Phase I trial of alpelisib in combination with concurrent cisplatin-based chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck

D Day; A Prawira; A Spreafico; J Waldron; R Karithanam; M Giuliani; I Weinreb; J Kim; J Cho; A Hope; A Bayley; J Ringash; S V Bratman; R Jang; B O'Sullivan; L L Siu; A R Hansen

doi:10.1016/j.oraloncology.2020.104753

Phase I trial of alpelisib in combination with concurrent cisplatin-based chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck

Oral Oncol. 2020 Sep:108:104753. doi: 10.1016/j.oraloncology.2020.104753. Epub 2020 May 25.

Authors

D Day¹, A Prawira¹, A Spreafico¹, J Waldron², R Karithanam¹, M Giuliani², I Weinreb³, J Kim², J Cho², A Hope², A Bayley², J Ringash², S V Bratman², R Jang¹, B O'Sullivan², L L Siu¹, A R Hansen⁴

Affiliations

¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/University of Toronto, Toronto, ON, Canada.
² Radiation Medicine Program, Princess Margaret Cancer Centre/University of Toronto, Toronto, ON, Canada.
³ Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON, Canada.
⁴ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre/University of Toronto, Toronto, ON, Canada. Electronic address: aaron.hansen@uhn.ca.

PMID: 32464516
DOI: 10.1016/j.oraloncology.2020.104753

Abstract

Background: Deregulation of the PI3K signalling pathway is frequent in squamous cell carcinoma of the head and neck (SCCHN) and may be implicated in radioresistance. We report on the results from a phase I 3 + 3 dose escalation study of alpelisib, a class I α-specific PI3K inhibitor in combination with concurrent cisplatin-based chemoradiation (CRT) in patients with locoregionally advanced SCCHN (LA-SCCHN).

Methods: Eligible patients had previously untreated LA-SCCHN and were candidates for CRT. The primary objective was to evaluate safety and determine the recommended phase II dose (RP2D). Alpelisib was given orally once daily at two dose levels: 200 mg and 250 mg. CRT consisted of cisplatin 100 mg/m² IV every three weeks and standard fractionation radiotherapy (IMRT) 70 Gy in 35 fractions.

Results: Nine patients were enrolled (six alpelisib 200 mg, three 250 mg). Oropharynx was the primary site in all patients (seven p16-positive; five T1-2N2M0, four T3-4N2-3M0 [AJCC 7th edition]). All patients completed CRT within seven weeks. Grade 3 alpelisib-related toxicities occurred in four patients. No dose-limiting toxicity (DLT) was observed at 200 mg among three DLT-evaluable patients. Two of two DLT-evaluable patients treated at 250 mg experienced DLTs (inability to complete ≥75% alpelisib secondary to radiation dermatitis and febrile neutropenia). Thus, RP2D was declared at 200 mg. After median follow-up of 39.7 months, two patients developed pulmonary metastases despite locoregional control. Three-year overall survival was 77.8% (95% CI 36.5%-93.9%).

Conclusion: Alpelisib at 200 mg has a manageable safety profile in combination with cisplatin-based CRT in LA-SCCHN.

Keywords: Chemoradiation; Chemoradiotherapy; Cisplatin; Head and neck cancer; Locoregionally advanced squamous cell carcinoma of the head and neck; PI3K inhibition; PI3K inhibitor; Phase I clinical trial.

Publication types

Clinical Trial, Phase I
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Chemoradiotherapy / methods*
Cisplatin / pharmacology
Cisplatin / therapeutic use*
Female
Humans
Middle Aged
Squamous Cell Carcinoma of Head and Neck / drug therapy*
Thiazoles / pharmacology
Thiazoles / therapeutic use*

Substances

Thiazoles
Alpelisib
Cisplatin