A phase I trial of WEE1 inhibition with chemotherapy and radiotherapy as adjuvant treatment, and a window of opportunity trial with cisplatin in patients with head and neck cancer: the WISTERIA trial protocol

Research output: Contribution to journalArticle

Authors

  • James S. Good
  • Joshua Savage
  • Rhys Mant
  • Laura Llewellyn
  • Martin Forster
  • Stefano Schipani
  • Kevin Harrington
  • Joseph J Sacco
  • Patrick Murray
  • Christina Yap
  • Hisham Mehanna

External organisations

  • Simbec Research Ltd
  • The Clatterbridge Cancer Centre, Wirral, UK.
  • Beatson West of Scotland Cancer Centre
  • St James' University Hospital, Leeds, UK.
  • UNIVERSITY HOSPITAL BIRMINGHAM NHS FOUNDATION TRUST
  • UCL
  • The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK.
  • Institute for Cancer Research

Abstract

Introduction
Head and neck squamous cell carcinoma (HNSCC) patients with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features post-surgery. Whilst cure rates are improved, overall survival remains sub-optimal and treatment has a significant negative impact on quality of life.
Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemo-radiation. Our hypothesis is that combining chemo-radiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor Adavosertib (AZD1775).

Methods and analysis
This Phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy pre-operatively (Group A) as a window of opportunity trial, and in combination with post-operative cisplatin-based chemo-radiation (Group B).
Modified time-to-event continual reassessment method (TITE-CRM) will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (Group A), and 30% monitored up to 12 weeks (Group B). Secondary outcomes are disease-free survival times (Groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for Group A; and quality of life in Group B.

Ethics and dissemination
Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences.

Trial Registration
European Medicines Agency (EudraCT: 2015-003583-37); ISRCTN is 76291951 (http://www.isrctn.com/ISRCTN76291951); Clinicaltrials.gov identifier is NCT03028766 (http://clinicaltrials.gov/ct2/show/NCT03028766).

Details

Original languageEnglish
Article numbere033009
JournalBMJ open
Volume10
Issue number3
Publication statusPublished - 16 Mar 2020

Keywords

  • TITE-CRM, head and neck squamous cell carcinoma, wee1 inhibitor, chemoradiation, window of opportunity study

ASJC Scopus subject areas