6008 Background: Elevated VEGF-A and VEGF-C have been reported in thyroid tumor tissue compared with normal thyroid. AG is a potent, small molecule inhibitor of VEGF receptors 1, 2 and 3. The efficacy and safety of AG therapy in pts with advanced thyroid cancers was examined in this single-arm, multi-center study. Methods: 60 pts with metastatic or unresectable locally-advanced thyroid cancer refractory to, or not suitable candidates for, 131iodine (131I) treatment, with measurable disease received AG at a starting dose of 5 mg orally BID. The primary endpoint was response rate (RR) by RECIST criteria. A Simon 2-stage minimax design was used (a=0.1; β=0.1; null RR=5%; alternative RR=20%). Samples were collected pretreatment and q8wks to explore relationships between clinical response and plasma soluble proteins. Results: Median age was 59 yrs (26–84), 35 (58%) were male. Histological subtypes included papillary: 29 pts (48%); follicular: 15 pts (25%)-11 (18%) with Hurthle cell variant; medullary: 12 pts (20%); anaplastic: 2 pts (3%), and other/unknown: 2 pts (3%). 53 pts (88%) had prior surgery, 42 (70%) had prior 131I treatment, 27 (45%) had prior external beam radiation, and 9 (15%) had prior chemotherapy. Partial response (PR) by investigator report was achieved in 13 pts (22% CI: 12.1, 34.2), with 31- 68% maximum tumor regression and duration of response (DOR) of 1–16 months. 30 pts (50%) have stable disease with a duration range of 4–13 months and 13–67% maximum tumor regression in 28 pts. Response assessments are ongoing. The treatment duration range is 6–670 days with 38 pts currently on study. Median PFS has not been reached with a median follow up of 273 days. The most common treatment-related adverse events were fatigue (37%), proteinuria (27%), stomatitis/mucositis (25%), diarrhea (22%), hypertension (20%) and nausea (18%). AG therapy consistently decreased soluble VEGFR2 and VEGFR3, and increased VEGF in the blood, demonstrating pharmacodynamic activity against targeted VEGF receptors. Conclusions: AG has substantial anti-tumor activity in advanced thyroid cancer with demonstrated pharmacodynamic activity. A global pivotal trial testing AG in doxorubicin refractory thyroid cancer is ongoing. [Table: see text]