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Everolimus represents an approved therapy for patients with advanced well/moderately differentiated pancreatic NETs. Although some patients could benefit from this drug in terms of long-term tumor growth control, others are resistant upfront or become resistant during treatment. Therefore, it is crucial to detect some biological factors which can help to identify the responsive tumors. Given that Everolimus is a biological agent and its mechanism of action can be partially directed towards angiogenesis its effects can be studied on different levels and with different methods. Upfront and early surrogate predictive markers of activity/efficacy can be studied on tumor tissue, tumor imaging, and peripheral blood. mTOR pathways alterations, circulating endothelial cells, and other circulating angoigenic factors will be correlated with clinical outcome. Tumor perfusion and circulating markers will be studied also as markers of response compared with the morphological imaging.
Full description
• Background:: Everolimus has been reported to be effective compared with placebo in well/moderately differentiated pancreatic NETs in terms of progression-free survival (PFS) improvement. However, a number of patients are refractory upfront or become resistant after few months of therapy. Therefore, it is crucial to detect some biological factors which can help to identify the responsive tumors. Everolimus is a biological agent and its mechanism of action can be partially directed towards angiogenesis. This can be studied on different levels and with different methods. Upfront and early surrogate predictive markers of activity/efficacy can be studied on tumor tissue, on tumor imaging, and on the peripheral blood. Tumor study with diffusion-MRI and angiogenic circulating markers can be studied also as markers of response compared with the morphological imaging.
Material and Methods :
Circulating Endothelial Cells (CECs) and Circulating endothelial progenitors (CEPs) will be performed by flow cytometry. The monoclonal antibodies used for the search of CECs and CEPs include: cluster of differentiation antigen 45 (CD45), CD31, CD133, CD146, CD34, VEGFR-2, 7-amino-actinomycin D (7-AAD) and Syto1. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), VEGFR-2 and thrombospondin-1 (TSP-1) will be also detected on the peripheral blood.
On the tumor tissue the following determinations will be performed, including:
Diffusion-weighted imaging (DWI) has been shown to be able to provide information regarding the cellular density and properties of the extracellular matrix and the apparent diffusion coefficient (ADC) value calculated using DWI can serve as a marker of cellularity. Given that tumor cellularity is contributed largely by cellular proliferation, the ADC value can be a surrogate biomarker for tumor-cell proliferation . ADC-Magnetic Resonance Imaging (MRI) will be performed at baseline, after 1 month and after three months of therapy.
Study design
Baseline, after 1 month of therapy, after three months of therapy and at progression:
Baseline biopsy of a metastatic site and possibly a new biopsy at the time of tumor progression
Correlation of biological parameters with clinical outcome ( tumor response and progression free survival, Response Evaluation Criteria in Solid Tumors , RECIST 1.0 criteria)
• Statistical analysis: This is an exploratory study on the potential predictive value of some biological factors (CECs, VEGF and bFGF among them) expressed in terms of reducing risk of progression in patients with advanced pancreatic NETs treated with Everolimus.
We will use two-tailed log-rank test (α = 0.05, 1-β = 0.20) to test the hypothesis of 30% a reduction in risk (hazard rate; HR) equal to HR = 0.30 for those belonging to the following layers:
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54 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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