Background: Overexpression of cyclin D1 and inactivation of p16 occur in the majority ( > 90%) of HPV-unrelated HNSCC. Resistance to cetuximab and cisplatin, the two most effective systemic agents in HNSCC, is in part attributable to cyclin D1 overexpression which can be targeted with inhibitors of the cyclin D axis. Palbociclib is a selective inhibitor of CDK4/6. Methods: A phase I trial was performed to determine the maximum tolerated dose (MTD) of palbociclib added to cetuximab. Palbociclib was given orally q.d. on days 1-21 of each 28 day cycle and cetuximab was given weekly (400 mg/m², then 250 mg/m²). Palbociclib was given at 100 mg/d (level 1) or 125 mg/d (level 2: max dose). Fibonacci (3+3) design was utilized. Eligible patients (pts) had incurable HNSCC (p16 -or +) and adequate organ function. Correlative studies included total and p- Rb (IHC), p16 (IHC), and PK analysis of palbociclib. Tumor response assessment using RECIST criteria 1.1 was performed every 2 cycles. Results: Nine pts were enrolled (5 platin and cetuximab-resistant and 1 cetuximab-resistant ; 5 p16- and 4 p16+): 3 pts on dose level 1 and 6 pts on dose level 2. Mild (grade 1/2) neutropenia and thrombocytopenia occurred in 2 pts on dose level 1 and in 4 and 3 pts, respectively, on dose level 2. The MTD was not reached as there were no dose limiting toxicities and no AE-related treatment discontinuations. Tumor response assessment following cycle 2 showed partial response in 2 pts (both at dose level 2; both p16 – HNSCC; one with cetuximab- and platin-resistant disease), stable disease in 5 pts (one with cetuximab-resistant disease with an 18% decrease in target lesions), progression in 1 pt, and not yet evaluable in 1 pt. Median time-to-progression was 112 (range: 28-182) days. Conclusions: The MTD of palbociclib was not reached during the phase I study; 125 mg/d given on days 1-21 of a 28 day cycle when added to cetuximab, was determined as the recommended phase II dose. Impressively, tumor responses occurred in pts with cetuximab- and platin-resistant HNSCC. Phase II of the trial is enrolling pts with p16-/Rb+ HNSCC on Arm 1 (platin-resistant disease) and Arm 2 (cetuximab-resistant disease). Clinical trial information: NCT02101034