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Do not attempt cardiopulmonary resuscitation

Description: Auto Generated Title On these pages I discuss the clinical law on which our nursing and medical staff rely when caring
Url: /HealthProfessionals/Clinical-law-updates/Do-not-attempt-cardiopulmonary-resuscitation.aspx

EGGA Oct 2018 Southampton - Course and bursary Information sheet

Description: Essential Guide to Grant Applications 2018 What is it? An interactive, innovative and free to attend three-day masterclass, funded and
Url: /Media/Southampton-Clinical-Research/SoAR/EGGA-Oct-2018-Southampton-Course-and-bursary-Information-sheet.pdf

Press release: Hospital trust announces appointment of new chief executive

Description: University Hospital Southampton NHS Foundation Trust has announced the appointment of a new chief executive.
Url: /AboutTheTrust/Newsandpublications/Latestnews/2018/May-2018/Press-release-Hospital-trust-announces-appointment-of-new-chief-executive.aspx

Separating conjoined twins

Description: Nearly twenty years ago, a court was faced with an agonising decision: whether the proposed separation of conjoined twins was lawful
Url: /HealthProfessionals/Clinical-law-updates/Separating-conjoined-twins.aspx

Press release: Current screening programme for baby hip problems has "failed"

Description: Orthopaedic surgeons in Southampton have said selective screening introduced in 1986 to identify hip problems in babies in England has "failed
Url: /AboutTheTrust/Newsandpublications/Latestnews/2019/March/Press-release-Current-screening-programme-for-baby-hip-problems-has-failed.aspx

Doctrine of double effect

Description: Auto Generated Title It is inevitable that we cause our patients harm during our attempts to deal with their disease or
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How do we deal with patient consultations over DNACPR

Description: Auto Generated Title On these pages I discuss the clinical law on which our nursing and medical staff rely when caring
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PDF document

Description: Originally uploaded to http://cdn.flamehaus.com/Valve_Handbook_LowRes.pdf Handbook courtesy of Valve HANDBOOK FOR NEW EM
Url: /Media/UHS-website-2019/Docs/Zengenti-Mock/PDF-document.pdf

