Background: Low and intermediate grade neuroendocrine tumors (NETs) are incurable once they metastasize. Cytoreductive surgery and locoregional therapies play an important role in their management, but ultimately most patients are treated with systemic therapies. In clinical studies, combination of temozolomide (TMZ) and capecitabine (CAP) demonstrated significant response rates (> 50%) in patients with advanced pancreatic NETs. Trifluridine/tipiracil (FTD/TPI), also known as TAS-102, is a new anti-metabolite agent that is non-cross resistant with 5-fluorouracil (5-FU) and CAP and that has a different toxicity profile from CAP. In clinical trials, FTD/TPI has been associated with limited toxicities in patients with chemotherapy refractory (including 5-FU and CAP) metastatic colorectal cancer. Given that CAP has demonstrated activity in metastatic NETs, we hypothesize that FTD/TPI in combination with TMZ will be well tolerated and will be efficacious in metastatic NETs. Methods: This is a two-part investigator-initiated phase IB clinical trial (NCT02943733). Part 1 is a dose escalation portion of the study that will determine maximum tolerated doses of FTD/TPI administered in combination with TMZ in patients with advanced NETs. Patients with low and intermediate grade NETs of any origin are eligible for part 1. This part follows a classical “3+3” design to establish the phase 2 doses. Both drugs are oral agents that are administered on a 28 day cycle. FTD/TPI is taken twice a day on days 1-5 and days 8-12. TMZ is taken daily on days 8-12. This schedule was selected based on the pre-clinical data demonstrating schedule-dependent synergism between 5-FU and TMZ. Because of concern for overlapping bone marrow toxicities between the two agents, TMZ is started at the dose of 100 mg/m2 and escalated to a goal dose of 200mg/m2 daily if no dose limiting toxicities are observed. FTD/TPI is started at a goal dose of 35 mg/m2. Part 2 of the study will enroll estimated 15 patients with metastatic pancreatic NETs. Primary endpoint of part 2 is overall response rate, and secondary endpoints are progression free survival, disease control rate and overall survival. Part 1 of the trial is currently open to enrollment. Clinical trial information: NCT02943733