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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: The WISTERIA Trial
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-033009
Article Type: Protocol
Date Submitted by the 16-Jul-2019 Author:
Complete List of Authors: Kong, Anthony; University of Birmingham, Institute of Cancer and Genomic Sciences Good, James; University Hospitals Birmingham NHS Foundation Trust Kirkham, Amanda; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Savage, Joshua; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Mant, Rhys; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Llewellyn, Laura; SIMBEC Research Limited
Parish, Joanna; University of Birmingham, Institute of Cancer and http://bmjopen.bmj.com/ Genomic Sciences Spruce, Rachel; University of Birmingham, InHANSE, Institute of Cancer and Genomic Sciences Forster, Martin; University College London Schipani, Stefano; University of Glasgow, Beatson West of Scotland Cancer Centre Harrington, Kevin; Institute of Cancer Research Sacco, Joseph; Clatterbridge Cancer Centre NHS Foundation Trust Murray, Patrick; Leeds Teaching Hospitals NHS Trust Middleton, Gary; University of Birmingham, Institute of Immunology and on September 30, 2021 by guest. Protected copyright. Immunotherapy Yap, Christina; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Mehanna, H; University of Birmingham, InHANSE, Institute of Cancer and Genomic Sciences
head and neck squamous cell carcinoma, TITE-CRM, wee1 inhibitor, Keywords: chemoradiation, window of opportunity study, wisteria
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1 2 3 4 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 adjuvant treatment, and a Window of Opportunity trial with Cisplatin in 6 7 Patients with Head and Neck Cancer: The WISTERIA Trial 8 9 10 11 12 AUTHORS 13 Kong A*1, Good J*2, Kirkham AJ3 , Savage J3, Mant R3, Llewellyn L8, Parish J1, Spruce R1, Forster M4, 14 Schipani S5, Harrington K6, Sacco JJ7, Murray P10, Middleton G 9, Yap Cǂ3, Mehanna Hǂ1† 15 16 17 *Joint first authors 18 ǂJoint senior authors For peer review only 19 20 † Corresponding author 21 22 23 Corresponding author: 24 Professor Hisham Mehanna 25 26 InHANSE, Institute of Cancer and Genomic Sciences 27 University of Birmingham 28 Edgbaston 29 Birmingham 30 31 B15 2TT 32 [email protected] 33 0121 414 6547 34 35 36 37 Author Affiliations http://bmjopen.bmj.com/ 38 1 Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK 39 2 University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, 40 41 Mindelsohn Way, Edgbaston, Birmingham, UK 42 3 Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomics Sciences, University of 43 Birmingham, Edgbaston, Birmingham, UK 44 4
University College Hospital London, Fitzrovia, London, UK on September 30, 2021 by guest. Protected copyright. 45 5 46 Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, UK 47 6 Royal Marsden/The Institute of Cancer Research,NIHR Biomedical Research Centre, London, UK 48 7 The Clatterbridge Cancer Centre, Wirral/University of Liverpool, Liverpool, UK 49 8 50 Simbec Research Ltd, Simbec Research Campus, Pentrebach, Merthyr Tydfil, South Wales, UK 51 9 Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, 52 UK 53 10 St James’ University Hospital, Leeds Teaching Hospitals NHS Trust 54 55 56 57 Keywords (5 max): TITE-CRM, head and neck squamous cell carcinoma, wee1 inhibitor, 58 chemoradiation, window of opportunity study 59 60 Word count excluding abstract, figures, tables, boxes and appendices: 4405
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1 2 3 4 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 Introduction 7 Head and neck squamous cell carcinoma (HNSCC) patients with locally advanced disease often 8 9 require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant 10 radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological 11 features post-surgery. Whilst cure rates are improved, overall survival remains sub-optimal and 12 13 treatment has a significant negative impact on quality of life. 14 Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the 15 therapeutic effects of chemo-radiation. Our hypothesis is that combining chemo-radiation with a 16 WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, 17 18 thereby enhancing clinicalFor outcomes, peer without review increased toxicity only. This trial explores the associated 19 effect of WEE1 kinase inhibitor Adavosertib (AZD1775). 20 21 22 23 Methods and analysis 24 This Phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of 25 26 AZD1775 in combination with cisplatin chemotherapy pre-operatively (Group A) as a window of 27 opportunity trial; and in combination with post-operative cisplatin-based chemo-radiation (Group B). 28 Modified time-to-event continual reassessment method (TITE-CRM) will determine the 29 recommended dose, recruiting upto 21 patients per group. Primary outcomes are recommended 30 31 doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days 32 (Group A), and 30% monitored up to 12 weeks (Group B). Secondary outcomes are disease-free 33 survival times (Groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) 34 35 effects, identification and correlation of potential biomarkers with PD markers of DNA damage, 36 determine rate of resection status and surgical complications for Group A; and quality of life in 37 Group B. http://bmjopen.bmj.com/ 38 39 40 Ethics and dissemination 41 Research Ethics Committee, Edgbaston, West Midlands (REC, reference 16/WM/0501) initial 42 approval received on 18/01/2017. Results will be disseminated via peer reviewed publication and 43 44 presentation at international conferences. 45 on September 30, 2021 by guest. Protected copyright. 46 Trial Registration 47 48 European Medicines Agency (EudraCT: 2015-003583-37); ISRCTN is 76291951 49 (http://www.isrctn.com/ISRCTN76291951); Clinicaltrials.gov identifier is NCT03028766 50 (http://clinicaltrials.gov/ct2/show/NCT03028766). 51 52 53 54 55 56 57 58 59 60
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BOX 1: Strengths and Limitations BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Strengths of the study: 7 The study is one of the first to explore a WEE1 inhibitor in combination with cisplatin and 8 9 radiotherapy, and the first to do so in head and neck cancer 10 Allows collection of tissues for translational research to examine the pharmacodynamic 11 effects of WEE1 and WEE1 in combination with cisplatin 12 13 Uses an efficient TITE-CRM design which allows dose assignments to be performed with the 14 flexibility of continual patient accrual or temporary accrual suspension to permit sufficient 15 accumulation of safety information as necessary. It uses both partial and complete DLT 16 information of all accumulated patients and dose information to inform dose 17 18 recommendationFor peer review only 19 20 Limitations of the study: 21 The window of opportunity study utilises a single dose of WEE1 followed by a separate single 22 dose of cisplatin due to the short timescale between diagnosis and standard treatment 23 24 Additional biopsies in the pre-operative setting may affect the patient enrolment 25 The oral administration of AZD1775 may affect recruitment in post-operative patients 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Head and neck cancers are the sixth most common cancer worldwide1, with 12,000 new cases per 5 6 year in the UK (CRUK head and neck cancer statistics). The most common types are squamous cell 7 carcinoma (HNSCC) arising from laryngeal, oral cavity , oropharynx and hypopharyngeal subsites2. 8 Primary surgery is the standard of care for cancers of the oral cavity, and for more advanced cancers 9 10 of the larynx and hypopharynx, whilst (chemo)-radiation is the standard approach to oropharyngeal 11 disease. Post-operative radiotherapy (PORT), or post-operative chemoradiation (POCRT), is often 12 recommended in the setting of high-risk features such as a positive margin, multiple involved nodes, 13 extra-capsular spread, and peri-neural infiltration. 14 15 The role of concomitant chemotherapy was established by the Meta-Analysis of Chemotherapy on 16 Head and Neck Cancer (MACH-NC) in 20092. This study pooled individual patient data from 93 trials 17 involving 16,485 patients receiving either definitive local therapy alone (surgery or radiotherapy) or 18 For peer review only 19 local therapy plus chemotherapy (induction, concomitant or adjuvant). Concomitant therapy was 20 assessed in 50 trials involving 9605 patients; chemotherapy decreased the risk of death with a 21 hazard ratio of 0.81, translating into a 6.5% overall survival advantage at 5 years as a result of 22 23 improved disease-free survival. No benefit was seen in patients aged over 70 years. This provides 24 robust evidence that the ability of radiotherapy to secure local control can be enhanced by systemic 25 therapy. 26 Acute toxicity and long-term sequelae of POCRT have a considerable negative health impact, and 27 3 28 despite intensive treatment, five year overall survival is sub-optimal at 53% . Loco-regional relapse is 29 particularly difficult to salvage, and local control is therefore closely correlated with overall survival. 30 Morbidity imposed by local recurrence in the absence of distant metastatic disease is considerable 31 32 and can be extremely challenging to palliate adequately. There is an urgent need to develop novel 33 approaches that achieve improved loco-regional disease control and reduce treatment-related 34 morbidity for this patient group. Achieving this may translate into improved overall survival and an 35 enhancement in patient-related outcome measures. 36 37 http://bmjopen.bmj.com/ 38 Chemotherapy, radiotherapy and DNA damage response 39 Cellular DNA damage response (DDR) is central to the preservation of genomic integrity. Cancer 40 41 development is a multistep process where deregulation of the DDR contributes to phenotypes such 42 as sustained cell proliferation and resistance to cell death. This increase in endogenous DNA damage 43 necessitates the acquisition of compensatory mechanisms if the cell is to avoid death through 44
uncontrolled genomic instability. Importantly, these compensatory changes may constitute a on September 30, 2021 by guest. Protected copyright. 45 46 molecular ‘Achilles heel’ that is vulnerable to therapeutic exploitation with a new generation of 47 targeted agents. POCRT exploits the differential DDR in malignant and normal tissues to eradicate 48 microscopic residual disease. Ionising radiation (IR) generates a variety of biological changes within 49 50 irradiated tissue, with double-stranded DNA (dsDNA) breaks being therapeutically significant (figure 51 1). IR-induced cell death is also immunogenic, with recruitment of immune effectors to the 52 irradiated tumour micro-environment contributing to a successful outcome4. Platinum-based 53 54 chemotherapy accentuates IR-induced cell death, in part via the suppression of homologous 55 recombination (HR), the primary repair mechanism for dsDNA damage in irradiated cells4. 56 Manipulation of the DDR pathway therefore represents a rational means by which the therapeutic 57 index of POCRT might be improved. Cell cycle checkpoints are integral components of the DDR, 58 59 allowing the cell to pause progression through the cell cycle to repair DNA damage. Checkpoints are 60 regulated by a network of phosphorylation cascades. p53, encoded by TP53, is a key regulator of the
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G1/S checkpoint. TP53 mutations, which are seen in 60-70% of HNSCC cases , are sufficient to impair BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 the function of this checkpoint and thereby create a critical reliance on the later G2/M checkpoint. In 6 addition, p53 function can be inactivated by various mechanisms, including somatic and germline 7 mutations as well as polymorphisms6,7. 8 Pharmacological abrogation of the G /M checkpoint has been shown to differentially sensitise 9 2 8 10 normal and tumour cells to the effect of DNA damaging agents such as cisplatin and IR . 11 12 13 14 WEE1 kinase and AZD1775 15 WEE1 kinase is a key regulator of the G2/M checkpoint and a promising therapeutic target. It is a 16 serine-threonine kinase involved in phosphorylation and inactivation of cyclin-dependent kinase 1 17 (CDK1), the only one of 14 similar proteins to be indispensable for mitotic entry. Along with a 18 For peer review only 19 number of other proteins, WEE1 triggers G2/M arrest in response to DNA damage. However,
20 inhibition of WEE1 leads to high CDK1 activity, allowing cells to progress through the G2/M 21 checkpoint without opportunity to repair damaged DNA, leading to potentially catastrophic levels of 22 9,10 23 unrepaired DNA damage induction of cell death . WEE1 also has an effect on CDK2 as its inhibition 24 leads to high CDK2 activity and aberrant DNA replication, resulting in stalled replication forks and 25 DNA double-stranded breaks. WEE1 upregulation is seen in a variety of human cancers and is 26 11, 12 27 inversely associated with prognosis in some models . Two separate kinomic screens in HNSCC 28 identified WEE1 expression as a particularly strong determinant of cell survival13, 14, indicating that 29 HNSCC may be a fruitful setting in which to investigate the clinical effects of WEE1 inhibition. 30 Adavosertib (AZD1775) is a potent, selective small molecule inhibitor of WEE1. It has been shown to 31 32 potentiate the activity of various chemotherapeutic agents in vitro and in vivo. Some studies suggest 33 the sensitising effect is only seen in p53-deficient tumours14-16 although not exclusively17. It has also 34 been show to enhance IR-induced cell death in TP53-mutant cell lines. 35 18 36 Co-exposure of AZD1775 and cisplatin were found to reduce clonogenic survival , demonstrating 37 this combination therapy has the ability to overcome cisplatin resistance in HNSCC. Similar effects of http://bmjopen.bmj.com/ 38 this compound on radiation-induced cell death have been seen in models of typically radio-resistant 39 cancer such as pontine glioma19, glioblastoma20, and pancreatic adenocarcinoma21. Importantly, one 40 41 study has shown that WEE1 inhibition by AZD1775 sensitises acute myelogenous leukaemia and lung 42 cancer cell lines to cytarabine chemotherapy independently of p53 status22, suggesting that p53 43 mutation as a predictive biomarker for response to WEE1 inhibition may be cancer and/or 44 45 chemotherapy specific. WEE1 has also been implicated in maintaining genomic stability through on September 30, 2021 by guest. Protected copyright. 46 stabilisation of replication forks - down-regulation reduces replication fork speed during S-phase, 47 generating potentially lethal dsDNA breaks23. By impacting both cell cycle progression and DNA 48 damage repair, WEE1 inhibition may potentiate cell death in response to chemotherapy and IR. This 49 50 suggests that there may be an additive effect on clinical outcome in combination with POCRT, as 51 well as potential synergy. 52 AZD1775 is being tested in many clinical settings including in combination with radiotherapy in 53 54 childhood pontine glioma (NCT01922076), with temozolomide and radiotherapy in glioblastoma 55 (NCT01849146), and with cisplatin and radiotherapy in cervical cancer (NCT01958658). 56 In summary, the available mechanistic data lend strong support to combining AZD1775 with cisplatin 57 and with POCRT in the clinic. Given that the predictive effect of TP53 mutation on such combinations 58 59 has yet to be clinically validated, this study does not prospectively stratify patients based on any 60
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such clinical or biological characteristic. Biomarker data generated, however, will be important in BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 understanding the mechanism of action and informing future combination studies. 6 7 8 Incorporating AZD1775 into clinical management 9 A recent randomised phase III study of neo-adjuvant chemotherapy in a Chinese population with 10 11 locally advanced resectable oral cavity cancer showed that docetaxel, cisplatin and 5-fluorouracil 12 (TPF) treatment generated a response rate of 80%, with an exploratory analysis showing that clinical 13 responders had improved overall survival and local control24. There was no improvement in overall 14 15 survival for the study group as a whole compared to the control group without upfront TPF 16 chemotherapy, possibly because patients who would ordinarily have received POCRT received PORT 17 alone in this study. In an earlier study, TP53 mutation conferred increased resistance to pre- 18 operative cisplatin-basedFor chemotherapy peer in oralreview cancer25. Whilst only neo-adjuvant chemotherapy has yet 19 20 to find a definitive role prior to surgery, these findings raise the possibility that chemo-sensitisation 21 may further improve outcomes. 22 The pre-operative Group A sets out to test this hypothesis by combining one week of AZD1775 23 2 24 alone, with a second week of cisplatin (40 mg/m ) with AZD1775. This short course of treatment will 25 minimise any delay between diagnosis and definitive surgery and prevent unacceptable delay for the 26 non-responders from getting standard treatment. If this is a promising combination, the long-term 27 aim is to test AZD1775 in the neoadjuvant setting to downstage the disease through treatment with 28 29 cisplatin and AZD1775 in the pre-operative setting, which may decrease the extent of surgery, and 30 may also reduce the need for PORT/POCRT by reducing the involved margin rate. Many patients with 31 tumours that have high-risk histopathological features develop relapsed disease within the 32 33 anatomical area treated to a high radiation dose. Chemo- and radio-sensitisation via inhibition of the 34 G2/M checkpoint by AZD1775 has the potential to improve outcomes with acceptable toxicity. This 35 possibility is the basis of the treatment delivered in the Group B cohort. 36 37 http://bmjopen.bmj.com/ 38 39 METHODS 40 41 Wisteria trial objectives 42 Primary objectives are to determine the recommended dose and safety profile of AZD1775 with 43 cisplatin in the Group A pre-operative (window-of-opportunity) setting, and with 44
cisplatin/radiotherapy in the Group B post-operative setting. Other objectives: obtain information on September 30, 2021 by guest. Protected copyright. 45 46 regarding Group A and B disease-free survivals; evaluate AZD1775 pharmacodynamic (PD) effects 47 when administered with cisplatin (Group A); identify and correlate potential predictive biomarkers 48 with PD markers of DNA damage (Group A); determine the rate of R0, R1 or R2 resection status and 49 50 surgical complication (Group A); and Group B quality of life (QoL). 51 52 Trial design 53 54 Wisteria is an open-label, dose-finding, multicentre Phase I trial to determine the highest safest dose 55 of AZD1775 in combination with a single dose of cisplatin in the pre-operative setting as a window of 56 opportunity trial (Group A); and to determine the maximum tolerated dose (MTD) of AZD1775 in 57 combination with cisplatin/radiotherapy in the post-operative setting (Group B): both groups recruit 58 59 and run in parallel (Figure 2). The dose-escalation design is based on the modified time to event 60
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continual reassessment method (TITE-CRM) , requiring a maximum of 21 patients per group, and BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 encompassing up to four dose levels of AZD1775. 6 The MTDs of AZD1775 for both groups are expected to differ given the additional toxicities of 7 radiotherapy in Group B. The DLT monitoring periods are defined in table 1. Conservative target 8 dose limiting toxicity (DLT) rates are selected to minimise the likelihood of compromising individual 9 10 patient’s radical surgery and/or post-operative radiotherapy. To maximise recruitment, reduce trial 11 suspension time between cohorts, whilst balancing safety and optimal patient allocation, screening 12 cohorts of up to five patients will be allowed if the dose has previously been tested. Recruited 13 14 patients will be allocated to the current recommended dose up to a maximum of five. Patients who 15 become unevaluable may be replaced. 16 The model will be updated after every two to three evaluable patients, with any subsequent eligible 17 patients (not already receiving treatment) allocated to the latest recommended dose cohort. 18 For peer review only 19 Subsequent cohorts will be assigned a dose level using all the data observed until either - the MTD is 20 determined, the maximum sample size is reached, or the trial is stopped early due to unacceptable 21 DLT levels at the lowest dose. 22 23 24 25 Patient population, screening and consent 26 Group A patients are those with biopsy proven squamous cell carcinoma of the oral cavity, larynx or 27 hypopharynx (having accessible tumours for re-biopsy under local anaesthetic or via ultrasound- 28 guided biopsy), and due to undergo surgery. Patients in Group B consist of those already diagnosed 29 with oral cavity, larynx or hypopharynx squamous cell carcinoma, who have undergone surgery and 30 31 are considered at risk of relapse after surgery (i.e. with positive margins and/or nodal extracapsular 32 spread). Patients with cancer of the oropharynx will not be included. Patients who meet the criteria 33 will be supplied with the Patient Information Sheet. If informed consent is given the patient undergoes 34 a full screening evaluation to ensure they satisfy the eligibility criteria prior to registration (Boxes 2 35 and 3). 36 37 http://bmjopen.bmj.com/ 38 Dose selection 39 30, 31 40 Based on AstraZeneca studies , the Wisteria trial uses 3-day dosing, giving AZD1775 weekly to 41 coincide with cisplatin administration thereby potentiating the DNA damage effects. The maximum 42 total dose of AZD1775 1800 mg in combination with 1 dose of 40mg/m2 cisplatin for Group A is 43 44 substantially lower than AZD1775 monotherapy dose 2250mg every 21 days (225mg twice per day 45 orally over 2.5 days per week for 2 weeks per 21-day cycle) used in Do et al (2015); and although in on September 30, 2021 by guest. Protected copyright. 46 combination with cisplatin, the highest dose level (Dose Level 2) is likely to be safe. 47 A similar dose escalation algorithm will be carried out in Group B with a higher acceptable target DLT 48 49 level of 30% allowing for multiple dosing of cisplatin with radiotherapy in combination with 50 AZD177532-34. Trial doses and schedule are set out in table 1. AZD1775 is administered orally. The 51 feasibility of the oral administration will be evaluated in post-operative patients. 52 53 54 55 56 57 58 59 60
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Table 1: Details of the Wisteria TITE-CRM trial design for Groups A and B BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Group A Group B 7 Maximum 8 Number of Up to 21 patients in each Group 9 Patients 10 Dose closest to where 25% MTD Definition Dose closest to where 30% patients experience a DLT 11 patients experience a DLT 12 Patients to have received the 13 Minimum minimum of AZD1775 and Patients to have received a minimum of the first two 14 Treatment To Be Cisplatin doses scheduled up to weeks of treatment as scheduled 15 DLT Evaluable and including day 8 16 17 Minimum of 30 days from start of 18 treatmentFor up peerto 42 days for delaysreview Minimum only of 56 days (8 weeks) from start of 19 DLT Reporting in surgery due to treatment radiotherapy, and up to 84 days (12 weeks), i.e. up to 20 Period related toxicity (if this exceeds 42 6 weeks from end of post-operative chemo-radiation 21 days then this delay will be therapy. 22 classified as a DLT). 23 AZD1775 PO AZD1775 PO BID Cisplatin (iv) Cisplatin (iv) Radiotherapy 24 BID 3 days 3 days over 1 hr over 1 hr (5 days per week 25 (Days 1-3, 8-10) (Days 2-4 weeks 1, 2, (Day 8) (Day 2 weeks 1-5) over 6 weeks) 26 Dose Levels : 4 & 5) 27 28 -1 75 mg 50 mg 29 0 (starting dose 30 100 mg 75 mg 31 level) 40 mg/m2 40 mg/m2 54-65 Gy in 30# 32 1 125 mg 100 mg 33 34 35 2 150 mg 125 mg 36 37 (iv) Intravenous; (PO) By Mouth; (BID) Twice A Day; (Gy) Gray - unit of radiation dose; (#) Daily Fractions http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Box 2: Inclusion criteria – all patients BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Histologically confirmed diagnosis of oral, laryngeal or hypopharyngeal squamous cell 7 carcinoma 8 Multi-Disciplinary Team (MDT) recommendation for surgical resection with curative intent 9 10 Eastern Cooperative Oncology Group (ECOG) performance status 0/131 11 Age ≥18 to ≤70 years 12 Creatinine clearance, measured by Glomerular Filtration Rate (GFR), ≥ 60 ml/min at baseline 13 calculated using local practice calculation. If this is ≤ 60 ml/min then an isotopic GFR may be 14 15 carried out and must be > 60 ml/min 16 Acceptable cardiac function. If significant cardiac history, then required for patient to have 17 Left Ventricular Ejection Fraction (LVEF) ≥55% by echocardiogram (ECHO) or Multiple Gated 18 For peer review only 19 Acquisition Scan (MUGA, if ECHO is equivocal) 20 Normal liver and bone marrow function: 21 o Haemoglobin (Hb) ≥10.0 g/dL or ≥100 g/L 22 23 o Absolute neutrophil count (ANC) ≥1.5 x 109/L 24 o Absolute platelet count ≥100 x 109/L 25 o Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≤2.5 upper limit of 26 normal (ULN) 27 28 o Total bilirubin ≤1.5 ULN (except for patients with known Gilbert’s syndrome) 29 Male and female participants must agree to take appropriate measures to prevent 30 pregnancy. Contraceptive measures should be used for 2 weeks prior to trial entry, during 31 32 the trial and for at least 6 months after last receiving treatment. Acceptable methods of 33 contraception include total abstinence (if this is the patient’s usual and preferred lifestyle 34 choice), tubal ligation, combined oral, transdermal or intra-vaginal hormonal contraceptives, 35 medroxyprogesterone injections (e.g. Depo-Provera), copper-banded intra-uterine devices; 36 37 hormone impregnated intra-uterine systems and vasectomised partners. All methods of http://bmjopen.bmj.com/ 38 contraception (with the exception of total abstinence) should be used in combination with 39 the use of a condom by their male sexual partner for intercourse. 40 41 42 43 In addition to general criteria 44 Group A – Accessible tumours for re-biopsy to be taken under local anaesthetic or via on September 30, 2021 by guest. Protected copyright. 45 ultrasound-guided biopsy 46 47 Group B – High-risk histopathological features after surgical resection, i.e. nodal extra- 48 capsular spread and/or tissue resection margin <1 mm as agreed at MDT 49 Group B – Patients who have previously registered to Group A can be considered for 50 51 inclusion in Group B 52 53 54 55 56 57 58 59 60