Papers Trust Board - 29 November 2022

Description: Date Time Location Chair Agenda Trust Board – Open Session 29/11/2022 9:00 - 13:20 Conference Room, Heartbeat/Microsoft Teams Jenni Douglas-Todd 1 Chair’s Welcome, Apologies and Declarations of Interest 9:00 Note apologies for absence, and to hear any declarations of interest relating to any item on the Agenda. 2 Staff Story The staff story provides an opportunity for the Board to reflect on the experiences of patients and staff within the Trust and understand what the Trust could do better. 3 Minutes of Previous Meeting held on 29 September 2022 9:20 Approve the minutes of the previous meeting held on 29 September 2022 4 Matters Arising and Summary of Agreed Actions To discuss any matters arising from the minutes, and to agree on the status of any actions assigned at the previous meeting. 5 QUALITY, PERFORMANCE and FINANCE Quality includes: clinical effectiveness, patient safety, and patient experience 5.1 Briefing from the Chair of the Charitable Funds Committee (Oral) 9:30 Dave Bennett, Chair 5.2 Briefing from the Chair of the Finance and Investment Committee (Oral) 9:35 Jane Bailey, Chair 5.3 Briefing from the Chair of the Quality Committee (Oral) 9:40 Tim Peachey, Chair 5.4 Chief Executive Officer's Report 9:45 Receive and note the report Sponsor: David French, Chief Executive Officer 5.5 Integrated Performance Report for Month 7 10:05 Review and discuss the Trust's performance as reported in the Integrated Performance Report. Sponsor: David French, Chief Executive Officer 5.6 Finance Report for Month 7 10:35 Review and discuss the finance report Sponsor: Ian Howard, Chief Financial Officer 5.7 People Report for Month 7 10:45 Review and discuss the people report Sponsor: Steve Harris, Chief People Officer 6 Break 10:55 7 Infection Prevention and Control 2022-23 Q2 Report 11:05 Review and discuss the report Sponsor: Gail Byrne, Chief Nursing Officer Attendees: Julian Sutton, Interim Lead Infection Control Director/Julie Brooks, Head of Infection Prevention Unit 8 Medicines Management Annual Report 2021-22 11:15 Receive and discuss the report Sponsor: Paul Grundy, Chief Medical Officer Attendee: James Allen, Chief Pharmacist 9 Equality, Diversity and Inclusivity (EDI) Update including Workforce Race 11:25 Equality Standard (WRES) and Workforce Disability Equality Standard (WDES) Results 2022 Receive and discuss the reports Sponsor: Steve Harris, Chief People Officer Attendee: Ceri Connor, Director of OD and Inclusion 10 Annual Ward Staffing Nursing Establishment Review 11:35 Discuss and approve the review Sponsor: Gail Byrne, Chief Nursing Officer Attendee: Rosemary Chable, Head of Nursing for Education, Practice and Staffing 11 Guardian of Safe Working Hours Quarterly Report 11:45 Receive and discuss the report Sponsor: Paul Grundy, Chief Medical Officer Attendee: Diana Hulbert, Guardian of Safe Working Hours and Emergency Department Consultant 12 Learning from Deaths 2022/23 Quarter 2 Report 11:55 Review and discuss the report Sponsor: Paul Grundy, Chief Medical Officer Attendee: Ellis Banfield, Associate Director of Patient Experience 13 Freedom to Speak Up Report 12:05 Review and discuss the report Sponsor: Gail Byrne, Chief Nursing Officer Attendee: Christine Mbabazi, Equality & Inclusion Adviser/Freedom to Speak Up Guardian Page 2 14 Annual Assurance Process and Self-assessment against the NHS 12:15 England Core Standards for Emergency Preparedness, Resilience and Response (EPRR) Review and discuss the report Sponsor: Joe Teape, Chief Operating Officer Attendee: John Mcgonigle, Emergency Planning & Resilience Manager 15 STRATEGY and BUSINESS PLANNING 15.1 Board Assurance Framework (BAF) Update 12:25 Review and discuss the update Sponsor: Gail Byrne, Chief Nursing Officer Attendee: Craig Machell, Associate Director of Corporate Affairs and Company Secretary 16 CORPORATE GOVERNANCE, RISK and INTERNAL CONTROL 16.1 Register of Seals and Chair's Actions Report 12:35 Receive and ratify In compliance with the Trust Standing Orders, Financial Instructions, and the Scheme of Reservation and Delegation. Sponsor: Jenni Douglas-Todd, Trust Chair 16.2 Review of Standing Financial Instructions 2022-23 12:40 Review and approve the SFIs Sponsor: Ian Howard, Chief Financial Officer Attendee: Phil Bunting, Director of Operational Finance 16.3 Corporate Governance Update 12:50 Receive and discuss the update Sponsor: Gail Byrne, Chief Nursing Officer Attendee: Craig Machell, Associate Director of Corporate Affairs and Company Secretary 17 Any other business 13:00 Raise any relevant or urgent matters that are not on the agenda 18 Note the date of the next meeting: 31 January 2023 19 Items circulated to the Board for reading 19.1 CRN: Wessex 2022-23 Q2 Performance Report Note the report Sponsor: Paul Grundy, Chief Medical Officer Page 3 20 Resolution regarding the Press, Public and Others Sponsor: Jenni Douglas-Todd, Trust Chair To agree, as permitted by the National Health Service Act 2006 (as amended), the Trust's Constitution and the Standing Orders of the Board of Directors, that representatives of the press, members of the public and others not invited to attend to the next part of the meeting be excluded due to the confidential nature of the business to be transacted. 21 Follow-up discussion with governors 13:05 Page 4 3 Minutes of Previous Meeting held on 29 September 2022 1 Draft Minutes TB 29 Sept 22 OS v2 Minutes Trust Board – Open Session Date Time Location Chair Present 29/09/2022 9:00 – 13:00 Microsoft Teams Jenni Douglas-Todd (JD-T) Jane Bailey (JB), Non-Executive Director (NED) Gail Byrne (GB), Chief Nursing Officer Cyrus Cooper (CC), NED (from item 5.4 part two) Jenni Douglas-Todd (JD-T), Chair Keith Evans (KE), NED David French (DAF), Chief Executive Officer Paul Grundy (PG), Chief Medical Officer Steve Harris (SH), Chief People Officer Jane Harwood (JH), NED Ian Howard (IH), Chief Financial Officer Tim Peachey (TP), NED Joe Teape (JT), Chief Operating Officer In attendance Jane Fisher, Head of Health and Safety Services (JF) (for item 7.3) Sarah Herbert, Deputy Chief Nursing Officer (SHe) (for item 5.7) Femi Macaulay (FM), Associate NED Corinne Miller, Named Nurse for Safeguarding Adults (CM) (for item 5.8) Karen McGarthy, Named Nurse for Safeguarding Children (KMcG) (for item 5.8) Christine McGrath (CMcG), Director of Strategy and Partnerships Helen Potton, Associate Director of Corporate Affairs and Company Secretary (Interim) (HP) Helen Ralph, Manager, Transformation Team (HR) (for item 6.1) Annabel Shawcroft, Clinical Programme Officer, Transformation Team (AS) (for item 6.1) Jason Teoh, Director of Data and Analytics (JTe) (for item 5.11) Diana Ward, Clinical Outcomes Manager (DW) (for item 5.10) One member of the public (observing) 3 governors (observing) 5 members of staff (observing) 1 members of the public (observing) Apologies Dave Bennett (DB), NED 1. Chair’s Welcome, Apologies and Declarations of Interest JD-T welcomed all those attending the meeting which was being held by Microsoft Teams. Apologies were received from DB. CC would be joining the meeting later. 2. Patient Story HP introduced the Patient Story which focused on the experience of a mother and daughter who had used the Trust’s services. Mum advised that during the pandemic, her daughter had been diagnosed with cancer in her abdomen at the age of nine years old. Page 1 Her daughter had surgery followed by nine rounds of chemotherapy at the Trust followed by radiotherapy in London. Whilst on maintenance chemotherapy her daughter had relapsed and sadly a decision was made that further treatment would not be beneficial. Her daughter’s response was to write a “bucket list”. Some of the items were for herself but some related to changes that she wanted for other people including wanting parents to be fed. Her daughter could not understand why, when she was asked what she wanted to eat, that this did not extend to her mum, when her mum was in the hospital supporting her. Her daughter had not wanted mum to leave to go and eat, and no one else could come to sit with her because of the COVID restrictions. Her daughter was scared and going through gruelling treatment and that made it very difficult for mum to leave her. In addition, her treatment had affected her smell, making her feel unwell which resulted in her mum eating in the ensuite toilet as there was nowhere else to sit and eat. After her daughter died, mum had been working on items from her daughter’s bucket list, with senior representatives of the NHS. Work focused on putting in place a national programme to feed parents, improve food for children and also the provision of play specialists. In terms of food, mum had been working with UHS’ Patient Support Hub since January. Initially snack and toiletry boxes were put into every parent room but now, every children’s ward across Portsmouth and Southampton, a total of 17 wards, received food and drink every week. A charity, Sophie’s Legacy, had been set up and a trial had started that provided parents with a £4 food voucher for the restaurant, which was in addition to the support provided by the Patient Support Hub. The initiative had been well received by parents. The hope is to roll this out across the Country as looking after parents was important to enable them to support the care of their children. JD-T thanked mum for sharing noting how devastating it must have been to lose her daughter and how amazing it was that she and her daughter had wanted to support others in this difficult time. GB also thanked mum for sharing the experience and the work that was being done in her daughter’s name, which was important to continue. DAF noted how extraordinary that at the age of nine her daughter was considering the future of others. DAF asked whether mum had good links with the hospital charity and SH confirmed that he would make contact to ensure that this happened. Action: SH JT noted the importance of good facilities being available including good quality, affordable food. It was important for the Board to look at this and also to look at the estate to ensure that there was appropriate spaces provided for parents. 3. Minutes of the Previous Meeting held on 28 July 2022 The minutes of the meeting held on 28 July 2022 were approved as an accurate record of the meeting save for the following amendments: Page 2 • Page 3 – Correct spelling of Beachcroft • Page 3 – 5.3 third bullet – should read compliant not complaint. 4. Maters Arising and Summary of Agreed Actions Actions that were due had been completed. Action 763 – The complaint data was being compiled and would be sent out shortly. The remaining actions were not yet due but were being taken forward. 5. QUALITY, PERFORMANCE and FINANCE 5.1 Briefing from the Chair of the Audit and Risk Committee KE provided a briefing following the meeting on 12 September. The External Auditors had signed off their opinion on the financial statements with a clean opinion being given. From the Internal Auditors three reviews had been completed. The incident management review had focused on smaller incidents, noting that major incidents would normally be highlighted quickly. A large number had been tested and the conclusion was that the Trust needed to work on turning the reports around within the ten-day period. The Cyber Security review was one of significant assurance. However, the report highlighted that the Trust did not have formal documentation in terms of a Cyber Security Strategy and that not much training was provided for staff. Finally, in terms of General Data Protection Regulation (GDPR) and personal information, the Trust was required to have a “record of processing activities” (ROPA). The Trust undertook hundreds of activities but did not have a ROPA for every activity and the recommendation was to review and put in place an appropriate policy to enable a more general approach for wider coverage. The final review was stage 2 of how the Trust managed and governed IT projects. The report had focused on three areas: • The initial assessment of the benefits of the IT project which had been found to be thorough and well thought out and documented. • More guidance was recommended on how to evaluate benefits particularly in terms of non financial benefits including safety benefits. • There were very few post benefit assessments being completed which would help with learning. Plans were in place to put additional controls in place by March 2023 and a review would take place as part of their follow up procedures. JT reminded members that he had arranged for Cyber training for the Board and had agreed to provide further assurance around some of the arrangements and the Internal Audit was aligned to this. JT noted that staffing arrangements would need to be reviewed as currently there was only one colleague within the digital team that worked on cyber security issues. HP informed the Board that work was already underway in terms of the work around ROPAs. Action: JT Page 3 5.2 Briefing from the Chair of the Finance and Investment Committee JB provided an update from the last meeting noting that discussions had taken place around the current financial position and the operational plan, both of which were due to be discussed in the closed board meeting. There was significant challenge particularly around the deficit position but overall there was a really good grip on exactly where the Trust currently was, with appropriate decisions being made to reflect the balance between managing the financial position, whilst continuing to support our people and activity. A number of ongoing actions around productivity were being addressed together with a clearer view of the future cash position of the Trust. Finally, JB noted that Model Hospital data had been reviewed to enable the Trust to drive efficiencies compared to other hospitals and to facilitate learning. 