MetNET1 trial designed to assess Everolimus, Octreotide LAR, and Metformin activity in advanced pWDNETs

Pancreatic neuroendocrine tumors (pNETs) often involve abnormal PI3K-Akt-mTOR pathway signaling and IGF1-mediated autocrine activation, driving proliferation. Everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in pNETs, alone or with Octreotide LAR, but struggles to significantly prolong overall survival (OS). Metformin, an AMPK activator, shows anti-cancer activity by decreasing insulin/IGF1 levels and inhibiting TSC1-2/mTOR complex. Retrospective data suggests Metformin may enhance Everolimus+Octreotide benefits in diabetic pWDNET patients, addressing the OS limitation.

This paper describes the design of the MetNET1 prospective trial (EudraCT 2014-000888-41). The study will investigate the antiproliferative potential of Metformin in combination with Everolimus and Octreotide LAR in pWDNETs. The main objective is to evaluate the progression-free survival rate at 12 months. Secondary objectives include safety, overall survival, and response rate evaluation. A sub-study will analyze circulating biomarker levels, specifically IL-6 and IGF1, in blood samples.

This paper describes the protocol for the MetNET1 prospective trial, which aims to investigate the activity and safety of Everolimus + Octreotide LAR + Metformin in advanced pancreatic well-differentiated neuroendocrine tumors (pWDNETs). The primary endpoint is the progression-free survival rate at 12 months. Secondary endpoints include overall survival, response rate, and safety. > The rationale for this trial is supported by prior retrospective experience, which suggested that Metformin improved clinical benefit in diabetic patients receiving Everolimus + Octreotide combination therapy for pWDNETs. The study will also include a sub-study to evaluate circulating biomarker levels, specifically IL-6 and IGF1, in blood samples to better understand the underlying mechanisms and potentially identify predictive markers.