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Box 3: Exclusion criteria – all patients BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Any previous treatment for the same cancer, or previous head and neck malignancy, apart 7 from laser excision of carcinoma in situ, with minimal residual functional deficit, or 8 registration and treatment in Group A prior to surgery 9 Patients with cancer of the oropharynx or non-primary cancer will not be included 10 11 Any metastatic disease from any primary site 12 Use of an Investigational Medicinal Product (IMP) concurrently or within 4 weeks of starting 13 this trial 14 15 Uncontrolled inter-current illness, which will interfere with patient’s trial participation, e.g.: 16 o myocardial infarction within 6 months 17 o congestive cardiac failure 18 For peer review only 19 o unstable angina 20 o symptomatic cardiomyopathy 21 o chronic infections 22 active peptic ulcer or liver disease 23 o 24 o serious psychiatric condition limiting ability to comply with trial protocol 25 Clinical evidence of current heart failure (≥New York Heart Association (NYHA) Class II32) 26 Clinical evidence of atrial fibrillation (heart rate >100 bpm, within 6 months prior to trial 27 28 entry) 29 Unstable ischaemic heart disease (Myocardial Infarction within 6 months prior to trial entry 30 or angina requiring the use of nitrates greater than once weekly) 31 32 Patients who have a history of Torsades de Pointes (unless all risk factors that contributed to 33 Torsades have been corrected) 34 Active gastro-intestinal disease that might limit absorption of study drug, e.g. coeliac 35 36 disease, Crohn’s disease, ulcerative colitis, pancreatic insufficiency 37 Evidence of any psychological, familial, sociological or geographical condition potentially http://bmjopen.bmj.com/ 38 hampering protocol compliance 39 40 Participation in another interventional clinical trial whilst taking part in this trial 41 Patients who are unable to discontinue any prohibited drug, including live vaccines, and 42 unable to tolerate a washout period for at least 14 days prior to trial entry (including: 43 CYP3A4 inhibitors; CYP3A4 inducers; CYP3A, CYP3A4, CYP2C19, CYP1A2 sensitive substrates 44 45 or substrates with narrow therapeutic range; P-gp substrates, strong P-gp inhibitors; and on September 30, 2021 by guest. Protected copyright. 46 BCRP substrates33) 47 Patients with any contraindications to cisplatin use 48 49 Clinical judgement by the Investigator that the patient should not participate in the study 50 Known hypersensitivity to the study drugs or active substances or excipients of the 51 preparations 52 53 Pregnant or breastfeeding patients 54 Significant pre-existing neuropathy which currently interferes with the patient’s daily life 55 Mean resting corrected QTc interval using the Fridericia formula34 >450 msec (male) and 56 57 >470 msec (female) (as calculated per institutional standards) obtained from 3 58 electrocardiograms (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome 59 Inability to swallow oral medications 60
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Trial treatments BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Group A (pre-operative): patients will receive specified dose of AZD1775 by mouth (PO) twice per 6 day (BID) at 12 hour intervals (2 hours before or after food) for 3 days, commencing on days 1 and 8, 7 with 40 mg/m2 IV cisplatin delivered over 1 hour on day 8. A missed dose of more than 6 hours 8 9 should be skipped. If vomiting occurs, patient should not retake the dose but wait until next 10 scheduled dose. Surgery is not to exceed 42 days from start of neo-adjuvant chemotherapy. 11 12 Group B (post-operative): patients will receive specified dose of AZD1775 PO BID for 3 days, 13 2 14 commencing on days 2, 9, 23 and 30, and 40 mg/m IV cisplatin delivered over 1 hour on days 2, 9, 15 16, 23 and 30 (days are timed from the start of radiotherapy delivery). Radiotherapy (65Gy and 16 54Gy in 30 fractions given for 5 days per week over 6 weeks: D1-5, D8-12, D15-19, D22-26, D29-33, 17 D36-40, to high risk and low risk volumes respectively) will commence within 3 months of surgery 18 For peer review only 19 and given concurrently with chemotherapy. 20 21 For both Groups A and B, cisplatin dose banding is not permitted. BSA to be calculated according to 22 23 local practice; if weight changes >10% then cisplatin dose should be re-calculated. 24 AZD1775 (morning dose) should be administered prior to cisplatin, and Group B to receive cisplatin 25 one hour before radiotherapy; standard supportive treatment, including premedication with anti- 26 27 emetics (excluding Aprepitant and Fosaprepitant), is allowed according to standard practice 28 guidelines. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Trial outcome measures BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Primary outcome measures: the recommended doses of AZD1775 (determined by the modified 6 TITE-CRM) for Group A and B. 7 Group A: the highest safe dose in combination with cisplatin with a predefined target 8 9 DLT probability of 25% for up to 42 days from start of treatment 10 Group B: the MTD in combination with cisplatin/radiotherapy with a target DLT of 30% 11 for up to 12 weeks from the start of treatment. 12 13 Safety profile of AZD1775 in both Group A and B. 14 15 Secondary outcome measure: disease-free survival time for both Groups and recorded from 16 commencement of treatment to the date of disease recurrence, patient death or end of trial follow- 17 18 up period. For peer review only 19 20 Tertiary research outcome measures: pharmacodynamic (PD) effects of AZD1775 and correlation 21 22 with TP53 mutation status; pharmacokinetic (PK) effects of AZD1775 will be determined; optimise, 23 validate and test feasibility of assays to investigate serum, ctDNA and RNA biomarkers; investigate 24 the feasibility of immune function testing in a multicentre setting; complete pathological response 25 rate for Group A; positive resection margin status in Group A; surgical complication in Group A; and 26 27 quality of life (QoL) in Group B using European Organization for Research and Treatment of Cancer 28 (EORTC) C30 (version 3.0) 35, EORTC QLQ-H&N3536 and M.D. Anderson Dysphagia Inventory 29 (MDADI)37, as summarised in Box 4. 30 31 Assessment data will be collected as listed in appendix tables 1 and 2. 32 33 Dose limiting toxicity and dose management 34 35 Pre-defined DLTs have been specified by the Clinical Investigators (Box 5), and recorded toxicity 36 profiles for the Wisteria treatments are given in appendix table 3. Toxicity is assessed using the 37 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.038 unless http://bmjopen.bmj.com/ 38 otherwise specified. Any patient requiring a toxicity-related dose delay of more than 21 days must 39 40 be discontinued from the study unless there is approval from the Chief Investigator for the patient to 41 continue. For Group A, if any treatment-related Grade ≥3 toxicity develops in week one, cisplatin 42 and AZD1775 are discontinued in week two. For Group B, if calculated GFR falls below 60 mL/min, 43 44 immediately before any cycle of concomitant chemotherapy, weekly cisplatin should be 45 discontinued and consideration given to substitute with weekly carboplatin (AUC =1.5), according to on September 30, 2021 by guest. Protected copyright. 46 routine local practice. 47 In both groups a full blood count is obtained at the beginning of each week. If haematological 48 49 toxicity occurs, treatment should be modified as per appendix tables 4 and 5. For non- 50 haematological toxicities, treatment should also be modified as per appendix tables 6 to 10. 51 52 53 54 55 56 57 58 59 60
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Box 4: Trial summaries of Group A and Group B BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Summary of Group A 7 Setting Patients undergoing surgical resection 8 9 Design Modified TITE-CRM 10 Chemotherapy Cisplatin 40 mg/m2 IV over 1 hour on Day 8 11 AZD1775 AZD1775 PO BID for 3 days on Days 1-3 and 8-10 12 Dose-recommendation according to the modified TITE-CRM model 13 14 Surgery Resection within 42 days of start of neo-adjuvant treatment 15 DLT reporting The minimal reporting period is 30 days from start of treatment, but 16 period patients will be monitored up to 42 days for delay in surgery due to 17 treatment-related toxicity 18 PK samples ForPharmacokinetic peer samples review will be collected only pre- and post- the fifth dose 19 of AZD1775 on Days 3 and 10 (4 samples per patient) 20 21 PD markers Assess CDC2, pCDC2, γH2AX, p53, p16, HH3, pHH3, Ki67, C3, CC3, p21, 22 WEE1, pWEE1, PDL-1 and TILS, and other markers of particular interest 23 Follow-up Clinically for at least 12 weeks from start of treatment 24 25 26 27 Summary of Group B 28 Setting Post-operative patients with high risk disease (involved resection 29 30 margins +/or extracapsular nodal spread) receiving chemo-radiation 31 Design Modified TITE-CRM 32 Chemotherapy Cisplatin 40 mg/m2 IV over 1 hour on Day 2 of Weeks 1-5 of 33 radiotherapy 34 Radiotherapy External beam radiation therapy (30 fractions over six weeks) to start 35 within 3 months of surgery. Dose levels are 65 Gy for positive margin, 36
60 Gy to lymph node levels that have been dissected, and 54 Gy to http://bmjopen.bmj.com/ 37 38 elective lymph node areas. A dose of 65 Gy may also be applied to areas 39 of gross extra-capsular spread at the discretion of the treating clinician. 40 AZD1775 AZD1775 PO BID for 3 days on Days 2-4 of Weeks 1, 2, 4 and 5 (No 41 treatment with AZD1775 during Weeks 3 and 6). 42 Dose-recommendation will be according to modified TITE-CRM model. 43 DLT reporting The minimal reporting period is 56 days (8 weeks) from start of 44 45 period radiotherapy, but patients will be monitored for DLTs up to 84 days (12 on September 30, 2021 by guest. Protected copyright. 46 weeks), i.e. up to 6 weeks from the end of POCRT 47 PK samples Pharmacokinetic samples will be collected pre- and post- the fifth dose 48 of AZD1775 on Week 1 – Day 4 (2 samples per patient) 49 PD markers Assess CDC2, pCDC2, p53, p16, WEE1, pWEE1, PDL-1 and TILS and other 50 markers of particular interest in resection tumour samples 51 52 Follow-up Clinically for at least one year from start of treatment 53 54 The selection of PD markers to test are different for Group A and Group B as Group A enables examination of 55 samples pre-and post-treatment with AZD1775. 56 57 58 59 60
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Box 5: Dose limiting toxicities BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Patients experiencing any of the following Adverse Reactions (ARs) during the reporting period will 6 be considered to have experienced a DLT: 7 8 Grade 3 or 4 neutropenia lasting for >7 days despite adequate Granulocyte-Colony 9 Stimulating Factor (G-CSF) support 10 11 Grade 4 febrile neutropenia, which includes grade 3 febrile neutropenia accompanied by 12 systemic inflammatory response syndrome / sepsis or other life-threatening consequences 13 A third occurrence of Grade 2 or worse neutropenia despite G-CSF support 14 15 Grade 3 or 4 thrombocytopenia lasting ≥7 days 16 Any occurrence of Grade 4 anaemia 17 Any occurrence of Grade 4 mucositis 18 For peer review only 19 Any occurrence of Grade 3 nausea despite preventative and supportive care according to 20 local practice. Tube feeding is not considered a DLT 21 Any occurrence of Grade 4 vomiting despite preventative and supportive care according to 22 23 local practice. Tube feeding is not considered a DLT 24 Any occurrence of Grade 4 diarrhoea despite preventative and supportive care according to 25 local practice 26 27 Any AR which results in an omission of chemotherapy administration and/or study 28 treatment for > 14 days 29 A start-of-treatment-to-surgery time of > 42 days in Group A as a result of a treatment- 30 related toxicity 31 32 Grade 3 mucositis lasting > 42 days after the end of treatment in Group B 33 An overall treatment time of > 49 days from the first day of radiotherapy in Group B as a 34 result of a treatment-related toxicity 35 36 Any Grade 3 or 4 non-haematological AR (except for fatigue, nausea, vomiting and 37 diarrhoea) for which medical intervention that lasts >7 days is required and the investigators http://bmjopen.bmj.com/ 38 deem that this AR is more severe or prolonged than what would be expected of standard 39 40 treatment. Tube feeding is not considered a DLT. 41 Any clinically significant occurrence which investigators within the Trial Management Group 42 (TMG) agree would place the patient at undue safety risk 43 44
If inability to swallow the AZD1775 capsule develops during the course of trial treatment, this event on September 30, 2021 by guest. Protected copyright. 45 46 should be noted in the relevant section on the Suspected DLT form and reported immediately. 47 However, this is not considered a DLT in itself. 48 49 50 51 52 53 54 55 56 57 58 59 60
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Concomitant medications BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 All concomitant medications received within 14 days before the first dose of study medication and 6 for 12 weeks after the last dose of study medication should be recorded. Medications may be 7 administered for maintenance of existing conditions prior to study enrolment or for a new condition 8 9 that develops while on study. The treatments and medications listed in appendix 11 are prohibited 10 or to be used with caution while in this study. No other investigational therapy or anticancer agents, 11 other than the study medications, should be given to patients. If such agents are required for a 12 patient, then the patient must first be withdrawn from the study. Live vaccines are not permitted. 13 14 15 Discontinuation of investigational medicinal product 16 Patients should discontinue trial treatment in the following circumstances: Intolerable toxicity; 17 18 confirmed disease recurrence;For peerpregnancy; severe review non-compliance only to protocol; development of any 19 study specific criteria for discontinuation; and investigator decision, for example if the patient 20 requires a prohibited concomitant medication. 21 22 23 24 25 Safety monitoring – adverse events and serious adverse events 26 All medical occurrences which meet the definition of an adverse event (AE) or serious adverse event 27 (SAE) (as defined in Box 6) should be reported. This includes abnormal laboratory findings of grade 3 28 and above only. Adverse events will be monitored for and reported from date of informed consent 29 30 until the 12 week follow up visit for Group A and until the 12 month follow up visit for Group B. 31 Investigators should report SAEs within 24 hours of first knowledge of the event, until 12 week 32 follow up visit. After this time, expedited reporting is no longer required and should be reported as 33 34 an AE. Any post study serious unexpected serious adverse reactions (SUSARs) should be reported 35 within 24 hours. An independent Safety Committee will review all SAEs. Fatal or life threatening 36 SUSARs will be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) and 37 http://bmjopen.bmj.com/ Research Ethics Committee (REC) within 7 days. Detailed follow-up information will be provided 38 39 within an additional 8 days. All other events categorised as SUSARs will be reported within 15 days. 40 The MHRA and REC will be notified immediately if a significant safety issue is identified during the 41 course of the trial. All SAEs relating to AZD1775 will be reported to AstraZeneca within 24 hours of 42 43 notification. 44 on September 30, 2021 by guest. Protected copyright. 45 Data collection and monitoring 46 47 Data will be collected via a set of forms capturing details of eligibility, baseline characteristics, 48 treatment and outcome details. This trial will use an electronic remote data capture (eRDC) system. 49 SAE reporting and Notification of Pregnancy will be paper-based. All missing and ambiguous data will 50 be queried. In all cases it remains the responsibility of the Investigator to ensure that data are 51 52 accurate. Details regarding data collection for Group A and B are given in appendix tables 1 and 2. 53 The Investigator will permit trial-related monitoring, audits, ethical review, and regulatory 54 inspection(s) at their site, providing direct access to source data/documents. 55 56 57 58 59 60
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Box 6: Adverse event and serious adverse event definitions BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Adverse Event 6 Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 7 product and which does not necessarily have a causal relationship with this treatment. 8 9 10 Serious Adverse Event 11 Any untoward medical occurrence or effect that at any dose may: 12 13 Result in death 14 15 Is life-threatening 16 Requires hospitalisation or prolongation of existing in-patient hospitalisation 17 Results in persistent or significant disability or incapacity 18 For peer review only 19 Is a congenital anomaly/birth defect 20 Is considered medically significant by the Clinical Investigator 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Statistical methodology BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 The AZD1775 dose is allocated to patients according to a modified Bayesian TITE-CRM, using an 6 empiric dose-toxicity model, F(x,β) given as: 7 퐹(푥,훽) = 푥exp (훽) 푓표푟 0 < 푥 < 1 8 9 where model parameter β is assumed random and follows a normal distribution and will be 10 estimated by its posterior mean28. At the point of model-update, patients who have started 11 treatment but have not experienced DLT (and have completed their full DLT assessment) will be 12 included in the probability calculation with a weight equal to the proportion of the full DLT 13 14 assessment period they have completed. Patients who experience DLT within the assessment period 15 or complete the full assessment period are assigned full weight. The model also enables inclusion of 16 partial patient information that cannot be formally evaluated for DLTs due to withdrawal, treatment 17 discontinuation or death, which are unrelated to treatment, within the DLT assessment period. 18 For peer review only 19 Table 1 displays the four dose levels of AZD1775 for Group A and Group B. For both groups, dosing 20 starts at level 0 and allows for possible escalation to two higher levels, or de-escalation to a lower 21 dose, as recommended by the TITE-CRM, without skipping untried doses in escalation. The TITE-CRM 22 23 model aims to recommend the next dose with estimated DLT probability closest to the target DLT 24 level, taking into account the practical considerations as detailed below: 25 26 27 Practical Considerations 28 Restriction is applied to avoid skipping of untried doses in escalation 29 Stop early due to safety concerns if there is sufficient evidence that the posterior probability of 30 31 DLT at the lowest dose is greater than the target DLT rate, implying that the lowest dose is too 32 toxic 33 Stop early if sufficient patients have been allocated to the current MTD (and remains the 34 recommended dose level for the next cohort if the trial continues) before the full recruitment of 35 36 21 patients 37 The minimum DLT period is set at 30 days for Group A and 8 weeks for Group B. This means that http://bmjopen.bmj.com/ 38 partial information of no DLT in a patient can only be included in the model if they have been 39 40 followed up for at least 30 days or 8 weeks in Group A and B respectively. (The full DLT 41 assessment periods are 42 days and 12 weeks in Group A and B respectively.) This feature can 42 easily be accommodated using the TITE-CRM model 43 44 A “look ahead” strategy will be implemented if the next recommended dose level by the 45 modified TITE-CRM model will not be influenced by the outcome of the remaining patient(s) of a on September 30, 2021 by guest. Protected copyright. 46 particular cohort (DLT or no DLT). By implementing this strategy, the next cohort can be 47 recruited immediately without awaiting the final observations from the current cohort, thus 48 49 reducing waiting time between cohorts 50 51 52 Analysis of outcome measures 53 The primary outcome measures are the recommended doses of AZD1775 in Group A and Group B, 54 55 and the safety profile of the combination therapy. To be DLT evaluable, Group A patients must have 56 received AZD1775 and cisplatin doses scheduled up to and including Day 8; Group B patients must 57 have received at least the first two weeks of treatment. The recommended doses of AZD1775 will be 58 59 those that have an estimated DLT rate closest to the target DLT rate: 25% for Group A; 30% for 60 Group B. DLT rates and corresponding 90% probability intervals will be reported. Safety will be
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monitored in patients treated with at least one dose of the trial treatment until end of follow-up. All BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 adverse reactions, adverse events, serious adverse events, suspected unexpected serious adverse 6 reactions, deaths, deviations and withdrawals experienced by trial patients, throughout the trial’s 7 duration, will be reported separately for Group A and Group B. 8 Disease-free survival in Group A and Group B patients will be reported separately. Patients will be 9 10 followed-up for 12 months after which, time to event outcomes will be assessed using the method 11 of Kaplan and Meier. Median diease free survival with corresponding 95% confidence intervals will 12 be reported where appropriate. Further analysis will be performed separately on subsets of Group A 13 14 and B patients who have completed at least 90% of AZD1775 trial scheduled treatments. 15 Tertiary outcome measures will be explored and reported descriptively using basic descriptive 16 statistics where appropriate: 17 18 PD effects ofFor AZD1775 peer and correlation review with TP53 mutation only status: Expression levels of 19 20 parameters (Box 4) changes over time and correlation with TP53 mutation status will be 21 reported. 22 PK effects of AZD1775: Blood samples for PK analyses are collected (as scheduled in 23 appendix tables 1 and 2). Circulatory levels of AZD1775 and changes over time will be 24 25 reported. 26 Complete pathological response rate for Group A: Pathology data will be reported along 27 with the results of the FFPE tissue samples. Response rate will be reported as the number of 28 29 evaluable Group A patients showing a response (numerator) divided by the total number of 30 Group A evaluable patients (denominator). 31 Positive resection margin status in Group A: This will be reported as the number and 32 33 percentage of Group A patients showing positive resection margins. 34 Surgical complications in Group A: This will be reported by category of surgical complication 35 with severity and given as numbers and percentages. 36 37 Quality of Life (QoL) in Group B: QoL data is gathered over time and will be reported as http://bmjopen.bmj.com/ 38 changes over time and plotted. In addition to the descriptive analyses, the repeated 39 measures over time data may be modelled, if appropriate, with a linear mixed effects model 40 (taking subject correlation into account) using linear or more flexible models. 41 42 43 44 Interim analyses will be performed once each cohort of patients has been recruited and assessed 45 within the defined assessment timeframe of DLTs. In each meeting, the Safety Committee will be on September 30, 2021 by guest. Protected copyright. 46 presented with recruitment and safety data, together with a statistical report for next dose- 47 48 recommendation. Additional meetings might be convened if late onset DLTs were observed. The 49 Safety Committee will decide whether to progress to the recommended dose as indicated by the 50 modified TITE-CRM model. The final analyses will be conducted in two parts: (i) analyses of the 51 52 primary outcome measures of MTDs for Groups A and B, to be carried out approximately three 53 months after the safety review of the last cohort in each group; (ii) longer term outcomes – including 54 secondary and tertiary outcome measures and updated safety data, to be carried out one year after 55 the end of trial. 56 57 58 59 60
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TRIAL ORGANISATION AND STRUCTURE BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 The Trial is sponsored by the University of Birmingham, UK and conducted under the auspices of the 6 Cancer Research UK Clinical Trials Unit, University of Birmingham, UK according to their local 7 procedures. 8 9 The Trial Managemant Group (TMG) will include as a minimum: Chief Investiagtor, Co-Investigators, 10 Lead and Trial Statisticians, Trial Management Team Leader and Trial Co-ordinator (other 11 appropriate key personnel will be invited to attend meetings as required). This group will be 12 responsible for legal obligations, day-to-day running and management of the Trial. 13 14 The Safety Committee provides support on decisions surrounding review of DLT information and 15 dose changing decsions. Membership of this group includes the TMG, independent members and 16 selected Principal Investigators. 17 18 For peer review only 19 20 ETHICS AND DISSEMINATION 21 22 The protocol has been approved by the Research Ethics Committee, Edgbaston, West Midlands (REC, 23 reference 16/WM/0501). The first REC approval date was 18/01/2017, with five subsequent 24 approved amendments. This article refers to protocol version 5.0, dated 27/11/2018. 25 th 26 The trial will be performed in accordance with the 18 World Medical Association General Assembly, 27 Helsinki, Finland, June 1964, amended at the 48th World Medical Association General Assembly, 28 Somerset West, Republic of South Africa, October 1996 (website: 29 http://www.wma.net/en/30publications/10policies/b3/index.html); conducted in accordance with 30 31 the Research Governance Framework for Health and Social Care, the applicable UK Statutory 32 Instruments, (which include the Medicines for Human Use Clinical Trials 2004 and subsequent 33 amendments, The Human Tissue Act 2008) and Good Clinical Practice (GCP) E6(R2); and carried out 34 35 under a Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical Trials 36 regulations. The protocol and subsequent amendments will be submitted to and approved by REC http://bmjopen.bmj.com/ 37 prior to circulation. Personal data recorded on all documents will be regarded as strictly confidential 38 and will be handled and stored in accordance with the General Data Protection Regulation 2016/679 39 40 and the Data Protection Act (2018). 41 Trial findings will be published in a peer reviewed journal and disseminated at appropriate 42 conferences, departmental and scientific meetings. 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 Acknowledgements 50 Wisteria was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC 51 Network. 52 53 54 Authors’ contributions 55 The study was conceived by Hisham Mehanna and James Good; designed by Hisham Mehanna, 56 James Good, Anthony Kong, and Christina Yap; and the protocol written by Hisham Mehanna, 57 58 Anthony Kong, James Good, Christina Yap, Laura Llewellyn, Rhys Mant, Amanda Kirkham, Rachel 59 Spruce, Nikos Batis, Jill Brookes, Joshua Savage, Joe Sacco, Martin Forster and Kevin Harrington. 60