5.3 Chief Executive Officer’s Report DAF noted that this was the first time that the Board had met since the death of Her Majesty Queen Elisabeth II and wanted to formally recognise the fantastic public service that she had given. The state funeral, which gave an additional bank holiday, provided the Trust with some challenging operational issues, with little guidance being provided in terms of what the best approach should be. Where staff were not involved in urgent or emergency care, such as within outpatients, electives and day case procedures, they were given the choice that if they wanted to work that would be gratefully received, but similarly if they wanted to take the day off to pay their respects, they were able to. Some staff wanted to work and others wanted to take the day. More than two thirds of the scheduled activity had been undertaken. DAF thanked all staff for all of their hard work and dedication. He also noted that: • The pilot of the care village had been very successful and would be discussed further in the next item. • Junior doctor pay rates had been quite challenging and was symptomatic of where the Trust was with many members of the workforce. The Royal College of Nursing (RCN) had notified the Trust of an intended ballot for strike action. Also, the British Medical Association (BMA) had published a rate card that they wanted trusts to pay, which was in many cases, significantly above current ratees. DAF noted that there were groups of staff who had indicated that they would not work for the Trust unless paid the new rates. It was a period of instability and people were understandably wanting to protect their income which was manifesting in the behaviours that we were seeing. • The HR team had been recognised by the Chartered Institute of Professional Management (CIPD), for a National awards which was a testament to the good work that SH and his team did. • The number of COVID positive cases was increasing with around 70 currently in the hospital. Mask wearing had been re-introduced in clinical areas in an attempt to limit the number of nosocomial transmissions. Care homes were not willing to accept patients with COVID which would impact potential discharges. In terms of staff Page 4 absence from COVID this was also increasing and staff were being encouraged to have both COVID and influenza vaccinations. • UHS was in the process of finalising an IT contract which, at first glance looked like it could be a replacement for our Emergency Department (ED) IT system. The initial contract was small but included from a strategic perspective, as the Trust had recognised the potential for having a longer-term development partner. UHS remained committed to its “Best of Breed” strategy but had been struggling to recruit and retain the people needed to develop the systems and this could be a step to delivering this by working together in partnership. Ultimately this could result in UHS not only being able to bring to develop our systems but also had the potential to bring to the market a number of our IT products that we had developed. • At the previous month’s board, the Trust had been aware of its segmentation under the Single Oversight Framework (SOF) review, but had omitted to formally advise the board. The Trust remained in segment 2, with 1 being good and 4 being bad. Trusts in segments 3 and 4 received more dedicated support and oversight. This was a vote of confidence from the regulators in the Trust despite the challenges it was facing. TP noted that the BMA pay card had received much criticism and should be resisted unless there was a proper negotiation about the rates. In terms of the IT partnership this was excellent news. PG noted that the Trust had been very clear through the Local Medical Councils (LMC), and individual conversations with teams, that the Trust would not be entering into negotiations about the BMA rates. It was growing as an issue but was an untenable position to hold in front of the rest of the workforce. Meetings were taking place with teams noting that it was not just about money. PG had been clear with his medical consultant colleagues that he was not able to recommend that consultants were paid as much in one day for an overtime operating list, which was greater than the amount some staff received in a month. In a cost-of-living crisis this was wrong. Many colleagues had understood this approach but there was still many who were very unhappy. JH congratulated SH for the award noting that this was a very difficult award to achieve, with tough competition, and that to achieve it during the pandemic was outstanding. Decision: The Board noted the report. 5.4 Integrated Performance Report for Month 5 (part one) JT noted the challenges that the Trust was currently under and in particular highlighted: • The previous day had been particularly tough with every space in the hospital full and lots of patients in the ED waiting for beds. This was replicated nationally with many organisations had declared critical incidents due to the pressures being faced. It was caused by increased numbers of COVID positive patients and a big spike in the number of delayed patients in the hospital which had hit 245 patients at the start of the week, with almost a quarter of the bed base who could be treated elsewhere. Page 5 • There was a record number of cancer referrals with the waiting list being the highest it had ever been. The Trust continued to deliver more diagnostic capacity than it had ever delivered but continued to struggle with capacity in view of the increased demand. This was a very difficult position alongside a time where staff morale was low and staff were tired due to the pressures over the last couple of years. • One of the two spotlights related to cancer and the Board had a study session the following week with a deep dive. Referrals had grown by about 25% per month from around 1600 two-week referrals to consistently above 2000 per month. The backlog of patients who had breached 62 days had gone up three-fold in the last two years from around 100 to 370 patients. The overall number of patients on the cancer pathway had also doubled in this period. This was challenging for a group of patients that the Trust wanted to prioritise in terms of access to services and care. • Across the Wessex Alliance footprint the backlog remained better than the rest of the Country but it was not where we would want to be in terms of cancer services. It was likely that our performance would dip as we started to treat those patients which would impact the 62 day target, despite the levels of activity and delivering relatively well in terms of our peer groups. • There were some excellent new pathways being developed including the dermatology dream pathway which would make a significant impact on the skin pathway once implemented. Work was also being done with the cancer allowance to map what we had, against what we needed to understand better the gaps. DAF noted that the cancer performance metrics were a measure of the patients that had been treated. Once you had a number of patients above the 62 days, if you did not treat them and let them remain on the waiting list. your measure would remain strong. However, this was not the right thing to do but once you had treated them this would impact that metric which was likely to be poor over the coming months. TP noted that the waiting had continued to get bigger which would suggest that either the Trust was not coping with the numbers coming through and people were therefore waiting longer and longer or that there was a higher rate of cancer in the population. Was this as a result of COVID reducing the body’s ability to fight small cancers that would normally disappear. JD-T also noted the highest number of referrals happening in August and wondered whether there was any national modelling being done around this. JT informed members that Professor Peter Johnson would be one of the presenters at the board study session and this would be a good opportunity to explore this. Anecdotally we appeared to be seeing more sicker patients who had a number of co-morbidities presenting as more complex patients and work was underway to investigate this further particularly from an inequality lens in terms of the demographics that were being referred on the two week wait referrals. PG noted that during COVID people tended to not present which was part of the reason for a backlog of presentations but that diagnosis appeared to also be increasing. Understanding why was not yet known and a discussion in the study session would be helpful to understand that particularly better. In terms of the appraisals spotlight SH noted: Page 6 • That a key element from the People Strategy was the Trust’s ability to provide meaningful progression for our staff. From the feedback given in the staff survey many staff believed that during the pandemic they had not received the development, training or the appraisal focus that they would have wanted. • Work to address that included a multi disciplinary team who had focused on refreshing the appraisal paperwork which had been well received. The team had a wide breadth of staff including clinical, operational and trade union representatives. Previously the number of appraisals carried out had been good but the quality had been low so training for appraisals had been reviewed to improve the quality of the appraisal discussion. Whilst the Trust was better than its peers, this simply highlighted that the NHS was not particularly good at appraisals. • A pilot had been implemented to better align appraisals with objective setting to enable them to cascade down to staff better which would conclude shortly and would feed into the process. JD-T noted that Division D consistently outperformed the other Divisions in terms of completed appraisals. In addition the staff survey showed that they were the only division that achieved a green in terms of an appraisal helping staff to undertake their job. This showed a correlation between the two and wondered what was the learning was. SH noted that Division D had historically had good rates of completion and had been involved in the refresh and had highlighted the need to focus at every level of the team. JH asked whether those within Division D had better promotion and development opportunities which could link back into the value of conducting a good appraisal. SH advised that there was nothing obvious but Division D had some good engagement scores overall but this could be looked at further. GB noted that the new appraisal paperwork had removed the need to consider how an individual contributed to the values of the organisation, and although the values were still referenced, questioned how through appraisal the behaviours and values continued to sit within the process. SH noted that the review of the values work was important and it would be good to look at how that could be brought back into the appraisal process to add value. Decision: The Board noted the report. 