Background: Changes in the retinoblastoma (Rb) tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). In the pre-clinical setting, loss or downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have contributed to NET development. Separately, rigorous investigation of everolimus in WDNETs has demonstrated a survival benefit in this patient (pt) population. Pre-clinical data suggests that the Cdk4/Cdk6 inhibitor LEE011 is synergistically active with everolimus. The aim of this study is to evaluate the efficacy and safety of LEE011 in combination with everolimus in pts with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, pancreatic). Methods: This study is a multicenter, non-randomized, open-label phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with WDNET of foregut origin, low to intermediate grade, unresectable and/or metastatic, disease progression ≤ 12 months prior to enrollment, ECOG 0-1. Between 15 and 43 patients will be enrolled from three sites across the US. LEE011 300mg daily, 3 weeks on and 1 week off, in combination with everolimus 2.5mg daily (final dosing based on phase 1b clinical trial performed in metastatic breast cancer; LEE011X2106) will be administered orally until disease progression, unacceptable toxicity, investigator decision, or pt withdrawal. All enrolled pts will be followed by telephone contact for overall survival until death or consent withdrawal. The primary endpoint, progression free survival, will be assessed based on radiographic review by RECISTv1.1. Main secondary endpoints include establishing the safety of this drug combination in this patient population, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the Rb pathway and/or WDNET pathogenesis. This trial began enrollment in 2/27/2017, with 10 patients enrolled to date. Clinical trial information: NCT03070301