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Amanda Kirkham, Anthony Kong, James Good and Christina Yap wrote the manuscript with input BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 from all authors. 6 7 Funding 8 Cancer Research UK (code C19677/A20959) and AstraZeneca through the CRUK’s Combinations 9 10 Alliance and Experimental Cancer Medicine Centre (ECMC). 11 The Combinations Alliance, a Cancer Research UK model, aims to drive academic-industrial 12 partnership, generating novel treatment options that would otherwise unlikely be realised. Novel 13 14 combination ideas are generated and delivered via the UK’s Experimental Cancer Medicine Centre 15 (ECMC) network of clinical and scientific experts working together to accelerate innovation in early- 16 phase oncology research for patient benefit. 17 18 For peer review only 19 Competing interests 20 HM, AK, RM, JS, CF, JG, RS, Report grants from CRUK, and AZ during the conduct of the study. 21 JS reports personal fees from Eli Lilly and Company outside the submitted work. 22 23 KH reports grants and personal fees from ASTRA ZENECA, during the conduct of the study; personal fees from 24 AMGEN, personal fees from BMS, personal fees from BOEHRINGER INGELHEIM, personal fees from MERCK 25 SERONO, personal fees from MSD, personal fees from PFIZER, outside the submitted work; 26 HM reports personal fees from BMS, MSD outside the submitted work. 27 JS reports grants from AstraZeneca, grants from BMS, personal fees from BMS, personal fees from MSD, 28 personal fees from Immunocore, personal fees from Delcath, personal fees from Pierre Fabre, outside the 29 30 submitted work. 31 32 33 Patient consent 34 35 All patients must give written informed consent to the Investigator prior to Trial registration 36 (appendices 16 and 17). 37 http://bmjopen.bmj.com/ 38 Patient and public involvement 39 40 No patient or public involvement contributed to the design of this trial. 41 42 Provenance and peer review 43 44 Not commissioned; externally peer reviewed. 45 on September 30, 2021 by guest. Protected copyright. 46 Ethich approval 47 Research Ethics Committee (REC, reference 16/WM/0501) 48 49 50 Open access 51 This is an Open Access article distributed in accordance with the terms in the Creative Commons 52 53 Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this 54 work, for commercial use, provided the original work is properly cited. See 55 http://creativecommons.org/licenses/by/4.0/ 56 57 58 59 60
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 REFERENCES 6 7 1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2009. CA Cancer J Clin 2009;59:225-249. 8 2. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143- 9 1154. 10 3. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without 11 12 concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 13 2004;350:1945-52. 14 4. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Sem Rad Onc 2015;25:11-17. 15 16 5. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of 17 genomics. Nat Rev Clin Oncol 2015;12:11-26. 18 6. Olivier M, HollsteinFor M, Hainaut peer P. TP53 review mutations in human only cancers: origins, consequences, 19 and clinical use. Cold Spring Harb Perspect Biol 2010;2(1):a001008. 20 21 7. Petitjean A, Achatz MI, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional 22 selection and impact on cancer prognosis and outcomes. Oncogene 2007;26(15):2157-65. 23 8. Dillon MT, Good JS, Harrington KJ. Selective targeting of the G2/M cell cycle checkpoint to 24 25 improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol) 2014;26:257-85. 26 9. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of WEE1 kinase by MK-1775 27 selectively sensitizes p53-deficient tumour cells to DNA-damaging agents. Mol Can Ther 28 2009;8:2992-3000. 29 30 10. Van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 31 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 32 Cancer Ther 2013;12:2675-84. 33 34 11. Magnussen GI, Holm R, Emilsen E, et al. High Expression of WEE1 Is Associated with Poor 35 Disease-Free Survival in Malignant Melanoma: Potential for Targeted Therapy. BMJ Cancer 36 2013;13:288. 37 http://bmjopen.bmj.com/ 12. Mir SE, de Witt Hamer PC, Krawxzyk PM, et al. In Silico Analysis of Kinase Expression Identifies 38 39 WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma. Cancer Cell 2010;18:244- 40 57. 41 13. Wu Z, Doondeea JB, Gholami AM, et al. Quantitative chemical proteomics reveals new 42 43 potential drug targets in head and neck cancer. Mol Cell Proteomics 2011;10:M111.011635. 44 14. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of WEE1 kinase by MK-1775 on September 30, 2021 by guest. Protected copyright. 45 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Can Ther 2009; 46 8:2992-3000. 47 48 15. Bridges KA, Hirai H, Buser CA, et al. MK-1775, a novel WEE1 kinase inhibitor, radiosensitizes 49 p53-defective human tumor cells. Clin Cancer Res 2011;17: 5638-48. 50 16. Khanh D, Doroshow JH, Kummar S. WEE1 kinase as a target for cancer therapy. Cell Cycle 51 52 2013;12:3159-64. 53 17. Van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 54 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 55 56 Cancer Ther 2013;12:2675-84. 57 18. Osman AA, Monroe MM, Ortega Alves MV, et al. Wee-1 Kinase Inhibition Overcomes Cisplatin 58 Resistance Associated with High-Risk TP53 Mutations in Head and Neck Cancer through 59 Mitotic Arrest Followed by Senescence. Mol Cancer Ther 2015;14:608-19. 60
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19. Caretti V, Hiddingh L, Lagerweij T, et al. WEE1 kinase inhibition enhances the radiation BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 response of diffuse intrinsic pontine gliomas. Mol Cancer Ther 2013;12:141-50. 6 20. Sarcar B, Kahali S, Prabhu AH, et al. Targeting radiation-induced G(2) checkpoint activation 7 with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther 2011;12:2405- 8 14. 9 10 21. Kamak D, Engelke CG, Parsels LA, et al. Combined inhibition of WEE1 and PARP1/2 for 11 radiosensitization in pancreatic cancer. Clin Cancer Res 2014;20:5085-96. 12 22. van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 13 14 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 15 Cancer Ther 2013;12:2675-84. 16 23. Guertin AD, Li J, Liu Y, et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single- 17 agent anticancer therapy. Mol Cancer Ther 2013;12:1442-52. 18 For peer review only 19 24. Zhong L, Zhang C, Ren G, et al. Randomized Phase III Trial of Induction Chemotherapy With 20 Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally 21 Advanced Resectable Oral Squamous Cell Carcinoma. J Clin Oncol 2012;30:1-12. 22 23 25. Perrone F, Bossi P, Cortelazzi B, et al. TP53 mutations and pathologic complete response to 24 neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell 25 carcinoma. J Clin Oncol 2010;28:761-6. 26 26. O’Quigley J, Pepe M, Fisher L. Continual reassessment method. Biometrics 1990; 46:33–48. 27 28 27. Cheung YK. Dose Finding by the Continual Reassessment Method. New York: Chapman & 29 Hall/CRC Press 2011. 30 28. Cheung YK, Chappell R. Sequential Designs for Phase I Clinical Trials with Late-Onset Toxicities. 31 32 Biometrics 2000;56(4):1177-82. 33 29. Yap C, Craddock C, Quigley JO, et al. Comparing the implementation of a Modified Continual 34 Reassessment Method to a 3+3 Design in a Phase I Acute Myeloid Leukaemia Trial. Clin Trials 35 2013;10(2):75. 36 37 30. Do KT, Wilsker D, Balasubramanian P, et al. Phase I study of single agent AZD1775 (MK1775), a http://bmjopen.bmj.com/ 38 WEE1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol 2015;33:3409- 39 3415. 40 41 31. Schellens JH, Leijen S, Shapiro G, et al. Update on a phase I pharmacologic and 42 pharmacodynamic study of MK1775, a WEE1 tyrosine kinase inhibitor in monotherapy and 43 combination with gemcitabine, cisplatin or carboplatin in patents with advance solid tumour. 44
ASCO 2011. Accessed at http://meetinglibrary.asco.org/content/62389 on September 30, 2021 by guest. Protected copyright. 45 46 32. Homma A, Inamura N, Oridate N, et al. Concomitant Weekly Cisplatin and Radiotherapy for 47 Head and Neck Cancer. Jpn J Clin Oncol 2011;41(8)980 – 986. 48 33. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT Plus Weekly Cisplatin for 49 50 Advanced Head and Neck Cancer: The University of Wisconsin Experience. Head Neck 2010; 51 32(5):599–606. 52 34. Jagdis A, Laskin J, Hao D, et al. Dose delivery analysis of weekly versus 3-weekly cisplatin 53 concurrent with radiation therapy for locally advanced nasopharyngeal carcinoma (NPC). Am J 54 55 Clin Oncol 2014 Feb;37(1):63-9. 56 35. Aaronson NK, Ahmedzai S, Bergman B, et al. European Organization for Research and 57 Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical 58 59 Trials in Oncology. J Natl Cancer Inst 1993;85:365-376. 60
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36. Bjordal K, de Graeff A, Fayers PM, et al. A 12 Country Field Study of the EORTC QLQ-C30 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 (version 3.0) and the Head and Neck Cancer Specific Module (EORTC QLQ-H&N35) in Head and 6 Neck Patients. Eur J Cancer 2000;36:1796-1807. 7 37. Chen AY, Frankowski R, Bishop-Leone J, et al. The development and validation of a dysphagia- 8 specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. 9 10 Anderson dysphagia inventory. Arch Otolaryngol Head Neck Surg 2001;127:870-6. 11 38. National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). 12 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix Table 1: Group A data collection schedule 1 12 Week Follow Baseline Baseline Baseline Week 1 Week 2 End of 4 Week 2 Up visit Pre- within 42 within 21 within 14 Treatment visit Follow Up 3 (from start of diagnosis days of days of days of #* # (within 7 days of visit D1 D2 D3 D8 D9 D10 treatment) 4 trial entry trial entry trial entry D10) +/- 3 days +/- 3 days 5 Informed consent – optional x 6 tumour sample 7 Optional tumour sample during x 8 diagnostic biopsy 9 Diagnostic CT scana x 10 Informed consentb x 11 ECHO/MUGAc x 12 Audiogramd For peerx reviewAs clinically onlyindicated 13 Medical historye x 14 Physical examf x x x 15 Weight (kg) and BSAg x x x
16 Height (cm) x http://bmjopen.bmj.com/ 17 Vital signsh x x x 18 ECOG status x x x 19 ECGi x Trial Entry x x x 20 Pregnancy testj x 21 Biochemistryk x x x x x x 22 Haematologyl x x x x x x 23 Isotopic GFRm x x
24 Adverse events x x x on September 30, 2021 by guest. Protected copyright. x x x 25 Concomitant medicationsn x x x x x x 26 Patient diary x x 27 Cisplatin administration x 28 AZD1775 administrationo AM & PM doses AM & PM doses 29 Surgeryp Within 42 days of first date of treatment 30 Blood samplesq x x x 31 Pharmacokinetic samplesr x x 32 Mandatory tumour biopsys x At time of Resection Collection of FFPE tumour 33 x 34 samples Review of surgical 35 x 36 complications t 37 Disease free survival On-going 38 39 40 41 42 24 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Group A data collection schedule notes 4 5 # Day 1 and Day 8 should not occur on a Monday. 6 * Day 1 should be within 6 weeks of informed consent. 7 a Diagnostic Computerised Tomography (CT) with contrast – neck and chest. To be performed within 42 days of trial entry. 8 b Informed consent must be obtained before any trial procedures occur. 9 c If significant cardiac history patient required to have ECHO. MUGA can be performed if ECHO is equivocal. To be performed within 21 days of start of trial 10 entry. 11 d Air and bone conduction audiogram. To be performed within 21 days of trial entry. 12 e Medical history – comprehensive medicalFor history, demographics, peer prior treatment. review only 13 f Physical examination includes complete review of systems and physical examination of pertinent organ systems and neurological assessment. 14 g During trial treatment, weight can be performed within 72 hours pre-dose of AZD1775. 15 h Blood pressure, pulse measurement, temperature and respiratory rate to be performed with the patient sitting for 5 minutes prior to the evaluation.
16 i Three ECGs, 2-5 minutes apart, to be performed at screening only. At all other time points a single ECG recording should be performedhttp://bmjopen.bmj.com/ at least 48h pre-dose 17 of AZD1775. 18 j Women of childbearing potential will require a negative pregnancy test (serum or urine) prior to trial entry. 19 k Blood samples for sodium, potassium, magnesium, urea, creatinine, calcium, phosphate, albumin, total protein, bilirubin, alkaline phosphatase, AST and/or 20 ALT. 21 Results of blood samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial treatment, blood 22 samples can be collected within 72 hours pre-dose of AZD1775. 23 l Haematology – Full Blood Count. Results of haematology samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose
24 on September 30, 2021 by guest. Protected copyright. of AZD1775. During trial treatment, haematology samples can be collected within 72 hours pre-dose of AZD1775. 25 m If creatinine clearance at screening is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. If GFR, calculated immediately before 26 any administration of concomitant chemotherapy, is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. 27 28 n Concomitant medication to be recorded starting on the date of signing of informed consent, throughout the trial. 29 o Morning dose to be administered prior to cisplatin on Day 8. 30 p Surgery must be performed within 42 days of first date of trial treatment but at least 6 days after the last cisplatin dose. 31 q Blood samples will be collected pre-dose on Day 1, at the End of Treatment Visit and at the 12 Week Follow Up Visit. Refer to WISTERIA Laboratory Manual. 32 r Pharmacokinetic samples to be collected before and 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Day 3 and Day 10. Refer to WISTERIA 33 Laboratory Manual. 34 s Tumour biopsy to be collected 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Day 3 and a biopsy to be taken at time of Resection.. To be 35 taken under local anaesthetic (includes biopsy of lymph nodes taken using ultrasound guided biopsy). Time from biopsy taken to fixing in formalin of the 36 biopsy is limited to 30 minutes. Refer to WISTERIA Laboratory Manual. 37 t Patients to be followed up for 12 months. Notification required if a patient relapses or dies. 38 39 40 41 42 25 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Appendix Table 2: Group B data collection schedule 4 5 Baseline Baseline FUP 6 and 12 Week 1 – Week 2 Week 3 Week 4 – Week 5 Week 6 Week 7 Weeks 8-11 Week 12 within 21 within 14 months from 6 End of Weekly Toxicity Follow Up days of days of start of 7 D1* Treatment Assessments # visit trial entry trial entry D2 D3 D4 D1 D2 D1 D2 D3 D4 D1 treatment 8 ~ 9 Informed consenta x b 10 ECHO/MUGA x c 11 Planning CT scan x Audiogramd x As clinically indicated 12 Medical historye xFor peer review only 13 Physical examf x x x x x 14 Weight (kg) and BSAg x x x x x 15 Height (cm) x h 16 Vital signs x x x x x http://bmjopen.bmj.com/ 17 ECOG status x x x x x ECGi x x x x x x 18 Trial Entry Pregnancy testj x 19 Biochemistryk x x x x x x x x x 20 Haematologyl x x x x x x x x x 21 Isotopic GFRm x x x x 22 Adverse events x x x x x x x x x 23 Concomitant n x x x x x x x x 24 medications on September 30, 2021 by guest. Protected copyright. 25 Radiotherapyo To start within 3 months of surgery AZD1775 AM & PM AM & PM 26 N/A N/A N/A 27 administrationp Doses Doses Cisplatin 28 x x x N/A administrationq 29 Patient diary x x 30 Quality of Life x x x x 31 Questionnairesr 32 Swallowing 33 Assessment x x x x 34 Questionnairer s 35 Blood samples x x x x Pharmacokinetic x 36 samplet 37 Collection of FFPE x 38 tumour samples 39 Disease free survivalu On-going 40 41 42 26 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Group B data collection schedule notes: 4 5 # Patients will undergo weekly toxicity assessment during treatment and weekly thereafter until all acute toxicities have resolved to Grade 1 or less; typically for 42-56 days (6-8 weeks), and 6 for no less than 42 days after completion of treatment, giving a total Dose Limiting Toxicity reporting period of 84 days (12 weeks) from start of treatment. 7 * Day 1 of week 1 should be within 4 weeks of consent. 8 ~ Week 1 – Day 1 starts on the first day of radiotherapy. 9 a Informed consent must be obtained before any trial procedures occur. 10 b If significant cardiac history patient required to have ECHO. MUGA can be performed if ECHO is equivocal. To be performed within 21 days of start of trial entry. 11 c CT with contrast – neck as part of radiotherapy preparation and planning at Baseline only. To be performed within 21 days of start of trial entry. 12 d Air and bone conduction audiogram.For To be performed peer within 21 days of trial review entry. only 13 e Medical history – comprehensive medical history, demographics, prior treatment. 14 f Physical examination includes complete review of systems and physical examination of pertinent organ systems and neurological assessment. 15 g During trial treatment, weight can be performed within 72 hours pre-dose of AZD1775.
16 h Blood pressure, pulse measurement, temperature and respiratory rate to be performed with the patient sitting for 5 minutes prior tohttp://bmjopen.bmj.com/ the evaluation. 17 i Three ECGs, 2-5 minutes apart, to be performed at baseline only. At all other time points a single ECG recording should be performed at least 48 hours pre-dose of AZD1775. 18 j Women of childbearing potential will require a negative pregnancy test (serum or urine) prior to trial entry. 19 k Blood samples for sodium, potassium, magnesium, urea, creatinine, calcium, phosphate, albumin, total protein, bilirubin, alkaline phosphatase, AST and/or ALT. 20 Results of blood samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial treatment, blood samples can be collected 21 within 72 hours pre-dose of AZD1775. 22 l Haematology – Full Blood Count. Results of haematology samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial 23 treatment, haematology samples can be collected within 72 hours pre-dose of AZD1775.
24 on September 30, 2021 by guest. Protected copyright. m If creatinine clearance at screening is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. If GFR, calculated immediately before any administration of 25 concomitant chemotherapy, is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. 26 n Concomitant medication to be recorded starting on the date of signing of informed consent, throughout the trial. 27 28 o Radiotherapy to start on Week 1 - Day 1. Refer to the WISTERIA Radiotherapy Guidelines. 29 p AZD1775 morning dose to be administered prior to cisplatin and at least 1 hour prior to radiotherapy. 30 q Cisplatin to be administered after morning dose of AZD1775 and at least 1 hour prior to radiotherapy. 31 r Questionnaires to be completed by patient in clinic at defined visits: pre-dose on Week 1 - Day 1, End of Treatment Visit, Week 12 Follow Up Visit, 6 Month Follow Up Visit and 12 Month 32 Follow Up Visit. 33 s Blood samples will be collected pre-dose on Week 1 - Day 1, at the End of Treatment Visit, the Week 12 Follow Up Visit, the 6 Month Follow Up Visit and the 12 Month Follow Up Visit. 34 Refer to WISTERIA Laboratory Manual. 35 t Pharmacokinetic sample to be collected before and 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Week 1 - Day 4 only. Refer to WISTERIA Laboratory Manual. 36 u Patients to be followed up for 12 months. Notification required if a patient relapses or dies. 37 38 39 40 41 42 27 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 47 BMJ Open
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Appendix Table 3: Toxicity Profiles BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Very common side effects Common side effects 6 Treatment Other side effects (1 patient in 10) (1 patient in 100) 7 8 AZD1775 Blood & lymphatic Neutropenia QTc prolongation 9 disorders including (rare, affecting 1 10 anaemia & patient in 10,000) 11 thrombocytopenia 12 Decreased appetite 13 Gastrointestinal 14 disorders including 15 diarrhoea, nausea, 16 vomiting & serum 17 electrolyte decreases 18 For Dyspepsia peer review only 19 AZD1775 in Asthensia Fatigue Constipation 20 combination with Leukopenia Febrile neutropenia Gastrointestinal 21 chemotherapy Loss of strength & Mucosal haemorrhage 22 weakness inflammation Lymphopenia 23 Myalgia Lymphocyte count 24 Stomatitis decrease 25 Pancytopenia 26 Sepsis 27 Tachycardia 28 Cisplatin Blood & lymphatic Sepsis 29 disorders including 30 Ear disorders 31 bone marrow failure, including ototoxicity 32 thrombocytopenia, Cardia disorders 33 leukopenia & anaemia including 34 Metabolism & arrhythmia, 35 nutrition disorders bradycardia & 36 including dehydration tachycardia 37 Renal & urinary Inflammation at http://bmjopen.bmj.com/ 38 disorders including injection site 39 hyperuricaemia Respiratory 40 disorders including 41 dyspnoea & 42 pneumonia 43 Radiotherapy Tiredness Due to swallowing 44 Pain & difficulty difficulties there is an on September 30, 2021 by guest. Protected copyright. 45 swallowing due to increased risk of 46 mouth ulceration chest infection 47 Thickened saliva & (pneumonia) during 48 secretions treatment 49 Dry mouth 50 Altered sense of taste 51 Nausea 52 Skin soreness & 53 ulceration 54 Hair loss to are near to 55 56 radiotherapy site 57 58 59 60
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 Appendix Table 4: Haematological Toxicity Dose Management – ANC, Platelets 6 Symptoms: Symptoms: Action 7 ANC Platelets 8 9 ≥1500/109/L And ≥75000/109/L No cisplatin or AZD1775 dose modification or 10 11 interruption. 12 13 <1500/109/L Or <75000/109/L Delay cisplatin and AZD1775 by 1 week intervals until 14 recovery. If DLT is reached, discontinue AZD1775 15 treatment but cisplatin may be resumed if deemed 16 appropriate by the investigators. 17 18 For peer review only 19 20 21 Appendix Table 5: Haematological Toxicity Dose Management – Neutropenia, Infection, 22 Febrile Neutropenia 23 24 Symptoms Action 25 26 Grade 3 febrile neutropenia (ANC <1000/109/L Hold cisplatin and AZD1775 dose until 27 + Temperature ≥38°C) or neutropenic sepsis recovery. If DLT is reached, discontinue 28 AZD1775 treatment but cisplatin may be 29 Grade 4 neutropenia (ANC <500/109/L >7 days) 30 resumed if deemed appropriate by the 31 Grade 4 thrombocytopenia (platelet count investigators. 32 9 33 <25,000/10 /L >7 days) 34 35 Grade 4 febrile neutropenia or Grade 4 Discontinue cisplatin and AZD1775 treatment. 36 infection with neutropenia (both defined as 37 http://bmjopen.bmj.com/ septic shock) 38 39 40 Thrombocytopenic haemorrhage (gross occult 41 bleeding) associated with a platelet count 42 <50,000/109/L 43 44
Febrile neutropenia ( 38° C) with or without Patient to be managed in a hospital setting on September 30, 2021 by guest. Protected copyright. 45 46 significant symptoms according to standard procedures, with the 47 urgent initiation of IV antibiotic therapy 48 according to local guidelines. 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 Appendix Table 6: Non-Haematological Toxicity Dose Management – General Disorders 6 CTCAE v4.03 Cisplatin AZD1775 7 8 Grade 0-2 No dose modification No dose modification 9 10 11 Grade 3 Hold until toxicity resolves to ≤ Hold until toxicity resolves to ≤ 12 Grade 1, and then resume at the Grade 1, and then resume at the 13 same dose with no modification if same dose with no modification. 14 no DLT is reached and if deemed Discontinue treatment if DLT is 15 16 appropriate by the investigators. reached 17 18 Grade 4 toxicity ForDiscontinue peer treatment review Discontinueonly treatment 19 (except anorexia) 20 21 22 23 24 Appendix Table 7: Non-Haematological Toxicity Dose Management – Hepatic 25 26 CTCAE v4.03 Cisplatin AZD1775 27 28 Grade 1-2 No dose modification No dose modification 29 30 31 Grade 3 Hold until resolves to Grade ≤1 or Hold until resolves to Grade ≤1 or 32 baseline, then resume cisplatin with baseline, then resume study drug 33 (manifested as no dose modification if no DLT is with no dose reduction. If not 34 elevations in ALT, reached and if deemed appropriate resolved within 28 days discontinue 35 AST, ALP or 36 by the investigators. study drug. Discontinue treatment if
bilirubin) http://bmjopen.bmj.com/ 37 DLT is reached. 38 39 Grade 4 Discontinue treatment Discontinue treatment 40 (Life threatening) 41 42 43 44 on September 30, 2021 by guest. Protected copyright. 45 Appendix Table 8: Non-Haematological Toxicity Dose Management – Diarrhoea or 46 47 Mucositis 48 CTCAE v4.03 Cisplatin AZD1775 49 50 Grade 3 Hold until toxicity resolves to ≤ Hold until toxicity resolves to ≤ 51 52 (requiring Grade 1, and then resume at the Grade 1, and then resume at the 53 hospitalisation) same dose with no modification if same dose with no modification. 54 no DLT is reached and if deemed Discontinue treatment if DLT 55 appropriate by the investigators. reached. 56 57 58 Grade 4 Discontinue treatment Discontinue treatment 59 60
