WISTERIA: WEE1 inhibitor with cisplatin and radiotherapy

ISRCTN	ISRCTN76291951
DOI	https://doi.org/10.1186/ISRCTN76291951
EudraCT/CTIS number	2015-003583-37
ClinicalTrials.gov number	NCT03028766
Secondary identifying numbers	32918

Submission date: 20/02/2017
Registration date: 21/02/2017
Last edited: 03/09/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-azd1775-for-head-and-neck-cancer-wisteria

Study website

Contact information

Mr Rhys Mant
Public

Early Drug Development Team
CRUK Clinical Trials Unit
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom

Phone	+44 121 414 6788
Email	wisteria@trials.bham.ac.uk

Study information

Study design	Non-randomized; Interventional; Design type: Treatment, Drug, Radiotherapy
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A 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
Study acronym	WISTERIA
Study objectives	The aim of this study is to determine how effective and safe it is to combine AZD1775 with cisplatin in the pre-operative setting (Group A) and with post-operative cisplatin based chemo-radiation (Group B) in patients with head and neck cancer.
Ethics approval(s)	West Midlands – Edgbaston REC, 18/01/2017, ref: 16/WM/0501
Health condition(s) or problem(s) studied	Head and neck cancer
Intervention	Current interventions as of 04/05/2018: Patients who have been diagnosed with cancer of the oral cavity, larynx or hypopharynx and are due to undergo surgery will be allocated to Group A. Patients who have been diagnosed with cancer of the oral cavity, larynx or hypopharynx, have undergone surgery and will require radiotherapy afterwards due to being considered to be at risk of relapse after surgery will be allocated to Group B. Group A: Patients will receive the cohort specified dose of AZD1775, twice a day for the first 3 days of each week for 2 weeks. Patients will receive cisplatin at the start of the second week of treatment. Patients in this group will commence surgery within 42 days of commencing pre-operative chemotherapy. Patients will be followed-up clinically for 3 months. Group B: Patients will receive the cohort specified dose of AZD1775, twice a day for 3 days, on Weeks 1, 2, 4 and 5. Patients will receive cisplatin at the start of each week of treatment for 5 weeks. Intensity Modulated Radiotherapy will be delivered 5 days a week (once daily, Monday to Friday) for 6 weeks commencing within 3 months of surgery. Patients will be followed up clinically for 12 months. Previous interventions: Patients who have been diagnosed with cancer of the oral cavity, larynx or hypopharynx and are due to undergo surgery will be allocated to Group A. Patients who have been diagnosed with cancer of the oral cavity, larynx or hypopharynx, have undergone surgery and will require radiotherapy afterwards due to being considered to be at risk of relapse after surgery will be allocated to Group B. Group A: Patients will receive the cohort specified dose of AZD1775, twice a day for the first 3 days of each week for 2 weeks. Patients will receive cisplatin at the start of the second week of treatment. Patients in this group will commence surgery within 42 days of commencing pre-operative chemotherapy. Patients will be followed-up clinically for 3 months. Group B: Patients will receive the cohort specified dose of AZD1775, twice a day for 3 days, for 5 weeks. Patients will receive cisplatin at the start of each week of treatment for 5 weeks. Intensity Modulated Radiotherapy will be delivered 5 days a week (once daily, Monday to Friday) for 6 weeks commencing within 42 days of surgery. Patients will be followed up clinically for 12 months.
Intervention type	Other
Primary outcome measure	1. Recommended dose(s) of AZD1775. For Group A this is measured as the highest safe dose of AZD1775 in combination with cisplatin with a predefined target Dose Limiting Toxicity probability of 25% for up to 42 days from start of treatment. For Group B this is measured as the maximum tolerated dose of AZD1775 in combination with cisplatin/radiotherapy with a target DLT of 30% for up to 12 weeks from the start of treatment. 2. Safety profile of AZD1775 for Group A and Group B is assessed by reporting of all adverse events, serious adverse events, suspected unexpected adverse reactions, deaths, deviations and withdrawal as assessed by the Safety Committee from registration, while on treatment and during follow up periods
Secondary outcome measures	Disease-free survival is measured as the time from trial entry to date of disease recurrence, progression or patient death until end of follow up period
Overall study start date	01/09/2015
Completion date	03/02/2021

