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Everolimus plus Octreotide LAR plus Metformin

Filippo De Braud, MD

Roberto Buzzoni, MD

Sara Pusceddu, MD

Abnormal PI3K-Akt-mTOR (mammalian target of rapamycin) 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 ( primitive neuroectodermal tumor) cells. Everolimus ,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 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 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 (adenosine monophosphate kinase) activation and consequently inhibition to TSC1(tuberous sclerosis complex 1) -2/mTOR complex, mediated to LKB1 oncogene expression. The investigators retrospective experience, despite in a limited group of pWDNET, highlights the role of MET to improve clinical benefit in diabetic pts receiving EVE-OCT (octreotide) combination.

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.

The main objective of this study is to evaluate progression free survival rate at 12 months of treatment. The secondary objectives are safety, overall survival, response rate evaluation.

A sub-study analysis will evaluate circulant biomarkers levels (IL 6, IGF1) in blood samples.

Activity and Safety of Everolimus+Octreotide LAR+Metformin in Advanced Pancreatic Well-differentiated NETs

Activity and Safety of Everolimus in Combination With Octreotide LAR and Metformin in Patients With Advanced Pancreatic Well-differentiated Neuroendocrine Tumors (pWDNETs): a Phase II, Open, Monocentric, Prospective Study

progression free survival rate at 12th month of treatment, according to RECIST criteria version 1.0

safety is measured according to the National cancer Institute-Common Toxicity Criteria v. 3.0 guidelines

overall survival is defined as the time interval between enrollment and the date of the death from any cause.

response rate is defined as the percentage of patients presenting objective responce of the disease, according to RECIST Criteria version 1.0.

the biochemical response is defined as the impact of study treatment on general neuroendocrine tumors biomarkers, Chromogranine A and Enolase neuron specific and circulating plasma IL6, IL8 and IGF-1 levels.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Activity and Safety of Everolimus+Octreotide LAR+Metformin in Advanced Pancreatic Well-differentiated NETs	NCT02294006	Well Differenti...	Everolimus plus...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Activity and Safety of Everolimus+Octreotide LAR+Metformin in Advanced Pancreatic Well-differentiated NETs	NCT02294006	Well Differenti...	Everolimus plus...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

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