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WEE1 Inhibitor With Cisplatin and Radiotherapy: A Trial in Head and Neck Cancer (WISTERIA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03028766
Recruitment Status : Recruiting
First Posted : January 23, 2017
Last Update Posted : September 29, 2017
Cancer Research UK
Information provided by (Responsible Party):
University of Birmingham

Brief Summary:
This trial is to determine what dose of a drug called AZD1775 can safely be given in combination with cisplatin before surgery and with chemo-radiotherapy after surgery in patients with Head and Neck Cancer. The Investigators will also get some preliminary information regarding the effectiveness of this combined treatment.

Condition or disease Intervention/treatment Phase
Hypopharynx Squamous Cell Carcinoma Oral Cavity Squamous Cell Carcinoma Larynx Cancer Drug: AZD1775 Drug: Cisplatin Radiation: Radiotherapy Phase 1

Detailed Description:

Patients with head and neck cancer with high-risk features are at increased risk of relapse after surgery. Surgery, often followed by cisplatin chemotherapy and radiotherapy is currently the standard treatment offered. Whilst chemo-radiotherapy improves cure rates, outcomes remain poor, and treatment has a significant impact on quality of life. Chemotherapy has yet to find a definitive role prior to surgery. There is therefore an urgent need to develop more effective treatments which improve cure rates for this patient population.

The purpose of this trial is to see whether incorporating a drug called AZD1775 into the management of head and neck cancer offers the possibility of addressing these clinical issues. AZD1775 is a drug that has been shown to increase the effect of cisplatin and of radiotherapy when tested in the laboratory. The blood samples and tumour biopsies taken during the trial will be important in learning as much as possible about the effects of AZD1775 on the body and to investigate how the tumour might develop resistance to the drug.

The WISTERIA trial is for patients aged between 18 and 70 years with cancer of the oral cavity, larynx and hypopharynx who are to undergo surgery. Patients recruited to Group A must have accessible tumours for re-biopsy, whilst patients recruited to Group B will be at high risk of relapse after surgery.

The primary objective of this trial is to see what dose of AZD1775 can safely be given in combination with cisplatin before surgery (Group A) and with chemo-radiotherapy after surgery (Group B). The Investigators will also get some preliminary information regarding the effectiveness of this combined treatment. To find the safe and effective dose of AZD1775, different doses will be tested for each Group.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : June 22, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Cisplatin
U.S. FDA Resources

Arm Intervention/treatment
Experimental: Group A - Pre-operative
Patients will receive the cohort specified dose of AZD1775 by mouth, twice a day for 3 days, commencing on days 1 and 8. Cisplatin 40mg/m2 IV delivered over 1 hour on day 8. Patients in this group will commence surgery within 42 days of commencing pre-operative chemotherapy.
Drug: AZD1775
AZD1775 is a potent, selective small molecule inhibitor of WEE1
Drug: Cisplatin
Chemotherapy drug
Experimental: Group B - Post-operative:
Patients will received the cohort specified dose of AZD1775 by mouth, twice a day for 3 days on days 2, 9, 23 and 30. Cisplatin 40mg/m2 IV delivered over 1 hour on days 2, 9, 16, 23 and 30. Intensity Modulated Radiotherapy will be delivered 5 days a week (once daily, Monday to Friday) for 6 weeks commencing within 42 days of surgery.
Drug: AZD1775
AZD1775 is a potent, selective small molecule inhibitor of WEE1
Drug: Cisplatin
Chemotherapy drug
Radiation: Radiotherapy
Intensity Modulated Radiotherapy
Other Name: IMRT

Primary Outcome Measures :
  1. Recommended dose(s) of AZD1775 [ Time Frame: Group A - Up to 42 days from start of treatment; Group B - Up to 12 weeks from the start of treatment ]

    Group A: 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.

