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.
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
Journal
Oral oncology
ISSN: 1879-0593
Titre abrégé: Oral Oncol
Pays: England
ID NLM: 9709118
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
07
05
2019
revised:
11
04
2020
accepted:
26
04
2020
pubmed:
29
5
2020
medline:
29
6
2021
entrez:
29
5
2020
Statut:
ppublish
Résumé
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). 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/m 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%). Alpelisib at 200 mg has a manageable safety profile in combination with cisplatin-based CRT in LA-SCCHN.
Sections du résumé
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/m
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.
Identifiants
pubmed: 32464516
pii: S1368-8375(20)30189-5
doi: 10.1016/j.oraloncology.2020.104753
pii:
doi:
Substances chimiques
Thiazoles
0
Alpelisib
08W5N2C97Q
Cisplatin
Q20Q21Q62J
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104753Informations de copyright
Copyright © 2020 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest AS declares consulting roles for Merck (compensated), Bristol-Myers Squibb (compensated), Novartis (compensated), Oncorus (compensated); and grant /research support (for clinical trials) from Novartis, Bristol-Myers Squibb, Symphogen, AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics and Janssen Oncology/Johnson & Johnson. MG declares an advisory role for AstraZeneca and research grant from Eli Lilly. SVB receives research funding from Nektar Therapeutics and is co-inventor of a patent relating to circulating tumor DNA analysis, which has been licensed to Roche Molecular Diagnostics. RJ declares consulting/advisory roles for Ipsen and Novartis; and research funding (for institution) from AstraZeneca, Merck, Novartis, Lilly, Boston Biomedical and Bristol-Myers Squibb. LLS declares consulting roles for Merck (compensated), Pfizer (compensated), Celgene (compensated), AstraZeneca/Medimmune (compensated), Morphosys (compensated), Roche (compensated), GeneSeeq (compensated), Loxo (compensated), Oncorus (compensated) and Symphogen (compensated); grant/ research support (for clinical trials) from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, Regeneron, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics and Mirati; and LLS’ spouse is a stockholder in Agios. ARH declares advisory/consulting roles for Genentech/Roche, Merck, GlaxoSmithKline, Bristol-Myers Squibb, Novartis, Boston Biomedical and Boehringer-Ingelheim. The remaining authors (DD, AP, JW, RK, IW, JK, JC, AH, AB, JR, BOS) declare no competing interests.