Finally, the final data analysis is performed (Fig.?1). Table?1 Requirements for the study Open in a separate window 1every 3?months; 2if no imaging has been performed within the last 4?weeks. 3to be performed at the beginning of each cycle. 4to be followed beyond the 30?days until resolution or stabilization Open in a separate window Fig. metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24?months with a minimum follow-up of 24?months. The primary endpoint is disease control after 6?months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6?months, the sample size calculation follows an exact binomial single-stage design. H0: p? ?=p0?=?60% versus H1: p? ?=p1?=?80%, alpha?=?0.05, beta?=?0.1. Discussion This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies CD114 in PNET. Trial registration EudraCT: 2017C001207-68. Date of registration: 2018.01.03. strong class=”kwd-title” Keywords: PanNET, PNET, Chemotherapy, Ramucirumab, DTIC, Neuroendocrine Background Worldwide, the incidence of neuroendocrine neoplasms (NEN) has increased over the last decades [1C3]. In contrast to metastatic NEN of the small intestine which are associated with median 10-year survival rates of 60C70%, metastatic pancreatic neuroendocrine tumors (PNET) have a significantly poorer outcome [3, 4]. Numerous efforts have been taken to improve the long-term outcome of PNET patients. However, the impact of current systemic therapeutic approaches is only modest. Recently, two treatment modalities with targeted agents have been approved: The mTOR inhibitor everolimus and the antiangiogenic multikinase inhibitor sunitinib. Both have demonstrated significant clinical efficacy in prolonging PFS in patients with pancreatic NET [5, 6]. Angiogenesis is a key hallmark of neuroendocrine tumors (NET). VEGF signaling has been described as major determinant of the high vascularity seen in NET both in preclinical models and in human disease [7]. Intratumoral and circulating VEGF levels have been associated with increased tumor aggressiveness and reduced survival of NET patients. Several preclinical studies and clinical trials have evaluated the impact of antiangiogenic approaches in patients with pancreatic NET [8]. The anti-angiogenic multikinase inhibitor sunitinib has shown significant effects on PFS as single agent. However, development of secondary resistance is almost inevitable. Likewise, chemotherapy with temozolomide or capecitabine in combination with the anti-VEGF antibody bevacizumab showed moderate improvements of progression-free survival (PFS) in pancreatic NET (PNET) in phase II trials, but secondary resistance is common LY2109761 and phase III data are still missing [9, 10]. The anti-VEGFR2 antibody ramucirumab alone or in combination with chemotherapy has LY2109761 shown significant effects as second-line treatment in gastric cancer patients [11, 12]. In contrast, antiangiogenic strategies using bevacizumab targeting VEGF as ligand have failed [13]. Similar to gastric cancer, pancreatic neuroendocrine neoplasms are characterized by high vascularity and a high stromal content containing various cellular components with high VEGFR2 expression such as macrophages and endothelial cells [14]. Based on the different VEGFR2-targeting mode of action of ramucirumab compared to VEGF-targeting bevacizumab, we hypothesized that ramucirumab is particularly effective in neuroendocrine neoplasms. Besides its efficacy as single agent and in combination with taxane-based chemotherapy in gastric cancer [11, 12], ramucirumab has been approved for non-small cell lung cancer [15] and in combination with FOLFIRI (leucovorin, fluorouracil, irinotecan) for treatment of patients with progressive metastatic colorectal cancer [16]. In NEN, streptozocin-based (STZ) chemotherapy is frequently used and recommended in symptomatic patients with high tumor load [17]. The use of the combination of doxorubicin with STZ is limited by potential cumulative cardiotoxicity (maximum doxorubicin dose must be less than 500?mg/m2) and has been largely replaced by the use of the combination of 5-fluorouracil (5-FU) with STZ LY2109761 [18]. However, randomized phase III data are lacking and thus most evidence was achieved with recently published large retrospective studies [19C21]. An alternative therapeutic option is the alkylating drug temozolomide (TEM) or its derivative dacarbazine (DTIC). While TEM is routinely.