamma-secretase inhibitor RO4929097 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase I/II clinical trial is study...
This randomized phase I/II clinical trial is studying the side effects and best dose of gamma-secretase/notch signalling pathway inhibitor RO4929097 when given together with vismodegib and...
RATIONALE: Gamma-secretase inhibitor RO4929097 and cediranib maleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate also may s...
This phase Ib/II trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 when given together with cisplatin, vinblastine, and temozolom...
Pharmacogenomic testing has recently become scalable and available to guide the treatment of major depressive disorder (MDD). The objective of the current meta-analysis was to determine if guidance fr...
Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. Gamma-secretase inhibitors inhibit Notch signaling by preventing ...
Gamma-secretase inhibitor suppressed Notch1 intracellular domain combination with p65 and resulted in the inhibition of the NF-κB signaling pathway induced by IL-1β and TNF-α in nucleus pulposus cells.
In this experiment, the cross-talk betweenNotch and the NF-κB signaling pathway was examined to reveal the mechanism of slowing down the type II collagen (ColII) and aggrecan degeneration affected by...
Despite their importance as human pathogens, entry of human papillomaviruses (HPVs) into cells is poorly understood. The transmembrane protease γ-secretase executes a crucial function during the earl...
The gamma-band auditory steady-state response (ASSR) is thought to reflect the function of parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and may be a candidate biomarker in early...
The detection of genetic variability (e.g., PHARMACOGENOMIC VARIANTS) relevant to PHARMACOGENETICS and PRECISION MEDICINE. The purpose of such genetic testing is to help determine the most effective treatment options and their optimum dosages with least potential risks for DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS.
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.
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.
An analogue of GAMMA-AMINOBUTYRIC ACID. It is an irreversible inhibitor of 4-AMINOBUTYRATE TRANSAMINASE, the enzyme responsible for the catabolism of GAMMA-AMINOBUTYRIC ACID. (From Martindale The Extra Pharmacopoeia, 31st ed)
Enzymes are proteins that catalyze (i.e., increase the rates of) chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical re...
In a clinical trial or interventional study, participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or change...