Background: Everolimus and sunitinib targeted therapy have proven efficacy in advanced PNET, with ORR 5-9% and PFS HR < 0.5 compared to placebo.Additionally, a single arm phase II study showed promising activity with temozolomide and capecitabine combination with an ORR of 70%. Rationale:PNETs are distinguished by their vascularlity and up-regulation of VEGF factors. In the preclinical setting, the combination of temozolomide and sunitinib appears to act synergistically by altering the tumor microenvironment enhancing activity of temozolomide. Pazopanib has shown activity in a single arm phase II study in advanced PNETs with a 6-month PFS rate of 80% and ORR of 17%. There is sufficient preclinical and clinical evidence suggesting that the combination of an anti-angiogenic agent with temozolomide is more efficacious, hence, our rationale for the current study. Methods: Objectives: (1) Determine the MTD and toxicity profile of temozolomide + pazopanib. (2) Describe the PK profile of this combination. (3) Observe the ORR. Trial Design:Open label Phase I study to determine the MTD and safety profile employing a 3+3 dose-escalation model of the combination of temozolomide and pazopanib in patients with advanced PNET who have received between 1-4 prior therapies. Cohort 1: temozolomide at 150 mg/m² on Days 1-7 and 15-21, and pazopanib 400 mg orally once daily continuously throughout cycle of 28 days. Once MTD is determined, PK sampling will be performed in 6 additional patients enrolled at the MTD. To date, eleven patients have been enrolled in cohort 1 and cohort -1. Cohort -1 is currently accruing at the reduced dose level of temozolomide 100mg/m² and pazopanib 400mg daily for the duration of the cycle. The trial is funded to proceed to a single arm phase II with exploratory end points: (1) Correlation of MGMT expression by IHC to ORR and PFS (2) tumor blood flow (perfusion CT imaging) relationship with ORR. (This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline.) Clinical Trial information: NCT01465659. Clinical trial information: NCT01465659