 In the mammalian cell cycle, entry into S phase is achieved by cyclin-dependent kinases 4 and 6 CDK46, which activate a family of E2F transcription factors by phosphorylating and deactivating the retinoblastoma protein pRb. LEE011 is an orally, highly selective small molecule inhibitor of CDK46 that potently induces G1 arrest with sub-micromolar IC50s in a variety of pRb-positive cancer cells. A recent study showed that an inhibitor of the CDK4-CCND1 complex showed promising results in SCCHN pre-clinical models. There is a strong rationale to investigate CDK inhibitors in this disease. In phase IbII study as a single agent, the major toxicities observed were Grade 3 and 4 fatigue 53.8, nausea 50.8, neutropenia 47.7, anemia 37.1, leukopenia 46.2, thrombocytopenia 34.1, diarrhea 32.6, vomiting 34.8, lymphocytes count decreased 30.3, anorexia 21.2, hyperglycemia 21.2, constipation 19.7, hypoalbuminemia 18.9, dyspnea 18.2 and cough 16.7. 