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 Appendix Table 9: Non-Haematological Toxicity Dose Management – Renal Toxicity 6 CTCAE v4.03 Cisplatin AZD1775 7 8 Grade ≥ 2 Hold until resolves to Grade ≤1 or Hold until toxicity resolves to ≤ 9 10 baseline. If GFR falls below 60 Grade 1, and then resume at the 11 mL/min, cisplatin should be same dose with no modification. 12 discontinued and consideration Discontinue treatment if DLT 13 given to substitution with reached 14 15 carboplatin AUC =1.5, according to 16 routine local practice. 17 18 For peer review only 19 20 21 Appendix Table 10: Non-Haematological Toxicity Dose Management – Neurotoxocity 22 CTCAE v4.03 Cisplatin AZD1775 23 24 Grade 1 No dose modification No dose modification 25 26 27 Grade 2 Hold until toxicity resolves to Grade No dose modification 28 ≤1. Resume with 1 dose level 29 reduction. 30 31 Grade 3 or 4 Discontinue treatment Discontinue treatment 32 33 34 35 36 Appendix 11: Disallowed medications and medication to be administered with caution 37 http://bmjopen.bmj.com/ A list of the main CYP3A4 substrates, inhibitors (strong and moderate) and inducers, CYP2C19 38 39 substrates, P-gp substrates and inhibitors and BCRP substrates are shown below: 40 Please note: Live vaccines are not permitted 41 42 43 This is not an exhaustive list and further details can be found at: 44 www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ on September 30, 2021 by guest. Protected copyright. 45 ucm093664.htm. 46 47 48 CYP3A4 Inhibitors 49 Strong 50 Boceprevir Indinavir Ritonavir 51 Clarithromycin Itraconazole Saquinavir 52 Cobicistat (GS-9350) Ketoconazole Telaprevir 53 Conivaptan LCL161 Telithromycin 54 55 Danoprevir Lopinavir Tipranavir 56 Elvitegravir Mibefradil Troleandomycin 57 Fosamprenavir Nefazodone Voriconazole 58 Grapefruit juice Nelfinavir 59 Idelalisib Posaconazole 60
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1 2 3 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 Moderate 7 ACT-178882 Darunavir Imatinib 8 Amprenavir Dronedarone Ledipasvir 9 Aprepitant Diltiazem Lomitapide 10 Atazanavir Erythromycin Netupitant 11 Casopitant FK1706 Schisandra sphenanthera 12 13 Ciprofloxacin Fluconazole Tofisopam 14 Crizotinib Fosamprenavir Verapamil 15 16 17 Weak 18 Almorexant For peerEverolimus review onlyPropiverine 19 20 Alprazolam Faldaprevir Ranitidine 21 AMD070 Fluvoxamine Ranolazine 22 Amiodarone Fosaprepitant (IV) Resveratrol 23 Amlodipine Ginkgo Roxithromycin 24 Atorvastatin Goldenseal Seville orange juice 25 Azithromycin GSK1292263 Simeprevir 26 27 Berberine GSK2248761 Sitaxentan 28 Bicalutamide Isoniazid Suvorexant 29 Blueberry juice Ivacaftor Tabimorelin 30 Chlorzoxazone Lacidipine Tacrolimus 31 Cilostazol I Linagliptin Teriflunomide 32 Cimetidine Lomitapide Ticagrelor 33 34 Clotrimazole M100240 Tipranavir/ritonavir 35 Cranberry juice Nilotinib Tolvaptan 36 Cyclosporine Oral contraceptives Zileuton http://bmjopen.bmj.com/ 37 Daclatasvir Pazopanib 38 Delavirdine Peppermint oil 39 40 41 42 CYP3A4 Inducers (Strong and Moderate) 43 Avasimibe Lersivirine Rifabutin 44 Bosentan Lopinavir Rifampin on September 30, 2021 by guest. Protected copyright. 45 Carbamazepine Mitotane Ritonavir 46 Efavirenz Modafinil Semagacestat 47 48 Enzalutamide Nafcillin St John's Wort 49 Etravirine Phenobarbital Thioridazine 50 Genistein Phenytoin Tipranavir 51 52 CYP3A4 Inducers (Weak) 53 Amprenavir Brivaracetam Garlic 54 55 Aprepitant Clobazam Gingko 56 Armodafinil Danshen Ginseng 57 AZD 7325 Dexamethasone Glycyrrhizin 58 Bexarotene Echinacea LCL161 59 Boceprevir Eslicarbazepine Methylprednisolone 60
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1 2 3 Nevirapine Raltegravir Ticagrelor 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from Oritavancin Ritonavir Ticlopidine 5 6 Oxcarbazepine Rufinamide Topiramate 7 PA-824 Sorafenib Troglitazone 8 Pleconaril Stribild Vemurafenib 9 Prednisone Telaprevir Vicriviroc and ritonavir 10 Quercetin Terbinafine Vinblastine 11 12 13 CYP3A and CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 14 ABT-384 Docetaxol Nilotinib 15 Alfentanil Dofetilide Nisoldipine 16 Aprepitant Doxorubicin Paclitaxel 17 Alfuzosin Ebastine Pazopanib 18 Almorexant For peerEletriptan review onlyPerospirone 19 20 Alpha-Dihydroergocryptine Elvitegravir Pimozide 21 Amiodarone Eplerenone Propafenone 22 Aplaviroc Ergotamine Propofol 23 Aprepitant Erlotinib Quetiapine 24 Astemizole Etoposide Quinidine 25 Atazanavir Everolimus Ranolazine 26 27 Atorvastatin Felodipine Ridaforolimus 28 Avanafil Fentanyl Romidepsin 29 Bexarotine Fluticasone Saquinavir 30 BIRL 355 Gefitinib Sildenafil 31 Bortezomib Halofantrine Simeprevir 32 Bosutinib Ibrutinib Simvastatin 33 34 Brecanavir Ifosfamide Sirolimus 35 Brotizolam Imatinib Tacrolimus 36 Budesonide Indinavir Temsirolimus http://bmjopen.bmj.com/ 37 Buspirone Ironotecan Terfenadine 38 Capravirine Ivacaftor Ticagrelor 39 Carbamazepine Ixabepilone Theoophylline 40 41 Casopitant L-771,688 Thioridazine 42 Cisapride, Lapatinib Thiotepa 43 Conivaptan Levomethadyl (LAAm) Tilidine 44 Cyclophosphamide Lomitapide Tipranavir on September 30, 2021 by guest. Protected copyright. 45 Cyclosporine Lopinavir Tolvaptan 46 Danoprevir Lovastatin Triazolam 47 48 Darifenacin Lurasidone Tretinoin 49 Darunavir Maraviroc, Ulipristal 50 Dasatinib Midazolam Vardenafil 51 Dihydroergotamine Midostaurin Vicriviroc 52 Disopyramide Mosapride Voclosporin 53 Dronedarone Neratinib 54 55 56 CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 57 Diazepam (R)-Lansoprazole (R)-Mephobarbital 58 Gliclazide (S)-Lansoprazole Omeprazole 59 Lansoprazole (S)-Mephenytoin (R)-Omeprazole 60
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1 2 3 Pantoprazole Rabeprazole 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from (+)-Pantoprazole Tilidine 5 6 CYP1A2 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 7 Alosetron Melatonin Theophylline 8 Caffeine Ramelteon Tizanidine 9 Duloxetine Tacrine 10 11 P-gp Substrates 12 13 Colchicine Indinavir Vincristine 14 Digoxin Paclitaxel 15 Fexofenadine Toptecan 16 17 If a patient requires initiation of digoxin during the study, or is already receiving treatment with digoxin, 18 monitoring of digoxin levelsFor is recommended peer according review to local practice only (as the levels of digoxin may increase). 19 20 Monitoring of digoxin levels is also recommended when the patient has completed dosing with study 21 treatment (as the levels of digoxin may then decrease). 22 23 P-gp Inhibitors (Strong) 24 Cyclosporine BCRP Substrates 25 Elacridar Daunorubicin 26 27 Erythromycin Doxorubicin 28 Itraconazole Rosuvastatin 29 Ketocoanzole Sulfasalazine 30 LY335979Quinidine Topotecan 31 Ritonavir 32 Valspodar 33 34 Verapamil 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 12: Wisteria Radiotherapy Guidelines – Larynx BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 7 extracapsular spread (ECS), if present. The extent of the operative bed is defined 8 with reference to pre-operative imaging of the primary tumour and to the operative 9 pathology. 10 11 Primary tumour: The superior border will lie at the level corresponding to the hyoid 12 on the pre-operative imaging for glottic and subglottic tumours, or 1 cm above the most cranial aspect of the tumour, whichever is most cranial. For supraglottic 13 tumours, the superior border will lie at the level of the tip of the epiglottis on pre- 14 operative imaging, or 1 cm superior to the most cranial aspect of the tumour, 15 whichever is most cranial. The inferior border will lie at the level corresponding with 16 the caudal aspect of the cricoid cartilage on pre-operative imaging, or 1 cm inferior 17 to the most caudal aspect of the tumour, whichever is most caudal. The stoma is 18 includedFor in CTV_6500 peer if there review is subglottic extension only of the primary tumour and a 19 positive margin, or ECS in level IV. 20 21 Nodes: For areas of nodal ECS, the whole level should be included. If a node with 22 ECS is present at a border between two lymph node levels, the level above/below 23 should also be included as appropriate. For nodal levels included in the CTV_6500, 24 the overlying sternocleidomastoid muscle (SCM) should be included. 25 CTV_6000 Include: 26 1. The operative bed if there is no positive margin, as defined above. 27 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 28 pN+. The whole level should be included. The SCM should not be included. 29 3. The stoma if there are lymph nodes without ECS in level IV, subglottic extension 30 without a positive margin, or an emergency tracheostomy was performed. 31 32 CTV_5400 IA Not included 33 IB Included if ipsilateral level II is node positive 34 II Always included bilaterally if not already included in CTV_6500 or 35 CTV_6000. If ipsilateral neck is node negative, superior border lies at 36 the inferior border of the transverse process of C1. If ipsilateral neck is 37 node positive, level II is extended superiorly to skull base to include http://bmjopen.bmj.com/ retrostyloid space. 38 III Always included bilaterally 39 IVa Always included bilaterally 40 V Included if ipsilateral neck is node positive 41 VI Included if there is subglottic extension of the primary tumour, soft 42 tissue extension from the primary into the neck, or hypopharyngeal 43 involvement 44 RP* Included if bulky ipsilateral nodes present on September 30, 2021 by guest. Protected copyright. 45 Stoma If not included in CTV_6500/6000 as defined above 46 47 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as 48 the upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 13: Wisteria Radiotherapy Guidelines – Hypopharynx BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 7 ECS, if present. The extent of the operative bed is defined with reference to pre- 8 operative imaging of the primary tumour and to the operative pathology. 9 10 Primary tumour: The superior border will lie at corresponding to the level of the hyoid 11 on pre-operative or 1 cm above the most cranial aspect of the tumour on pre- 12 operative imaging, whichever is most cranial. The inferior border will lie at the level 13 corresponding with the caudal aspect of the cricoid cartilage on pre-operative 14 imaging, or 1 cm inferior to the most caudal aspect of the tumour, whichever is most 15 caudal. The stoma (if present) is included in CTV_6500 if there is subglottic extension 16 of the primary tumour and a positive margin, or ECS in level IV. 17 18 Nodes:For For areas peer of nodal reviewECS, the whole level only should be included. If a node with 19 ECS is present at a border between two lymph node levels, the level above/below 20 should also be included as appropriate. For nodal levels included in the CTV_6500, 21 the overlying sternocleidomastoid muscle (SCM) should be included. 22 CTV_6000 Include: 23 1. The operative bed if there is no positive margin, as defined above. 24 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 25 pN+. The whole level should be included. The SCM should not be included. 26 3. The stoma (if present) if there are lymph nodes without ECS in level IV, subglottic 27 extension without a positive margin, or an emergency tracheostomy was performed. 28 CTV_5400 IA Not included 29 IB Included if ipsilateral level II is node positive 30 II Always included bilaterally if not already included in CTV_6500 or 31 CTV_6000. If ipsilateral neck is node negative, superior border lies at 32 the inferior border of the transverse process of C1. If ipsilateral neck is 33 node positive, level II is extended superiorly to skull base to include 34 retrostyloid space. 35 III Always included bilaterally 36 IV Always included bilaterally 37 V Included if ipsilateral neck is node positive http://bmjopen.bmj.com/ 38 VI Included if there is subglottic/oesophageal extension of the primary 39 tumour, or soft tissue extension from the primary into the neck 40 Included 41 RP* If not included in CTV_6500/6000 as defined above 42 Stoma Retropharyngeal (RP) 43 44 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as
the upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. on September 30, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 14: Wisteria Radiotherapy Guidelines – Lateralised Oral Cavity BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 7 ECS, if present. The extent of the operative bed is defined with reference to pre- 8 operative imaging of the primary tumour and to the operative pathology. 9 10 Primary tumour: The volume will depend on the primary site. For oral tongue 11 tumours, include the hemi-oral cavity including base of tongue. For buccal mucosal 12 tumours, include the entire mucosa including the retromolar trigone. For retromolar 13 trigone tumours, include the preoperative tumour volume and postoperative tumour 14 bed. Exclude uninvolved bone where possible. Generally, the superior border will be 15 at the level of the hard palate/inferior orbital rim and the inferior border at the level of 16 the hyoid. 17 18 Nodes:For For areas peer of nodal reviewECS, the whole level only should be included. If a node with 19 ECS is present at a border between two lymph node levels, the level above/below 20 should also be included as appropriate. For nodal levels included in the CTV_6500, 21 the overlying sternocleidomastoid muscle (SCM) should be included. 22 CTV_6000 Include: 23 1. The operative bed if there is no positive margin, as defined above. 24 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 25 pN+. The whole level should be included. The SCM should not be included. 26 CTV_5400 IA Included if tumour involves floor of mouth or anterior mandible 27 IB Always included ipsilaterally if not already included in CTV_6500 or 28 CTV_6000 29 II Always included ipsilaterally if not already included in CTV_6500 or 30 CTV_6000. If ipsilateral neck is node negative, superior border lies at 31 the inferior border of the transverse process of C1. If ipsilateral neck is 32 node positive, level II is extended superiorly to skull base. Include 33 contralateral nodes if pN2b/pN3 or primary depth of invasion > 4mm. 34 Always included ipsilaterally 35 III Included ipsilaterally if the oropharynx or anterior tongue are involved 36 IV Included if ipsilateral neck is node positive 37 Not included http://bmjopen.bmj.com/ 38 V Included if retromolar trigone primary 39 VI Not included 40 RP* Included if retromolar trigone primary 41 42 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as 43 the upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 44 on September 30, 2021 by guest. Protected copyright. 45 Please note: Laterality or otherwise the tumour should be discussed with the surgeon, radiologist and 46 pathologist and confirmed at MDT. 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 15: Wisteria Radiotherapy Guidelines – Non-Lateralised Oral Cavity BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 7 ECS, if present. The extent of the operative bed is defined with reference to pre- 8 operative imaging of the primary tumour and to the operative pathology. 9 10 Primary tumour: The volume will depend on the primary site. For oral tongue 11 tumours, include the whole oral cavity including base of tongue. Exclude uninvolved 12 bone where possible, but for floor of mouth tumours, consider including the alveolar 13 ridge. Generally, the superior border will be at the level of the hard palate/inferior 14 orbital rim and the inferior border at the level of the hyoid. If a mouth bite is used for 15 floor of mouth tumours, the superior border may be located at the midpoint of the 16 mouthbite. 17 18 Nodes:For For areas peer of nodal reviewECS, the whole level only should be included. If a node with 19 ECS is present at a border between two lymph node levels, the level above/below 20 should also be included as appropriate. For nodal levels included in the CTV_6500, 21 the overlying sternocleidomastoid muscle (SCM) should be included. 22 CTV_6000 Include: 23 1. The operative bed if there is no positive margin, as defined above. 24 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 25 pN+. The whole level should be included. The SCM should not be included. 26 CTV_5400 IA Included if tumour involves floor of mouth or anterior mandible 27 IB Always included bilaterally if not already included in CTV_6500 or 28 CTV_6000 29 II Always included bilaterally if not already included in CTV_6500 or 30 CTV_6000. If ipsilateral neck is node negative, superior border lies at 31 the inferior border of the transverse process of C1. If ipsilateral neck is 32 node positive, level II is extended superiorly to skull base. 33 Always included bilaterally. 34 III Included bilaterally if the oropharynx or anterior tongue are involved 35 IV Included if ipsilateral level IV is node positive 36 Not included 37 V Consider including if retromolar trigone primary http://bmjopen.bmj.com/ 38 VI 39 RP* Retropharyngeal (RP) 40 41 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as the upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 42 43 44 Please note: Laterality or otherwise the tumour should be discussed with the surgeon, radiologist and 45 pathologist and confirmed at MDT. on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 16: Informed Consent Form – Group A BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 7 8 9 Informed Consent Form 10 To be used for Group A only 11 12 13 14 15 16 17 18 For peer review only 19 20 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as adjuvant 21 22 treatment, and a Window of Opportunity trial with Cisplatin in Patients with Head and Neck 23 Cancer 24 25 EudraCT Reference: 2015-003583-37 26 27 28 Site: Patient Trial Number: 29 30 Principal ______Screening Number: 31 Investigator: ______SCR / 32 (If applicable) 33 1.1.1 Please initial 34 1.1.2 each box 35 36 1. I confirm that I have read and understand the Patient Information Sheet 37 Group A (version ...... dated ...... ) for the above trial. http://bmjopen.bmj.com/ 38 I have had the opportunity to consider the information, ask questions and 39 have had these answered satisfactorily. 40 41 2. I understand that my participation is voluntary and that I am free to 42 withdraw at any time without giving any reason, without my medical care 43 or legal rights being affected. I understand that if I withdraw from treatment 44 my doctor may continue to provide the Trial Office with information that 45 would routinely be collected about me and recorded in my medical notes. I on September 30, 2021 by guest. Protected copyright. 46 am aware that I can also withdraw consent for this data transfer. 47 48 3. I give permission for my initials, date of birth, and NHS number to be given 49 to the WISTERIA Trial Office when I am registered to the trial as well as a 50 copy of this consent form. 51 52 4. I understand that relevant sections of my medical notes and data collected 53 during the trial may be looked at by individuals from the WISTERIA Trial 54 Office, regulatory authorities, Sponsor and/or NHS bodies, where it is 55 relevant to my taking part in this research. I understand that this information 56 will be held in a confidential manner. I give permission for these individuals 57 to have access to my records. 58 59 60
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1 2 3 4 5. I understand that anonymised data from the trial may be provided to other BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 third parties (e.g. pharmaceutical companies or other academic institutions) 6 for research, safety monitoring or licensing purposes. I understand that this 7 may involve sending data outside of the United Kingdom to a European 8 country or the United States of America and that my name will not be given 9 to these third parties. 10 11 6. I agree to my GP being informed of my participation in this trial. 12 13 7. I understand that the WISTERIA Trial Office may access information held 14 by national cancer registries and within national databases to keep in touch 15 16 with me and to follow up on my health status. 17 8. I give permission for collection of samples of my blood and tissue to be used 18 in the WISTERIAFor trial. I peerunderstand reviewthat samples will beonly sent to the Institute 19 of Head and Neck Studies and Education (InHANSE), University of 20 21 Birmingham and other laboratories in the United Kingdom or overseas 22 (including Covance Laboratories Inc., based in the United States of 23 America). 24 9. I understand that DNA analysis may be performed on the samples taken for 25 the trial. 26 27 10. I consent to the storage of samples remaining at the end of the trial and 28 their use in future ethically approved research which may involve genetic 29 analysis, animal or in vitro models, commercial or private institutions, and 30 which may take place in the UK or overseas. 31 32 11. I understand that information which may identify me will be transferred 33 outside of the hospital and to the
the Clinical Trials Unit so long as strict confidentiality is maintained. http://bmjopen.bmj.com/ 37 38 *To be deleted as appropriate 39 12. I agree to take part in the above trial. 40 41 42 43 44 45 Name of patient Date Signature on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 Name of person taking consent Date Signature 51 52 You must have signed the 53 Site Signature & Delegation Log 54 55 This document was written using CRCTU-ICF-QCD-001, Version 2.0 56 57 58 59 60
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Appendix 17: Informed Consent Form – Group B BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 7 Informed Consent Form 8 9 To be used for Group B only 10 11 12 13 14 15 16 17 18 For peer review only 19 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as adjuvant 20 treatment, and a Window of Opportunity trial with Cisplatin in Patients with Head and Neck 21 22 Cancer 23 EudraCT Reference: 2015-003583-37 24 25 26 Site: ______Patient Trial Number: 27 28 Principal 29 Investigator: ______30 31 1.1.3 Please initial 32 1.1.4 each box 33 13. I confirm that I have read and understand the Patient Information Sheet 34 Group B (version ...... dated ...... ) for the above trial. 35 I have had the opportunity to consider the information, ask questions and 36 have had these answered satisfactorily. 37 14. I understand that my participation is voluntary and that I am free to http://bmjopen.bmj.com/ 38 withdraw at any time without giving any reason, without my medical care 39 or legal rights being affected. I understand that if I withdraw from treatment 40 my doctor may continue to provide the Trial Office with information that 41 would routinely be collected about me and recorded in my medical notes. 42 I am aware that I can withdraw consent for this data transfer. 43 44 15. I give permission for my initials, date of birth, and NHS number to be given 45 to the WISTERIA Trial Office when I am registered to the trial as well as a on September 30, 2021 by guest. Protected copyright. 46 copy of this consent form. 47 16. I understand that relevant sections of my medical notes and data collected 48 during the trial may be looked at by individuals from the WISTERIA Trial 49 Office, regulatory authorities, Sponsor and/or NHS bodies, where it is 50 relevant to my taking part in this research. I understand that this 51 information will be held in a confidential manner. I give permission for these 52 individuals to have access to my records. 53 54 17. I understand that anonymised data from the trial may be provided to other 55 third parties (e.g. pharmaceutical companies or other academic institutions) 56 for research, safety monitoring or licensing purposes. I understand that this 57 may involve sending data outside of the United Kingdom to a European 58 country or the United States of America and that my will not be given to 59 these third parties. 60
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1 2 3 18. I agree to my GP being informed of my participation in this trial. 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 19. I understand that the WISTERIA Trial Office may access information held 7 by national cancer registries and within national databases to keep in touch 8 with me and to follow up on my health status. 9 20. I give permission for the collection of samples of my blood and tissue to be 10 used in the WISTERIA trial. I understand that samples will be sent to the 11 Institute of Head and Neck Studies and Education (InHANSE), University 12 of Birmingham and other laboratories in the United Kingdom or overseas 13 (including Covance Laboratories Inc., based in the United States of 14 America). 15 16 21. I understand that DNA analysis may be performed on the samples taken 17 for the trial. 18 22. I consent to theFor storage peer of samples review remaining at the only end of the trial and 19 their use in future ethically approved research which may involve genetic 20 analysis, animal or in vitro models, commercial or private institutions, and 21 22 which may take place in the UK or overseas. 23 23. I understand that information which may identify me will be transferred 24 outside of the hospital and to the
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LEGENDS BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5
6 Figure 1: The differential effect of G2/M checkpoint inhibitor in sensitizing normal and cancer cells 7 (with TP53 mutations and deficient G /S checkpoint) to the effect of DNA damaging agents 8 1 9 10 Figure 2: Wisteria trial schema. Group A patients were required to have received a minimum 11 treatment of chemotherapy (cicplatin) and AZD1175 in combination to be DLT evaluable. Group B 12 13 patients were required to have received a minimum of two weeks of treatment (half the total 14 scheduled AZD1775 dose) to be DLT evaluable. 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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FIGURE 1 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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FIGURE 2 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 Wisteria Trial SPIRIT Checklist BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 7 Item Section/Item Placement of Information 8 Number 9 Administrative information 10 11 Title 1 Front page 12 Trial registration 2a Within Abstract 13 2b Within Abstract and Funding sections 14 Protocol version 3 Within Ethics and Dissemination section 15 Funding 4 Funding section 16 Roles and responsibilities 5a Front page, Author Affiliations, Authors’ Contributions 17 18 For peer sectionsreview only 19 5b Front page 20 5c Trial Organisation and Structure section 21 5d Trial Organisation and Structure section 22 Introduction 23 Background and rationale 6a Introduction sections 24 25 6b N/A 26 Objectives 7 Methods: Wisteria Trial Objectives section 27 Trial design 8 Methods: Trial Design section 28 Methods 29 Participants, interventions 30 and outcomes: 31 Study setting 9 Patient Population, Screening and Consent section 32 33 Eligibility criteria 10 Patient Population, Screening and Consent section, boxes 34 2 and 3 35 Interventions 11a Dose Selection section, Table 1, Trial Treatment section 36 11b Dose Limiting Toxicity and Dose Management section, http://bmjopen.bmj.com/ 37 Discontinuation of Investigational Medicinal Product 38 section, Statistical Methods section 39 11c Trial Schema, Trial Treatment section 40 41 11d Concomitant Medications section, Appendix 11 42 Outcomes 12 Trial Outcome Measures section, Box 4, Appendices 43 Tables 1 and 2 44 Participant timelines 13 Trial Schema, Appendices Tables 1 and 2 on September 30, 2021 by guest. Protected copyright. 45 Sample size 14 Trial Design section, Statistical Methods section 46 Recruitment 15 Trial Design section 47 48 Assignment of interventions 16 -17 Not applicable 49 (for controlled trials) 50 Data collection, management 51 and analysis: 52 Data collection methods 18a Data Collection and Monitoring section, Appendices 1 53 and 2 54 18b Analysis of Outcome Measures section 55 56 Data management 19 Data Collection and Monitoring section 57 Statistical methods 20 Statistical Methods section, Analysis of Outcome 58 Measures section 59 Monitoring: 60 Data monitoring 21a Trial Organisation and Structure section 21b Statistical Methods section, Analysis of Outcomes section
