Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024;2(1):6.
doi: 10.1038/s44276-023-00026-6. Epub 2024 Jan 29.

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

Anthony Kong #  1 , Amanda J Kirkham #  2 , Joshua S Savage  2 , Rhys Mant  2 , Siân Lax  2 , James Good  3 , Martin D Forster  4 , Joseph J Sacco  5 , Stephano Schipani  6 , Kevin J Harrington  7 , Christina Yap  8 , Hisham Mehanna  9
Affiliations

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

Anthony Kong et al. BJC Rep. 2024.

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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. WISTERIA trial profile.
The trial profiles of the two groups and three cohorts analysed in the WISTERIA trial. DLT dose-limiting toxicity.
Fig. 2
Fig. 2. Treatment pathways of registered patients.
Swimmer plots detailing the treatment pathways of patients registered to the WISTERIA trial. See Supplementary Appendix D for the patients’ full pathways including follow-up. All patients in Group A received 100 mg AZD1775 bd for three days during weeks one and two. Four patients in Group B received 75 mg AZD1775 bd for three days during weeks one and two. One patient received 75 mg AZD1775 bd for three days during weeks one, two, and four. One patient withdrew from the trial prior to receiving any treatment.
See this image and copyright information in PMC

References

    1. Cancer Research UK. Head and neck cancers statistics [Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/s.... Last Accessed: 23-Jan-2023.
    1. 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. 10.1056/NEJMoa032646 - PubMed
    1. 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. 10.1038/nrclinonc.2014.192 - PubMed
    1. 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. 10.1016/j.clon.2014.01.009 - PubMed
    1. 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. 10.1158/1535-7163.Mct-13-0025 - PubMed

LinkOut - more resources