Ignite Creation Date:
2024-05-06 @ 3:29 AM
Last Modification Date:
2024-10-26 @ 11:34 AM
Study NCT ID:
NCT02305810
Status:
COMPLETED
Last Update Posted:
2018-11-07
First Post:
2014-06-17
Brief Title:
A Biological Prospective Study in Patients With Metastatic Pancreatic NETs Treated With Everolimus
Sponsor:
European Institute of Oncology
Organization:
European Institute of Oncology
Study Overview
Official Title:
An Angiogenic Study in Patients With WellModerately Differentiated Metastatic Pancreatic Neuroendocrine Tumors Treated With Everolimus
Status:
COMPLETED
Status Verified Date:
2018-09
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:
Everolimus represents an approved therapy for patients with advanced wellmoderately 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 activityefficacy 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
Detailed Description:
Background Everolimus has been reported to be effective compared with placebo in wellmoderately 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 activityefficacy 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 10 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 005 1-β 020 to test the hypothesis of 30 a reduction in risk hazard rate HR equal to HR 030 for those belonging to the following layers
22uL vs 22uL for CEC at basal or
656 vs 656 for FGF levels after two months since start treatment or
325 vs 325 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 patientsyear 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
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 10 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 005 1-β 020 to test the hypothesis of 30 a reduction in risk hazard rate HR equal to HR 030 for those belonging to the following layers
22uL vs 22uL for CEC at basal or
656 vs 656 for FGF levels after two months since start treatment or
325 vs 325 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 patientsyear 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
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