5.5 Finance Report for Month 5 IH presented the report and highlighted: • The Trust continued to focus on the underlying deficit, which for months 1 – 4 had been around £3m which had slightly worsened to £3,5m as energy costs started to grow. A deep dive had taken place at the Finance & Investment (F&I) Committee looking at some of the actions being undertaken and some of the future forecasts before the energy cap would come in and whether this would help or otherwise. There would still be a small increase in run rate into the latter half of the year which would deteriorate the Trust’s underlying position as we entered the winter months. • The key drivers were consistent. As well as energy prices, there were some drug costs pressures as we were on a block contract, cost associated with COVID including backfill of staff together with all of the operational pressures that had already been discussed. Page 7 • Cost Improvement Programme (CIP) performance had improved following the introduction of the Cost Savings Group. The Trust was currently achieving more than 80% identified which should increase going forward. In month delivery had also been strong. Everything was being done to try and improve the financial position but there were a number of pressures that were outside our control that would impact this. • Elective recovery framework performance had dipped in line with the operational pressures discussed, but UHS continued to achieve 106%, above the required 104%. UHS was in the top Trusts both in the region and nationally in terms of activity levels compared to 2019/20 levels. However, this was not resolving the waiting list issue that continued to grow. UHS continued to do well in terms of 2019/20 levels compared to other Trusts but this did create a financial pressure. • The Trust had reported a £12m deficit. The Hampshire and Isle of Wight deficit was £53m. This was an outlier within the region, and the region was an outlier nationally. This had resulted in the system becoming an outlier in terms of financial performance which might have adverse consequences going forward including upon the SOF rating. • The underlying deficit reduced the Trust’s cash balance and that may put pressure on our future capital investment programme. KE referred to the financial risks table and asked what the difference was between the original worst case of £57m and the forecast assessments which showed, best, intermediate and worst case? IH noted that the original worstcase scenario had been presented to the Board as part of the planning submissions, to show the range of possible financial outcomes with everything that was known at the time. The current best, intermediate and worst case were the current assessments. KE noted that UHS could not control COVID costs, energy costs and inflationary measures and that this would need Treasury to provide support. IH reminded members that nationally there was a drive to find efficiencies. It was likely that many Trusts would go into deficit this year but it was not clear what the response would be to that. KE commended the work on the CIP which was a fantastic achievement. He questioned whether the position could improve further with more CIP savings. IH advised that a target date of Month 6 had been agreed in terms of everything being identified 100% and the position might improve next month. IH noted that UHS was at 106% activity levels with the national average being around 94%. The 12% from the Elective Recovery Fund (ERF) would be worth about £20m to the Trust. If the Trust had undertaken less activity the Trust’s financial position would be a lot less stark but UHS continued to put patients first and try and balance performance, money and quality. In response to a question from JD-T IH confirmed that as of today and what was currently known, UHS could still achieve the best-case scenario. DAF suggested that in view of what had happened in markets over the recent days it was unlikely that the NHS would want to approach the Treasury. UHS should proceed on the basis that there would be no financial support being provided. In those circumstances the Board would need to consider at what point more significant interventions would need to be made. Page 8 5.6 People Report for Month 5 JD-T noted that this was a new report for the board. Previously the report had been presented to the Trust Executive Committee (TEC) and following discussion in that forum a decision was made that it should be presented to the open board for discussion. SH presented the report and noted that the version before the Board was the detailed report presented to TEC. Going forward a more streamlined report, with key highlights, would be developed for the Board discussion. SH highlighted: • Some of the key actions that had been taken in relation to recruitment and retention and also the cost-of-living crisis. There had been discussions at a previous closed board meeting around concerns in relation to the recruitment and retention of certain staff groups and some actions had been put in place to mitigate those concerns. • SH highlighted the challenges around Advanced Clinical Practitioners (ACPs) and pay rates. A few local organisations including GP practices were providing a differential rate of pay with a higher pay band. In the short term this was being addressed by a recruitment and retention premium to bridge the gap, together with conducting a workforce review that would seek to understand the banding and whether there was a need for a permanent band change. However, it would be important to consider the possible impact on the change to other bands across the Trust and manage that appropriately. • UHS continued to undertake Health Care Assistant (HCA) recruitment well, but the challenge was retention. There were good pathways in place but work was needed to strengthen landing boards and increase the support available in the hubs and implement some band 2 to band 3 progression roles for those who did not want to utilise the nursing apprenticeship route. • Demand on the recruitment team had significantly increased with a 25% increase of requested support. Some additional resource had been agreed to support them both within the organisation but also to increase engagement outside of the organisation. • In terms of cost of living, SH had been undertaking a lot of work with partners across the Trust including trade unions and listening to staff voices. There were a number of elements that were not under the Trust’s control including the national pay award and the rising energy crisis so the approach being taking was to take a balanced and fair approach. A number of things would be implemented which would be highlighted to all staff. A substantial discount was being negotiated in the restaurant to help people to eat a broad range of foods at competitive prices. The cycle to work scheme was being expanded, and there was some targeted support for those with high mileage within the organisation. For the 200 or so families who used the nursery the price was being rolled back to April this year. • The Trust already has a range of general support which would be expanded to make sure that we were targeting the right people. Through a partnership with the ICS we were linking up with the Citizens Advice Bureau to provide really high quality financial advice to our staff. We were focusing on crisis, and working with the Charity, had set up a hardship fund of £20,000 which would be distributed to the most challenging cases where staff had been identified as a particular Page 9 hardship case they would be able to eat free at the restaurant. Arrangements had also been made with a local charity to provide vouchers and food parcels. Discussion had taken place as to whether a food bank should be set up on site which logistically would have been difficult, so the decision to work with the charity was agreed to be the best approach to deliver that service for us. • Discussions had taken place at the Trust Executive Committee (TEC) who had fully supported the measures noting the impact on the nonrecurrent spend. KE suggested that this was a very sensible, targeted group of things to support our people. However, asked if the cost of £2.3m was currently included in the financial reports. IH advised that it was not included although some of the nonrecurrent elements had a funding source so would not hit the underlying position. In terms of annual leave buy out there were accruals from previous years. However, there were some recurrent costs. The measures were targeted, proportionate and in line with the Trust’s values for the current pressures being faced and if the Trust did not do anything it would likely increase costs or consequences elsewhere. DAF noted that the report was the same as presented to the TEC at which there had been a more detailed conversation. It would be helpful to understand which areas of the report were more relevant and appropriate for the Board conversation which could be discussed at the next People and OD POD) Committee meeting. Action: SH. JH supported the proposals within the paper and noted that they had also been presented to the People and OD Committee (POD). POD would be tracking the progress of each of the initiatives to ensure that they were delivering as anticipated. JH asked if the Trust had looked at what others were doing to ensure that we were doing everything possible for our staff. SH confirmed that discussions had taken place locally and that the Trust was one of the first to implement the range of measures which were similar to those of others. Nationally, there had been a push to have a collective response, noting that the NHS employed 1.5m people and that there would be national support that would be available shortly. TP noted the importance of having a people report at the Board and whilst the contents were good suggested that they could be presented in a more accessible way. FM also noted the importance of the report and discussion but wondered what staff morale was. If the finance, performance and people report were considered as a whole it was clear that staff were facing a lot of pressure and there was insufficient staff due to high turnover. The volume of patients was increasing which meant that the staff that the Trust did have, had to work harder and longer with pay that was not great and a cost-of-living crisis to deal with. This must have an impact on staff morale and was there also an impact on patient care? SH noted that morale was challenged which was recognised in the executive updates. The Trust undertook a quarterly staff survey alongside the current national annual staff survey and those results have been included within the report. The recent results discussed motivation, engagement and advocacy in Page 10 the organisation and UHS scores were still consistently in the top 10 of the NHS. However, the entirety of that engagement score was deteriorating. Morale was challenged and how that impacted on care was discussed in other forums. GB chaired the Quality Governance Steering Group (QGSG) which fed into the Quality Committee and focused on quality whether that be from the engagement of our staff or other challenges. GB suggested that it was a mixed picture. People enjoyed working as a team and we can see them pull together and work as a team through the challenges. There were a number of different pockets in the organisation who believed that they were in a worst situation following the pandemic and it was important to move out of that space and recognise this as a whole. In terms of quality, it was important to retain a close focus on quality and in some other Trusts they were starting to experience a significant challenge with regards to their quality indicators. At UHS there were some potential early indications that were being closely monitored. Without a doubt staffing levels, and the way in which we looked at the wards, impacted on patient experience and outcome. JD-T noted that one of the proposals was for staff to be able to sell back annual leave and being able to easily access the bank but if this was considered in the wider context, we had staff who were tired and not able to take leave as they had sold it, and were looking to work extra hours on the bank. How did the Trust manage and balance this? How should we look at the overarching risks for the workforce, and consequently patient care and performance, and what were the things that we needed to do to balance that. It would be helpful if the report could address some of those challenges to help the Board’s understanding. In addition JD-T asked NEDs to feedback what they would want to see within the report to enable an effective discussion. Action: SH and All NEDs JH asked about exit surveys and wondered if there was any information from them that could support our approach. SH advised that approximately 30% of staff completed exit surveys which needed to be increased. Pay for the lower paid staff had become an issue. SH reminded members that he chaired the ICS people officers group and that group had been looking at how collectively they could support retention and were looking to purchase better exit surveys for the system pulling together their collective buying power. Decision: The Board noted the report. 