Background: PNETs are distinguished by increased vascularity and benefit from anti-angiogenic therapies. PZ is a tyrosine kinase inhibitor (TKI) of VEGFR-1-3, PDGFR-α, -β, and c-Kit with single agent activity in PNET (overall response rate (ORR) 22%, median PFS of 14 mo and median OS of 25mo). TM is an oral alkylating agent also with known single agent activity in well-differentiated NETs (PFS of 7 mo). The rationale for the combination of TM and VEGF TKI is based on preclinical synergism through alteration of the tumor microenvironment by VEGF TKI to enhance the activity of TM. Methods: This is an open-label phase I/II study to determine the maximum tolerated dose (MTD), safety profile, ORR and pharmacokinetics (PK) of TM and PZ in patients (pts) with advanced well-differentiated PNETs who received 1-4 prior therapies. In a 28-day cycle, TM was given days 1-7 and 15-21 with PZ 400 mg once daily continuously. Dose escalation cohorts of TM: (-2) 75 mg/m², (-1) 100 mg/m², and (1) 150 mg/m². PK analysis was performed for 6 pts at MTD. The phase II portion at MTD is ongoing. Results: 28 pts with advanced well-differentiated PNETs were enrolled in phase I between Feb 2013 and Jan 2016 (16 at cohort -2, 5 at cohort -1, and 7 at cohort 1). 2 pts were not evaluable for any endpoint. There were 5 dose-limiting toxicities (DLTs): hepatic dysfunction (2), thrombocytopenia (2) and neutropenia (1). The MTD was at dose level -2, TM 75 mg/m² and PZ 400 mg. The most common treatment-emergent adverse events were hepatic toxicity (16%), nausea (5%) and fatigue (5%). Best ORR was PR in 5 pts (25%) and SD in 9 pts (45%). At a median follow-up of 18.5 mo, the median PFS was 12.1 mo (95% CI, 5.7-25.1) and median OS was 36.2 mo (95% CI, 21.4-56.4). Conclusions: The combination of TM and PZ was tolerable at a dose level of -2 with hepatic toxicity and myelosuppression as the DLTs. The ORR was 25% with disease control rate of 70% in patients with previously treated advanced well-differentiated PNETs. The phase II component of the study is ongoing. Clinical trial information: NCT01465659