    Group B: 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 by reporting of all Adverse Events, Serious Adverse Events, Suspected Unexpected Adverse Reactions, deaths, deviations and withdrawal as assessed by the Safety Committee. [ Time Frame: From registration, while on treatment and during follow up periods ]
    Safety profile of AZD1775 in combination with cisplatin in Group A and cisplatin/radiotherapy in Group B.

Secondary Outcome Measures :
  1. Disease-free survival in Groups A and B [ Time Frame: Patients will be followed-up clinically for 12 weeks in Group A and for 12 months in Group B. ]
    Disease-free survival is defined as the time from trial entry to date of disease recurrence, progression or patient death until end of follow up period.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically confirmed diagnosis of oral, laryngeal or hypopharyngeal squamous cell carcinoma
  • Multi-Disciplinary Team (MDT) recommendation for surgical resection with curative intent
  • Eastern Cooperative Oncology Group (ECOG) performance status 0/1
  • Age ≥18 to ≤70 years
  • 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
  • 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)
  • Normal liver and bone marrow function:

    • Haemoglobin (Hb) ≥10.0 g/dL or ≥100 g/L
    • Absolute neutrophil count (ANC) ≥1.5 x 109/L
    • Absolute platelet count ≥100 x 109/L
    • Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≤2.5 upper limit of normal (ULN)
    • Total bilirubin ≤1.5 ULN (except for patients with known Gilbert's syndrome)
  • 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

Exclusion Criteria:

  • 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
  • Patients with cancer of the oropharynx or non-primary cancer will not be included
  • Any metastatic disease from any primary site
  • Use of an Investigational Medicinal Product (IMP) concurrently or within 4 weeks of starting this trial
  • Uncontrolled intercurrent illness, which will interfere with the patient's participation in the trial, e.g.:

    • myocardial infarction within 6 months
    • congestive cardiac failure
    • unstable angina
    • symptomatic cardiomyopathy
    • chronic infections
    • active peptic ulcer or liver disease
    • serious psychiatric condition limiting ability to comply with trial protocol
  • Clinical evidence of current heart failure (≥New York Heart Association (NYHA) Class II)
  • Clinical evidence of atrial fibrillation (with heart rate >100 bpm, within 6 months prior to trial entry)
  • Unstable ischaemic heart disease (Myocardial Infarction within 6 months prior to trial entry or angina requiring the use of nitrates greater than once weekly)
  • Patients who have a history of Torsades de pointes (unless all risk factors that contributed to Torsades de pointes have been corrected)
  • Active gastro-intestinal disease that might limit absorption of study drug, e.g. coeliac disease, Crohn's disease, ulcerative colitis, pancreatic insufficiency
  • Evidence of any psychological, familial, sociological or geographical condition potentially hampering protocol compliance
  • Participation in another interventional clinical trial whilst taking part in this trial
  • 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
  • Clinical judgement by the Investigator that the patient should not participate in the study
  • Known hypersensitivity to the study drugs or active substances or excipients of the preparations
  • Pregnant or breast feeding patients
  • Significant pre-existing neuropathy which currently interferes with the patient's daily life
  • 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
  • Inability to swallow oral medications

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03028766

Contact: Rhys Mant 0121 414 6788
Contact: Deborah Bird 0121 414 6754

United Kingdom
University Hospital Birmingham Nhs Foundation Trust Recruiting
Birmingham, West Midlands, United Kingdom, B15 2TH
Principal Investigator: Gary Middleton         
Sponsors and Collaborators
University of Birmingham
Cancer Research UK
Principal Investigator: Hisham Mehanna University of Birmingham

Responsible Party: University of Birmingham Identifier: NCT03028766     History of Changes
Other Study ID Numbers: RG_15-139
2015-003583-37 ( EudraCT Number )
First Posted: January 23, 2017    Key Record Dates
Last Update Posted: September 29, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
Laryngeal Diseases
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Laryngeal Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Squamous Cell
Neoplasms by Site
Otorhinolaryngologic Neoplasms
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Otorhinolaryngologic Diseases
Antineoplastic Agents