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

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.

Informations de copyright

© The Author(s) 2024.

Déclaration de conflit d'intérêts

COMPETING INTERESTSAK has received fees for consulting, advisory, speaker’s roles and/or research funding from PUMA BioTechnology, AstraZeneca, Merck, MSD, Bristol-Myers Squibb, Avvinity Therapeutics. MDF has received research funding from Boehringer Ingelheim, MSD, and Merck, honoraria from Bayer and MSD, and has been on advisory boards Immutep, Pharmamar, Oxford VacMedix, Amgen, AstraZeneca, Boxer, EQRx, Merck, Bristol-Myers Squibb, Guardant Health, Roche, Takeda, UltraHuman, Celgene, and Janssen. JJS has received research funding from BMS and AstraZeneca. SS has received consulting fees and honoraria from Sanofi. CY has received research funding from Novartis, Faron Pharmaceuticals, AstraZeneca, and Celgene, honoraria from Celgene and Faron Pharmaceuticals, and fees for speaker’s role from Bayer. KJH has received consulting fees from AstraZeneca, Merck-Serono, and Merck-Sharp-Dohme. HM received honoraria from AstraZeneca, travel support from Merck, and has been on advisory boards for Eisai Inc, Nanobiotix, and Merck. HM, JSS, and RM received funds from Cancer Research UK and AstraZeneca to fund this study. All other authors declare no competing interests.