Pancreatic Neuroendocrine Tumour Metastatic Clinical Trial
Official title:
An Angiogenic Study in Patients With Well/Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors Treated With Everolimus
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.
• 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 :
1. 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.
2. On the tumor tissue the following determinations will be performed, including:
- Subtype 2 somatostatin receptor,
- Phospho-AKT
- Phospho-mTOR
- Phospho-4E-BP1
- Phospho-p70-S6 kinase Rabbit anti-tuberous sclerosis complex 2 (TSC2) Cell
Signaling Technology
- Mouse anti-PTEN Cell Signaling Technology
3. 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:
- Abdomen DWI-MRI
- CEC, CEPs
- Circulating VEGF, VEGFR-2, bFGF, TSP-1
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:
- ≥ 2.2/uL vs < 2.2/uL for CEC at basal or
- ≤ 65.6 vs > 65.6 for FGF levels after two months since start treatment or
- ≤ 32.5 vs > 32.5 for VEGF levels after two months since start treatment The sample size
is calculated to compensate for the power loss of the log-rank test assuming an average
and uniform log-rank test drop-out of 10% and bearing in mind that the threshold values
refer to the 25th, 75th and 50th percentile distributions of CEC, bFGF, and VEGF,
respectively. Considering an accrual rate of 20 patients/year, a treatment period of 12
weeks with a follow-up of 1 year and for a sample size equal to 43 patients, the study
will have a total length of about 3 years and 6 months.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT02713763 -
Efficacy of Rechallenge With Sunitinib in Metastatic Pancreatic Neuroendocrine Tumor Previously Failed to Sunitinib
|
Phase 2 |