Abstract 1397
Background
Alterations in CDK4-cyclin D-retinoblastoma (Rb) pathway may lead to carcinogenesis in many cancers. Human Papilloma Virus (HPV) plays a major role in 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. Loss of p16 expression is known as a poor prognostic marker in SCCHN for survival. A novel therapy for p16/HPV-negative SCCHN is clearly an unmet medical need. Palbococlib is an orally active, highly selective inhibitor of the CDK4/6 with ability to block Rb phosphorylation. In a phase I study of palbociclib and cetuximab in refractory recurrent/metastatic SCCHN, the maximum tolerated dose (MTD) was not reached. In addition, palbociclib showed a radiosensitization property in a preclinical study. Thus, addition of palbociclib to cetuximab and IMRT provides a strong rationale to improve an efficacy for treatment of locally advanced SCCHN, especially in p16/HPV-negative tumor.
Trial design
This is a dose escalation phase I/II study designed to determine the MTD and toxicity of palbociclib, cetuximab, and IMRT for locally advanced SCCHN, using a classical 3 + 3 design. The study included locally advanced SCCHN of oral cavity, oropharynx, larynx, and hypopharynx. Nasopharyngeal carcinoma and other SCCHNs were excluded. Palbociclib has been escalated in 3 dose levels (DLs), starting from 75 mg, and escalated to 100 and 125 mg PO daily for 21 days on and 7 days off for 2 cycles. In all DLs, cetuximab was given at 400 mg/m2 IV on day -7 and then 250 mg/m2 IV weekly for 7 weeks. IMRT was delivered 5 days on and 2 days off with a total dose of 70 Gy for 33 fractions. At the MTD or RP2D, we will accrue up to 15 locally advanced p16-negative SCCHN patients to allow for definitive evaluation of tolerability, correlative endpoints and preliminary efficacy. Potential biomarkers involving the CDK4-cyclin D-Rb pathway alterations and HPV status will be explored. To date, a total of 8 patients were accrued in the study. The latest patient was accrued to the DL3 cohort, which is the last dose level.
Clinical trial identification
NCT03024489.
Legal entity responsible for the study
Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
Funding
Pfizer.
Editorial Acknowledgement
Disclosure
N. Ngamphaiboon: Research funding: Pfizer, MSD; Advisory board: Roche, MSD, Amgen; Lecture honorarium: Roche, AstraZeneca, Eli Lilly, Eisai, Amgen. N. Jinawath: Advisory Board: Amgen. All other authors have declared no conflicts of interest.