1163TiPACTIVITY AND SAFETY OF EVEROLIMUS IN COMBINATION WITH OCTREOTIDE LAR AND METFORMIN IN PATIENTS WITH ADVANCED PANCREATIC WELL-DIFFERENTIATED NEUROENDOCRINE TUMORS (PWDNETS): A SINGLE–CENTER, OPEN-LABEL, PHASE II, PROOF-OF-CONCEPT STUDY (METNET1 TRIAL)

ABSTRACT Background: Abnormal PI3K–Akt–mTOR pathway signaling and autocrine activation of the mTOR pathway, mediated through insulin-like growth factor 1 (IGF1), has been implicated in the proliferation of pNET cells. Everolimus (EVE), an mTOR inhibitor (a central regulator of growth/proliferation, cellular metabolism and angiogenesis) has shown antitumor benefit in pNETs alone and in combination with Octreotide LAR (OCT) in RADIANT-1 and RADIANT-3 studies. Despite EVE-based phase II/III trials improve progression-free survival (PFS) for pNETs, they are limited to significantly prolong overall survival (OS). Metformin (MET) has recently shown some anti-cancer activity, both in vitro and in vivo studies by antisecretory properties to decrease insulin and IGF1 levels and by antitumor effect due to AMPK activation and consequently inhibition to TSC1-2/mTOR complex, mediated to LKB1 oncogene expression. Our retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receving EVE-OCT combination. Trial design: Pts with advanced pWDNET, will receive a combination of EVE 10 mg/daily, OCT LAR 30 mg/month and MET 2000 mg/daily, until progression or inacceptable toxicity. Tumor radiological progression will be assessed every 4 months (mo). The primary objective is to evaluate the activity of EVE-OCT combination with MET in advanced pWDNETs through PFS rate, according to RECIST criteria. Based on RADIANT-3 results, with a PFS rate equal to 47% in 12 mo under the null hypothesis, the aim is to evaluate an increase of 20%. Secondary objective include safety, overall response rate (RR), OS, biomarkers RR defined as the impact of study treatment on circulating plasma Cromogranine A, IL6, and IGF1 levels. For a single-stage design, chosen a = 0.10 one-tailed and b = 0.10 (90% power), 43 pts will be enrolled. In April 2014 the trial received institutional ethic board approval and in June 2014 the enrollment was start. Recruitment is expected to be completed in July 2016. Study results will be anticipated in 2017. This study will investigate the antiproliferative potential of MET in combination with EVE and OCT in pWDNETs. MetNET1 prospective trial (EudraCT 2014-000888-41) may be helpful to either confirm or discard these preliminary findings. Disclosure: All authors have declared no conflicts of interest.