Author:
Kong Anthony,Kirkham Amanda J.,Savage Joshua S.,Mant Rhys,Lax Siân,Good James,Forster Martin D.,Sacco Joseph J.,Schipani Stephano,Harrington Kevin J.,Yap Christina,Mehanna Hisham
Abstract
Abstract
Background
Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents.
Methods
WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years. Primary outcomes were adverse events and defining recommended dose and schedule of AZD1775 in combination with cisplatin in pre-operative (Group A), or with cisplatin/radiotherapy in post-operative (Group B) patients. Dose determination was guided by a modified time-to-event continual reassessment method (mTITE-CRM).
Results
Between 30-Oct-2017 and 15-Jul-2019, nine patients were registered: Three into Group A and six into Group B. WISTERIA was closed early due to poor recruitment. Five dose-limiting toxicities (DLTs) were reported in four Group B patients. Seven serious adverse events were reported in four patients: One in Group A, and three in Group B. Three were related to treatment. No treatment-related deaths were reported.
Conclusions
WISTERIA did not complete its primary objectives due to poor recruitment and toxicities reported in Group B. However, use of the novel mTITE-CRM improved flexibility in reducing accrual suspension periods and should be considered for future trials in complex patient populations.
Clinical Trial Registration
ISRCTN76291951
Publisher
Springer Science and Business Media LLC
Reference37 articles.
1. Cancer Research UK. Head and neck cancers statistics [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/head-and-neck-cancers. Last Accessed: 23-Jan-2023.
2. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350:1937–44. https://doi.org/10.1056/NEJMoa032646
3. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. Nat Rev Clin Oncol. 2015;12:11–26. https://doi.org/10.1038/nrclinonc.2014.192
4. Dillon MT, Good JS, Harrington KJ. Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol). 2014;26:257–65. https://doi.org/10.1016/j.clon.2014.01.009
5. Guertin AD, Li J, Liu Y, Hurd MS, Schuller AG, Long B, et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Mol Cancer Ther. 2013;12:1442–52. https://doi.org/10.1158/1535-7163.Mct-13-0025