Safety of lanreotide 120 mg ATG in combination with metformin in patients with advanced well-differentiated gastro-intestinal (GI) or lung carcinoids. A pilot, one-arm, open-label, prospective study: The MetNET-2 trial

Background: In the CLARINET trial, lanreotide 120 mg resulted in a 53% reduction in the risk of death or disease progression, compared with placebo, in GI-NET patients. Metformin (MET) has recently shown some anti-proliferative activity, both in vitro and in vivo studies, thanks to its ability to decrease insulin and IGF1 levels; in addition, it exerts an antitumor effect due to AMPK activation and consequent inhibition of the TSC1-2/mTOR complex. Our retrospective experience in a large group of pancreatic NET, has suggested that MET may provide additional clinical benefit in diabetic pts receiving everolimus and/or somatostatin analogues. This study evaluates the safety of lanreotide 120 mg ATG in combination with metformin in patients with progressive advanced well-differentiated GI or lung carcinoids. Methods: Pts with advanced GI or lung carcinoids will receive a combination of lanreotide 120 mg ATG mg/month and MET 2550 mg/day, until progression or inacceptable toxicity. Tumor radiological progression will be assessed every 4 months. The primary objective is to evaluate the incidence of adverse events (AEs) and severe AEs. A 1-stage Hern design will be used. The null hypothesis that the serious adverse events rate related to the treatment is [25%] will be tested against a one-sided alternative. 20 patients with available tissue specimens will be enrolled. The null hypothesis will be rejected if =2 patients will experience a severe toxicity. This design yields a type I error rate of 10% and power of 85% when the true toxicity rate is = 5%. The expression of 111 genes potentially involved in the pathways related to MET (e.g., LKB1, TP53, KRAS, IGF1R, VEGFR, PDGFR, AKT, PIK3CA, PTEN, mTOR) will be assessed by a Target NGS approach (IONTORRENT Technology/PGM machine). Other endpoints include time to progression, symptomatic response and biochemical response (chromogranine A levels). Results: In March 2016, the trial received institutional ethic board approval and in April 2016 the enrollment was started (EudraCT 2015-004626-34). Recruitment will be completed by April 2017. Study results will be available in 2017. Conclusions: This study will investigate the safety of the combination of MET and lanreotide 120 mg ATG and the correlation between tumor mutations and response to this therapy.