Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer

Abstract

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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).</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Clinical Trial Registration</jats:title> <jats:p>ISRCTN76291951</jats:p> </jats:sec>