Background: SCCHN is the sixth most common cancer worldwide. Current second-line treatments for human papillomavirus (HPV)–negative, R/M SCCHN have marginal effectiveness and significant toxicity. Therefore, improved treatment options are needed. Inhibition of the cyclin D1/cyclin-dependent kinase (CDK)4/Rb axis using the selective CDK4/6 inhibitor palbociclib (PAL) represents a rational treatment approach for patients (pts) with incurable, cetuximab-naive, HPV-negative SCCHN because loss of RB1 is infrequent but loss of CDKN2A expression or amplification of CCND1 occurs in most cases; the majority of a large cell line panel responded at low nanomolar concentrations of PAL; and PAL exhibited significant single-agent activity in a series of HNSCC patient-derived xenograft (PDX) models. A combinatorial approach with the epidermal growth factor receptor (EGFR) inhibitor cetuximab may further enhance antitumor effects because EGFR overexpression is considered an important driver in SCCHN pathogenesis; EGFR inhibition demonstrated strong synergy in combination with PAL in vitro; and PAL plus cetuximab showed significant antitumor activity in an HNSCC PDX model. A phase 1 trial established the safety of combining PAL with cetuximab in pts with incurable SCCHN, with a decrease in tumor target lesions observed in approximately 50% of pts (Michel, ASCO 2015, Abs: 6043). Methods: Patients with HPV-negative, cetuximab-naive R/M SCCHN after failure of 1 platinum-containing regimen will be randomized 1:1 to receive either 125 mg PAL orally daily for 21 days followed by a 7-day break in combination with weekly cetuximab (initial dose, 400 mg/m² followed by 250 mg/m²) or placebo plus the same regimen of cetuximab. The primary objective is to compare overall survival for both treatment arms. Secondary and exploratory objectives include evaluation of progression-free survival, PK/PD relationships, patient-reported outcome measures, and biomarker analyses. Clinical trial information: NCT02499120