5.4 Integrated Performance Report for Month 5 (part two) Having noted the previous discussions under items 5.5 and 5.6 JD-T suggested that a discussion on the remaining of the IPR would be helpful and the following questions and comments were made: • JB noted that on pages 31 and 35, F1 – F5 this suggested that in terms of digital we believed that this was going to transform our efficiencies but it was not clear what the metrics indicated nor were some of them very high. PG suggested that there was an amazing resource in my medical record which we were not really making the most of. Work was needed to raise awareness with both patients and clinicians. Having used it as a patient it had been really helpful and enabled him to go paperless. JT noted that there was a business case that was overdue Page 11 for my medical record around how we industrialised it across the Trust which should provide some huge benefits and would bring a timeline back as to when this would happen. Action: JT JT noted that there was some big digital change happening with the rolling out of speech recognition and some E tools. In addition it would be helpful to look at the indicators to understand whether they were the right ones and review them as part of the digital updates which could be discussed at F&I. Action: JT The Board discussed the importance of giving people an overwhelming reason to access my medical record noting that the NHS App had initially been used for COVID vaccinations but could now enable people to order prescriptions and book appointments. JD-T noted the Serious Incident reports and the number of harm falls which looked higher than previously and wondered in terms of the pressures we were seeing and the issues around workforce should the Board be concerned about this? GB advised that it had recently been falls awareness week. There had been a number of successful programmes in the Trust including bay watch, but with reduced staffing numbers that had became a challenge and some more deliberate high impact actions were needed to reduce those falls. A deep dive into this would be brought to a future meeting. Action: GB GB confirmed that COVID numbers were rising. There were 66 patients with COVID some of whom were both asymptomatic and symptomatic. 5.7 Break The break took place prior to the Safeguarding Annual Report. 5.8 Safeguarding Annual Report 2021-22 and Strategy 2022-25 JDT suggested that the strategy should be discussed first noting that both had been discussed at the Quality Committee. KMcG presented the strategy which had previously been presented to the Trust Board two years ago before Covid. The strategy had been reviewed and updated in line with new legislation and aligned to UHS values and now included maternity services. Some of the strategy linked to children and adult reviews and making safeguarding personal together with our partners and developing stronger links within maternity, the emergency department and the wider hospital. Joining this up with the domestic abuse strategy and ensuring that we were always improving particularly around training and education including level 3 requirements. In terms of the Annual Report from a children’s perspective there were three main highlights: Page 12 • A significant increase, from 3700 to 6004, in the number of information sharing forms (ICF) which come through the ED where a child may possibly be at risk. In particular numbers had increased in the number of children presenting with mental health problems, particularly the 0 – 4 age group. This had been discussed at the Health Safeguarding Looked After Children Partnership who were looking at the 0 – 19 service provision which had changed significantly with COVID and a possible pattern of children of parents accessing through ED rather than going via their GP. • In terms of mental health, for any child who presented in the ED with a mental health condition an ICF would be completed. The number of presentations remained high. Alongside this the number of deliberate harm incidents had risen from 676 to 898, drugs and alcohol referrals had risen as had assaults over the preceding year. • Level 3 safeguarding training was at about 61%. There were two main reasons for this which was capacity and demand for the service and also a change of reporting requirements impacting just over 2000 staff. Training was on the Integrated Care Board (ICB) Risk Register as it was a wider system issue. In terms of the Annual Report for adults CM highlighted the following: • A 31% increase in safeguarding activity from the previous year with a 162% increase in Section 42 inquiries. This was due to a number of reasons including the impact of COVID including the removal of social distancing rules. • A 35% increase in the number of allegations made against people in a position of trust which was something that was being seen across other local provider organisations. These were highly sensitive cases and required significant safeguarding oversight and management alongside collaboration with HR colleagues and the relevant clinical areas, which had a significant impact on the team. • The creation of a new Mental Capacity Act (MCA), Deprivation of Liberty (DoL) and Liberty Protection Safeguards (LPS) team who supported people over the age of 16. Both locally and nationally this was one of the first teams that had been established. The team had worked to embed MCA as every day business which was key to the preparation for when LPS become law later next year or early the following year. • In terms of Learning Disability and Autism there was a lack of local provision which had been acknowledged by the ICS and work was underway in relation to service review and what this needed to look like going forward. GB thanked the team noting how hard they worked to safeguard vulnerable adults and children. GB referenced the Panorama programme that had aired the previous night in terms of a number of safeguarding issues against a Mental Health Trust. Whilst often allegations against staff were not grounded they were taken very seriously and investigated thoroughly. JB noted the 35% increase against staff and wanted to understand what the outcomes of the investigations were and whether they were justified and whether allegations were being made against different groups. CM advised that one of the key areas of allegations focused on restraint and that the level Page 13 of restraint applied was disproportionate. These would always be reviewed. Security staff worked in pairs and wore body cameras which would always be reviewed. There had not been any cases recently where that had proved to be an issue. Although there had been a big increase the total number of cases was 38 so not large numbers. The previous year there had been 23 cases. CC questioned what element of this sat within the Trust and what sat with the ICS? SH noted the importance of remembering the broader picture. Nationally there had been a rise of safeguarding incidents, but it was important to remember that our workforce formed part of that population and had struggled with lockdown and were experiencing hardship. JD-T noted the need for a system approach to manage the increased mental health demand. However, safeguarding was a key focus for the Care Quality Commission (CQC) inspections post COVID, and a local provider had recently been deemed to be inadequate due to safeguarding issues and was an issue for UHS to pay particular attention to. KMcG noted that through legislation children had the Local Area Designated Officer (LADO) which was lacking in adults, which provided a really strong link with that external partner. TP noted that there had been a detailed presentation on this in the Quality Committee. This was a national trend in increased safeguarding problems. Whatever pressure we are put under it was important not to let our safeguarding procedures slip and it needed to be protected to ensure that it worked well. Decision: The Board received the report. 5.9 Medical Appraisal and Revalidation Annual Report including Board Statement of Compliance PG presented the report which was a statement of compliance with the medical regulations and had a robust and strong process in place. PG noted that a new appraisal system had been introduced which had been well received and enabled the ability for medical staff to collect all of their appraisal information within one system instead of the previous three systems. This was beneficial for not only staff but also for those managing the process as it provided real time feedback and information both from a quality assurance perspective but also would enable better management of the process and improve appraisal rates in the future. JD-T asked whether the doctor appraisal information was included within the IPR information that the Board received and SH confirmed that it was reported separately but included in the report and currently stood at 76.7%. CC suggested that the system was good but asked whether everyone was using it. PG confirmed that the system was a mandatory one and would be the only system going forward in the future. In terms of how many staff had undertaken the process this was a little ahead of the rest of the staff. However, the system enabled us to keep better track as people would need to have completed four appraisals within the previous five years to go forward with revalidation which provided a good incentive to keep on top of this. Page 14 JD-T asked for Board members to confirm that they approved the statement of compliance. Decision: The Board noted the report and approved the statement of compliance. 5.10 Clinical Outcomes Summary PG introduced the comprehensive summary noting that the clinical lead who had ran the service for a number of years, had now left UHS and a process of recruitment was currently underway which would provide an opportunity to refresh and review. DW presented the paper and focused on the outcome programme which was unique to UHS, with 64 services out of 86 reporting their outcomes. A total of 484 outcomes had been reported all of which had been reviewed by TP via the Quality Committee. There was a thriving clinical audit programme in place. The outcomes reported per care group covered a large proportion of patients and dealt with both national and international work. In particular DW highlighted: • The Research and Development (R&D) team and the work that they had undertaken internationally on the COVID booster trial. • The Bone Marrow Transparent unit. • Maternity and the nest support teams who focused on women who may need additional support because of serious mental illness, or they were from socially challenging situations, or were non-English speaking, addiction, were homeless or were suffering from domestic abuse and other difficult situations. 12% of patients that were being seen in maternity required nest care. KE asked why 18 services were not reported and DW advised that it was because they did not have the mechanisms in place to know what their outcomes were and work was underway to support them to develop those processes. KE asked whether any of the reds within the report were really poor and JD-T noted that the data used was for 2020 and did not understand why it was so out of date. TP advised that data was provided from national audits was often two years behind, because there was a year of collection, a year of analysis and then it would be published. Within his experience he had never come across a hospital that had measured nearly 500 clinical outcomes let alone p
Url: /Media/UHS-website-2019/Docs/About-the-Trust/Trust-governance-and-corporate-docs/2022-Trust-documents/Papers-Trust-Board-29-November-2022.pdf