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Harms 22 Box 5, Safety Monitoring section BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Auditing 23 Data Collection and Monitoring section, Trial 5 6 Organisation and Structure section 7 Ethics and dissemination 8 Research ethics approval 24 Ethics and Dissemination abstract and main body section, 9 Ethical Approval section 10 Protocol amendments 25 Ethics and Dissemination section 11 Consent or assent 26a Patient Consent section, Appendices 16 and 17 12 13 26b Ethics and Dissemination section 14 Confidentiality 27 Ethics and Dissemination section 15 Declaration of interests 28 Competing Interests section 16 Access to data 29 Ethics and Dissemination section, Open Access section 17 Ancillary and post-trial care 30 Trial Treatment section, Box 4, (re. follow up) 18 DisseminationFor policy peer31a Ethicsreview and Dissemination only section, Open Access section 19 Appendices 20 21 Informed consent materials 32 Appendices 16 and 17 22 Biological specimens 33 Tertiary Research Outcome Measures section, 23 Appendices Tables 1 and 2, Analysis of Outcome 24 Measures section 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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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: The WISTERIA Trial Protocol
ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-033009.R1
Article Type: Protocol
Date Submitted by the 15-Jan-2020 Author:
Complete List of Authors: Kong, Anthony; University of Birmingham, Institute of Cancer and Genomic Sciences Good, James; University Hospitals Birmingham NHS Foundation Trust Kirkham, Amanda; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Savage, Joshua; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Mant, Rhys; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Llewellyn, Laura; SIMBEC Research Limited
Parish, Joanna; University of Birmingham, Institute of Cancer and http://bmjopen.bmj.com/ Genomic Sciences Spruce, Rachel; University of Birmingham, InHANSE, Institute of Cancer and Genomic Sciences Forster, Martin; University College London Schipani, Stefano; University of Glasgow, Beatson West of Scotland Cancer Centre Harrington, Kevin; Institute of Cancer Research Sacco, Joseph; Clatterbridge Cancer Centre NHS Foundation Trust Murray, Patrick; Leeds Teaching Hospitals NHS Trust Middleton, Gary; University of Birmingham, Institute of Immunology and on September 30, 2021 by guest. Protected copyright. Immunotherapy Yap, Christina; University of Birmingham, Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences Mehanna, H; University of Birmingham, InHANSE, Institute of Cancer and Genomic Sciences
Primary Subject Oncology Heading:
Secondary Subject Heading: Research methods
head and neck squamous cell carcinoma, TITE-CRM, wee1 inhibitor, Keywords: chemoradiation, window of opportunity study, wisteria
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1 2 3 4 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 adjuvant treatment, and a Window of Opportunity trial with Cisplatin in 6 7 Patients with Head and Neck Cancer: The WISTERIA Trial Protocol 8 9 10 11 12 AUTHORS 13 Kong A*1, Good J*2, Kirkham AJ3 , Savage J3, Mant R3, Llewellyn L8, Parish J1, Spruce R1, Forster M4, 14 Schipani S5, Harrington K6, Sacco JJ7, Murray P10, Middleton G 9, Yap Cǂ3, Mehanna Hǂ1† 15 16 17 *Joint first authors 18 ǂJoint senior authorsFor peer review only 19 20 †Corresponding author 21 22 23 Corresponding author: 24 Professor Hisham Mehanna 25 26 InHANSE, Institute of Cancer and Genomic Sciences 27 University of Birmingham 28 Edgbaston 29 Birmingham 30 31 B15 2TT 32 [email protected] 33 0121 414 6547 34 35 36 37 Author Affiliations http://bmjopen.bmj.com/ 38 1 Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK 39 2 University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, 40 41 Mindelsohn Way, Edgbaston, Birmingham, UK 42 3 Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomics Sciences, University of 43 Birmingham, Edgbaston, Birmingham, UK 44 4
University College Hospital London, Fitzrovia, London, UK on September 30, 2021 by guest. Protected copyright. 45 5 46 Beatson West of Scotland Cancer Centre, Institute of Cancer Sciences, University of Glasgow, UK 47 6 Royal Marsden/The Institute of Cancer Research, NIHR Biomedical Research Centre, London, UK 48 7 The Clatterbridge Cancer Centre, Wirral/University of Liverpool, Liverpool, UK 49 8 50 Simbec Research Ltd, Simbec Research Campus, Pentrebach, Merthyr Tydfil, South Wales, UK 51 9 Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, 52 UK 53 10 St James’ University Hospital, Leeds Teaching Hospitals NHS Trust 54 55 56 57 Keywords (5 max): TITE-CRM, head and neck squamous cell carcinoma, wee1 inhibitor, 58 chemoradiation, window of opportunity study 59 60 Word count excluding abstract, figures, tables, boxes and appendices: 6139
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1 2 3 4 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 Introduction 7 Head and neck squamous cell carcinoma (HNSCC) patients with locally advanced disease often require 8 multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy 9 10 with concurrent chemotherapy is offered to patients with high-risk pathological features post-surgery. 11 Whilst cure rates are improved, overall survival remains sub-optimal and treatment has a significant 12 negative impact on quality of life. 13 14 Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic 15 effects of chemo-radiation. Our hypothesis is that combining chemo-radiation with a WEE1 inhibitor 16 will affect the biological response to DNA damage caused by cisplatin and radiation, thereby 17 enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of 18 For peer review only 19 WEE1 kinase inhibitor Adavosertib (AZD1775). 20 21 Methods and analysis 22 23 This Phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of 24 AZD1775 in combination with cisplatin chemotherapy pre-operatively (Group A) as a window of 25 opportunity trial, and in combination with post-operative cisplatin-based chemo-radiation (Group B). 26 27 Modified time-to-event continual reassessment method (TITE-CRM) will determine the recommended 28 dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with 29 predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (Group A), and 30 30% monitored up to 12 weeks (Group B). Secondary outcomes are disease-free survival times (Groups 31 32 A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and 33 correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection 34 status and surgical complications for Group A; and quality of life in Group B. 35 36 37 Ethics and dissemination http://bmjopen.bmj.com/ 38 Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval 39 40 received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation 41 at international conferences. 42 43 44 Trial Registration 45 European Medicines Agency (EudraCT: 2015-003583-37); ISRCTN is 76291951 on September 30, 2021 by guest. Protected copyright. 46 (http://www.isrctn.com/ISRCTN76291951); Clinicaltrials.gov identifier is NCT03028766 47 (http://clinicaltrials.gov/ct2/show/NCT03028766). 48 49 50 51 52 53 54 55 56 57 58 59 60
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Strengths and Limitations BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Strengths of the study: 7 The study is one of the first to explore a WEE1 inhibitor in combination with cisplatin and 8 9 radiotherapy, and the first to do so in head and neck cancer. 10 Allows collection of tissues for translational research to examine the pharmacodynamic effects 11 of WEE1 and WEE1 in combination with cisplatin. 12 13 Uses an efficient TITE-CRM design which allows dose assignments to be performed with the 14 flexibility of continual patient accrual or temporary accrual suspension to permit sufficient 15 accumulation of safety information as necessary. 16 17 Limitations of the study: 18 For peer review only 19 Additional biopsies in the pre-operative setting may affect the patient enrolment. 20 The oral administration of AZD1775 may affect recruitment in post-operative patients if they 21 have difficulty or are unable to swallow. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Head and neck cancers are the sixth most common cancer worldwide1, with 12,000 new cases per 5 6 year in the UK (CRUK head and neck cancer statistics). The most common types are squamous cell 7 carcinoma (HNSCC) arising from laryngeal, oral cavity, oropharynx and hypopharyngeal subsites2. 8 Primary surgery is the standard of care for cancers of the oral cavity, and for more advanced cancers 9 10 of the larynx and hypopharynx, whilst (chemo)-radiation is the standard approach to oropharyngeal 11 disease. Post-operative radiotherapy (PORT), or post-operative chemoradiation (POCRT), is often 12 recommended in the setting of high-risk features such as a positive margin, multiple involved nodes, 13 extra-capsular spread, and peri-neural infiltration. 14 15 The role of concomitant chemotherapy was established by the Meta-Analysis of Chemotherapy on 16 Head and Neck Cancer (MACH-NC) in 20092. This study pooled individual patient data from 93 trials 17 involving 16,485 patients receiving either definitive local therapy alone (surgery or radiotherapy) or 18 For peer review only 19 local therapy plus chemotherapy (induction, concomitant or adjuvant). Concomitant therapy was 20 assessed in 50 trials involving 9605 patients; chemotherapy decreased the risk of death with a hazard 21 ratio of 0.81, translating into a 6.5% overall survival advantage at 5 years as a result of improved 22 23 disease-free survival. No benefit was seen in patients aged over 70 years. This provides robust 24 evidence that the ability of radiotherapy to secure local control can be enhanced by systemic therapy. 25 Acute toxicity and long-term sequelae of POCRT have a considerable negative health impact, and 26 despite intensive treatment, five year overall survival is sub-optimal at 53%3. Loco-regional relapse is 27 28 particularly difficult to salvage, and local control is therefore closely correlated with overall survival. 29 Morbidity imposed by local recurrence in the absence of distant metastatic disease is considerable 30 and can be extremely challenging to palliate adequately. There is an urgent need to develop novel 31 32 approaches that achieve improved loco-regional disease control and reduce treatment-related 33 morbidity for this patient group. Achieving this may translate into improved overall survival and an 34 enhancement in patient-related outcome measures. 35 36 37 Chemotherapy, radiotherapy and DNA damage response http://bmjopen.bmj.com/ 38 Cellular DNA damage response (DDR) is central to the preservation of genomic integrity. Cancer 39 development is a multistep process where deregulation of the DDR contributes to phenotypes such 40 41 as sustained cell proliferation and resistance to cell death. This increase in endogenous DNA damage 42 necessitates the acquisition of compensatory mechanisms if the cell is to avoid death through 43 uncontrolled genomic instability. Importantly, these compensatory changes may constitute a 44
molecular ‘Achilles heel’ that is vulnerable to therapeutic exploitation with a new generation of on September 30, 2021 by guest. Protected copyright. 45 46 targeted agents. POCRT exploits the differential DDR in malignant and normal tissues to eradicate 47 microscopic residual disease. Ionising radiation (IR) generates a variety of biological changes within 48 irradiated tissue, with double-stranded DNA (dsDNA) breaks being therapeutically significant. IR- 49 50 induced cell death is also immunogenic, with recruitment of immune effectors to the irradiated 51 tumour micro-environment contributing to a successful outcome4. Platinum-based chemotherapy 52 accentuates IR-induced cell death, in part via the suppression of homologous recombination (HR), the 53 4 54 primary repair mechanism for dsDNA damage in irradiated cells . Manipulation of the DDR pathway 55 therefore represents a rational means by which the therapeutic index of POCRT might be improved. 56 Cell cycle checkpoints are integral components of the DDR, allowing the cell to pause progression 57 through the cell cycle to repair DNA damage. Checkpoints are regulated by a network of 58 59 phosphorylation cascades. p53, encoded by TP53, is a key regulator of the G1/S checkpoint. TP53 60 mutations, which are seen in 60-70% of HNSCC cases5, are sufficient to impair the function of this
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checkpoint and thereby create a critical reliance on the later G2/M checkpoint. In addition, p53 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 function can be inactivated by various mechanisms, including somatic and germline mutations as well 6 as polymorphisms6,7.
7 Pharmacological abrogation of the G2/M checkpoint has been shown to differentially sensitise normal 8 and tumour cells to the effect of DNA damaging agents such as cisplatin and IR8. 9 10 11 12 WEE1 kinase and AZD1775 13 14 WEE1 kinase is a key regulator of the G2/M checkpoint and a promising therapeutic target. It is a 15 serine-threonine kinase involved in phosphorylation and inactivation of cyclin-dependent kinase 1 16 (CDK1), the only one of 14 similar proteins to be indispensable for mitotic entry. Along with a number 17 of other proteins, WEE1 triggers G /M arrest in response to DNA damage. However, inhibition of WEE1 18 For peer2 review only 19 leads to high CDK1 activity, allowing cells to progress through the G2/M checkpoint without the 20 opportunity to repair damaged DNA, leading to potentially catastrophic levels of unrepaired DNA 21 damage induction of cell death9,10. WEE1 also has an effect on CDK2 as its inhibition leads to high CDK2 22 23 activity and aberrant DNA replication, resulting in stalled replication forks and DNA double-stranded 24 breaks. WEE1 upregulation is seen in a variety of human cancers and is inversely associated with 25 prognosis in some models11, 12. Two separate kinomic screens in HNSCC identified WEE1 expression as 26 13, 14 27 a particularly strong determinant of cell survival , indicating that HNSCC may be a fruitful setting in 28 which to investigate the clinical effects of WEE1 inhibition. 29 Adavosertib (AZD1775) is a potent, selective small molecule inhibitor of WEE1. It has been shown to 30 potentiate the activity of various chemotherapeutic agents in vitro and in vivo. Some studies suggest 31 14-16 17 32 the sensitising effect is only seen in p53-deficient tumours although not exclusively . It has also 33 been shown to enhance IR-induced cell death in TP53-mutant cell lines. 34 Co-exposure of AZD1775 and cisplatin were found to reduce clonogenic survival18, demonstrating this 35 36 combination therapy has the ability to overcome cisplatin resistance in HNSCC. Similar effects of this 37 compound on radiation-induced cell death have been seen in models of typically radio-resistant http://bmjopen.bmj.com/ 38 cancer such as pontine glioma19, glioblastoma20, and pancreatic adenocarcinoma21. Importantly, one 39 study has shown that WEE1 inhibition by AZD1775 sensitises acute myelogenous leukaemia and lung 40 22 41 cancer cell lines to cytarabine chemotherapy independently of p53 status , suggesting that p53 42 mutation as a predictive biomarker for response to WEE1 inhibition may be cancer and/or 43 chemotherapy specific. WEE1 has also been implicated in maintaining genomic stability through 44 45 stabilisation of replication forks - down-regulation reduces replication fork speed during S-phase, on September 30, 2021 by guest. Protected copyright. 46 generating potentially lethal dsDNA breaks23. By impacting both cell cycle progression and DNA 47 damage repair, WEE1 inhibition may potentiate cell death in response to chemotherapy and IR. This 48 suggests that there may be an additive effect on clinical outcome in combination with POCRT, as well 49 50 as potential synergy. 51 AZD1775 is being tested in many clinical settings including in combination with docetaxel and cisplatin 52 in head and neck squamous cell carcinoma (NCT02508246) 24, with radiotherapy in childhood pontine 53 54 glioma (NCT01922076), with temozolomide and radiotherapy in glioblastoma (NCT01849146), and 55 with cisplatin and radiotherapy in cervical cancer (NCT01958658). 56 In summary, the available mechanistic data lend strong support to combining AZD1775 with cisplatin 57 and with POCRT in the clinic. Given that the predictive effect of TP53 mutation on such combinations 58 59 has yet to be clinically validated, this study does not prospectively stratify patients based on any such 60
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clinical or biological characteristic. Biomarker data generated, however, will be important in BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 understanding the mechanism of action and informing future combination studies. 6 7 Incorporating AZD1775 into clinical management 8 A recent randomised phase III study of neoadjuvant chemotherapy in a Chinese population with locally 9 10 advanced resectable oral cavity cancer showed that docetaxel, cisplatin and 5-fluorouracil (TPF) 11 treatment generated a response rate of 80%, with an exploratory analysis showing that clinical 12 responders had improved overall survival and local control25. There was no improvement in overall 13 14 survival for the study group as a whole compared to the control group without upfront TPF 15 chemotherapy, possibly because patients who would ordinarily have received POCRT received PORT 16 alone in this study. In an earlier study, TP53 mutation conferred increased resistance to pre-operative 17 cisplatin-based chemotherapy in oral cancer26. Whilst neoadjuvant chemotherapy has yet to find a 18 For peer review only 19 definitive role prior to surgery, these findings raise the possibility that chemo-sensitisation may 20 further improve outcomes. 21 The pre-operative Group A sets out to test this hypothesis by combining one week of AZD1775 alone, 22 2 23 with a second week of cisplatin (40 mg/m ) with AZD1775. This short course of treatment will minimise 24 any delay between diagnosis and definitive surgery and prevent unacceptable delay for the non- 25 responders from getting standard treatment. If this is a promising combination, the long-term aim is 26 to test AZD1775 in the neoadjuvant setting to downstage the disease through treatment with cisplatin 27 28 and AZD1775 in the pre-operative setting, which may decrease the extent of surgery, and may also 29 reduce the need for PORT/POCRT by reducing the involved margin rate. Many patients with tumours 30 that have high-risk histopathological features develop relapsed disease within the anatomical area 31 32 treated to a high radiation dose. Chemo- and radio-sensitisation via inhibition of the G2/M checkpoint 33 by AZD1775 has the potential to improve outcomes with acceptable toxicity. This possibility is the 34 basis of the treatment delivered in the Group B cohort. 35 36 37 http://bmjopen.bmj.com/ 38 METHODS 39 40 Wisteria trial objectives 41 Primary objectives are to determine the recommended dose and safety profile of AZD1775 with 42 cisplatin in the Group A pre-operative (window-of-opportunity) setting, and with 43 44 cisplatin/radiotherapy in the Group B post-operative setting. Other objectives: obtain information 45 regarding Group A and B disease-free survivals; evaluate AZD1775 pharmacodynamic (PD) effects on September 30, 2021 by guest. Protected copyright. 46 when administered with cisplatin (Group A); identify and correlate potential predictive biomarkers 47 with PD markers of DNA damage (Group A); determine the rate of R0, R1 or R2 resection status and 48 49 surgical complication (Group A); and Group B quality of life (QoL). 50 51 Trial design 52 53 Wisteria is an open-label, dose-finding, multicentre Phase I trial to determine the highest safest dose 54 of AZD1775 in combination with a single dose of cisplatin in the pre-operative setting as a window of 55 opportunity trial (Group A); and to determine the maximum tolerated dose (MTD) of AZD1775 in 56 combination with cisplatin/radiotherapy in the post-operative setting (Group B): both groups recruit 57 58 and run in parallel (Figure 1). The dose-escalation design is based on the modified time to event 59 60
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continual reassessment method (TITE-CRM) , requiring a maximum of 21 patients per group, and BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 encompassing up to four dose levels of AZD1775. 6 The MTDs of AZD1775 for both groups are expected to differ given the additional toxicities of 7 radiotherapy in Group B. The DLT monitoring periods are defined in table 1. Conservative target dose 8 limiting toxicity (DLT) rates are selected to minimise the likelihood of compromising individual 9 10 patient’s radical surgery and/or post-operative radiotherapy. To maximise recruitment, reduce trial 11 suspension time between cohorts, whilst balancing safety and optimal patient allocation, screening 12 cohorts of up to five patients will be allowed if the dose has previously been tested. Recruited patients 13 14 will be allocated to the current recommended dose up to a maximum of five. Patients who become 15 unevaluable may be replaced. 16 The model will be updated after every two to three evaluable patients, with any subsequent eligible 17 patients (not already receiving treatment) allocated to the latest recommended dose cohort. 18 For peer review only 19 Subsequent cohorts will be assigned a dose level using all the data observed until either - the MTD is 20 determined, the maximum sample size is reached, or the trial is stopped early due to unacceptable 21 DLT levels at the lowest dose. 22 23 24 Patient population, screening and consent 25 Group A patients are those with biopsy proven squamous cell carcinoma of the oral cavity, larynx or 26 hypopharynx (having accessible tumours for re-biopsy under local anaesthetic or via ultrasound- 27 28 guided biopsy), and due to undergo surgery. Patients in Group B consist of those already diagnosed 29 with oral cavity, larynx or hypopharynx squamous cell carcinoma, who have undergone surgery and 30 are considered at risk of relapse after surgery (i.e. with positive margins and/or nodal extracapsular 31 32 spread). Patients with cancer of the oropharynx will not be included. Since HPV is only routinely tested 33 in oropharyngeal squamous cell carcinoma or unknown primary of squamous cell carcinoma in the 34 NHS, HPV status was not determined or requested for the tumours as part of the study. Patients who 35 meet the criteria will be supplied with the Patient Information Sheet. If informed consent (appendix 1 36 37 and 2) is given the patient undergoes a full screening evaluation to ensure they satisfy the eligibility http://bmjopen.bmj.com/ 38 criteria prior to registration (Boxes 1 and 2). 39 40 41 Dose selection 42 Based on AstraZeneca studies31, 32, the Wisteria trial uses 3-day dosing, giving AZD1775 weekly to 43 coincide with cisplatin administration thereby potentiating the DNA damage effects. The maximum 44 2 total dose of AZD1775 1800 mg in combination with 1 dose of 40mg/m cisplatin for Group A is on September 30, 2021 by guest. Protected copyright. 45 46 substantially lower than AZD1775 monotherapy dose 2250mg every 21 days (225mg twice per day 47 orally over 2.5 days per week for 2 weeks per 21-day cycle) used in Do et al (2015); and although in 48 combination with cisplatin, the highest dose level (Dose Level 2) is likely to be safe. 49 50 A similar dose escalation algorithm will be carried out in Group B with a higher acceptable target DLT 51 level of 30% allowing for multiple dosing of cisplatin with radiotherapy in combination with AZD177533- 52 35. Trial doses and schedule are set out in table 1. AZD1775 is administered orally. The feasibility of the 53 54 oral administration will be evaluated in post-operative patients. 55 56 57 58 59 60
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1 2 3 Table 1: Details of the Wisteria TITE-CRM trial design for Groups A and B 4 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 Group A Group B 6 7 Maximum 8 Number of Up to 21 patients in each Group 9 Patients 10 Dose closest to where 25% MTD Definition Dose closest to where 30% patients experience a DLT 11 patients experience a DLT 12 Patients to have received the Minimum 13 minimum of AZD1775 and Patients to have received a minimum of the first two Treatment To Be 14 Cisplatin doses scheduled up to weeks of treatment as scheduled DLT Evaluable 15 and including day 8 16 17 Minimum of 30 days from start of 18 treatmentFor up peerto 42 days for delaysreview Minimum only of 56 days (8 weeks) from start of 19 DLT Reporting in surgery due to treatment radiotherapy, and up to 84 days (12 weeks), i.e. up to 20 Period related toxicity (if this exceeds 42 6 weeks from end of post-operative chemo-radiation 21 days then this delay will be therapy. 22 classified as a DLT). 23 AZD1775 PO AZD1775 PO BID Cisplatin (iv) Cisplatin (iv) Radiotherapy 24 BID 3 days 3 days over 1 hr over 1 hr (5 days per week 25 (Days 1-3, 8-10) (Days 2-4 weeks 1, 2, (Day 8) (Day 2 weeks 1-5) over 6 weeks) 26 Dose Levels : 4 & 5) 27 28 -1 75 mg 50 mg 29 0 (starting dose 30 100 mg 75 mg level) 2 2 31 40 mg/m 40 mg/m 54-65 Gy in 30# 32 1 125 mg 100 mg 33 34 35 2 150 mg 125 mg 36 37 (iv) Intravenous; (PO) By Mouth; (BID) Twice A Day; (Gy) Gray - unit of radiation dose; (#) Daily Fractions http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Box 1: Inclusion criteria – all patients BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Histologically confirmed diagnosis of oral, laryngeal or hypopharyngeal squamous cell 7 carcinoma 8 Multi-Disciplinary Team (MDT) recommendation for surgical resection with curative intent 9 10 Eastern Cooperative Oncology Group (ECOG) performance status 0/131 11 Age ≥18 to ≤70 years 12 Creatinine clearance, measured by Glomerular Filtration Rate (GFR), ≥ 60 ml/min at baseline 13 calculated using local practice calculation. If this is ≤ 60 ml/min then an isotopic GFR may be 14 15 carried out and must be > 60 ml/min 16 Acceptable cardiac function. If significant cardiac history, then required for patient to have 17 Left Ventricular Ejection Fraction (LVEF) ≥55% by echocardiogram (ECHO) or Multiple Gated 18 For peer review only 19 Acquisition Scan (MUGA, if ECHO is equivocal) 20 Normal liver and bone marrow function: 21 o Haemoglobin (Hb) ≥10.0 g/dL or ≥100 g/L 22 23 o Absolute neutrophil count (ANC) ≥1.5 x 109/L 24 o Absolute platelet count ≥100 x 109/L 25 o Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≤2.5 upper limit of 26 normal (ULN) 27 28 o Total bilirubin ≤1.5 ULN (except for patients with known Gilbert’s syndrome) 29 Male and female participants must agree to take appropriate measures to prevent pregnancy. 30 Contraceptive measures should be used for 2 weeks prior to trial entry, during the trial and 31 32 for at least 6 months after last receiving treatment. Acceptable methods of contraception 33 include total abstinence (if this is the patient’s usual and preferred lifestyle choice), tubal 34 ligation, combined oral, transdermal or intra-vaginal hormonal contraceptives, 35 medroxyprogesterone injections (e.g. Depo-Provera), copper-banded intra-uterine devices; 36 37 hormone impregnated intra-uterine systems and vasectomised partners. All methods of http://bmjopen.bmj.com/ 38 contraception (with the exception of total abstinence) should be used in combination with the 39 use of a condom by their male sexual partner for intercourse. 40 41 42 43 In addition to general criteria 44 Group A – Accessible tumours for re-biopsy to be taken under local anaesthetic or via on September 30, 2021 by guest. Protected copyright. 45 ultrasound-guided biopsy 46 47 Group B – High-risk histopathological features after surgical resection, i.e. nodal extra- 48 capsular spread and/or tissue resection margin <1 mm as agreed at MDT 49 Group B – Patients who have previously registered to Group A can be considered for inclusion 50 51 in Group B 52 53 54 55 56 57 58 59 60
