The majority of Human Papilloma Virus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) has inactivation of p16, an inhibitor of the Cyclin-Dependent Kinases (CDK) 4 and 6, and 20-30% present CCND1 amplification. These alterations promote cell cycle progression and tumor proliferation. EGFR upregulation could also induce elevation of cyclin D1 and CDK4. Cetuximab, an anti-EGFR mAb, improves survival in combination with platinum-based chemotherapy in recurrent SCCHN. This study is investigating the combination of ribociclib, an orally highly selective inhibitor of CDKs 4/6, and cetuximab in recurrent SCCHN. p16-negative recurrent and/or metastatic SCCHN patients (pts) who progress after platinum-based chemotherapy were included in this phase 1 study. All the pts received cetuximab at the recommended dose (400 mg/m2 followed by 250 mg/m2/week, IV), combined with ribociclib (3 weeks on/1 week off), in a classical 3 + 3 dose-escalation design. The first dose level of ribociclib was 400 mg/day and the second dose level 600 mg/day. The primary endpoint was to determine the maximum tolerated dose (MTD) of Ribociclib in combination with cetuximab. Between April 2015 and January 2016, 10 pts (median age: 62.5 years; site location: larynx (2), hypopharynx (2), oropharynx (2), oral cavity (4)) were enrolled, including 6 pts previously treated with cetuximab. No dose limiting toxicities (DLTs) were observed at the first dose level. At the second dose level, 1 pt presented rapid disease progression and was therefore replaced as he could not be evaluated for toxicity. One pt out of 6 experienced DLT (Grade 4 thrombopenia lasting more than 7 days). The most common grade 3/4 treatment-related adverse events were neutropenia (n = 2), anemia (n = 2), thrombopenia (n = 1), hypocalcemia (n = 2), hypokaliemia (n = 2), hypomagnesemia (n = 1) and hypoglycemia (n = 1). No objective responses were observed but 4 pts achieved a stable disease according to RECIST v1.1, including 2 pts previously treated with cetuximab. The MTD of ribociclib in combination with standard dose of cetuximab is 600mg daily (3 weeks on/1 week off). An expansion cohort is currently ongoing.