BEACON protocol v8.0 07Mar2023 signed

Description: A randomised phase IIb trial of BE AC v izumab added to Temozolomide O ± Irin tecan for children with N refractory/relapsed euroblastoma Version 8.0 dated 07-Mar-2023 Dinutuximab beta amendment Coordinating Sponsor: Sponsor Protocol Number: CAS Code: EudraCT Number: ISRCTN Reference Number: ITCC Number: Roche Study Reference Number: Email: University of Birmingham RG_ 11-087 BN2008 2012-000072-42 40708286 032 MO28245 beacon@trials.bham.ac.uk This application is supported by the facilities funded through Birmingham Science City: Translational Medicine Clinical Research Infrastructure and Trials Platform, an Advantage West Midlands (AWM) funded project which forms part of the Science City University of Warwick and University of Birmingham Research Alliance. BEACON-Neuroblastoma Protocol_vn 8.0_vd 07Mar2023 Page1 of 157 BEACON-Neuroblastoma Trial Protocol AMENDMENTS The following amendments and/or administrative changes have been made to this protocol since the implementation of the first approved version Amendment Date of number amendment Protocol version number Type of amendment SA 1 29-Jan-2013 2.0 Substantial Amendment N/A 23-Apr-2013 2.0a Non-Substantial Amendment N/A 01-Jul-2013 2.0b Non-Substantial Amendment Summary of amendment Introduction of the recommendation of weekly monitoring of blood counts for all patients receiving irinotecan. Addition of planned vaccination with live vaccination to exclusion criteria and prohibited medications section. ITCC Number has been corrected. Roche Study Reference Number and ISRCTN Reference Number have been added. Contact details for Plasma & Tumour Angiogenesis-Related Biomarkers have been amended. Table numbers have been corrected. Addition of guidance for research bone marrow sampling in Schedule of Activities table and sections 7.4.2.2 and 7.5.2. Addition of paragraph to sections 7.2, 7.6.1 – 7.6.4 detailing arrangements for handling dose modifications for Irinotecan + Temozolomide for patients receiving Bevacizumab. Discontinuation rules for osteonecrosis of the jaw and eye disorders added to table 13 in section 7.6.4. Correction to table number references in section 7.6.3. Clarification made in section 13.4.1 concerning Planned Interim Analysis. SA 3 06-Oct-2014 4.0 Substantial Amendment Changes to the Trial Personnel section of the protocol to include the addition of contact details for Denmark and Ireland Lead Investigators. Amendments to reflect the changes in study sampling requirements to Trial Synopsis, Schedule of Activities table and sections 1.2.6, 2.1, 2.2, 5.1, 5.2, 7.3, 7.4.2 and 7.5. Amendment to exclusion criteria in Trial Synopsis and section 4.2. Changes to the Schedule of Activities table to include the addition of an echocardiogram to be performed at screening and Tanner staging at screening and yearly in follow up. Changes to the time line for measuring renal function prior to commencing treatment in the Trial Synopsis, Schedule of Activities and section 4.1. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 3 of 157 BEACON-Neuroblastoma Trial SA 4 06-Oct-2014 4.0 SA 5 30-Jul-2015 5.0 Substantial Amendment Substantial Amendment Protocol Option to fax emergency randomisation removed. Telephone only in section 6.2 Changes to guidelines in section 7.2 for dose calculation in patients whose weight exceeds the 98th centile for age. Removal of enhanced data collection for Adverse Events of Special Interest (AESI) in section 7.6 and 9.1.2. Addition of option to extend treatment delay with agreement from Sponsor in Section 7.6.1 Addition of necrotising fasciitis as an adverse event requiring bevacizumab discontinuation in section 7.6.4. Changes to section 7.10 concerning the documenting of concomitant medications in patient medical notes and administration of bisphosphonates. Changes to section 9.1 regarding reporting of laboratory adverse events. Clarification on the arrangements for Follow Up Form completion for patients who do not require further follow up visits in section 11. Changes to bevacizumab and irinotecan preparation and dispensing guidelines in sections 8.2.4 and 8.3.3. Clarification on fasting arrangements prior to temozolomide administration added to section 8.4.3. Changes to events that should be reported on an Expected SAR Form in section 9.1.3.1. Clarification on SAEs that should be reported to F.Hoffman-La Roche Ltd in section 9.2.6 Addition of Trial Management Group meeting frequency in section 14.4. Changes to the wording of irinotecan randomisation in section 13.4.2. Addition of guidelines for dose reduction and discontinuation of temozolomide for liver toxicity in tables 8, 9, 10 & 11. Reference to the National Coordinating Centres has been changed to National CoSponsor throughout. Reference to Sponsor has been changed to Coordinating Sponsor. Change of Chief Investigator to Professor Pamela Kearns. Change of Principal Investigator at Royal Marsden Hospital to Dr Sucheta Vaidya. No changes made to the Protocol version. Chief Investigator and UK Lead Investigator changed to Dr Lucas Moreno Switzerland details added Schedule of events table amended for End Of Treatment clarity BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 4 of 157 BEACON-Neuroblastoma Trial N/A 23-Sep-2015 5.0a SA 6 16-Jan-2019 6.0a Protocol Topotecan added to the study as a new trial question and 2 new randomisation arms. The following sections are amended accordingly: Synopsis (Primary Objectives, sample size, Trial Duration, Trial therapy) Section 1 Background and rationale (Trial rationale) Section 3 Trial design (Randomisation) Section7.1 and 7.2 Treatment details Section7.6.1 Dose modifications Table 6 amended, Tables 11 and 12 added Section 8.4 Pharmaceutical Information Section 13 Statistical considerations The following changes were made to the Eligibility: Inclusion criteria – further details regarding birth control Exclusion criteria – Defined wash out period following prior IMP according to IMP half-life or 14 days. Lifestyle guidelines - further details regarding birth control Section 7.6 Dose modifications Figure 1 – reference to “chemo” changed to Temozolomide/Irinotecan/Topotecan” for clarity Section 8.2.4 Reference to “chemo” removed for clarity Section 7.6.4 AEs requiring Bevacizumab discontinuation – additional AEs added following Bevacizumab IB v22 Addendum Additional mRNA and exploratory sampling. Non-Substantial Amendment Substantial amendment The requirement for confirmatory scans was removed from the Schedule of Activities and Response assessment section 7.4.3. Lead Investigator for France amended to Dr Marion Gambart Minor wording corrections and clarifications Schedule of events table corrected Introduction of two new treatment arms (dinutuximab beta) for additional 64 patients Addition of eligibility criteria, schedule of events, treatment details, duration, cross over and dose modification details for new dinutuximab beta arms Adaptation of objectives, trial design, supporting treatment, pharmaceutical information and statistical consideration sections with new, relevant information. BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 5 of 157 BEACON-Neuroblastoma Trial N/A 11-Apr-2019 6.0b SA 7 07-Feb-2020 7.0 SA 22 07-Mar-2023 8.0 Protocol Non-Substantial Amendment Substantial Amendment Substantial Amendment Minor wording corrections and clarifications Version amended from 6.0 to 6.0a to add. Additional rationale to update typographical errors.) Trial Synopsis: Clarification of recruitment targets Clarification of Section 10 title: “Dinutuximab beta and topotecan randomisations” Clarification that not all biological studies will be open at any one time (Section 10.2 and 15.5) Minor wording corrections and clarifications Urgent Safety Measure – implemented on 28th January 2020 Closure of Temozolomide (T) and Dinutuximab beta and Temozolomide (dBT) arms with immediate effect. Section 1.1 Background Section 1.2.3 Benefit Risk assessment Section 3.1 Randomisation Section 10 Headings changed Section 10.3 Trial therapy Update of contact details Change of definition of End of Trial (Section 21). Protocol previously defined two stages of end of trial (6 months after last patient completes treatment and 12 months after last data capture after 5 years follow up). This has been combined into one End of Trial definition: 6 months after last patient last visit (i.e. after 5 years follow up) Also addition of option to email SAE form (Section 18.2.1.2) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 6 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL PERSONNEL Chief Investigator: Co-Investigators: Exploratory Biomarkers Dr Lucas Moreno Dr. Lucas Moreno, MD, PhD Director Paediatric Oncology & Haematology Division Vall d’Hebron Barcelona Hospital Campus Passeig de la Vall d’Hebron, 119-129, 08035, Barcelona, Spain  +34 93 489 3000  +34 93 489 4060  lucas.moreno@vhebron.net Professor Keith Wheatley Professor of Clinical Trials Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 415 9119  k.wheatley@bham.ac.uk Dr Juliet Gray Associate Professor and Consultant in Paediatric Oncology Southampton Children’s Hospital Tremona Road Southampton SO16 6YD  +44 (0) 790 1507929  juliet.gray@uhs.nhs.uk Dr Gudrun Schleiermacher Senior Scientist Institute Curie 26 rue d'Ulm 75248 Paris cedex 05 France  +33 (0)1 56 24 45 50  +33 (0)1 56 24 66 30  gudrun.schleiermacher@curie.net Professor Louis Chesler Paediatric Tumour Biology Team Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0) 208 722 4035 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 7 of 157 BEACON-Neuroblastoma Trial Protocol  louis.chesler@icr.ac.uk Functional Imaging Study: Professor Andrew Peet Institute of Child Health University of Birmingham Whittall Street Birmingham, UK B4 6NH  +44 (0) 121 333 8234  +44 (0) 121 333 8241  a.peet@bham.ac.uk Dr Dow-Mu Koh Consultant Radiologist in Functional Imaging Royal Marsden Hospital Downs Road, Sutton, Surrey, UK SM2 5PT  +44 (0) 208 6613857  dow-mu.koh@icr.ac.uk Professor Martin Leach Co-Director, Cancer Research UK and EPSRC Centre for Cancer Imaging, Director, NIHR Clinical Research Facility Deputy Head, Division of Radiotherapy and Imaging Institute of Cancer Research and Royal Marsden Hospital (University of London), Downs Road, Sutton Surrey, UK SM2 5PT  +44 (0 208 661 3338  Martin.Leach@icr.ac.uk Molecular Monitoring mRNA Study: Professor Sue Burchill Leeds Institute of Cancer & Pathology St. James University Hospital Beckett Street Leeds, UK LS9 7TF  +44 (0) 113 206 5873  +44 (0) 113 242 9886  S.A.Burchill@leeds.ac.uk Professor Walter Gregory Clinical Trials Research Unit (CTRU) University of Leeds Clinical Trials Research House 71-75 Clarendon Road Leeds LS2 9PH  +44 (0) 113 343 1489  +44 (0) 113 343 1471 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 8 of 157 BEACON-Neuroblastoma Trial Protocol Trial Statistician: Trial Coordinator & Trial Office: Randomisation Service: SAE Reporting:  W.M.Gregory@leeds.ac.uk Miss Grace Holt Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 8328  +44 (0)121 414 3700  G.C.Holt@bham.ac.uk Miss Punam Mistry Children’s Cancer Trials Team Cancer Research UK Clinical Trials Unit (CRCTU) Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  beacon@trials.bham.ac.uk Provided by the CRCTU at the University of Birmingham Randomisation should be performed by sites online at: https://www.cancertrials.bham.ac.uk/BEACONLive In case of any problems with online randomisation, randomisation can be performed over the phone by the CRCTU on: 0800 371 969 or +44 (0)121 414 3366 SAEs should be faxed to the BEACON-Neuroblastoma Trial Office, CRCTU, University of Birmingham, UK  + 44 (0)121 414 9520 or +44 (0)121 414 3700 National Coordinating Investigators: Austria – Lead Investigator: Prof Dr Ruth Ladenstein St. Anna Children’s Hospital and CCRI /Studies and Statistics Department for Integrated Research and Projects (S²IRP) Kinderspitalgasse 6, Zimmermannplatz 10 A-1090 Vienna Austria +43-1-40470-4750  +43-1- 40470- 7430  ruth.ladenstein@ccri.at BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 9 of 157 BEACON-Neuroblastoma Trial Belgium Lead Investigator: Prof Genevieve Laureys Ghent University Hospital 9000 Ghent De Pinterlaan 185 Belgium  +32 93 32 34 48  genevieve.laureys@uzgent.be Denmark – Lead Investigator: Dr Karsten Nysom Dept. of Paediatrics & Adolescent Medicine Rigshospitalet Blegdamsvej 9 DK2100 Copenhagen Denmark  +45 35 45 08 09  +45 35 45 50 55  Karsten.nysom@regionh.dk France – Lead Investigator: Dr Marion Gambart Unité d'Hémato-Oncologie Hôpital des Enfants 330, avenue de Grande Bretagne TSA 70034 31059 Toulouse Cedex France  +33 (0)5 34 55 86 11  +33 (0)5 34 55 86 12  gambart.m@chu-toulouse.fr Germany - Lead Investigator: Dr. Simone Hettmer Zentrum für Kinder- und Jugendmedizin UNIVERSITÄTSKLINIKUM FREIBURG Mathildenstr. 1, 79106 Freiburg Germany  +49 761 270-43000  +49 761 270-45180  simone.hettmer@uniklinik-freiburg.de Ireland – Lead Investigator: Dr Cormac Owens Our Lady’s Children’s Hospital Crumlin Road, Crumlin Dublin 12 Ireland  +35314096659  +35313453041  Cormac.owens@olchc.ie Protocol BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 10 of 157 BEACON-Neuroblastoma Trial Protocol Italy – Lead Investigator: Dr. Aurora Castellano U.O.Oncoematologia Ospedale Pediatrico Bambino Gesù Pzza S. Onofrio 4 00165 Roma Italy +39 06 68592957-2678  +39 06 68592826  aurora.castellano@opbg.net Netherlands – Lead Investigator: Dr. C Michel Zwaan Erasmus Medical Center Sophia’s Children's Hospital Dr. Molewaterplein 60 3015 GJ Rotterdam +31 (0) 10 703 6691  +31(0) 10 703 6681  c.m.zwaan@erasmusmc.nl Spain – Lead Investigator: Dr. Victoria Castel Instituto de Investigación Sanitaria Unidad de Oncología Pediátrica Hospital Universitario La Fe Bulevar Sur, S/N 46026 Valencia Spain +34 963862758 Ext 50040  +34 963494416  castel_vic@gva.es Switzerland – Lead Investigator: Dr. Nicolas Gerber University Children’s Hospital, Steinwiesstrasse 75, CH-8032 Zurich, Switzerland +41 44 266 31 17  +41 44 266 34 61  Nicolas.gerber@kispi.uzh.ch UK – Lead Investigator: Dr Lucas Moreno Honorary Research Fellow University of Birmingham Birmingham, UK B15 2TT  +44 (0)121 414 3788  +44 (0)121 414 9520  lucas.moreno@vhebron.net, lmorenom@ext.cnio.es BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 11 of 157 BEACON-Neuroblastoma Trial Protocol TRIAL SYNOPSIS Title A randomised phase IIb trial of bevacizumab added to temozolomide ± irinotecan for children with refractory/relapsed neuroblastoma – BEACON-Neuroblastoma Trial Trial Design A phase II, randomised, open label, international multicentre 3x2 factorial trial. The dinutuximab beta amendment did utilise a 2x2 factorial design it will now be a simple two-way randomisation. Objectives Primary: - To test whether bevacizumab added to a backbone chemotherapy regimen (temozolomide, irinotecan + temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma - To test whether the addition of irinotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma - To test whether the addition of topotecan to temozolomide increases the activity of chemotherapy in children with relapsed or refractory neuroblastoma (“topotecan