Background: In preclinical HNSCC models, combined EGFR and Src inhibition with radiation has additive and possibly synergistic effects. We conducted a 3+3 standard Ph1 trial to determine the maximum tolerated dose (MTD) of D, a multi-targeted tyrosine kinase inhibitor with activity against Src, combined with the EGFR monoclonal antibody Cet + IMRT +/- P in early stage II/III HNSCC (Cohort A) and more locally advanced stage III/IVa,b HNSCC (Cohort B) as definitive treatment for HNSCC. Secondary objectives were response, disease free survival and correlation with FDG-PET, exploratory biomarkers of EGFR, Src pathways and HPV status. Methods: Both cohorts A and B had a 14 day “run-in” prior to starting IMRT consisting of Cet 400mg/m² on day 1, then 250mg/m² day 8 & 14 , daily oral D day 8-14 . IMRT 200cGy/fx for 35 fractions began day 15-64 with concurrent D + Cet in Cohort A and D + Cet + P 75mg/m2 q 3 wk for Cohort B. Dose levels for daily D were 70 mg, 100 mg, 150 mg. Exploratory biomarkers, and PET scan were performed at baseline, day 14/15 and 8 weeks post chemoradiation. Results: A total of 21 pts enrolled, 3 withdrew consent. Primary site were Oropharynx (15), hypopharynx (3), Larynx (1). Sex: male (15), female (4). Tumor HPV ISH was positive (10) and HPV negative (8) pts. Within Cohort A: 70 mg (3), 100mg (3) was completed without DLT. In Cohort B:70 mg (7pts enrolled, 1 DLT with grade 3 infection, one pt was replaced), 100mg (3) completed with no DLT, and 150mg (2), noted DLT in 1 pt with febrile neutropenia. The study was closed due to slow accrual, MTD was not reached for Cohort A or B. Grade 3-4 toxicities: Cohort A :rash (1), mucositis (1), radiation dermatitis (1) Cohort B: febrile neutropenia (1), grade 3 skin infection(1), mucositis(2), dry mouth (1), dysphagia(1), diarrhea(1)and hypophosphatemia(1) were noted. The best overall response 8 wks post-treatment in Cohort A, CR+PR (5) and PD (1), in Cohort B , CR+PR ( 11/11). With longer follow-up, survival outcomes will be correlated with response and correlatives. Conclusions: Combination of D/Cet/IMRT and D/Cet/P/IMRT appears to be safe and well-tolerated only at dose level 70 and 100mg in HNSCC. Clinical trial information: NCT00882583