1123P - A phase I study of the CDK4/6 inhibitor, palbociclib in combination with cetuximab and intensity modulated radiation therapy (IMRT) for locally advanced squamous cell carcinoma of the head and neck (SCCHN); A result of dose escalation cohort

Abstract

BackgroundHPV induces many alterations in CDK4-Cyclin D-Rb and apoptotic pathways such as up-regulation of p16, loss of Rb and p53 functions in SCCHN carcinogenesis. Loss of p16 expression is known as a poor prognostic marker in SCCHN for survival. Palbociclib is a highly selective inhibitor of CDK4/6 by blocking Rb phosphorylation with radiosensitizing activity in preclinical studies. Addition of palbociclib to cetuximab and IMRT provides a strong rationale to improve efficacy of treatment in locally advanced SCCHN, especially in p16/HPV-negative tumour. MethodsThis is a phase I study designed to determine the maximum tolerated dose (MTD) and toxicity of palbociclib, cetuximab, and IMRT, using a classical 3+3 design (NCT03024489). The study included locally advanced SCCHN of oral cavity, oropharynx, larynx, and hypopharynx. Palbociclib dose was escalated with 3 dose levels (DLs), starting from 75 to 125mg/d orally for 21day-on and 7day-off for 2 cycles. For all DLs, cetuximab was administered at 400mg/m2IV on day -7 and then 250mg/m2weekly for 7 weeks. IMRT was delivered 5day-on and 2day-off with a total dose of 70Gy for 33 fractions. MRI and PET scans pre- and post-treatment was used to evaluate preliminary efficacy. ResultsA total of 13 eligible patients were enrolled in the dose escalation cohort. No MTD was observed. One DLT, febrile neutropenia (FN) was reported in 1 of 7 patients who received 125mg of palbociclib (DL3) at the 6thweek of IMRT. The FN recovered without G-CSF support within 7 days after discontinuation of palbociclib. Overall, toxicities were related to cetuximab and IMRT. Complete response was observed in 7 of 10 evaluable patients (70%), while overall objective response was demonstarted in 9 of 10 patients (90%). ConclusionsThe recommended phase 2 dose was palbociclib 125mg/d for 21 days on and 7 days off with full standard dose of cetuximab and IMRT for locally advanced SCCHN. MTD was not achieved. The combination was well tolerated with promising preliminary efficacy. The expansion cohort of palbociclib 125mg/d is currently accruing up to 15 locally advanced p16-negative SCCHN patients. Clinical trial identificationNCT#03024489. Legal entity responsible for the studyThe authors. FundingPfizer. DisclosureN. Ngamphaiboon: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Boehringer Ingelheim; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Taiho. T. Siripoon: Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Boehringer Ingelheim. S. Lukerak: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. N. Sankaseam: Research grant / Funding (institution): Roche; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca. E. Sirachainan: Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self): Sanofi/Aventis; Honoraria (self): Merck; Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Mundipharma; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): LF Asia; Honoraria (self): Diethelm Keller Logistics; Honoraria (self): BMS; Honoraria (self): Boehringer Ingelheim. All other authors have declared no conflicts of interest.