randomisation”) - To test whether dinutuximab beta added to a backbone chemotherapy regimen (temozolomide or temozolomide + topotecan) demonstrates activity in children with relapsed or refractory neuroblastoma (“dinutuximab beta randomisation”) Secondary: - To evaluate the safety of the regimens Tertiary: - To undertake preliminary evaluation of the changes in magnetic resonance imaging (MRI) derived functional imaging biomarkers of angiogenesis - To undertake preliminary evaluation of the role of circulating mRNA levels for tyrosine hydroxylase (TH), paired-like homeobox 2b (PHOX2B) and doublecortin (DCX) as prognostic/predictive biomarkers in this refractory/relapsed setting - To undertake a preliminary evaluation of the role of tumour molecular profiles in blood and archival tumour tissue profiles as prognostic and predictive biomarkers - To undertake a preliminary evaluation of biomarkers of response to anti-GD2 therapy (Fc/KIR polymorphisms, Antibody Dependant Cell-Mediated Cytotoxicity (ADCC) and Anti-Drug Antibodies (ADAs) and of dinutuximab beta pharmacokinetics (PK) Outcome Measures Primary Endpoint: - Best response (Complete Response [CR] or Partial Response [PR]) [1] at any time during the first 6 cycles of trial treatment - For the bevacizumab part 2 only: Progression-free survival (PFS) Secondary Endpoints: - Safety of the regimens: Incidence and severity of Adverse Events (AE)s - PFS - Overall survival (OS) - Event-free survival (EFS) BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 12 of 157 BEACON-Neuroblastoma Trial Protocol Exploratory/Tertiary Endpoints: - Changes in (MRI) derived functional imaging biomarkers of angiogenesis measured by quantitative dynamic contrast enhanced (DCE) MRI: primary biomarkers will be the transfer constant Ktrans [min-1] and initial area under the gadolinium uptake curve from 0 to 60 seconds (IAUGC60, mM Gd min) and secondary biomarkers will be tumour apparent diffusion coefficient (ADC, 10-6 cm2 s-1), native T1 and T2 relaxation times (ms) and transverse relaxation rate R2* - Changes in circulating mRNA levels for TH, PHOX2B and DCX in bone marrow and blood samples - Pilot descriptive study of angiogenesis and neuroblastoma markers that may include O6methylguanine-methyltransferase (MGMT) status, immunohistochemistry and immunofluorescence markers on tumour samples (such as microvessel density (MVD), CD31, Ki67, NRP1, VEGFR-1, VEGFR-2, C-KIT), DNA/RNA extraction from tissue sections for tumour mutation screening and tumour expression profiling - A preliminary correlation of the different biomarkers [Fc/KIR polymorphisms, Antibody – Dependent Cellular Toxicity (ADCC), and Anti-Drug Antibodies (ADAs)] will be made with parameters of anti-tumour activity (response rate, PFS and OS). PK parameters (dinutuximab beta trough levels) for this chemo-immunotherapy regimen will be described. Patient Population Children and young adults aged 1 to 21 years of age with relapsed/refractory neuroblastoma. Sample Size Approximately 224 patients, including 160 for the bevacizumab randomisation and 64 for the dinutuximab beta amendment. Trial Duration 8 years of patient recruitment, 5 years of patient follow up BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 13 of 157 BEACON-Neuroblastoma Trial Protocol Abbreviations ADA ANTI-DRUG ANTIBODIES ADCC ANTIBODY – DEPENDENT CELL-MEDIATED CYTOTOXICITY AE ADVERSE EVENT AESI ADVERSE EVENT OF SPECIAL INTEREST AFSAPPS COMPETENT AUTHORITY FOR FRANCE ALT ALANINE AMINOTRANSFERASE ANC ABSOLUTE NEUTROPHIL COUNT APPT ACTIVATED PARTIAL THROMBOPLASTIN TIME ASCT AUTOLOGOUS STEM CELL TRANSPLANTATION AST ASPARTATE AMINOTRANSFERASE AUC AREA UNDER THE CURVE AR ADVERSE REACTION BIT BEVACIZUMAB + IRINOTECAN + TEMOZOLOMIDE ARM BM BONE MARROW BP BLOOD PRESSURE BSA BODY SURFACE AREA BT BEVACIZUMAB + TEMOZOLOMIDE ARM BTTo BEVACIZUMAB + TEMOZOLOMIDE + TOPOTECAN ARM CI CHIEF INVESTIGATOR CIs CONFIDENCE INTERVALS COG CHILDREN’S ONCOLOGY GROUP CNS CENTRAL NERVOUS SYSTEM CR COMPLETE RESPONSE CRF CASE REPORT FORM CR UK CANCER RESEARCH UK CRCTU CANCER RESEARCH UK CLINICAL TRIALS UNIT (UNIVERSITY OF BIRMINGHAM) CRN CLINICAL RESEARCH NETWORK CSR CLINICAL STUDY REPORT CT COMPUTERISED TOMOGRAPHY CTC COMMON TERMINOLOGY CRITERIA CTCAE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS CXR CHEST X-RAY dBT DINUTUXIMAB BETA + TEMOZOLOMIDE ARM dBTTo DINUTUXIMAB BETA + TEMOZOLOMIDE + TOPOTECAN ARM DCX DOUBLECORTIN DLT DOSE LIMITING TOXICITY DMC DATA MONITORING COMMITTEE DNA DEOXYRIBONUCLEIC ACID ECHO ECHOCARDIOGRAM ECOG EASTERN COOPERATIVE ONCOLOGY GROUP EFS EVENT FREE SURVIVAL EMA EUROPEAN MEDICINES AGENCY ERDC ELECTRONIC REMOTE DATA CAPTURE EOT END OF TREATMENT FFPE FORMALIN-FIXED PARAFFIN EMBEDDED GCP GOOD CLINICAL PRACTICE G-CSF GRANULOCYTE COLONY STIMULATING FACTOR BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 14 of 157 BEACON-Neuroblastoma Trial Protocol GFR GM-CSF GGT GP GPOH HR IB ICF ICH IMP INR INRC INRG INSS IRF ISF IT ITCC IV MGMT MIBG MHRA MRD MRI MSKCC MTD MYCN NANT NCI NCS NR OS OTC PCP PD PFS PHOX2B PI PIS PK PMA PRES PO PPTP PR REC RECIST RNA GLOMERULAR FILTRATION RATE GRANULOCYTE-MONOCYTE COLONY STIMULATING FACTOR GAMMA-GLUTAMYL TRANSPEPTIDASE GENERAL PRACTITIONER GERMAN SOCIETY FOR PAEDIATRIC ONCOLOGY & HAEMATOLOGY HEART RATE INVESTIGATOR BROCHURE INFORMED CONSENT FORM INTERNATIONAL CONFERENCE ON HARMONISATION INVESTIGATIONAL MEDICINAL PRODUCT INTERNATIONAL NORMALISED RATIO INTERNATIONAL NEUROBLASTOMA RESPONSE CRITERIA INTERNATIONAL NEUROBLASTOMA RISK GROUP INTERNATIONAL NEUROBLASTOMA STAGING SYSTEM INSTITUTIONAL REVIEW BOARD INVESTIGATOR SITE FILE IRINOTECAN + TEMOZOLOMIDE ARM INNOVATIVE THERAPIES FOR CHILDREN WITH CANCER INTRAVENOUS O6-METHYGUANINE METHYLTRANSFERASE META-IODO-BENZYL-GUANIDINE MEDICINES AND HEALTHCARE PRODUCTS REGULATORY AGENCY MINIMAL RESIDUAL DISEASE MAGNETIC RESONANCE IMAGING MEMORIAL SLOAN KETTERING CANCER CENTRE MAXIMUM TOLERATED DOSE MYELOCYTOMATOSIS VIRAL RELATED ONCOGENE NEW AGENTS FOR NEUROBLASTOMA THERAPY NATIONAL COORDINATING INVESTIGATOR NATIONAL CO-SPONSOR NO RESPONSE OVERALL SURVIVAL OVER THE COUNTER PNEUMOCYSTIS CARNI PNEUMONITIS PROGRESSSIVE DISEASE PROGRESSION FREE SURVIVAL PAIRED-LIKE HOMEOBOX2B PRINCIPAL INVESTIGATOR PATIENT INFORMATION SHEET PHARMACOKINETICS POPULATION-MODELLING ANALYSIS POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME ORALLY PAEDIATRIC PRECLINICAL TESTING PROGRAM PARTIAL RESPONSE RESEARCH ETHICS COMMITTEE RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS RIBONUCLEIC ACID BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 15 of 157 BEACON-Neuroblastoma Trial Protocol RTKI RT-qPCR SAE SAR SCT SD SFOP SIOPEN SNP SPC SUSAR SWFI T TH TMA TMG TSC TTo TVD UAR UKCCSG ULN VTE VEGF VGPR WMA RECEPTOR TYROSINE KINASE INHIBITORS REVERSE TRANSCRIPTASE QUANTITATIVE POLYMERASE CHAIN REACTION SERIOUS ADVERSE EVENT SERIOUS ADVERSE REACTION STEM CELL TRANSPLANT STABLE DISEASE FRENCH SOCIETY OF PAEDIATRIC ONCOLOGY INTERNATIONAL SOCIETY PAEDIATRIC ONCOLOGY EUROPEAN NEUROBLASTOMA GROUP SINGLE NUCLEOTIDE POLYMORPHISM SUMMARY OF PRODUCT CHARACTERISTICS SUSPECTED UNEXPECTED SEVERE ADVERSE REACTION STERILE WATER FOR INJECTION TEMOZOLOMIDE ARM TYROSINE HYDROXYLASE TISSUE MICROARRAY TRIAL MANAGEMENT GROUP TRIAL STEERING COMMITTEE TEMOZOLOMIDE + TOPOTECAN ARM TOPOTECAN, VINCRISTINE & DOXORUBICIN UNEXPECTED ADVERSE REACTION UNITED KINGDOM CHILDREN’S CANCER STUDY GROUP UPPER LIMIT OF NORMAL VENOUS THROMBO-EMBOLISM VASCULAR ENDOTHELIAL GROWTH FACTOR VERY GOOD PARTIAL RESPONSE WORLD MEDICAL ASSOCIATION FORMULAE Mosteller formula: BSA (m²) = BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 16 of 157 BEACON-Neuroblastoma Trial Protocol Table of Contents Trial Synopsis ...................................................................................................................................... 12 Title .................................................................................................................................................... 12 Trial Design ........................................................................................................................................ 12 Objectives .......................................................................................................................................... 12 Outcome Measures............................................................................................................................ 12 Patient Population .............................................................................................................................. 13 Sample Size ....................................................................................................................................... 13 Trial Duration...................................................................................................................................... 13 Abbreviations ..................................................................................................................................... 14 1. Background and Rationale ............................................................................................................. 22 1.1 Background............................................................................................................................ 22 1.1.1 Background for the dinutuximab beta amendment............................................................ 28 1.2 Trial Rational.......................................................................................................................... 29 1.2.1 Justification for design ....................................................................................................... 29 1.2.2 Rationale for patient population ......................................................................................... 30 1.2.3 Benefit-risk assessment .................................................................................................... 31 1.2.4 Rationale for the selected backbone schedules: Temozolomide, irinotecan + temozolomide and temozolomide + topotecan .............................................................................. 31 1.2.5 Rationale for dosing schedule of bevacizumab................................................................. 32 1.2.6 Rationale for evaluating chemo-immunotherapy in the BEACON-Neuroblastoma Trial... 32 1.2.7 Rationale for dosing schedule of dinutuximab beta........................................................... 33 1.2.8 Rationale for the use of biomarker studies ........................................................................ 34 1.3 Relevance and future importance ......................................................................................... 35 2. Objectives and Outcome Measures ............................................................................................. 36 2.1 Objectives .............................................................................................................................. 36 2.2 Outcome Measures ............................................................................................................... 37 3. Trial Design ..................................................................................................................................... 37 3.1 Randomisation....................................................................................................................... 37 3.2 Duration of treatment............................................................................................................. 38 3.3 Frequency and duration of follow-up ..................................................................................... 38 4. Eligibility.......................................................................................................................................... 39 4.1 Lifestyle guidelines ................................................................................................................ 39 5. Schedule of activities..................................................................................................................... 39 6. Screening and Consent ................................................................................................................. 40 6.1 Informed Consent .................................................................................................................. 40 6.2 Screening............................................................................................................................... 41 7. Trial Entry........................................................................................................................................ 42 7.1 Procedure for online patient randomisation........................................................................... 42 7.2 Emergency Randomisation ................................................................................................... 42 8. Treatment Details ........................................................................................................................... 43 8.1 Definition of Investigational Medicinal Products (IMPs) ........................................................ 43 9. Bevacizumab randomisation......................................................................................................... 43 9.1 Eligibility criteria for the bevacizumab randomisation............................................................ 43 9.1.1 Inclusion criteria for the bevacizumab randomisation ....................................................... 43 9.1.2 Exclusion criteria for the bevacizumab randomisation ...................................................... 44 9.2 Schedule of activities for the bevacizumab randomisation ................................................... 45 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 17 of 157 BEACON-Neuroblastoma Trial Protocol 9.3 Trial Therapy (bevacizumab randomisation) ......................................................................... 49 9.3.1 Bevacizumab randomisation trial treatment ...................................................................... 49 9.4 Treatment Schedule..................................................................................................................... 51 9.4.1 Day 1 of Cycle 1 ................................................................................................................ 51 9.4.2 Day 1 of subsequent cycles............................................................................................... 51 9.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12) ........................................................ 52 9.4.4 End of Treatment ............................................................................................................... 52 9.4.5 Treatment Duration............................................................................................................ 52 9.5 Dose Modifications for the bevacizumab randomisation ....................................................... 53 9.5.1 Dose Modifications for AEs due to chemotherapy - for the bevacizumab randomisation. 