Background: Pazopanib (Pazo) is an angiogenesis tyrosine kinase inhibitor(TKI) targeting VEGFR-1, -2, and -3; PDGFR-α, -β; and c-Kit. Pazo has shown activity in a single arm phase II study in PNET with ORR 17%, 6mo PFS rate 80%. Temozolomide (tem) is an oral alkylating agent, which has shown promising activity (ORR70%) in combination with capecitabine in small retrospective PNET trial. In the preclinical setting, the combination of tem and VEGF TKI acts synergistically altering tumor micro environment enhancing tem activity, hence the rationale for our trial. This phase I study evaluates safety, and clinical benefit of tem+pazo in advanced PNET pts. Methods: Eligible pts have advanced well differentiated PNET, 0-4 prior therapy, prior tem was allowed, ECOG PS 0, 1, 2. Pts were enrolled into 3 sequential cohorts of tem(1) 150, (-1) 100, (-2) 75 mg/m2 PO QD(D1-7,15-21) + Pazo 400mg PO QD every 28 days. Endpoints included incidence DLT, MTD, adverse events (AE), PK of tem + its metabolite, and ORR. Results: As of 1/2016, 18 pts enrolled (cohort1=7; cohort-1=5, cohort-2=6). 7 females. Median (range) age=52 (21-71); 11(61%), 6(33%), 1(5%) had ECOG scores 0, 1 and 2. All received ≥1 28D cycle, median (range) number cycles=6 (1-41), median (range) time on treatment = 24 (4-164) weeks. There were 3 DLT: 2 (dose level 1) = grade 4 thrombocytopenia, and neutropenia, 1 (dose level-1) = grade 3 liver toxicity. MTD was tem 75/m2 QD (D1-7,15-21) + pazo 400 QD. 7 (39%) pts had grade 3-4 AE, most common being neutropenia (15%), thrombocytopenia (11%), liver toxicity (11%), and diarrhea (9%). Best ORR by RECIST:7 (39%) PR, 8 (44%) SD, 2 (11%) PD. Median PFS = 9.7 mo, 1 year OS rate = 94%. Conclusions: Pazo+tem combination at MTD dose is well tolerated, and has promising clinical activity in advanced PNET. PK cohort at MTD dose is ongoing. A single arm phase II trial is planned. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Novartis Pharmaceuticals Corporation (formerly GlaxoSmithKline, LLC). Clinical trial information: NCT01465659