Background: Up to 60% of HNSCC present as locally advanced disease (LAHNSCC). Although prognosis has improved significantly, 3 year PFS and OS remain at 62%, and 73% respectively (RTOG 0522) despite definitive cisplatin (Cis) based chemo-radiation (CRT), underscoring the need for improved regimens. Metformin (MET) is hypothesized to suppress tumor cell growth by mTOR pathway inhibition, which mediates the phosphoinositide 3-kinase/Akt signaling pathway (frequently deregulated in HNSCC). Retrospective studies suggest that MET improves survival in HNSCC patients (pts). Therefore, we conducted a phase I open-label single site dose escalation study combining MET with CRT in LAHNSCC (NCT02325401). Methods: Previously untreated LAHNSCC (Stage III/IV) pts were enrolled to receive escalating doses of MET with a 7-14 day lead-in prior to CRT based on modified toxicity probability interval design. Starting dose of MET was 2000mg daily in addition to Cis (100mg/m2 days 1, 22 and 43) and standard radiation (70Gy) (Table 1). Adverse events were categorized per CTCAE v4.03. Results: 20 pts were enrolled, (2 replaced due to withdrawal of consent during lead-in period). Most common grade ≥ 2 toxicities were nausea (25%), vomiting (25%), diarrhea (20%), and AKI (15%). Dose limiting toxicity (DLT) included Grade 3 diarrhea (cohort 3) and AKI (cohort 2). MTD was established at 2550mg daily in combination with CRT. Median age was 55 (46-65); majority pts were male (95%), Caucasian (95%), tobacco users (70%), and HPV positive (70%). After a median follow up of 18 months (range 1-26), 1-year PFS, and OS remain at 94%. 1 death was reported (sudden cardiac, unrelated, occurred > 8 weeks after stopping MET). Pharmacokinetic data showed that Cis did not affect MET steady state. Conclusions: For the first time, MET is shown to be safe and tolerable in combination with CRT with an impressive impact on survival in LAHNSCC pts. This warrants further investigation in a phase II trial, with the established MTD of 2550 mg as the recommended dose. Clinical trial information: NCT02325401