Background: In pre-clinical models of HNSCC, VEGFR, PDGFR, and c-kit are frequently overexpressed. Upregulation of angiogenesis by VEGFR activation is a mechanism of resistance to EGFR inhibitors. Inhibitors of VEGFR reduce the proliferative capacity of EGFR inhibitor–resistant HNSCC. Pazopanib is a small molecule inhibitor of VEGFR, PDGFR and c-kit. We hypothesized that pazopanib added to cetuximab would be feasible and could improve the efficacy of cetuximab in incurable HNSCC. A suspension formulation was chosen due to swallowing problems or requirement for gastrostomy tube in these patients. Methods: A phase I trial was performed to determine the maximum tolerated dose (MTD) of pazopanib suspension added to fixed doses of cetuximab. Pazopanib was given once daily and cetuximab was given once weekly (400 mg/m², then 250 mg/m²) over each 8 week cycle. Planned dose levels of pazopanib were 200 mg/d (level 1), 400 mg/d (level 2), 600 mg/d (level 3) and 800 mg/d (level 4). Fibonacci (3+3) design was utilized. Eligible pts had incurable HNSCC and adequate organ function. Tumor response assessment was performed per RECIST 1.1 criteria after each cycle. Results: Nineteen pts were enrolled: 3 on level 1 (no dose-limiting toxicity [DLT]), 6 on level 2 (1 DLT – grade 3 neutropenia), 7 on level 3 (1 DLT -grade 3 proteinuria; 1 non-evaluable due to early disease progression), and 3 on level 4 (no DLT to date with these 3 pts at cycle 1 week 3). Best overall response: 4 partial (PR, 25%), 7 stable (SD, 44%), 5 progression (31%) and 3 not evaluable. Median time-to-progression was 112 (range: 21-280) days. Disease control (PR+SD) as best overall response occurred in 2 of 2 pts with cetuximab-resistant disease, 5 of 6 (2 not yet evaluable) pts with platin- and cetuximab-resistant disease, 0 of 3 pts with platin-resistant disease, and 4 of 5 (1 not yet evaluable) pts with platin- and cetuximab-naïve disease. Conclusions: The MTD of pazopanib has not yet been reached during the phase I study. The PR (25%) and disease control (69%) rates compared favorably with prior trials of cetuximab alone. Clinical trial information: NCT01716416