Background: Angiogenesis plays an important role in tumorigenesis and progression of pNETs. Evofosfamide (EVO) is a DNA alkylator prodrug that selectively activates under hypoxia. Sunitinib as monotherapy shows a wide range of responses (9-24%) in similar populations. We hypothesized that sunitinib-induced hypoxia might increase the cytotoxic activity of EVO in patients with metastatic pNETS and naïve for systemic treatment other than somatostatin analogues (SSA). Methods: This is a phase-II, single-arm, and multicenter trial of EVO (340mg/m2 on days 8, 15 and 22 every 4 weeks) and sunitinib (37.5mg/day continuously). Primary endpoint was Objective Response Rate (ORR) by RECIST v1.1 assessed every 8 weeks. A Simon two-stage optimal design was used, considering a minimum of 3 responses in the first 18 pts in order to start with the second stage (power = 0.80, alpha = 0.05). Results: Between May/2015 and May/2018, 17 pts were included (median age was 62.4 y.o). Prior SSA was reported in 7 (41.2%) pts and 8 (47.1%) had a Ki-67 > 10%. There were 2 responders (11.8%; n = 1 complete and n = 1 partial response); stable disease was observed in 76.5%. Median (range) PFS and duration of response were 10.4 months (m) (2.9-17.9m) and, respectively 24.4m (13.7-35.2m), respectively. Grade 3 or 4 adverse events occurred in 11 (64.7%) pts, being neutropenia (33.3%), fatigue (16.7%), thrombocytopenia (11.1%), hand-foot syndrome (5.6%), and pancreatitis (5.6%) the most frequent. Toxicity led to treatment discontinuation in 5 (38.5%) pts. Dose reductions were reported in 20% (sunitinib) and 100 % (EVO) of pts. Conclusions: Combination of sunitinib and EVO failed to demonstrate activity in terms of tumor shrinkage as only two patients achieved response, therefore, second stage was not proceeded. While cross trial comparisons are difficult, response rate of 12% with the combination was disappointing. Concerns over toxicity arose; translational analysis are undergoing. Clinical trial information: NCT02402062