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Box 2: Exclusion criteria – all patients BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Any previous treatment for the same cancer, or previous head and neck malignancy, apart 7 from laser excision of carcinoma in situ, with minimal residual functional deficit, or registration 8 and treatment in Group A prior to surgery 9 Patients with cancer of the oropharynx or non-primary cancer will not be included 10 11 Any metastatic disease from any primary site 12 Use of an Investigational Medicinal Product (IMP) concurrently or within 4 weeks of starting 13 this trial 14 15 Uncontrolled inter-current illness, which will interfere with patient’s trial participation, e.g.: 16 o myocardial infarction within 6 months 17 o congestive cardiac failure 18 For peer review only 19 o unstable angina 20 o symptomatic cardiomyopathy 21 o chronic infections 22 active peptic ulcer or liver disease 23 o 24 o serious psychiatric condition limiting ability to comply with trial protocol 25 Clinical evidence of current heart failure (≥New York Heart Association (NYHA) Class II32) 26 Clinical evidence of atrial fibrillation (heart rate >100 bpm, within 6 months prior to trial entry) 27 28 Unstable ischaemic heart disease (Myocardial Infarction within 6 months prior to trial entry 29 or angina requiring the use of nitrates greater than once weekly) 30 Patients who have a history of Torsades de Pointes (unless all risk factors that contributed to 31 32 Torsades have been corrected) 33 Active gastro-intestinal disease that might limit absorption of study drug, e.g. coeliac disease, 34 Crohn’s disease, ulcerative colitis, pancreatic insufficiency 35 36 Evidence of any psychological, familial, sociological or geographical condition potentially 37 hampering protocol compliance http://bmjopen.bmj.com/ 38 Participation in another interventional clinical trial whilst taking part in this trial 39 40 Patients who are unable to discontinue any prohibited drug, including live vaccines, and 41 unable to tolerate a washout period for at least 14 days prior to trial entry (including: CYP3A4 42 inhibitors; CYP3A4 inducers; CYP3A, CYP3A4, CYP2C19, CYP1A2 sensitive substrates or 43 substrates with narrow therapeutic range; P-gp substrates, strong P-gp inhibitors; and BCRP 44 45 substrates33) on September 30, 2021 by guest. Protected copyright. 46 Patients with any contraindications to cisplatin use 47 Clinical judgement by the Investigator that the patient should not participate in the study 48 49 Known hypersensitivity to the study drugs or active substances or excipients of the 50 preparations 51 Pregnant or breastfeeding patients 52 53 Significant pre-existing neuropathy which currently interferes with the patient’s daily life 54 Mean resting corrected QTc interval using the Fridericia formula34 >450 msec (male) and >470 55 msec (female) (as calculated per institutional standards) obtained from 3 electrocardiograms 56 57 (ECGs) 2-5 minutes apart at study entry, or congenital long QT syndrome 58 Inability to swallow oral medications 59 60
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Trial treatments BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Group A (pre-operative): patients will receive specified dose of AZD1775 by mouth (PO) twice per day 6 (BID) at 12 hour intervals (2 hours before or after food) for 3 days, commencing on days 1 and 8, with 7 40 mg/m2 IV cisplatin delivered over 1 hour on day 8. A missed dose of more than 6 hours should be 8 9 skipped. If vomiting occurs, patient should not retake the dose but wait until next scheduled dose. 10 Surgery is not to exceed 42 days from start of neoadjuvant chemotherapy. 11 12 Group B (post-operative): patients will receive specified dose of AZD1775 PO BID for 3 days, 13 2 14 commencing on days 2, 9, 23 and 30, and 40 mg/m IV cisplatin delivered over 1 hour on days 2, 9, 16, 15 23 and 30 (days are timed from the start of radiotherapy delivery). Radiotherapy (65Gy and 54Gy in 16 30 fractions given for 5 days per week over 6 weeks: D1-5, D8-12, D15-19, D22-26, D29-33, D36-40, to 17 high risk and low risk volumes respectively as per Wisteria Radiotherapy Guidelines, see appendices 18 For peer review only 19 3-6) will commence within 3 months of surgery and given concurrently with chemotherapy. 20 21 For both Groups A and B, cisplatin dose banding is not permitted. BSA to be calculated according to 22 23 local practice; if weight changes >10% then cisplatin dose should be re-calculated. 24 AZD1775 (morning dose) should be administered prior to cisplatin, and Group B to receive cisplatin 25 one hour before radiotherapy; standard supportive treatment, including premedication with anti- 26 27 emetics (excluding Aprepitant and Fosaprepitant), is allowed according to standard practice 28 guidelines. 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Trial outcome measures BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Primary outcome measures: the recommended doses of AZD1775 (determined by the modified TITE- 6 CRM) for Group A and B. 7 Group A: the highest safe dose in combination with cisplatin with a predefined target 8 9 DLT probability of 25% for up to 42 days from start of treatment 10 Group B: the MTD in combination with cisplatin/radiotherapy with a target DLT of 30% 11 for up to 12 weeks from the start of treatment. 12 13 Safety profile of AZD1775 in both Group A and B. 14 15 Secondary outcome measure: disease-free survival time for both Groups and recorded from 16 commencement of treatment to the date of disease recurrence, patient death or end of trial follow- 17 18 up period. For peer review only 19 20 Tertiary research outcome measures: pharmacodynamic (PD) effects of AZD1775 and correlation 21 22 with TP53 mutation status; pharmacokinetic (PK) effects of AZD1775 will be determined; optimise, 23 validate and test feasibility of assays to investigate serum, ctDNA and RNA biomarkers; investigate the 24 feasibility of immune function testing in a multicentre setting; complete pathological response rate 25 for Group A; positive resection margin status in Group A; surgical complication in Group A; and quality 26 27 of life (QoL) in Group B using European Organization for Research and Treatment of Cancer (EORTC) 28 C30 (version 3.0) 36, EORTC QLQ-H&N3537 and M.D. Anderson Dysphagia Inventory (MDADI)38, as 29 summarised in Box 3. 30 31 Assessment data will be collected as listed in appendix tables 7 and 8. 32 33 Dose limiting toxicity and dose management 34 35 Pre-defined DLTs have been specified by the Clinical Investigators (Box 4), and recorded toxicity 36 profiles for the Wisteria treatments are given in appendix table 9. Toxicity is assessed using the 37 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.039 unless http://bmjopen.bmj.com/ 38 otherwise specified. Any patient requiring a toxicity-related dose delay of more than 21 days must be 39 40 discontinued from the study unless there is approval from the Chief Investigator for the patient to 41 continue. For Group A, if any treatment-related Grade ≥3 toxicity develops in week one, cisplatin and 42 AZD1775 are discontinued in week two. For Group B, if calculated GFR falls below 60 mL/min, 43 44 immediately before any cycle of concomitant chemotherapy, weekly cisplatin should be discontinued 45 and consideration given to substitute with weekly carboplatin (AUC =1.5), according to routine local on September 30, 2021 by guest. Protected copyright. 46 practice. 47 In both groups a full blood count is obtained at the beginning of each week. If haematological toxicity 48 49 occurs, treatment should be modified as per appendix tables 10 and 11. For non-haematological 50 toxicities, treatment should also be modified as per appendix tables 12 to 16. 51 52 53 54 55 56 57 58 59 60
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Box 3: Trial summaries of Group A and Group B BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 Summary of Group A 7 Setting Patients undergoing surgical resection 8 9 Design Modified TITE-CRM 10 Chemotherapy Cisplatin 40 mg/m2 IV over 1 hour on Day 8 11 AZD1775 AZD1775 PO BID for 3 days on Days 1-3 and 8-10 12 Dose-recommendation according to the modified TITE-CRM model 13 14 Surgery Resection within 42 days of start of neoadjuvant treatment 15 DLT reporting The minimal reporting period is 30 days from start of treatment, but 16 period patients will be monitored up to 42 days for delay in surgery due to 17 treatment-related toxicity 18 PK samples ForPharmacokinetic peer samples review will be collected only pre- and post- the fifth dose 19 of AZD1775 on Days 3 and 10 (4 samples per patient) 20 21 PD markers Assess CDK1, pCDK1, γH2AX, p53, p16, HH3, pHH3, Ki67, C3, CC3, p21, 22 WEE1, pWEE1, PDL-1 and TILS, and other markers of particular interest 23 Follow-up Clinically for at least 12 weeks from start of treatment 24 25 26 27 Summary of Group B 28 Setting Post-operative patients with high risk disease (involved resection 29 30 margins +/or extracapsular nodal spread) receiving chemo-radiation 31 Design Modified TITE-CRM 32 Chemotherapy Cisplatin 40 mg/m2 IV over 1 hour on Day 2 of Weeks 1-5 of 33 radiotherapy 34 Radiotherapy External beam radiation therapy (30 fractions over six weeks) to start 35 within 3 months of surgery. Dose levels are 65 Gy for positive margin, 36
60 Gy to lymph node levels that have been dissected, and 54 Gy to http://bmjopen.bmj.com/ 37 38 elective lymph node areas. A dose of 65 Gy may also be applied to areas 39 of gross extra-capsular spread at the discretion of the treating clinician. 40 AZD1775 AZD1775 PO BID for 3 days on Days 2-4 of Weeks 1, 2, 4 and 5 (No 41 treatment with AZD1775 during Weeks 3 and 6). 42 Dose-recommendation will be according to modified TITE-CRM model. 43 DLT reporting The minimal reporting period is 56 days (8 weeks) from start of 44 45 period radiotherapy, but patients will be monitored for DLTs up to 84 days (12 on September 30, 2021 by guest. Protected copyright. 46 weeks), i.e. up to 6 weeks from the end of POCRT 47 PK samples Pharmacokinetic samples will be collected pre- and post- the fifth dose 48 of AZD1775 on Week 1 – Day 4 (2 samples per patient) 49 PD markers Assess CDK1, pCDK1, p53, p16, WEE1, pWEE1, PDL-1 and TILS and other 50 markers of particular interest in resection tumour samples 51 52 Follow-up Clinically for at least one year from start of treatment 53 54 The selection of PD markers to test are different for Group A and Group B as Group A enables examination of 55 samples pre-and post-treatment with AZD1775. 56 57 58 59 60
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Box 4: Dose-limiting toxicities BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Patients experiencing any of the following Adverse Reactions (ARs) during the reporting period will be 6 considered to have experienced a DLT: 7 8 Grade 3 or 4 neutropenia lasting for >7 days despite adequate Granulocyte-Colony Stimulating 9 Factor (G-CSF) support 10 11 Grade 4 febrile neutropenia, which includes grade 3 febrile neutropenia accompanied by 12 systemic inflammatory response syndrome/sepsis or other life-threatening consequences 13 A third occurrence of Grade 2 or worse neutropenia despite G-CSF support 14 15 Grade 3 or 4 thrombocytopenia lasting ≥7 days 16 Any occurrence of Grade 4 anaemia 17 Any occurrence of Grade 4 mucositis 18 For peer review only 19 Any occurrence of Grade 3 nausea despite preventative and supportive care according to local 20 practice. Tube feeding is not considered a DLT 21 Any occurrence of Grade 4 vomiting despite preventative and supportive care according to 22 23 local practice. Tube feeding is not considered a DLT 24 Any occurrence of Grade 4 diarrhoea despite preventative and supportive care according to 25 local practice 26 27 Any AR which results in an omission of chemotherapy administration and/or study treatment 28 for > 14 days 29 A start-of-treatment-to-surgery time of > 42 days in Group A as a result of a treatment-related 30 toxicity 31 32 Grade 3 mucositis lasting > 42 days after the end of treatment in Group B 33 An overall treatment time of > 49 days from the first day of radiotherapy in Group B as a result 34 of a treatment-related toxicity 35 36 Any Grade 3 or 4 non-haematological AR (except for fatigue, nausea, vomiting and diarrhoea) 37 for which medical intervention that lasts >7 days is required and the investigators deem that http://bmjopen.bmj.com/ 38 this AR is more severe or prolonged than what would be expected of standard treatment. 39 40 Tube feeding is not considered a DLT. 41 Any clinically significant occurrence which investigators within the Trial Management Group 42 (TMG) agree would place the patient at undue safety risk 43 44
If the inability to swallow the AZD1775 capsule develops during the course of trial treatment, this on September 30, 2021 by guest. Protected copyright. 45 46 event should be noted in the relevant section on the Suspected DLT form and reported immediately. 47 However, this is not considered a DLT in itself. 48 49 50 51 52 53 54 55 56 57 58 59 60
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Concomitant medications BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 All concomitant medications received within 14 days before the first dose of study medication and for 6 12 weeks after the last dose of study medication should be recorded. Medications may be 7 administered for maintenance of existing conditions prior to study enrolment or for a new condition 8 9 that develops while on study. The treatments and medications listed in appendix 17 are prohibited or 10 to be used with caution while in this study. No other investigational therapy or anticancer agents, 11 other than the study medications, should be given to patients. If such agents are required for a patient, 12 then the patient must first be withdrawn from the study. Live vaccines are not permitted. 13 14 15 Discontinuation of investigational medicinal product 16 Patients should discontinue trial treatment in the following circumstances: Intolerable toxicity; 17 18 confirmed disease recurrence;For peer pregnancy; severereview non-compliance only to protocol; development of any 19 study-specific criteria for discontinuation; and investigator decision, for example, if the patient 20 requires a prohibited concomitant medication. 21 22 23 Safety monitoring – adverse events and serious adverse events 24 All medical occurrences which meet the definition of an adverse event (AE) or serious adverse event 25 (SAE) (as defined in Box 5) should be reported. This includes abnormal laboratory findings of grade 3 26 27 and above only. Adverse events will be monitored for and reported from date of informed consent 28 until the 12 week follow up visit for Group A and until the 12 month follow up visit for Group B. 29 Investigators should report SAEs within 24 hours of first knowledge of the event, until 12 week follow 30 31 up visit. After this time, expedited reporting is no longer required and should be reported as an AE. 32 Any post-study serious unexpected serious adverse reactions (SUSARs) should be reported within 24 33 hours. An independent Safety Committee will review all SAEs. Fatal or life-threatening SUSARs will be 34 35 reported to the Medicines and Healthcare products Regulatory Agency (MHRA) and Research Ethics 36 Committee (REC) within 7 days. Detailed follow-up information will be provided within an additional 37 8 days. All other events categorised as SUSARs will be reported within 15 days. The MHRA and REC http://bmjopen.bmj.com/ 38 will be notified immediately if a significant safety issue is identified during the course of the trial. All 39 40 SAEs relating to AZD1775 will be reported to AstraZeneca within 24 hours of notification. 41 42 Data collection and monitoring 43 44 Data will be collected via a set of forms capturing details of eligibility, baseline characteristics, 45 treatment and outcome details. This trial will use an electronic remote data capture (eRDC) system. on September 30, 2021 by guest. Protected copyright. 46 SAE reporting and Notification of Pregnancy will be paper-based. All missing and ambiguous data will 47 be queried. In all cases, it remains the responsibility of the Investigator to ensure that data are 48 49 accurate. Details regarding data collection for Group A and B are given in appendix tables 7 and 8. The 50 Investigator will permit trial-related monitoring, audits, ethical review, and regulatory inspection(s) at 51 their site, providing direct access to source data/documents. 52 53 54 55 56 57 58 59 60
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Box 5: Adverse event and serious adverse event definitions BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Adverse Event 6 Any untoward medical occurrence in a patient or clinical trial subject administered a medicinal 7 product and which does not necessarily have a causal relationship with this treatment. 8 9 10 Serious Adverse Event 11 Any untoward medical occurrence or effect that at any dose may: 12 13 Result in death 14 15 Is life-threatening 16 Requires hospitalisation or prolongation of existing in-patient hospitalisation 17 Results in persistent or significant disability or incapacity 18 For peer review only 19 Is a congenital anomaly/birth defect 20 Is considered medically significant by the Clinical Investigator 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Statistical methodology BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 The AZD1775 dose is allocated to patients according to a modified Bayesian TITE-CRM, using an 6 empiric dose-toxicity model, F(x,β) given as: 7 퐹(푥,훽) = 푥exp (훽) 푓표푟 0 < 푥 < 1 8 9 where model parameter β is assumed random and follows a normal distribution and will be estimated 10 by its posterior mean29. At the point of model-update, patients who have started treatment but have 11 not experienced DLT (and have completed their full DLT assessment) will be included in the probability 12 calculation with a weight equal to the proportion of the full DLT assessment period they have 13 14 completed. Patients who experience DLT within the assessment period or complete the full 15 assessment period are assigned full weight. The model also enables inclusion of partial patient 16 information that cannot be formally evaluated for DLTs due to withdrawal, treatment discontinuation 17 or death, which are unrelated to treatment, within the DLT assessment period. 18 For peer review only 19 Table 1 displays the four dose levels of AZD1775 for Group A and Group B. For both groups, dosing 20 starts at level 0 and allows for possible escalation to two higher levels, or de-escalation to a lower 21 dose, as recommended by the TITE-CRM, without skipping untried doses in escalation. The TITE-CRM 22 23 model aims to recommend the next dose with estimated DLT probability closest to the target DLT 24 level, taking into account the practical considerations as detailed below: 25 26 27 Practical Considerations 28 Restriction is applied to avoid skipping of untried doses in escalation 29 Stop early due to safety concerns if there is sufficient evidence that the posterior probability of 30 31 DLT at the lowest dose is greater than the target DLT rate, implying that the lowest dose is too 32 toxic 33 Stop early if sufficient patients have been allocated to the current MTD (and remains the 34 recommended dose level for the next cohort if the trial continues) before the full recruitment of 35 36 21 patients 37 The minimum DLT period is set at 30 days for Group A and 8 weeks for Group B. This means that http://bmjopen.bmj.com/ 38 partial information of no DLT in a patient can only be included in the model if they have been 39 40 followed up for at least 30 days or 8 weeks in Group A and B respectively. (The full DLT assessment 41 periods are 42 days and 12 weeks in Group A and B respectively.) This feature can easily be 42 accommodated using the TITE-CRM model 43 44 A “look ahead” strategy will be implemented if the next recommended dose level by the modified 45 TITE-CRM model will not be influenced by the outcome of the remaining patient(s) of a particular on September 30, 2021 by guest. Protected copyright. 46 cohort (DLT or no DLT). By implementing this strategy, the next cohort can be recruited 47 immediately without awaiting the final observations from the current cohort, thus reducing 48 49 waiting time between cohorts 50 51 52 Analysis of outcome measures 53 The primary outcome measures are the recommended doses of AZD1775 in Group A and Group B, 54 55 and the safety profile of the combination therapy. To be DLT evaluable, Group A patients must have 56 received AZD1775 and cisplatin doses scheduled up to and including Day 8; Group B patients must 57 have received at least the first two weeks of treatment. The recommended doses of AZD1775 will be 58 59 those that have an estimated DLT rate closest to the target DLT rate: 25% for Group A; 30% for Group 60 B. DLT rates and corresponding 90% probability intervals will be reported. Safety will be monitored in
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patients treated with at least one dose of the trial treatment until end of follow-up. All adverse BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 reactions, adverse events, serious adverse events, suspected unexpected serious adverse reactions, 6 deaths, deviations and withdrawals experienced by trial patients, throughout the trial’s duration, will 7 be reported separately for Group A and Group B. 8 Disease-free survival in Group A and Group B patients will be reported separately. Patients will be 9 10 followed-up for 12 months after which, time to event outcomes will be assessed using the method of 11 Kaplan and Meier. Median disease-free survival with corresponding 95% confidence intervals will be 12 reported where appropriate. Further analysis will be performed separately on subsets of Group A and 13 14 B patients who have completed at least 90% of AZD1775 trial scheduled treatments. 15 Tertiary outcome measures will be explored and reported descriptively using basic descriptive 16 statistics where appropriate: 17 18 PD effects ofFor AZD1775 peer and correlation review with TP53 mutationonly status: Expression levels of 19 20 parameters (Box 3) changes over time and correlation with TP53 mutation status will be 21 reported. 22 PK effects of AZD1775: Blood samples for PK analyses are collected (as scheduled in appendix 23 tables 7 and 8). Circulatory levels of AZD1775 and changes over time will be reported. 24 25 Complete pathological response rate for Group A: Pathology data will be reported along with 26 the results of the FFPE tissue samples. Response rate will be reported as the number of 27 evaluable Group A patients showing a response (numerator) divided by the total number of 28 29 Group A evaluable patients (denominator). 30 Positive resection margin status in Group A: This will be reported as the number and 31 percentage of Group A patients showing positive resection margins. 32 33 Surgical complications in Group A: This will be reported by category of surgical complication 34 with severity and given as numbers and percentages. 35 Quality of Life (QoL) in Group B: QoL data is gathered over time and will be reported as 36 37 changes over time and plotted. In addition to the descriptive analyses, the repeated measures http://bmjopen.bmj.com/ 38 over time data may be modelled, if appropriate, with a linear mixed effects model (taking 39 subject correlation into account) using linear or more flexible models. 40 41 Interim analyses will be performed once each cohort of patients has been recruited and assessed 42 43 within the defined assessment timeframe of DLTs. In each meeting, the Safety Committee will be 44 presented with recruitment and safety data, together with a statistical report for next dose- 45 recommendation. Additional meetings might be convened if late onset DLTs were observed. The on September 30, 2021 by guest. Protected copyright. 46 Safety Committee will decide whether to progress to the recommended dose as indicated by the 47 48 modified TITE-CRM model. The final analyses will be conducted in two parts: (i) analyses of the primary 49 outcome measures of MTDs for Groups A and B, to be carried out approximately three months after 50 the safety review of the last cohort in each group; (ii) longer term outcomes – including secondary and 51 52 tertiary outcome measures and updated safety data, to be carried out one year after the end of trial. 53 54 55 56 TRIAL ORGANISATION AND STRUCTURE 57 The Trial is sponsored by the University of Birmingham, UK and conducted under the auspices of the 58 Cancer Research UK Clinical Trials Unit, University of Birmingham, UK according to their local 59 60 procedures.
