An Angiogenic Study in Patients With Well/Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors Treated With Everolimus
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 54
- 试验地点
- 1
- 主要终点
- Circulating angiogenic factors, molecular imaging and tumor tissue factors changes during treatment with RAD001 at baseline, week 4, week 12 and at disease progression.
研究概览
简要总结
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.
详细描述
• 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:
- 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
- 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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological diagnosis of metastatic well/moderately differentiated pancreatic neuroendocrine tumor
- •Patient incoming to be treated with everolimus outside clinical trials or within a clinical trial that permits the concurrent inclusion in an ancillary trial
- •Written informed consent must be signed and dated by the patient and the investigator prior to inclusion.
排除标准
- •Patients with poorly differentiated neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoid, small cell carcinoma, Merkel cell carcinoma.
- •Patients with pancreatic NETs not eligible to be treated with everolimus
- •Patients with ongoing everolimus treatment
- •Prior therapy with mTOR inhibitors
研究组 & 干预措施
Single arm receiving everolimus
single treatment arm receiving everolimus 10 mg daily
干预措施: Everolimus 10 mg daily (Drug)
结局指标
主要结局
Circulating angiogenic factors, molecular imaging and tumor tissue factors changes during treatment with RAD001 at baseline, week 4, week 12 and at disease progression.
时间窗: Baseline, week 4, week 12 up to tumor progression
Angiogenic factors (circulating endothelial cells, CECs; serum VEGF, bFGF, VEGFR-2, TSP-1) determined by serum samples; tumor tissue mTOR pathway alterations determined by Immunohistochemical staining ; ADC (apparent diffusion coefficient) calculated by Magnetic Resonance Imaging (MRI)
次要结局
- RR (response rate) , including SD (stable disease) and PR (partial response)(Baseline to best tumor response or unacceptable toxicity)
- Overall survival (OS)(Baseline to death)
- TTP, time to progression(Baseline to tumor progression or unacceptable toxicity)