Background: Systemic chemotherapy plays a role in treating neuroendocrine tumors. Trifluridine/tipiracil (FTD/TPI), known as TAS-102, is an antineoplastic agent that is non-cross resistant with 5-fluorouracil and capecitabine and that has a different toxicity profile. We are presenting results from a phase 1 portion of the study evaluating safety of FTD/TPI in combination with TMZ in patients in neuroendocrine tumors. Methods: Phase 1 portion to the study utilized “3+3” design to determine maximum tolerated doses (MTD) of FTD/TPI and TMZ when administered in combination. Patients with advanced NETs of any grade were eligible for participation. FTD/TPI was taken twice a day on days 1-5 and 8-12 and TMZ was taken daily on days 8-12 of a 28 day cycle. 3 dose levels (Lv) were evaluated. FTD/TPI was started at a goal dose of 35 mg/m² twice daily. Three doses of TMZ were studied: 100, 150 and 200 mg/m². Growth factor support was required during DLT evaluation period for all patients starting with the fourth subject on study. Results: Sixteen evaluable subjects (6 females, median age 64) enrolled in the phase 1 portion of the study (4 on Lv1, 6 on Lv2, 6 on Lv3). 3/16 had high-grade tumors, 8/16 had non-GI or unknown primary. No DLTs were observed on Lv1. One DLT was observed on Lv2 (grade 3 fatigue and inability to resume treatment) and 1 DLT on Lv3 (grade 4 thrombocytopenia). Overall the treatment was well tolerated. 7 subjects had grade ≥3 AEs at least possibly related to treatment, with neutropenia and lymphopenia being the most common. 4 subjects required dose reductions. 7 subjects remain on active treatment. 4 subjects discontinued treatment due to AEs and 1 due to clinical disease progression. Efficacy data is being collected and will be presented at the meeting. Conclusions: This study established MTD of FTD/TPI (35mg/m² twice daily) and TMZ (200 mg/m²). This regimen is well tolerated. Enrollment into expansion cohort for patients with advanced Grade 1-2 pancreatic NETs is ongoing (NCT02943733). Clinical trial information: NCT02943733