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	70 Years
Sex	Both
Target number of participants	Planned Sample Size: 42; UK Sample Size: 42
Total final enrolment	9
Key inclusion criteria	Current inclusion criteria as of 04/05/2018: 1. Histologically confirmed diagnosis of oral, laryngeal or hypopharyngeal squamous cell carcinoma 2. Multi-Disciplinary Team (MDT) recommendation for surgical resection with curative intent 3. Eastern Cooperative Oncology Group (ECOG) performance status 0/1 4. Aged between 18 and 70 years 5. Creatinine clearance, measured by Glomerular Filtration Rate (GFR), > = 60 ml/min at baseline calculated using local practice calculation. If this is < = 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min 6. Acceptable cardiac function. If significant cardiac history, then required for patient to have Left Ventricular Ejection Fraction (LVEF) > = 55% by echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA, if ECHO is equivocal) 7. Normal liver and bone marrow function: 7.1. Haemoglobin (Hb) > = 10.0 g/dL or > = 100 g/L 7.2. Absolute neutrophil count (ANC) > = 1.5 x 109/L 7.3. Absolute platelet count > = 100 x 109/L 7.4. Aspartate transaminase (AST) or alanine aminotransferase (ALT) < = 2.5 upper limit of normal (ULN) 7.5. Total bilirubin < = 1.5 ULN (except for patients with known Gilbert’s syndrome) 8. Male and female participants must agree to take appropriate measures to prevent pregnancy. Contraceptive measures should be used for 2 weeks prior to trial entry, during the trial and for at least 6 months after last receiving treatment. Acceptable methods of contraception include total abstinence (if this is the patient’s usual and preferred lifestyle choice), tubal ligation, combined oral, transdermal or intra-vaginal hormonal contraceptives, medroxyprogesterone injections (e.g. Depo-Provera), copper-banded intra-uterine devices; hormone impregnated intra-uterine systems and vasectomised partners. All methods of contraception (with the exception of total abstinence) should be used in combination with the use of a condom by their male sexual partner for intercourse. 9. Inclusion criteria Group A – in addition to general criteria: Accessible tumours for re-biopsy under local anaesthetic or via ultrasound guided biopsy 10. Inclusion criteria Group B – in addition to general criteria: 10.1. High-risk histopathological features after surgical resection, i.e. nodal extra-capsular spread and/or tissue resection margin <1 mm as agreed at MDT 10.2. Patients who have previously registered to Group A can be considered for inclusion in Group B Previous inclusion criteria: 1. Histologically confirmed diagnosis of oral, laryngeal or hypopharyngeal squamous cell carcinoma 2. Multi-Disciplinary Team (MDT) recommendation for surgical resection with curative intent 3. Eastern Cooperative Oncology Group (ECOG) performance status 0/1 4. Aged between 18 and 70 years 5. Creatinine clearance, measured by Glomerular Filtration Rate (GFR), > = 60 ml/min at baseline calculated using local practice calculation. If this is < = 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min 6. Acceptable cardiac function. If significant cardiac history, then required for patient to have Left Ventricular Ejection Fraction (LVEF) > = 55% by echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA, if ECHO is equivocal) 7. Normal liver and bone marrow function: 7.1. Haemoglobin (Hb) > = 10.0 g/dL or > = 100 g/L 7.2. Absolute neutrophil count (ANC) > = 1.5 x 109/L 7.3. Absolute platelet count > = 100 x 109/L 7.4. Aspartate transaminase (AST) or alanine aminotransferase (ALT) < = 2.5 upper limit of normal (ULN) 7.5. Total bilirubin < = 1.5 ULN (except for patients with known Gilbert’s syndrome) 8. Male and female participants must agree to take appropriate measures to prevent pregnancy. Contraceptive measures should be used for 2 weeks prior to trial entry, during the trial and for at least 6 months after last receiving treatment. Acceptable methods of contraception include total abstinence (if this is the patient’s usual and preferred lifestyle choice), tubal ligation, combined oral, transdermal or intra-vaginal hormonal contraceptives, medroxyprogesterone injections (e.g. Depo-Provera), copper-banded intra-uterine devices; hormone impregnated intra-uterine systems and vasectomised partners. All methods of contraception (with the exception of total abstinence) should be used in combination with the use of a condom by their male sexual partner for intercourse. Inclusion criteria Group A – in addition to general criteria: Accessible tumours for re-biopsy under local anaesthetic, e.g. oral cancer Inclusion criteria Group B – in addition to general criteria: High-risk histopathological features after surgical resection, i.e. nodal extra-capsular spread and/or tissue resection margin < 1 mm as agreed at MDT
Key exclusion criteria	1. Any previous treatment for the same cancer, or previous head and neck malignancy, apart from laser excision of carcinoma in situ, with minimal residual functional deficit 2. Patients with cancer of the oropharynx will not be included 3. Any metastatic disease from any primary site 4. Use of an Investigational Medicinal Product concurrently or within 4 weeks of starting this trial 5. Uncontrolled intercurrent illness, which will interfere with the patient’s participation in the trial, e.g.: 5.1. Myocardial infarction within 6 months 5.2. Congestive cardiac failure 5.3. Unstable angina 5.4. Symptomatic cardiomyopathy 5.5. Chronic infections 5.6. Active peptic ulcer or liver disease 5.7. Serious psychiatric condition limiting ability to comply with trial protocol 6. Clinical evidence of current heart failure (> = New York Heart Association (NYHA) Class II) 7. Clinical evidence of atrial fibrillation (with heart rate > 100 bpm, within 6 months prior to starting treatment) 8. Unstable ischaemic heart disease (Myocardial Infarction within 6 months prior to trial entry or angina requiring the use of nitrates greater than once weekly) 9. Active gastro-intestinal disease that might limit absorption of study drug, e.g. coeliac disease, Crohn’s disease, ulcerative colitis, pancreatic insufficiency 10. Evidence of any psychological, familial, sociological or geographical condition potentially hampering protocol compliance 11. Participation in another interventional clinical trial whilst taking part in this trial 12. Patients who are unable to discontinue any prohibited drug and unable to tolerate a washout period for at least 14 days prior to trial entry 13. Clinical judgement by the Investigator that the patient should not participate in the study 14. Known hypersensitivity to the study drugs or active substances or excipients of the preparations 15. Pregnant or lactating patients 16. Significant pre-existing neuropathy which currently interferes with the patient’s daily life 17. Mean resting corrected QTc interval using the Fridericia formula (QTcF) > 450 msec (male) and > 470 msec (female) (as calculated per institutional standards) obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome 18. Inability to swallow oral medications
Date of first enrolment	22/06/2017
Date of final enrolment	31/10/2019

