Ignite Creation Date:
2024-05-05 @ 10:11 PM
Last Modification Date:
2024-10-26 @ 10:15 AM
Study NCT ID:
NCT01051791
Status:
TERMINATED
Last Update Posted:
2017-12-19
First Post:
2010-01-18
Brief Title:
Phase II Study of RAD001 Head and Neck Cancer
Sponsor:
Julie E Bauman MD MPH
Organization:
University of Pittsburgh
Study Overview
Official Title:
Phase II Study of RAD001 for Treatment of Refractory Recurrent Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Status:
TERMINATED
Status Verified Date:
2017-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To carry out exploratory studies to determine if activity of this regimen correlates with tumor and patient associated markers of the EGF-RmTOR pathway These markers may correlate with activity of this regimen and provide exploratory insights in to the mechanism of this treatment approach
Expression of the pathway components including EGF-R and phosphorylated EGF-R p-EGF-R ERK and p-ERK Akt and p-AktT308 and S473 p70s6k and p-p70s6k S6 and p-S6 HIF-1-alpha p27 and 4E-BP1 will be assessed Mutation and FISH analysis for EGF-R expression will also be performed on tumor samples Biopsies will be obtained at the following times pre-treatment and after 4 weeks one cycle of treatment If available original diagnostic tissue may be submitted in place of the pre-treatment biopsy
Expression of the pathway components including EGF-R and phosphorylated EGF-R p-EGF-R ERK and p-ERK Akt and p-AktT308 and S473 p70s6k and p-p70s6k S6 and p-S6 HIF-1-alpha p27 and 4E-BP1 will be assessed Mutation and FISH analysis for EGF-R expression will also be performed on tumor samples Biopsies will be obtained at the following times pre-treatment and after 4 weeks one cycle of treatment If available original diagnostic tissue may be submitted in place of the pre-treatment biopsy
Detailed Description:
The study of the efficacy of RAD001 will proceed in two stages after the method of Simon In the first stage 15 patients will be accrued and treated If 9 or fewer patients show clinical benefit the study will be terminated If 10 or more patients show clinical benefit the study will proceed to the second stage accruing an additional 26 patients If the second stage is complete and a total of 29 or more patients show clinical benefit among the 41 patients treated the treatment CBR for will be considered high enough to warrant further study Conversely if the evaluation of RAD001 concludes at the first stage or if 28 or fewer patients experience a clinical benefit after completing the second stage the therapy will not be considered for further study
Current knowledge about the molecular mechanisms of cancer-related pathways involved in cellular signaling cell cycle regulation and cell death is yielding therapies directed at specific components of these pathways such as the epidermal growth factor receptor EGF-R the mammalian target of rapamycin mTOR the vascular endothelial growth factor receptor VEGF-R and the insulin-like growth factor receptor IFG-R Both small molecule and monoclonal antibody therapies directed against these targets are available Furthermore immunohistochemistry IHC fluorescence in situ hybridization FISH and mutation analysis are available for profiling expression of pathway components raising the possibility of individualized prognosis and therapy
One receptor in particular is both a prognostic factor and a therapeutic target in HNSCC Upregulation of EGF-R expression and aberrant activation of kinase cascades downstream of this receptor occur early in the process of carcinogenesis and play a major role in malignant progression1 The level of EGF-R expression correlates with recurrence and poor prognosis in HNSCC A well tolerated anti-EGF-R monoclonal antibody cetuximab has shown remarkable activity against HNSCC including statistically significant improvement in survival for patients with locally advanced disease treated with radiotherapy leading to its regulatory approval for this disease2 Unfortunately despite survival advances achieved with EGF-R inhibitors the majority 60 of patients with advanced disease are refractory to EGF-R directed therapies3 One anticipated mechanism by which the current regimen may fail in some patients is the upregulation of escape pathways downstream of the EGF-R A pathway of particular interest is the PI3AKTmTOR axis within which the mTOR protein may be targeted by the tyrosine kinase inhibitor RAD001
In order to investigate pathway components that may act as an escape mechanism while concurrently targeting a downstream kinase that may enable rescue from resistance to EGF-R directed therapies we propose this prospective phase II single-arm single-agent interventional clinical trial of RAD001 for patients with refractory SCCHN The primary outcome is activity of RAD001 while secondary outcomes include safety toxicity and extensive laboratory correlates to be performed on tumor tissues By carrying out this clinic-translational trial of the novel mTOR inhibitor RAD001 in patients with refractory SCCHN we aim to explore mechanisms of activity of and resistance to inhibitors of the EGF-R pathway components while measuring the clinical activity of RAD001
Current knowledge about the molecular mechanisms of cancer-related pathways involved in cellular signaling cell cycle regulation and cell death is yielding therapies directed at specific components of these pathways such as the epidermal growth factor receptor EGF-R the mammalian target of rapamycin mTOR the vascular endothelial growth factor receptor VEGF-R and the insulin-like growth factor receptor IFG-R Both small molecule and monoclonal antibody therapies directed against these targets are available Furthermore immunohistochemistry IHC fluorescence in situ hybridization FISH and mutation analysis are available for profiling expression of pathway components raising the possibility of individualized prognosis and therapy
One receptor in particular is both a prognostic factor and a therapeutic target in HNSCC Upregulation of EGF-R expression and aberrant activation of kinase cascades downstream of this receptor occur early in the process of carcinogenesis and play a major role in malignant progression1 The level of EGF-R expression correlates with recurrence and poor prognosis in HNSCC A well tolerated anti-EGF-R monoclonal antibody cetuximab has shown remarkable activity against HNSCC including statistically significant improvement in survival for patients with locally advanced disease treated with radiotherapy leading to its regulatory approval for this disease2 Unfortunately despite survival advances achieved with EGF-R inhibitors the majority 60 of patients with advanced disease are refractory to EGF-R directed therapies3 One anticipated mechanism by which the current regimen may fail in some patients is the upregulation of escape pathways downstream of the EGF-R A pathway of particular interest is the PI3AKTmTOR axis within which the mTOR protein may be targeted by the tyrosine kinase inhibitor RAD001
In order to investigate pathway components that may act as an escape mechanism while concurrently targeting a downstream kinase that may enable rescue from resistance to EGF-R directed therapies we propose this prospective phase II single-arm single-agent interventional clinical trial of RAD001 for patients with refractory SCCHN The primary outcome is activity of RAD001 while secondary outcomes include safety toxicity and extensive laboratory correlates to be performed on tumor tissues By carrying out this clinic-translational trial of the novel mTOR inhibitor RAD001 in patients with refractory SCCHN we aim to explore mechanisms of activity of and resistance to inhibitors of the EGF-R pathway components while measuring the clinical activity of RAD001
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None