Cyclin D kinase 4 (CDK4) is a key regulator of the G1-S transition in the cell cycle.
Alterations in CDK4-cyclin D-retinoblastoma (Rb) pathway may lead to carcinogenesis in many
cancers. Several mechanisms have been described: (i) Amplification or overexpression of
cyclin D1, (ii) Amplification of CDK4, (iii) Activating mutation of CDK4, and (iv) Loss of
the CDK4 inhibitor, p16 (CDKN2A). Human Papilloma Virus (HPV) plays a major role in squamous
cell carcinoma of head and neck (SCCHN) carcinogenesis. It induces many alterations in the
CDK4-Cyclin D-Rb and apoptotic pathways such as up-regulation of p16, loss of Rb and p53
functions. A novel therapy for HPV-negative SCCHN is clearly an unmet medical need.
Palbococlib (PD 0332991) is an orally active, highly selective inhibitor of the CDK4/6 with
ability to block Rb phosphorylation in the low nanomolar range. The most advanced development
is in a treatment of metastatic breast cancer. In addition, palbociclib showed a
radiosensitization property. Since combination of cetuximab and radiation improved PFS and
overall survival (OS) in locally advanced unresectable SCCHN when compared with radiation
alone, these provide a strong rationale to evaluate a combination of palbociclib, cetuximab,
and radiation for locally advanced unresectable SCCHN. Because many genetic alterations in
SCCHN significantly involve in the CDK4-cyclin D-Rb pathway, predictive biomarker(s) of
palbociclib in this combination will be explored.
Thus, the investogators propose a non-randomized, dose escalation, phase I study designed to
determine the maximum tolerated dose (MTD) and toxicity of palbociclib, cetuximab, and IMRT
for locally advanced unresectable SCCHN.