Locations

Countries of recruitment

England
Scotland
United Kingdom

Study participating centres

Queen Elizabeth Hospital Birmingham

Mindelsohn Way
Birmingham
B15 2TH
United Kingdom

Royal Marsden Hospital

Fulham Road
London
SW3 6JJ
United Kingdom

University College London Hospital

235 Euston Road
London
NW1 2PG
United Kingdom

Clatterbridge Cancer Centre

Clatterbridge Road
Wirral
CH63 4JY
United Kingdom

Beatson West of Scotland Cancer

1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

St James's University Hospital

Leeds Teaching Hospitals NHS Trust
Beckett St
Leeds
LS9 7TF
United Kingdom

Sponsor information

University of Birmingham
University/education

Edgbaston
Birmingham
B15 2TT
England
United Kingdom

Phone	+44 121 414 6788
Email	wisteria@trials.bham.ac.uk
"ROR"	https://ror.org/03angcq70

Funders

Funder type

Charity

Cancer Research UK
Private sector organisation / Other non-profit organizations

Alternative name(s): CR_UK, Cancer Research UK - London, CRUK
Location: United Kingdom

Results and Publications

Intention to publish date	01/04/2023
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal.
IPD sharing plan	Current IPD sharing statement as of 28/10/2022: Scientifically sound proposals from appropriately qualified researchers will be considered for data sharing. Requests should be made by returning a Data Sharing Request Form to newbusiness@trials.bham.ac.uk; this captures the research requirements, statistical analysis plan, and intended publication schedule. Requests will be reviewed by the Cancer Research UK Clinical Trials Unit (CRCTU) Directors in discussion with the Chief Investigator (CI), Trial Management Group (TMG) and independent Trial Safety Committee (TSC). They will consider the scientific validity of the request, qualifications of the researchers, CI, TMG & TSC views, consent arrangements, practicality of anonymizing the requested data & contractual obligations. If supportive of the request, and where not already obtained, Sponsor consent for data transfer will be sought before notifying applicants of the outcome. It is anticipated that applicants will be notified within 3 months of receipt of the original request. Previous IPD sharing statement: The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article	protocol	16/03/2020	17/02/2021	Yes	No
Basic results	version 1.0a	16/02/2023	16/02/2023	No	No
HRA research summary			28/06/2023	No	No
Results article		29/01/2024	07/02/2024	Yes	No
Plain English results			18/03/2024	No	Yes
Results article	Results and lessons learned	29/01/2024	03/09/2024	Yes	No

Additional files

ISRCTN76291951_BasicResults_V1.0a_16Feb23.pdf

Editorial Notes

03/09/2024: Publication reference added.
18/03/2024: Cancer Research UK plain English results added.
07/02/2024: Publication reference added.
16/02/2023: The basic results of this trial have been re-uploaded as an additional file.
28/10/2022: IPD sharing statement updated.
07/10/2022: The intention to publish date was changed from 03/02/2022 to 01/04/2023.
04/10/2022: The basic results of this trial have been uploaded as an additional file.
15/03/2021: IPD sharing statement added.
09/03/2021: The following changes were made to the trial record:
1. The overall trial end date was changed from 29/01/2021 to 03/02/2021.
2. The intention to publish date was changed from 29/01/2022 to 03/02/2022.
3. St James's University Hospital was added as a trial participating centre.
17/02/2021: Publication reference added.
14/11/2019: The following changes have been made:
1. The total final enrolment has been added.
2. The overall trial end date has been changed from 01/12/2019 to 29/01/2021.
3. The intention to publish date has been changed from 31/12/2019 to 29/01/2022.
04/07/2019: ClinicalTrials.gov number added.
28/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Head and Neck Cancer; UKCRC code/ Disease: Cancer/ Malignant neoplasms of lip, oral cavity and pharynx, Cancer/ Malignant neoplasms of thyroid and other endocrine glands" to "Head and neck cancer" following a request from the NIHR.
25/01/2019: The following changes have been made:
1. The recruitment end date has been changed from 31/10/2018 to 31/10/2019.
2. The trial website has been changed from http://www.birmingham.ac.uk/research/activity/mds/trials/crctu/index.aspx to https://www.birmingham.ac.uk/research/activity/mds/trials/crctu/trials/wisteria/index.aspx .
04/05/2018: The following changes have been made:
1. The interventions have been changed.
2. The participant inclusion criteria have been changed.
3. Southampton University Hospital has been removed from the trial centres and Beatson West of Scotland Cancer added.
25/10/2017: Internal review.
16/10/2017: Cancer Help UK lay summary link added to plain English summary field.
25/09/2017: Internal review.
15/09/2017: Internal review.
23/06/2017: The recruitment start date was changed from 01/07/2017 to 22/06/2017.
07/06/2017: The recruitment start date was changed from 01/04/2017 to 01/07/2017.