Background: Diabetic patients with head and neck squamous cell carcinoma (HNSCC) receiving the oral hypoglycemic, metformin, demonstrated improved survival compared to those not on metformin when treated with curative intent cisplatin and radiation (CRT) in retrospective analyses. Pre-clinically, metformin has been shown to inhibit mTOR, a signaling pathway that regulates cell growth and survival, commonly activated in HNSCC. Pretreatment with metformin resulted in a decrease in oral cavity tumors in mice. Here we are prospectively investigating escalating doses of metformin in combination with CRT in locally advanced HNSCC in non-diabetic patients, and the mechanism by which metformin may exert its effect. Methods: Patients with locally advanced HNSCC receive oral metformin administered in escalating doses (1000mg BID, 850mg TID or 1000mg TID) for 7-14 days prior to initiation of cisplatin (100 mg/m2 administered on days 1, 22 and 43) along with concurrent radiation therapy (70 Gy). Initially, metformin was escalated to assigned cohort dose over 7 days prior to CRT. However, quick escalation was poorly tolerated and therefore, the protocol was modified to allow a slower dose escalation over 14 days. Metformin is continued throughout treatment. Blood samples are collected before and after metformin as well as during chemotherapy. Flow cytometry to detect percent circulating immune activated cells (CD8+ and PD-1+) and clinical laboratory tests including serum glucose, vitamin B12 and C-peptide levels are being performed. Clinical trial information: NCT02325401