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The Trial Management Group (TMG) will include as a minimum: Chief Investigator, Co-Investigators, BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Lead and Trial Statisticians, Trial Management Team Leader and Trial Co-ordinator (other appropriate 6 key personnel will be invited to attend meetings as required). This group will be responsible for legal 7 obligations, day-to-day running and management of the Trial. 8 The Safety Committee provides support on decisions surrounding the review of DLT information and 9 10 dose changing decisions. Membership of this group includes the TMG, independent members and 11 selected Principal Investigators. 12 13 14 15 ETHICS AND DISSEMINATION 16 The protocol has been approved by the Research Ethics Committee, Edgbaston, West Midlands (REC, 17 18 reference 16/WM/0501).For The firstpeer REC approval review date was 18/01/2017, only with five subsequent approved 19 amendments. This article refers to protocol version 5.0, dated 27/11/2018. 20 The trial will be performed in accordance with the 18th World Medical Association General Assembly, 21 th 22 Helsinki, Finland, June 1964, amended at the 48 World Medical Association General Assembly, 23 Somerset West, Republic of South Africa, October 1996 (website: 24 http://www.wma.net/en/30publications/10policies/b3/index.html); conducted in accordance with 25 the Research Governance Framework for Health and Social Care, the applicable UK Statutory 26 27 Instruments, (which include the Medicines for Human Use Clinical Trials 2004 and subsequent 28 amendments, The Human Tissue Act 2008) and Good Clinical Practice (GCP) E6(R2); and carried out 29 under a Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical Trials 30 31 regulations. The protocol and subsequent amendments will be submitted to and approved by REC 32 prior to circulation. Personal data recorded on all documents will be regarded as strictly confidential 33 and will be handled and stored in accordance with the General Data Protection Regulation 2016/679 34 35 and the Data Protection Act (2018). 36 Trial findings will be published in a peer-reviewed journal and disseminated at appropriate 37 conferences, departmental and scientific meetings. http://bmjopen.bmj.com/ 38 39 40 41 Acknowledgements 42 Wisteria was supported by Experimental Cancer Medicine Centres (ECMC) funding and by the ECMC 43 44 Network. 45 on September 30, 2021 by guest. Protected copyright. 46 Authors’ contributions 47 The study was conceived by Hisham Mehanna and James Good; designed by Hisham Mehanna, James 48 49 Good, Anthony Kong, and Christina Yap; and the protocol written by Hisham Mehanna, Anthony Kong, 50 James Good, Christina Yap, Laura Llewellyn, Rhys Mant, Amanda Kirkham, Rachel Spruce, Joshua 51 Savage (JSS), Joseph Sacco (JS), Martin Forster, Joanna Parish, Martin Forster, Stefano Schipani, Patrick 52 53 Murray, Gary Middleton and Kevin Harrington. Amanda Kirkham, Anthony Kong, James Good, Joshua 54 Savage and Christina Yap wrote the manuscript with input from all authors. 55 56 Funding 57 58 Cancer Research UK (code C19677/A20959) and AstraZeneca through the CRUK’s Combinations 59 Alliance and Experimental Cancer Medicine Centre (ECMC). AstraZeneca provides AZD1775 to 60
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participating sites free-of-charge, and was consulted over the trial design but are not involved in the BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 trial management group or safety committee. 6 The Combinations Alliance, a Cancer Research UK model, aims to drive academic-industrial 7 partnership, generating novel treatment options that would otherwise unlikely be realised. Novel 8 combination ideas are generated and delivered via the UK’s Experimental Cancer Medicine Centre 9 10 (ECMC) network of clinical and scientific experts working together to accelerate innovation in early- 11 phase oncology research for patient benefit. 12 13 14 Competing interests 15 HM, AK, RM, JS, CF, JG, RS, Report grants from CRUK, and AZ during the conduct of the study. 16 JSS reports personal fees from Eli Lilly and Company outside the submitted work. 17 KH reports grants and personal fees from ASTRA ZENECA, during the conduct of the study; personal 18 For peer review only 19 fees from AMGEN, personal fees from BMS, personal fees from BOEHRINGER INGELHEIM, personal 20 fees from MERCK SERONO, personal fees from MSD, personal fees from PFIZER, outside the submitted 21 work. 22 23 HM reports personal fees from BMS, MSD outside the submitted work. 24 JS reports grants from AstraZeneca, grants from BMS, personal fees from BMS, personal fees from 25 MSD, personal fees from Immunocore, personal fees from Delcath, personal fees from Pierre Fabre, 26 outside the submitted work. 27 28 29 Patient consent 30 All patients must give written informed consent to the Investigator prior to Trial registration. 31 32 33 Patient and public involvement 34 No patient or public involvement contributed to the design of this trial. 35 36 37 Provenance and peer review http://bmjopen.bmj.com/ 38 Not commissioned; externally peer-reviewed. 39 40 41 Ethics approval 42 Research Ethics Committee (REC reference 16/WM/0501). 43 44
Open access on September 30, 2021 by guest. Protected copyright. 45 46 This is an Open Access article distributed in accordance with the terms in the Creative Commons 47 Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this 48 work, for commercial use, provided the original work is properly cited. See 49 50 http://creativecommons.org/licenses/by/4.0/ 51 52 53 54 55 56 57 58 59 60
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REFERENCES BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2009. CA Cancer J Clin 2009;59:225-249. 5 6 2. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008;359:1143- 7 1154. 8 3. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant 9 10 chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-52. 11 4. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Sem Rad Onc 2015;25:11-17. 12 5. Kang H, Kiess A, Chung CH. Emerging biomarkers in head and neck cancer in the era of genomics. 13 Nat Rev Clin Oncol 2015;12:11-26. 14 15 6. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and 16 clinical use. Cold Spring Harb Perspect Biol 2010;2(1):a001008. 17 7. Petitjean A, Achatz MI, Borresen-Dale AL, et al. TP53 mutations in human cancers: functional 18 For peer review only 19 selection and impact on cancer prognosis and outcomes. Oncogene 2007;26(15):2157-65. 20 8. Dillon MT, Good JS, Harrington KJ. Selective targeting of the G2/M cell cycle checkpoint to 21 improve the therapeutic index of radiotherapy. Clin Oncol (R Coll Radiol) 2014;26:257-85. 22 23 9. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of WEE1 kinase by MK-1775 24 selectively sensitizes p53-deficient tumour cells to DNA-damaging agents. Mol Can Ther 25 2009;8:2992-3000. 26 10. Van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 27 28 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 29 Cancer Ther 2013;12:2675-84. 30 11. Magnussen GI, Holm R, Emilsen E, et al. High Expression of WEE1 Is Associated with Poor 31 32 Disease-Free Survival in Malignant Melanoma: Potential for Targeted Therapy. BMJ Cancer 33 2013;13:288. 34 12. Mir SE, de Witt Hamer PC, Krawxzyk PM, et al. In Silico Analysis of Kinase Expression Identifies 35 WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma. Cancer Cell 2010;18:244- 36 37 57. http://bmjopen.bmj.com/ 38 13. Wu Z, Doondeea JB, Gholami AM, et al. Quantitative chemical proteomics reveals new potential 39 drug targets in head and neck cancer. Mol Cell Proteomics 2011;10:M111.011635. 40 41 14. Hirai H, Iwasawa Y, Okada M, et al. Small-molecule inhibition of WEE1 kinase by MK-1775 42 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Mol Can Ther 2009; 43 8:2992-3000. 44
15. Bridges KA, Hirai H, Buser CA, et al. MK-1775, a novel WEE1 kinase inhibitor, radiosensitizes on September 30, 2021 by guest. Protected copyright. 45 46 p53-defective human tumor cells. Clin Cancer Res 2011;17: 5638-48. 47 16. Khanh D, Doroshow JH, Kummar S. WEE1 kinase as a target for cancer therapy. Cell Cycle 48 2013;12:3159-64. 49 50 17. Van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 51 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 52 Cancer Ther 2013;12:2675-84. 53 18. Osman AA, Monroe MM, Ortega Alves MV, et al. Wee-1 Kinase Inhibition Overcomes Cisplatin 54 55 Resistance Associated with High-Risk TP53 Mutations in Head and Neck Cancer through Mitotic 56 Arrest Followed by Senescence. Mol Cancer Ther 2015;14:608-19. 57 19. Caretti V, Hiddingh L, Lagerweij T, et al. WEE1 kinase inhibition enhances the radiation response 58 59 of diffuse intrinsic pontine gliomas. Mol Cancer Ther 2013;12:141-50. 60
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20. Sarcar B, Kahali S, Prabhu AH, et al. Targeting radiation-induced G(2) checkpoint activation with BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Mol Cancer Ther 2011;12:2405-14. 6 21. Kamak D, Engelke CG, Parsels LA, et al. Combined inhibition of WEE1 and PARP1/2 for 7 radiosensitization in pancreatic cancer. Clin Cancer Res 2014;20:5085-96. 8 22. van Linden AA, Baturin D, Ford JB, et al. Inhibition of WEE1 sensitizes cancer cells to 9 10 antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Mol 11 Cancer Ther 2013;12:2675-84. 12 23. Guertin AD, Li J, Liu Y, et al. Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent 13 14 anticancer therapy. Mol Cancer Ther 2013;12:1442-52. 15 24. Méndez E, Rodriguez CP, Kao MC, et al. A Phase I Clinical Trial of AZD1775 in Combination with 16 Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck 17 Squamous Cell Carcinoma. Clin Cancer Res 2018;24: 2740-2748 18 For peer review only 19 25. Zhong L, Zhang C, Ren G, et al. Randomized Phase III Trial of Induction Chemotherapy With 20 Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally 21 Advanced Resectable Oral Squamous Cell Carcinoma. J Clin Oncol 2012;30:1-12. 22 23 26. Perrone F, Bossi P, Cortelazzi B, et al. TP53 mutations and pathologic complete response to 24 neoadjuvant cisplatin and fluorouracil chemotherapy in resected oral cavity squamous cell 25 carcinoma. J Clin Oncol 2010;28:761-6. 26 27. O’Quigley J, Pepe M, Fisher L. Continual reassessment method. Biometrics 1990; 46:33–48. 27 28 28. Cheung YK. Dose Finding by the Continual Reassessment Method. New York: Chapman & 29 Hall/CRC Press 2011. 30 29. Cheung YK, Chappell R. Sequential Designs for Phase I Clinical Trials with Late-Onset Toxicities. 31 32 Biometrics 2000;56(4):1177-82. 33 30. Yap C, Craddock C, Quigley JO, et al. Comparing the implementation of a Modified Continual 34 Reassessment Method to a 3+3 Design in a Phase I Acute Myeloid Leukaemia Trial. Clin Trials 35 2013;10(2):75. 36 37 31. Do KT, Wilsker D, Balasubramanian P, et al. Phase I study of single agent AZD1775 (MK1775), a http://bmjopen.bmj.com/ 38 WEE1 kinase inhibitor, in patients with refractory solid tumors. J Clin Oncol 2015;33:3409-3415. 39 32. Schellens JH, Leijen S, Shapiro G, et al. Update on a phase I pharmacologic and 40 41 pharmacodynamic study of MK1775, a WEE1 tyrosine kinase inhibitor in monotherapy and 42 combination with gemcitabine, cisplatin or carboplatin in patents with advance solid tumour. 43 ASCO 2011. Accessed at http://meetinglibrary.asco.org/content/62389 44
33. Homma A, Inamura N, Oridate N, et al. Concomitant Weekly Cisplatin and Radiotherapy for on September 30, 2021 by guest. Protected copyright. 45 46 Head and Neck Cancer. Jpn J Clin Oncol 2011;41(8)980 – 986. 47 34. Traynor AM, Richards GM, Hartig GK, et al. Comprehensive IMRT Plus Weekly Cisplatin for 48 Advanced Head and Neck Cancer: The University of Wisconsin Experience. Head Neck 2010; 49 50 32(5):599–606. 51 35. Jagdis A, Laskin J, Hao D, et al. Dose delivery analysis of weekly versus 3-weekly cisplatin 52 concurrent with radiation therapy for locally advanced nasopharyngeal carcinoma (NPC). Am J 53 Clin Oncol 2014 Feb;37(1):63-9. 54 55 36. Aaronson NK, Ahmedzai S, Bergman B, et al. European Organization for Research and 56 Treatment of Cancer QLQ-C30: A Quality-of-Life Instrument for Use in International Clinical 57 Trials in Oncology. J Natl Cancer Inst 1993;85:365-376. 58 59 60
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37. Bjordal K, de Graeff A, Fayers PM, et al. A 12 Country Field Study of the EORTC QLQ-C30 (version BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 3.0) and the Head and Neck Cancer Specific Module (EORTC QLQ-H&N35) in Head and Neck 6 Patients. Eur J Cancer 2000;36:1796-1807. 7 38. Chen AY, Frankowski R, Bishop-Leone J, et al. The development and validation of a dysphagia- 8 specific quality-of-life questionnaire for patients with head and neck cancer: the M. D. Anderson 9 10 dysphagia inventory. Arch Otolaryngol Head Neck Surg 2001;127:870-6. 11 39. National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). 12 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 13 14 15 16 FIGURE LEGENDS 17 18 For peer review only 19 Figure 1: Wisteria trial schema. Group A patients were required to have received a minimum 20 treatment of chemotherapy (cisplatin) and AZD1175 in combination to be DLT evaluable. Group B 21 patients were required to have received a minimum of two weeks of treatment (half the total 22 scheduled AZD1775 dose) to be DLT evaluable. 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 Wisteria trial schema. Group A patients were required to have received a minimum treatment of 26 chemotherapy (cisplatin) and AZD1175 in combination to be DLT evaluable. Group B patients were required 27 to have received a minimum of two weeks of treatment (half the total scheduled AZD1775 dose) to be DLT 28 evaluable. 29 338x190mm (300 x 300 DPI) 30 31 32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39 40 on September 30, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 45 BMJ Open
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Appendix 1: Informed Consent Form – Group A BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 6 To be printed on hospital headed paper 7 8 9 10 Informed Consent Form 11 12 To be used for Group A only 13 14 15 16 17 18 For peer review only 19 20 21 22 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as adjuvant 23 treatment, and a Window of Opportunity trial with Cisplatin in Patients with Head and Neck 24 Cancer 25 26 EudraCT Reference: 2015-003583-37 27 28
29 Site: Patient Trial Number:
30 Principal ______31 / 32 Investigator: ______Screening Number: SCR 33 (If applicable) 34 Please initial 35 each box 36 1. I confirm that I have read and understand the Patient Information Sheet Group A http://bmjopen.bmj.com/ 37 (version ...... dated ...... ) for the above trial. I have had the 38 opportunity to consider the information, ask questions and have had these 39 40 answered satisfactorily. 41 2. I understand that my participation is voluntary and that I am free to withdraw at 42 any time without giving any reason, without my medical care or legal rights being 43 affected. I understand that if I withdraw from treatment my doctor may continue 44
to provide the Trial Office with information that would routinely be collected about on September 30, 2021 by guest. Protected copyright. 45 46 me and recorded in my medical notes. I am aware that I can also withdraw 47 consent for this data transfer. 48 3. I give permission for my initials, date of birth, and NHS number to be given to the 49 WISTERIA Trial Office when I am registered to the trial as well as a copy of this 50 51 consent form. 52 4. I understand that relevant sections of my medical notes and data collected during 53 the trial may be looked at by individuals from the WISTERIA Trial Office, 54 regulatory authorities, Sponsor and/or NHS bodies, where it is relevant to my 55 taking part in this research. I understand that this information will be held in a 56 57 confidential manner. I give permission for these individuals to have access to my 58 records. 59 60
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1 2 3 4 5. I understand that anonymised data from the trial may be provided to other third BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 parties (e.g. pharmaceutical companies or other academic institutions) for 6 research, safety monitoring or licensing purposes. I understand that this may 7 involve sending data outside of the United Kingdom to a European country or the 8 United States of America and that my name will not be given to these third parties. 9 10 6. I agree to my GP being informed of my participation in this trial. 11 12 7. I understand that the WISTERIA Trial Office may access information held by 13 national cancer registries and within national databases to keep in touch with me 14 and to follow up on my health status. 15 16 8. I give permission for collection of samples of my blood and tissue to be used in the 17 WISTERIA trial. I understand that samples will be sent to the Institute of Head and 18 Neck Studies and EducationFor (InHANSE),peer review University of Birmingham only and other 19 laboratories in the United Kingdom or overseas (including Covance Laboratories 20 21 Inc., based in the United States of America). 22 9. I understand that DNA analysis may be performed on the samples taken for the 23 trial. 24 25 10. I consent to the storage of samples remaining at the end of the trial and their use 26 in future ethically approved research which may involve genetic analysis, animal 27 or in vitro models, commercial or private institutions, and which may take place in 28 the UK or overseas. 29 30 11. I understand that information which may identify me will be transferred outside of 31 the hospital and to the
42 43 Name of patient Date Signature 44
on September 30, 2021 by guest. Protected copyright. 45 46
47 48 Name of person taking consent Date Signature 49 You must have signed the 50 51 Site Signature & Delegation Log
52 53 This document was written using CRCTU-ICF-QCD-001, Version 2.0 54 55 56 57 58 59 60
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1 2 3 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Appendix 2: Informed Consent Form – Group B 5 6 7 To be printed on hospital headed paper 8
9 10 11 Informed Consent Form 12 13 To be used for Group B only 14 15 16 17 18 For peer review only 19 20 21 22 23 A Phase I trial of WEE1 inhibition with Chemotherapy and Radiotherapy as adjuvant 24 treatment, and a Window of Opportunity trial with Cisplatin in Patients with Head and Neck 25 Cancer 26 EudraCT Reference: 2015-003583-37 27 28
29 Site: ______Patient Trial Number: 30
31 Principal 32 Investigator: ______33 Please initial 34 each box 35 13. I confirm that I have read and understand the Patient Information Sheet Group B 36
(version ...... dated ...... ) for the above trial. I have had the http://bmjopen.bmj.com/ 37 opportunity to consider the information, ask questions and have had these 38 answered satisfactorily. 39 40 14. I understand that my participation is voluntary and that I am free to withdraw at 41 any time without giving any reason, without my medical care or legal rights being 42 affected. I understand that if I withdraw from treatment my doctor may continue 43 to provide the Trial Office with information that would routinely be collected about 44 me and recorded in my medical notes. I am aware that I can withdraw consent 45 for this data transfer. on September 30, 2021 by guest. Protected copyright. 46 15. I give permission for my initials, date of birth, and NHS number to be given to the 47 WISTERIA Trial Office when I am registered to the trial as well as a copy of this 48 consent form. 49 50 16. I understand that relevant sections of my medical notes and data collected during 51 the trial may be looked at by individuals from the WISTERIA Trial Office, 52 regulatory authorities, Sponsor and/or NHS bodies, where it is relevant to my 53 taking part in this research. I understand that this information will be held in a 54 confidential manner. I give permission for these individuals to have access to my 55 records. 56 57 58 59 60
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1 2 3 17. I understand that anonymised data from the trial may be provided to other third BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 parties (e.g. pharmaceutical companies or other academic institutions) for 5 research, safety monitoring or licensing purposes. I understand that this may 6 involve sending data outside of the United Kingdom to a European country or the 7 United States of America and that my will not be given to these third parties. 8 9 18. I agree to my GP being informed of my participation in this trial. 10 11 19. I understand that the WISTERIA Trial Office may access information held by 12 national cancer registries and within national databases to keep in touch with me 13 and to follow up on my health status. 14 15 20. I give permission for the collection of samples of my blood and tissue to be used 16 in the WISTERIA trial. I understand that samples will be sent to the Institute of 17 Head and Neck Studies and Education (InHANSE), University of Birmingham and 18 other laboratories in For the United peer Kingdom review or overseas only (including Covance 19 Laboratories Inc., based in the United States of America). 20 21. I understand that DNA analysis may be performed on the samples taken for the 21 trial. 22 23 22. I consent to the storage of samples remaining at the end of the trial and their use 24 in future ethically approved research which may involve genetic analysis, animal 25 or in vitro models, commercial or private institutions, and which may take place in 26 the UK or overseas. 27 23. I understand that information which may identify me will be transferred outside of 28 the hospital and to the
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Appendix 3: Wisteria Radiotherapy Guidelines – Larynx BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 7 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 8 extracapsular spread (ECS), if present. The extent of the operative bed is defined 9 with reference to pre-operative imaging of the primary tumour and to the operative pathology. 10
11 Primary tumour: The superior border will lie at the level corresponding to the hyoid 12 on the pre-operative imaging for glottic and subglottic tumours, or 1 cm above the 13 most cranial aspect of the tumour, whichever is most cranial. For supraglottic 14 tumours, the superior border will lie at the level of the tip of the epiglottis on pre- 15 operative imaging, or 1 cm superior to the most cranial aspect of the tumour, 16 whichever is most cranial. The inferior border will lie at the level corresponding with 17 the caudal aspect of the cricoid cartilage on pre-operative imaging, or 1 cm inferior to 18 the mostFor caudal aspectpeer of the review tumour, whichever only is most caudal. The stoma is 19 included in CTV_6500 if there is subglottic extension of the primary tumour and a 20 positive margin, or ECS in level IV. 21 22 Nodes: For areas of nodal ECS, the whole level should be included. If a node with 23 ECS is present at a border between two lymph node levels, the level above/below 24 should also be included as appropriate. For nodal levels included in the CTV_6500, 25 the overlying sternocleidomastoid muscle (SCM) should be included. 26 CTV_6000 Include: 27 1. The operative bed if there is no positive margin, as defined above. 28 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 29 pN+. The whole level should be included. The SCM should not be included. 30 3. The stoma if there are lymph nodes without ECS in level IV, subglottic extension 31 without a positive margin, or an emergency tracheostomy was performed. 32 33 CTV_5400 IA Not included IB Included if ipsilateral level II is node positive 34 II Always included bilaterally if not already included in CTV_6500 or 35 CTV_6000. If ipsilateral neck is node negative, superior border lies at 36
the inferior border of the transverse process of C1. If ipsilateral neck is http://bmjopen.bmj.com/ 37 node positive, level II is extended superiorly to skull base to include 38 retrostyloid space. 39 III Always included bilaterally 40 IVa Always included bilaterally 41 V Included if ipsilateral neck is node positive 42 VI Included if there is subglottic extension of the primary tumour, soft 43 tissue extension from the primary into the neck, or hypopharyngeal 44 involvement 45 RP* Included if bulky ipsilateral nodes present on September 30, 2021 by guest. Protected copyright. 46 Stoma If not included in CTV_6500/6000 as defined above 47 48 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as the upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 49
50 51 52 53 54 55 56 57 58 59 60
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Appendix 4: Wisteria Radiotherapy Guidelines – Hypopharynx BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 7 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 8 ECS, if present. The extent of the operative bed is defined with reference to pre- 9 operative imaging of the primary tumour and to the operative pathology. 10 11 Primary tumour: The superior border will lie at corresponding to the level of the hyoid 12 on pre-operative or 1 cm above the most cranial aspect of the tumour on pre- 13 operative imaging, whichever is most cranial. The inferior border will lie at the level 14 corresponding with the caudal aspect of the cricoid cartilage on pre-operative 15 imaging, or 1 cm inferior to the most caudal aspect of the tumour, whichever is most caudal. The stoma (if present) is included in CTV_6500 if there is subglottic extension 16 of the primary tumour and a positive margin, or ECS in level IV. 17
18 Nodes: FForor areas peerof nodal ECS, review the whole level shouldonly be included. If a node with 19 ECS is present at a border between two lymph node levels, the level above/below 20 should also be included as appropriate. For nodal levels included in the CTV_6500, 21 the overlying sternocleidomastoid muscle (SCM) should be included. 22 23 CTV_6000 Include: 24 1. The operative bed if there is no positive margin, as defined above. 25 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 26 pN+. The whole level should be included. The SCM should not be included. 27 3. The stoma (if present) if there are lymph nodes without ECS in level IV, subglottic extension without a positive margin, or an emergency tracheostomy was performed. 28 29 CTV_5400 IA Not included 30 IB Included if ipsilateral level II is node positive 31 II Always included bilaterally if not already included in CTV_6500 or 32 CTV_6000. If ipsilateral neck is node negative, superior border lies at 33 the inferior border of the transverse process of C1. If ipsilateral neck is 34 node positive, level II is extended superiorly to skull base to include 35 retrostyloid space. 36 III Always included bilaterally 37 IV Always included bilaterally http://bmjopen.bmj.com/ 38 V Included if ipsilateral neck is node positive 39 VI Included if there is subglottic/oesophageal extension of the primary tumour, or soft tissue extension from the primary into the neck 40 Included 41 RP* If not included in CTV_6500/6000 as defined above 42 Stoma Retropharyngeal (RP) 43 44 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as the 45 upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 5: Wisteria Radiotherapy Guidelines – Lateralised Oral Cavity BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 7 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 8 ECS, if present. The extent of the operative bed is defined with reference to pre- 9 operative imaging of the primary tumour and to the operative pathology. 10 11 Primary tumour: The volume will depend on the primary site. For oral tongue tumours, 12 include the hemi-oral cavity including base of tongue. For buccal mucosal tumours, 13 include the entire mucosa including the retromolar trigone. For retromolar trigone 14 tumours, include the preoperative tumour volume and postoperative tumour bed. 15 Exclude uninvolved bone where possible. Generally, the superior border will be at the level of the hard palate/inferior orbital rim and the inferior border at the level of the 16 hyoid. 17
18 Nodes: For areas peerof nodal ECS, review the whole level shouldonly be included. If a node with 19 ECS is present at a border between two lymph node levels, the level above/below 20 should also be included as appropriate. For nodal levels included in the CTV_6500, 21 the overlying sternocleidomastoid muscle (SCM) should be included. 22 23 CTV_6000 Include: 24 1. The operative bed if there is no positive margin, as defined above. 25 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 26 pN+. The whole level should be included. The SCM should not be included. 27 CTV_5400 IA Included if tumour involves floor of mouth or anterior mandible 28 IB Always included ipsilaterally if not already included in CTV_6500 or 29 CTV_6000 30 II Always included ipsilaterally if not already included in CTV_6500 or 31 CTV_6000. If ipsilateral neck is node negative, superior border lies at 32 the inferior border of the transverse process of C1. If ipsilateral neck is 33 node positive, level II is extended superiorly to skull base. Include 34 contralateral nodes if pN2b/pN3 or primary depth of invasion > 4mm. 35 Always included ipsilaterally 36 III Included ipsilaterally if the oropharynx or anterior tongue are involved 37 IV Included if ipsilateral neck is node positive http://bmjopen.bmj.com/ 38 Not included 39 V Included if retromolar trigone primary VI Not included 40 RP* Included if retromolar trigone primary 41 42 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as the 43 upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 44
on September 30, 2021 by guest. Protected copyright. 45 46 Please note: Laterality or otherwise the tumour should be discussed with the surgeon, radiologist and pathologist and 47 confirmed at MDT. 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 6: Wisteria Radiotherapy Guidelines – Non-Lateralised Oral Cavity BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Volume Definition and description 6 7 CTV_6500 Include the operative bed if a positive margin is present, and the nodal levels with 8 ECS, if present. The extent of the operative bed is defined with reference to pre- 9 operative imaging of the primary tumour and to the operative pathology. 10 11 Primary tumour: The volume will depend on the primary site. For oral tongue tumours, 12 include the whole oral cavity including base of tongue. Exclude uninvolved bone 13 where possible, but for floor of mouth tumours, consider including the alveolar ridge. 14 Generally, the superior border will be at the level of the hard palate/inferior orbital rim 15 and the inferior border at the level of the hyoid. If a mouth bite is used for floor of mouth tumours, the superior border may be located at the midpoint of the mouthbite. 16
17 Nodes: For areas of nodal ECS, the whole level should be included. If a node with 18 ECS is presentFor at peera border between review two lymph node only levels, the level above/below 19 should also be included as appropriate. For nodal levels included in the CTV_6500, 20 the overlying sternocleidomastoid muscle (SCM) should be included. 21 22 CTV_6000 Include: 23 1. The operative bed if there is no positive margin, as defined above. 24 2. Dissected lymph node levels in which there is no ECS if that side of the neck is 25 pN+. The whole level should be included. The SCM should not be included. 26 CTV_5400 IA Included if tumour involves floor of mouth or anterior mandible 27 IB Always included bilaterally if not already included in CTV_6500 or 28 CTV_6000 29 II Always included bilaterally if not already included in CTV_6500 or 30 CTV_6000. If ipsilateral neck is node negative, superior border lies at 31 the inferior border of the transverse process of C1. If ipsilateral neck is 32 node positive, level II is extended superiorly to skull base. 33 Always included bilaterally. 34 III Included bilaterally if the oropharynx or anterior tongue are involved 35 IV Included if ipsilateral level IV is node positive 36 Not included 37 V Consider including if retromolar trigone primary http://bmjopen.bmj.com/ 38 VI 39 RP* Retropharyngeal (RP) 40 * In the WISTERIA trial, we recommend that the cranial border of the retropharyngeal nodal level is defined as the 41 upper edge of the body of C1 or the upper extent of the hard palate, whichever is more cranial. 42 43 Please note: Laterality or otherwise the tumour should be discussed with the surgeon, radiologist and pathologist and 44 45 confirmed at MDT. on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 7: Group A data collection schedule 1 12 Week Follow 2 Baseline Baseline Baseline Week 1 Week 2 End of 4 Week Up visit 3 Pre- within 42 within 21 within 14 Treatment visit Follow Up (from start of diagnosis days of days of days of #* # (within 7 days of visit 4 D1 D2 D3 D8 D9 D10 treatment) trial entry trial entry trial entry D10) +/- 3 days 5 +/- 3 days 6 Informed consent – optional x 7 tumour sample Optional tumour sample during 8 x 9 diagnostic biopsy 10 Diagnostic CT scana x 11 Informed consentb x 12 ECHO/MUGAc x d For peer review only 13 Audiogram x As clinically indicated 14 Medical historye x f 15 Physical exam x x x Weight (kg) and BSAg x x x 16 http://bmjopen.bmj.com/ 17 Height (cm) x h 18 Vital signs x x x 19 ECOG status x x x i Entry Trial 20 ECG x x x x j 21 Pregnancy test x k 22 Biochemistry x x x x x x Haematologyl x x x x x x 23 Isotopic GFRm x x 24 on September 30, 2021 by guest. Protected copyright. Adverse events x x x x x x 25 Concomitant medicationsn x x x x x x 26 Patient diary x x 27 Cisplatin administration x 28 AZD1775 administrationo AM & PM doses AM & PM doses 29 Surgeryp Within 42 days of first date of treatment 30 Blood samplesq x x x 31 Pharmacokinetic samplesr x x 32 Mandatory tumour biopsys x At time of Resection 33 Collection of FFPE tumour x 34 samples 35 Review of surgical x 36 complications 37 Disease free survivalt On-going 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Group A data collection schedule notes 4 # Day 1 and Day 8 should not occur on a Monday. 5 * Day 1 should be within 6 weeks of informed consent. 6 a Diagnostic Computerised Tomography (CT) with contrast – neck and chest. To be performed within 42 days of trial entry. 7 b Informed consent must be obtained before any trial procedures occur. 8 c If significant cardiac history patient required to have ECHO. MUGA can be performed if ECHO is equivocal. To be performed within 21 days of start of trial 9 10 entry. 11 d Air and bone conduction audiogram. To be performed within 21 days of trial entry. 12 e Medical history – comprehensive medical history, demographics, prior treatment. f Physical examination includes completeFor review of systems peer and physical examination review of pertinent organ systems only and neurological assessment. 13 14 g During trial treatment, weight can be performed within 72 hours pre-dose of AZD1775. 15 h Blood pressure, pulse measurement, temperature and respiratory rate to be performed with the patient sitting for 5 minutes prior to the evaluation. i Three ECGs, 2-5 minutes apart, to be performed at screening only. At all other time points a single ECG recording should be performed at least 48h pre-dose 16 http://bmjopen.bmj.com/ 17 of AZD1775. 18 j Women of childbearing potential will require a negative pregnancy test (serum or urine) prior to trial entry. 19 k Blood samples for sodium, potassium, magnesium, urea, creatinine, calcium, phosphate, albumin, total protein, bilirubin, alkaline phosphatase, AST and/or 20 ALT. 21 Results of blood samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial treatment, blood 22 samples can be collected within 72 hours pre-dose of AZD1775. 23 l Haematology – Full Blood Count. Results of haematology samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose
24 of AZD1775. During trial treatment, haematology samples can be collected within 72 hours pre-dose of AZD1775. on September 30, 2021 by guest. Protected copyright. 25 m If creatinine clearance at screening is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. If GFR, calculated immediately before 26 any administration of concomitant chemotherapy, is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. 27 n Concomitant medication to be recorded starting on the date of signing of informed consent, throughout the trial. 28 o Morning dose to be administered prior to cisplatin on Day 8. 29 p Surgery must be performed within 42 days of first date of trial treatment but at least 6 days after the last cisplatin dose. 30 q Blood samples will be collected pre-dose on Day 1, at the End of Treatment Visit and at the 12 Week Follow Up Visit. Refer to WISTERIA Laboratory Manual. 31 r Pharmacokinetic samples to be collected before and 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Day 3 and Day 10. Refer to WISTERIA 32 Laboratory Manual. 33 s Tumour biopsy to be collected 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Day 3 and a biopsy to be taken at time of Resection.. To be 34 35 taken under local anaesthetic (includes biopsy of lymph nodes taken using ultrasound guided biopsy). Time from biopsy taken to fixing in formalin of the 36 biopsy is limited to 30 minutes. Refer to WISTERIA Laboratory Manual. 37 t Patients to be followed up for 12 months. Notification required if a patient relapses or dies. 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Appendix 8: Group B data collection schedule 4 5 Baseline Baseline FUP 6 and 12 Week 1 – Week 2 Week 3 Week 4 – Week 5 Week 6 Week 7 Weeks 8-11 Week 12 6 within 21 within 14 months from End of Weekly Toxicity Follow Up 7 days of days of start of D1* Treatment Assessments # visit trial entry trial entry D2 D3 D4 D1 D2 D1 D2 D3 D4 D1 treatment 8 ~ 9 Informed consenta x 10 ECHO/MUGAb x 11 Planning CT scanc x 12 Audiogramd x As clinically indicated e For peer review only 13 Medical history x 14 Physical examf x x x x x g 15 Weight (kg) and BSA x x x x x Height (cm) x 16 http://bmjopen.bmj.com/ Vital signsh x x x x x 17 ECOG status x x x x x 18 ECGi x x x x x x Trial Entry Trial 19 Pregnancy testj x 20 Biochemistryk x x x x x x x x x 21 Haematologyl x x x x x x x x x Isotopic GFRm x x x x
22 23 Adverse events x x x x x x x x x Concomitant
x x x x x x on September 30, 2021 by guest. Protected copyright. x x 24 medicationsn 25 Radiotherapyo 26 To start within 3 months of surgery AZD1775 AM & PM AM & PM N/A N/A N/A 27 administrationp Doses Doses 28 Cisplatin x x x N/A 29 administrationq 30 Patient diary x x 31 Quality of Life r x x x x 32 Questionnaires 33 Swallowing Assessment x x x x 34 Questionnairer 35 Blood sampless x x x x 36 Pharmacokinetic x 37 samplet Collection of FFPE 38 x tumour samples 39 u 40 Disease free survival On-going 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from
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1 2 3 Group B data collection schedule notes: 4 # Patients will undergo weekly toxicity assessment during treatment and weekly thereafter until all acute toxicities have resolved to Grade 1 or less; typically for 42-56 days (6-8 weeks), and 5 for no less than 42 days after completion of treatment, giving a total Dose Limiting Toxicity reporting period of 84 days (12 weeks) from start of treatment. 6 * Day 1 of week 1 should be within 4 weeks of consent. 7 ~ Week 1 – Day 1 starts on the first day of radiotherapy. 8 a Informed consent must be obtained before any trial procedures occur. 9 10 b If significant cardiac history patient required to have ECHO. MUGA can be performed if ECHO is equivocal. To be performed within 21 days of start of trial entry. 11 c CT with contrast – neck as part of radiotherapy preparation and planning at Baseline only. To be performed within 21 days of start of trial entry. 12 d Air and bone conduction audiogram. To be performed within 21 days of trial entry. e Medical history – comprehensive medicalFor history, demographics, peer prior treatment. review only 13 14 f Physical examination includes complete review of systems and physical examination of pertinent organ systems and neurological assessment. 15 g During trial treatment, weight can be performed within 72 hours pre-dose of AZD1775. h Blood pressure, pulse measurement, temperature and respiratory rate to be performed with the patient sitting for 5 minutes prior to the evaluation. 16 http://bmjopen.bmj.com/ 17 i Three ECGs, 2-5 minutes apart, to be performed at baseline only. At all other time points a single ECG recording should be performed at least 48 hours pre-dose of AZD1775. 18 j Women of childbearing potential will require a negative pregnancy test (serum or urine) prior to trial entry. 19 k Blood samples for sodium, potassium, magnesium, urea, creatinine, calcium, phosphate, albumin, total protein, bilirubin, alkaline phosphatase, AST and/or ALT. 20 Results of blood samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial treatment, blood samples can be collected 21 within 72 hours pre-dose of AZD1775. 22 l Haematology – Full Blood Count. Results of haematology samples collected at screening visit can be used for Day 1 eligibility if within 72 hours of first dose of AZD1775. During trial 23 treatment, haematology samples can be collected within 72 hours pre-dose of AZD1775.
