Clinical trial NCT01051791
Conditions: Squamous Cell Carcinoma of the Head and Neck
Keywords: RAD001 Everolimus
Sponsor: Julie E. Bauman, MD, MPH
Start date: 2010-01-01; Completion date: 2016-08-05
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To carry out exploratory studies to determine if activity of this regimen correlates with tumor and patient associated markers of the EGF-R/mTOR 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-Akt(T308 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 progression.1 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 disease.2 Unfortunately, despite survival advances achieved with EGF-R inhibitors, the majority (\~60%) of patients with advanced disease are refractory to EGF-R directed therapies.3 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 PI3/AKT/mTOR 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.

Arms: arm 1: The study of the efficacy of everolimus will proceed in two stages after the method of Simon1. 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 everolimus 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.

1
Interventions: intervention 1: Everolimus 10mg daily
Intervention descriptions: intervention 1: RAD001 is a pill that will be taken orally (by mouth), at a dose of 10 mg, once a day for 28 days.

Protocol documents: