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; Amanda J. Kirkham; Joshua S. Savage; Rhys Mant; Siân Lax; James Good; Martin D. Forster; Joseph J. Sacco; Stephano Schipani; Kevin J. Harrington; Christina Yap; Hisham Mehanna

doi:10.1038/s44276-023-00026-6

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
, Amanda J. Kirkham
, Joshua S. Savage
, Rhys Mant
, Siân Lax
, James Good
, Martin D. Forster
, Joseph J. Sacco
, Stephano Schipani
, Kevin J. Harrington
, Christina Yap
, Hisham Mehanna^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

64 Downloads (Pure)

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

Original language	English
Article number	6
Number of pages	9
Journal	BJC Reports
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s44276-023-00026-6
Publication status	Published - 29 Jan 2024

Bibliographical note

Funding:
This work was funded by Cancer Research UK [C19677/A20959] and AstraZeneca through Cancer Research UK’s Combinations Alliance. AZD1775 was provided free of charge by AstraZeneca. Staff at the CRCTU are supported by a core funding grant from Cancer Research UK [C22436/A25354]. WISTERIA was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC Network. MDF is supported by the UCL/UCLH NIHR Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility, supported by the UCL ECMC. The trial was initiated and conducted independently by the trial investigators. The funders had no role in trial design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the trial and had final responsibility for the decision to submit for publication.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

wisteria
clinical trial
head and neck cancer
AZD1775
squamous cell carcinoma
cisplatin
window of opportunity study
wee1 inhibitor

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1038/s44276-023-00026-6Licence: Creative Commons: Attribution (CC BY)

KongA2024ResultsFinal published version, 783 KBLicence: Creative Commons: Attribution (CC BY)

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
Kong, A., Good, J. S., Kirkham, A., Savage, J., Mant, R., Llewellyn, L., Parish, J., Spruce, R., Forster, M., Schipani, S., Harrington, K., Sacco, J. J., Murray, P., Middleton, G., Yap, C. & Mehanna, H., 16 Mar 2020, In: BMJ Open. 10, 3, 11 p., e033009.
Research output: Contribution to journal › Article › peer-review

Open Access
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6 Citations (Scopus)

248 Downloads (Pure)

1 Finished
1 Active

Cancer Research UK Clinical Trials Unit, Birmingham - Adult Unit
Bach, S. (Co-Investigator), Bowden, S. (Co-Investigator), Craddock, C. (Co-Investigator), Rea, D. (Co-Investigator), Kearns, P. (Principal Investigator), Wheatley, K. (Co-Investigator), Billingham, L. (Co-Investigator) & Steven, N. (Co-Investigator)
Cancer Research UK
1/10/18 → 30/09/28
Project: Research
Wisteria - Wee inhibitor with Cisplatin and Radiotherapy: A trial in head and neck cancer
Kong, A. (Co-Investigator), Mehanna, H. (Principal Investigator), Parish, J. (Co-Investigator) & Windridge, D. (Co-Investigator)
Cancer Research UK, Astra Zeneca Uk Limited
1/09/15 → 31/12/24
Project: Research

Cite this

Kong, A., Kirkham, A. J., Savage, J. S., Mant, R., Lax, S., Good, J., Forster, M. D., Sacco, J. J., Schipani, S., Harrington, K. J., Yap, C., & Mehanna, H. (2024). Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer. BJC Reports, 2(1), Article 6. https://doi.org/10.1038/s44276-023-00026-6

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

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",

keywords = "wisteria, clinical trial, head and neck cancer, AZD1775, squamous cell carcinoma, cisplatin, window of opportunity study, wee1 inhibitor",

author = "Anthony Kong and Kirkham, \{Amanda J.\} and Savage, \{Joshua S.\} and Rhys Mant and Si{\^a}n Lax and James Good and Forster, \{Martin D.\} and Sacco, \{Joseph J.\} and Stephano Schipani and Harrington, \{Kevin J.\} and Christina Yap and Hisham Mehanna",

note = "Funding: This work was funded by Cancer Research UK [C19677/A20959] and AstraZeneca through Cancer Research UK{\textquoteright}s Combinations Alliance. AZD1775 was provided free of charge by AstraZeneca. Staff at the CRCTU are supported by a core funding grant from Cancer Research UK [C22436/A25354]. WISTERIA was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC Network. MDF is supported by the UCL/UCLH NIHR Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility, supported by the UCL ECMC. The trial was initiated and conducted independently by the trial investigators. The funders had no role in trial design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the trial and had final responsibility for the decision to submit for publication.",

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T1 - Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer

AU - Kong, Anthony

AU - Kirkham, Amanda J.

AU - Savage, Joshua S.

AU - Mant, Rhys

AU - Lax, Siân

AU - Good, James

AU - Forster, Martin D.

AU - Sacco, Joseph J.

AU - Schipani, Stephano

AU - Harrington, Kevin J.

AU - Yap, Christina

AU - Mehanna, Hisham

N1 - Funding: This work was funded by Cancer Research UK [C19677/A20959] and AstraZeneca through Cancer Research UK’s Combinations Alliance. AZD1775 was provided free of charge by AstraZeneca. Staff at the CRCTU are supported by a core funding grant from Cancer Research UK [C22436/A25354]. WISTERIA was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC Network. MDF is supported by the UCL/UCLH NIHR Biomedical Research Centre and runs early phase studies in the NIHR UCLH Clinical Research Facility, supported by the UCL ECMC. The trial was initiated and conducted independently by the trial investigators. The funders had no role in trial design, data collection, data analysis, data interpretation or writing of the report. The corresponding author had full access to all the data in the trial and had final responsibility for the decision to submit for publication.

PY - 2024/1/29

Y1 - 2024/1/29

N2 - 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

AB - 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

KW - wisteria

KW - clinical trial

KW - head and neck cancer

KW - AZD1775

KW - squamous cell carcinoma

KW - cisplatin

KW - window of opportunity study

KW - wee1 inhibitor

U2 - 10.1038/s44276-023-00026-6

DO - 10.1038/s44276-023-00026-6

M3 - Article

SN - 2731-9377

VL - 2

JO - BJC Reports

JF - BJC Reports

IS - 1

M1 - 6

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Research output

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

Projects

Cancer Research UK Clinical Trials Unit, Birmingham - Adult Unit

Wisteria - Wee inhibitor with Cisplatin and Radiotherapy: A trial in head and neck cancer

Cite this