24 m If creatinine clearance at screening is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. If GFR, calculated on September 30, 2021 by guest. Protected copyright. immediately before any administration of 25 concomitant chemotherapy, is ≤ 60 ml/min then an isotopic GFR may be carried out and must be > 60 ml/min. 26 n Concomitant medication to be recorded starting on the date of signing of informed consent, throughout the trial. 27 o Radiotherapy to start on Week 1 - Day 1. Refer to the WISTERIA Radiotherapy Guidelines. 28 p AZD1775 morning dose to be administered prior to cisplatin and at least 1 hour prior to radiotherapy. 29 q Cisplatin to be administered after morning dose of AZD1775 and at least 1 hour prior to radiotherapy. 30 r Questionnaires to be completed by patient in clinic at defined visits: pre-dose on Week 1 - Day 1, End of Treatment Visit, Week 12 Follow Up Visit, 6 Month Follow Up Visit and 12 Month 31 32 Follow Up Visit. 33 s Blood samples will be collected pre-dose on Week 1 - Day 1, at the End of Treatment Visit, the Week 12 Follow Up Visit, the 6 Month Follow Up Visit and the 12 Month Follow Up Visit. 34 Refer to WISTERIA Laboratory Manual. 35 t Pharmacokinetic sample to be collected before and 2-5 hours after fifth dose of AZD1775 (before the sixth dose) on Week 1 - Day 4 only. Refer to WISTERIA Laboratory Manual. 36 u Patients to be followed up for 12 months. Notification required if a patient relapses or dies. 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 39 of 45 BMJ Open
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Appendix 9: Toxicity Profiles BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Very common side effects Common side effects Treatment Other side effects 6 (1 patient in 10) (1 patient in 100) 7 AZD1775 Blood & lymphatic Neutropenia QTc prolongation 8 disorders including (rare, affecting 1 9 anaemia & patient in 10,000) 10 thrombocytopenia 11 Decreased appetite 12 Gastrointestinal 13 disorders including 14 diarrhoea, nausea, 15 vomiting & serum 16 17 electrolyte decreases 18 For Dyspepsia peer review only 19 AZD1775 in Asthensia Fatigue Constipation 20 combination with Leukopenia Febrile neutropenia Gastrointestinal 21 chemotherapy Loss of strength & Mucosal haemorrhage 22 weakness inflammation Lymphopenia 23 Myalgia Lymphocyte count 24 Stomatitis decrease 25 Pancytopenia 26 Sepsis 27 Tachycardia 28 Cisplatin Blood & lymphatic Sepsis 29 disorders including Ear disorders 30 bone marrow failure, including ototoxicity 31 thrombocytopenia, Cardia disorders 32 leukopenia & anaemia including 33 Metabolism & arrhythmia, 34 nutrition disorders bradycardia & 35 including dehydration tachycardia 36
Renal & urinary Inflammation at http://bmjopen.bmj.com/ 37 disorders including injection site 38 hyperuricaemia 39 Respiratory 40 disorders including 41 dyspnoea & 42 pneumonia 43 Radiotherapy Tiredness Due to swallowing 44 Pain & difficulty difficulties there is an 45 swallowing due to increased risk of on September 30, 2021 by guest. Protected copyright. 46 mouth ulceration chest infection 47 Thickened saliva & (pneumonia) during 48 secretions treatment 49 Dry mouth 50 Altered sense of taste 51 Nausea 52 Skin soreness & 53 ulceration 54 Hair loss to are near to 55 radiotherapy site 56 57 58 59 60
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Appendix 10: Haematological Toxicity Dose Management – ANC, Platelets BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 Symptoms: Symptoms: Action 6 7 ANC Platelets 8 9 9 9 ≥1500/10 /L And ≥75000/10 /L No cisplatin or AZD1775 dose modification or 10 interruption. 11 12 <1500/109/L Or <75000/109/L Delay cisplatin and AZD1775 by 1 week intervals until 13 recovery. If DLT is reached, discontinue AZD1775 14 treatment but cisplatin may be resumed if deemed 15 appropriate by the investigators. 16 17
18 For peer review only 19 20 Appendix 11: Haematological Toxicity Dose Management – Neutropenia, Infection, Febrile 21 Neutropenia 22 23 Symptoms Action 24 25 Grade 3 febrile neutropenia (ANC <1000/109/L Hold cisplatin and AZD1775 dose until 26 + Temperature ≥38°C) or neutropenic sepsis recovery. If DLT is reached, discontinue 27 AZD1775 treatment but cisplatin may be 28 Grade 4 neutropenia (ANC <500/109/L >7 days) 29 resumed if deemed appropriate by the 30 investigators. 31 Grade 4 thrombocytopenia (platelet count 9 32 <25,000/10 /L >7 days) 33 34 Grade 4 febrile neutropenia or Grade 4 Discontinue cisplatin and AZD1775 treatment. 35 infection with neutropenia (both defined as 36 37 septic shock) http://bmjopen.bmj.com/ 38 39 Thrombocytopenic haemorrhage (gross occult 40 bleeding) associated with a platelet count 41 <50,000/109/L 42 43 Febrile neutropenia ( 38° C) with or without Patient to be managed in a hospital setting 44 45 significant symptoms according to standard procedures, with the on September 30, 2021 by guest. Protected copyright. 46 urgent initiation of IV antibiotic therapy 47 according to local guidelines. 48 49 50 51 52 53 54 55 56 57 58 59 60
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Appendix 12: Non-Haematological Toxicity Dose Management – General Disorders BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 CTCAE v4.03 Cisplatin AZD1775 6 7 Grade 0-2 No dose modification No dose modification 8 9 10 Grade 3 Hold until toxicity resolves to ≤ Hold until toxicity resolves to ≤ 11 Grade 1, and then resume at the Grade 1, and then resume at the 12 same dose with no modification if same dose with no modification. 13 14 no DLT is reached and if deemed Discontinue treatment if DLT is 15 appropriate by the investigators. reached 16 17 Grade 4 toxicity Discontinue treatment Discontinue treatment 18 (except anorexia) For peer review only 19 20 21 22 23 Appendix 13: Non-Haematological Toxicity Dose Management – Hepatic 24 25 CTCAE v4.03 Cisplatin AZD1775 26 27 Grade 1-2 No dose modification No dose modification 28 29 Grade 3 Hold until resolves to Grade ≤1 or Hold until resolves to Grade ≤1 or 30 baseline, then resume cisplatin with baseline, then resume study drug 31 (manifested as no dose modification if no DLT is with no dose reduction. If not 32 elevations in ALT, 33 reached and if deemed appropriate resolved within 28 days discontinue AST, ALP or 34 by the investigators. study drug. Discontinue treatment if 35 bilirubin) DLT is reached. 36 37 http://bmjopen.bmj.com/ 38 Grade 4 Discontinue treatment Discontinue treatment 39 (Life threatening) 40 41 42 43 Appendix 14: Non-Haematological Toxicity Dose Management – Diarrhoea or Mucositis 44 45 CTCAE v4.03 Cisplatin AZD1775 on September 30, 2021 by guest. Protected copyright. 46 47 Grade 3 Hold until toxicity resolves to ≤ Hold until toxicity resolves to ≤ 48 49 (requiring Grade 1, and then resume at the Grade 1, and then resume at the 50 hospitalisation) same dose with no modification if same dose with no modification. 51 no DLT is reached and if deemed Discontinue treatment if DLT 52 appropriate by the investigators. reached. 53 54 55 Grade 4 Discontinue treatment Discontinue treatment 56 57 58 59 60
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Appendix 15: Non-Haematological Toxicity Dose Management – Renal Toxicity BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 5 CTCAE v4.03 Cisplatin AZD1775 6 7 Grade ≥ 2 Hold until resolves to Grade ≤1 or Hold until toxicity resolves to ≤ 8 9 baseline. If GFR falls below 60 Grade 1, and then resume at the 10 mL/min, cisplatin should be same dose with no modification. 11 discontinued and consideration Discontinue treatment if DLT 12 13 given to substitution with reached 14 carboplatin AUC =1.5, according to 15 routine local practice. 16 17 18 For peer review only 19 Appendix 16: Non-Haematological Toxicity Dose Management – Neurotoxocity 20 21 22 CTCAE v4.03 Cisplatin AZD1775 23 24 Grade 1 No dose modification No dose modification 25 26 Grade 2 Hold until toxicity resolves to Grade No dose modification 27 ≤1. Resume with 1 dose level 28 reduction. 29 30 31 Grade 3 or 4 Discontinue treatment Discontinue treatment 32 33 34 35 Appendix 17: Disallowed medications and medication to be administered with caution 36 37 A list of the main CYP3A4 substrates, inhibitors (strong and moderate) and inducers, CYP2C19 http://bmjopen.bmj.com/ 38 substrates, P-gp substrates and inhibitors and BCRP substrates are shown below: 39 Please note: Live vaccines are not permitted 40 41 42 This is not an exhaustive list and further details can be found at: 43 www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ 44 45 ucm093664.htm on September 30, 2021 by guest. Protected copyright. 46 47 CYP3A4 Inhibitors (Strong) 48 Boceprevir Indinavir Ritonavir 49 Clarithromycin Itraconazole Saquinavir 50 Cobicistat (GS-9350) Ketoconazole Telaprevir 51 52 Conivaptan LCL161 Telithromycin 53 Danoprevir Lopinavir Tipranavir 54 Elvitegravir Mibefradil Troleandomycin 55 Fosamprenavir Nefazodone Voriconazole 56 Grapefruit juice Nelfinavir 57 Idelalisib Posaconazole 58 59 60
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1 2 3 CYP3A4 Inhibitors (Moderate) BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 ACT-178882 Darunavir Imatinib 5 Amprenavir Dronedarone Ledipasvir 6 7 Aprepitant Diltiazem Lomitapide 8 Atazanavir Erythromycin Netupitant 9 Casopitant FK1706 Schisandra sphenanthera 10 Ciprofloxacin Fluconazole Tofisopam 11 Crizotinib Fosamprenavir Verapamil 12 13 14 CYP3A4 Inhibitors (Weak) 15 Almorexant Everolimus Propiverine 16 Alprazolam Faldaprevir Ranitidine 17 AMD070 Fluvoxamine Ranolazine 18 Amiodarone For peerFosaprepitant review (IV) onlyResveratrol 19 20 Amlodipine Ginkgo Roxithromycin 21 Atorvastatin Goldenseal Seville orange juice 22 Azithromycin GSK1292263 Simeprevir 23 Berberine GSK2248761 Sitaxentan 24 Bicalutamide Isoniazid Suvorexant 25 Blueberry juice Ivacaftor Tabimorelin 26 27 Chlorzoxazone Lacidipine Tacrolimus 28 Cilostazol I Linagliptin Teriflunomide 29 Cimetidine Lomitapide Ticagrelor 30 Clotrimazole M100240 Tipranavir/ritonavir 31 Cranberry juice Nilotinib Tolvaptan 32 Cyclosporine Oral contraceptives Zileuton 33 34 Daclatasvir Pazopanib 35 Delavirdine Peppermint oil 36 http://bmjopen.bmj.com/ 37 CYP3A4 Inducers (Strong and Moderate) 38 Avasimibe Lersivirine Rifabutin 39 Bosentan Lopinavir Rifampin 40 41 Carbamazepine Mitotane Ritonavir 42 Efavirenz Modafinil Semagacestat 43 Enzalutamide Nafcillin St John's Wort 44 Etravirine Phenobarbital Thioridazine on September 30, 2021 by guest. Protected copyright. 45 Genistein Phenytoin Tipranavir 46
47 48 CYP3A4 Inducers (Weak) 49 Amprenavir Echinacea Oxcarbazepine 50 Aprepitant Eslicarbazepine PA-824 51 Armodafinil Garlic Pleconaril 52 AZD 7325 Gingko Prednisone 53 Bexarotene Ginseng Quercetin 54 55 Boceprevir Glycyrrhizin Raltegravir 56 Brivaracetam LCL161 Ritonavir 57 Clobazam Methylprednisolone Rufinamide 58 Danshen Nevirapine Sorafenib 59 Dexamethasone Oritavancin Stribild 60
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1 2 3 Telaprevir Ticlopidine Vemurafenib BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Terbinafine Topiramate Vicriviroc and ritonavir 5 Ticagrelor Troglitazone Vinblastine 6 7 8 CYP3A and CYP3A4 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 9 ABT-384 Docetaxol Nilotinib 10 Alfentanil Dofetilide Nisoldipine 11 Aprepitant Doxorubicin Paclitaxel 12 13 Alfuzosin Ebastine Pazopanib 14 Almorexant Eletriptan Perospirone 15 Alpha-Dihydroergocryptine Elvitegravir Pimozide 16 Amiodarone Eplerenone Propafenone 17 Aplaviroc Ergotamine Propofol 18 Aprepitant For peerErlotinib review onlyQuetiapine 19 20 Astemizole Etoposide Quinidine 21 Atazanavir Everolimus Ranolazine 22 Atorvastatin Felodipine Ridaforolimus 23 Avanafil Fentanyl Romidepsin 24 Bexarotine Fluticasone Saquinavir 25 BIRL 355 Gefitinib Sildenafil 26 27 Bortezomib Halofantrine Simeprevir 28 Bosutinib Ibrutinib Simvastatin 29 Brecanavir Ifosfamide Sirolimus 30 Brotizolam Imatinib Tacrolimus 31 Budesonide Indinavir Temsirolimus 32 Buspirone Ironotecan Terfenadine 33 34 Capravirine Ivacaftor Ticagrelor 35 Carbamazepine Ixabepilone Theoophylline 36 Casopitant L-771,688 Thioridazine http://bmjopen.bmj.com/ 37 Cisapride, Lapatinib Thiotepa 38 Conivaptan Levomethadyl (LAAm) Tilidine 39 Cyclophosphamide Lomitapide Tipranavir 40 41 Cyclosporine Lopinavir Tolvaptan 42 Danoprevir Lovastatin Triazolam 43 Darifenacin Lurasidone Tretinoin 44 Darunavir Maraviroc, Ulipristal on September 30, 2021 by guest. Protected copyright. 45 Dasatinib Midazolam Vardenafil 46 Dihydroergotamine Midostaurin Vicriviroc 47 48 Disopyramide Mosapride Voclosporin 49 Dronedarone Neratinib 50 51 CYP2C19 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 52 Diazepam (S)-Mephenytoin (+)-Pantoprazole 53 Gliclazide (R)-Mephobarbital Rabeprazole 54 55 Lansoprazole Omeprazole Tilidine 56 (R)-Lansoprazole (R)-Omeprazole 57 (S)-Lansoprazole Pantoprazole 58 59 CYP1A2 Sensitive Substrates or Substrates with a Narrow Therapeutic Range 60
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1 2 3 Alosetron Melatonin Theophylline BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Caffeine Ramelteon Tizanidine 5 Duloxetine Tacrine 6 7 8 P-gp Substrates 9 Colchicine Indinavir Vincristine 10 Digoxin Paclitaxel 11 Fexofenadine Toptecan 12 13 14 If a patient requires initiation of digoxin during the study, or is already receiving treatment with digoxin, 15 monitoring of digoxin levels is recommended according to local practice (as the levels of digoxin may increase). 16 Monitoring of digoxin levels is also recommended when the patient has completed dosing with study 17 treatment (as the levels of digoxin may then decrease). 18 For peer review only 19 20 P-gp Inhibitors (Strong) BCRP Substrates 21 Cyclosporine Daunorubicin 22 Elacridar Doxorubicin 23 Erythromycin Rosuvastatin 24 Itraconazole Sulfasalazine 25 Ketocoanzole Topotecan 26 27 LY335979Quinidine 28 Ritonavir 29 Valspodar 30 Verapamil 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 Wisteria Trial SPIRIT Checklist BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 5 6 7 Item Section/Item Placement of Information 8 Number 9 Administrative information 10 11 Title 1 Front page 12 Trial registration 2a Within Abstract 13 2b Within Abstract and Funding sections 14 Protocol version 3 Within Ethics and Dissemination section 15 Funding 4 Funding section 16 Roles and responsibilities 5a Front page, Author Affiliations, Authors’ Contributions 17 18 For peer sectionsreview only 19 5b Front page 20 5c Trial Organisation and Structure section 21 5d Trial Organisation and Structure section 22 Introduction 23 Background and rationale 6a Introduction sections 24 25 6b N/A 26 Objectives 7 Methods: Wisteria Trial Objectives section 27 Trial design 8 Methods: Trial Design section 28 Methods 29 Participants, interventions 30 and outcomes: 31 Study setting 9 Patient Population, Screening and Consent section 32 33 Eligibility criteria 10 Patient Population, Screening and Consent section, boxes 34 2 and 3 35 Interventions 11a Dose Selection section, Table 1, Trial Treatment section 36 11b Dose Limiting Toxicity and Dose Management section, http://bmjopen.bmj.com/ 37 Discontinuation of Investigational Medicinal Product 38 section, Statistical Methods section 39 11c Trial Schema, Trial Treatment section 40 41 11d Concomitant Medications section, Appendix 11 42 Outcomes 12 Trial Outcome Measures section, Box 4, Appendices 43 Tables 1 and 2 44 Participant timelines 13 Trial Schema, Appendices Tables 1 and 2 on September 30, 2021 by guest. Protected copyright. 45 Sample size 14 Trial Design section, Statistical Methods section 46 Recruitment 15 Trial Design section 47 48 Assignment of interventions 16 -17 Not applicable 49 (for controlled trials) 50 Data collection, management 51 and analysis: 52 Data collection methods 18a Data Collection and Monitoring section, Appendices 1 53 and 2 54 18b Analysis of Outcome Measures section 55 56 Data management 19 Data Collection and Monitoring section 57 Statistical methods 20 Statistical Methods section, Analysis of Outcome 58 Measures section 59 Monitoring: 60 Data monitoring 21a Trial Organisation and Structure section 21b Statistical Methods section, Analysis of Outcomes section
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Harms 22 Box 5, Safety Monitoring section BMJ Open: first published as 10.1136/bmjopen-2019-033009 on 16 March 2020. Downloaded from 4 Auditing 23 Data Collection and Monitoring section, Trial 5 6 Organisation and Structure section 7 Ethics and dissemination 8 Research ethics approval 24 Ethics and Dissemination abstract and main body section, 9 Ethical Approval section 10 Protocol amendments 25 Ethics and Dissemination section 11 Consent or assent 26a Patient Consent section, Appendices 16 and 17 12 13 26b Ethics and Dissemination section 14 Confidentiality 27 Ethics and Dissemination section 15 Declaration of interests 28 Competing Interests section 16 Access to data 29 Ethics and Dissemination section, Open Access section 17 Ancillary and post-trial care 30 Trial Treatment section, Box 4, (re. follow up) 18 DisseminationFor policy peer31a Ethicsreview and Dissemination only section, Open Access section 19 Appendices 20 21 Informed consent materials 32 Appendices 16 and 17 22 Biological specimens 33 Tertiary Research Outcome Measures section, 23 Appendices Tables 1 and 2, Analysis of Outcome 24 Measures section 25 26 27 28 29 30 31 32 33 34 35 36 37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44 45 on September 30, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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