56 9.5.2 Bevacizumab – Infusion-related Reaction/Infusional Site Extravasation Management Guidelines ...................................................................................................................................... 62 9.5.3 Bevacizumab - Treatment Delays ..................................................................................... 63 9.5.4 Bevacizumab - Discontinuation ........................................................................................ 64 9.5.5 Bevacizumab - Toxicity Management guidelines .............................................................. 65 9.6 Central Venous Access Device (CVAD)................................................................................ 67 10 Dinutuximab beta and topotecan randomisations...................................................................... 68 10.1 Eligibility for the dinutuximab beta randomisation ................................................................. 68 10.1.1 Inclusion criteria for the dinutuximab beta randomisation ............................................. 68 10.1.2 Exclusion criteria for the dinutuximab beta randomisation ............................................ 69 10.2 Schedule of events for the dinutuximab beta and topotecan randomisations....................... 70 10.3 Trial therapy (dinutuximab beta and topotecan randomisations) .......................................... 74 10.3.1 Dinutuximab beta and topotecan trial treatment................................................................ 75 10.4 Treatment Schedule .............................................................................................................. 76 10.4.1 Day 1 of Cycle 1 ............................................................................................................ 76 10.4.2 Day 1 of subsequent cycles........................................................................................... 76 10.4.3 Post Cycle 6 (For patients continuing to Cycle 7-12 on chemotherapy only) ............... 77 10.4.4 End of Treatment ........................................................................................................... 77 10.4.5 Treatment Duration............................................................................................................ 78 10.4.6 Cross-over ......................................................................................................................... 78 10.5 Dose Modifications – dinutuximab beta and topotecan randomisations ............................... 79 10.5.1 Dose modifications for dinutuximab beta specific toxicities .......................................... 79 10.5.2 Dose modifications for haematological toxicity.............................................................. 81 10.5.3 Dose modifications for hepatic toxicity .......................................................................... 82 11 Treatment Compliance................................................................................................................... 84 12 Supportive Treatment .................................................................................................................... 84 12.1 Nausea and Vomiting ............................................................................................................ 84 12.2 Growth Factors ...................................................................................................................... 84 12.3 Fever and neutropenia .......................................................................................................... 84 12.4 Blood products....................................................................................................................... 84 12.5 Pneumocystis jirovecii pneumonia (PJP) prophylaxis ........................................................... 84 12.6 Management of side effects caused by non-selective NSAIDs as cyclooxygenase (COX) type I and II inhibitors ......................................................................................................................... 84 12.7 Supportive care during Dinutuximab beta infusion................................................................ 85 12.7.1 Pain Management.......................................................................................................... 85 12.7.2 Prevention of dinutuximab beta related infusion reactions............................................ 86 13 Concomitant Medication................................................................................................................ 87 14 Assessments .................................................................................................................................. 87 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 18 of 157 BEACON-Neuroblastoma Trial Protocol 14.1 Response assessment .......................................................................................................... 88 15 Biomarkers...................................................................................................................................... 88 15.1 Blood sampling safety ........................................................................................................... 88 15.2 MRI-derived functional imaging biomarkers of angiogenesis................................................ 90 15.3 Molecular monitoring mRNA.................................................................................................. 90 15.4 Neuroblastoma exploratory biomarker analyses ................................................................... 90 15.5 Sample Collection.................................................................................................................. 92 15.5.1 Peripheral blood samples .............................................................................................. 92 15.5.2 Bone Marrow Samples .................................................................................................. 92 15.5.3 Archival tumour samples ............................................................................................... 92 16 Patient Follow Up ........................................................................................................................... 93 16.1 Patient Withdrawal................................................................................................................. 93 17 Pharmaceutical Information .......................................................................................................... 94 17.1 Definition of Investigational Medicinal Product ...................................................................... 94 17.2 Bevacizumab ......................................................................................................................... 94 17.2.1 Bevacizumab - Drug Supply .......................................................................................... 94 17.2.2 Bevacizumab - Ordering ............................................................................................... 94 17.2.3 Bevacizumab - Formulation, Packaging and Labelling ................................................. 94 17.2.4 Bevacizumab - Preparation and Dispensing ................................................................. 95 17.2.5 Compatibility information ............................................................................................... 95 17.2.6 Bevacizumab - Administration ....................................................................................... 95 17.2.7 Bevacizumab – Accountability....................................................................................... 96 17.2.8 Bevacizumab - Destruction............................................................................................ 96 17.3 Cyclophosphamide ................................................................................................................ 96 17.4 Dinutuximab beta................................................................................................................... 96 17.5 Irinotecan ............................................................................................................................... 96 17.5.1 Irinotecan - Drug Supply ............................................................................................... 96 17.5.2 Irinotecan - Formulation, Packaging and Labelling ....................................................... 96 17.5.3 Irinotecan - Preparation and Dispensing ....................................................................... 97 17.5.4 Compatibility information ............................................................................................... 97 17.5.5 Irinotecan - Administration ............................................................................................. 97 17.6 Temozolomide ....................................................................................................................... 97 17.6.1 Temozolomide – Drug Supply ....................................................................................... 97 17.6.2 Temozolomide - Formulation, Packaging and Labelling ............................................... 97 17.6.3 Temozolomide - Administration ..................................................................................... 97 17.7 Topotecan.............................................................................................................................. 98 17.7.1 Topotecan - Drug Supply.............................................................................................. 98 17.7.2 Topotecan - Formulation, Packaging and Labelling ..................................................... 98 17.7.3 Topotecan - Preparation and Dispensing ..................................................................... 98 17.7.4 Topotecan - Compatibility information ........................................................................... 98 17.7.5 Topotecan - Administration........................................................................................... 99 18 Adverse Event Reporting .............................................................................................................. 99 18.1 Reporting Requirements........................................................................................................ 99 18.1.1 Adverse Events (AE) ..................................................................................................... 99 18.1.2 AESIs of Bevacizumab .................................................................................................. 99 18.1.3 Serious Adverse Advents (SAE).................................................................................... 99 18.1.4 Reporting period .......................................................................................................... 100 18.2 Reporting Procedure ........................................................................................................... 100 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 19 of 157 BEACON-Neuroblastoma Trial Protocol 18.2.1 Site............................................................................................................................... 100 18.2.2 Trial Office ................................................................................................................... 102 18.2.3 Reporting to the Competent Authority and main Research Ethics Committee ........... 102 18.2.4 Investigators ................................................................................................................ 102 18.2.5 Data Monitoring Committee ......................................................................................... 102 18.2.6 Manufacturer of Investigational Medicinal Product...................................................... 102 19 Data Handling and Record Keeping ........................................................................................... 103 19.1 Data Collection .................................................................................................................... 103 19.2 Archiving .............................................................................................................................. 103 20 Quality Management .................................................................................................................... 103 20.1 Site Set-up and Initiation ..................................................................................................... 103 20.2 On-site Monitoring ............................................................................................................... 104 20.3 Central Monitoring ............................................................................................................... 104 20.4 Audit and Inspection ............................................................................................................ 104 20.5 Notification of Serious Breaches ......................................................................................... 104 21 End of Trial Definition .................................................................................................................. 105 22 Statistical Considerations ........................................................................................................... 105 22.1 Trial Design.......................................................................................................................... 105 22.2 Definition of Outcome Measures ......................................................................................... 106 22.2.1 Primary ........................................................................................................................ 106 22.2.2 Secondary.................................................................................................................... 106 22.2.3 Exploratory/Tertiary ..................................................................................................... 106 22.3 Sample Size......................................................................................................................... 106 22.4 Interim and Main Analyses of Outcome Measures.............................................................. 108 22.4.1 Planned Interim Analyses ............................................................................................ 108 22.4.2 Main Analysis............................................................................................................... 108 22.5 Stopping Guidelines ............................................................................................................ 110 23 Trial Organisational Structure..................................................................................................... 110 23.1 Coordinating Sponsor .......................................................................................................... 110 23.2 Co-Sponsor Centres ........................................................................................................... 110 23.3 Relationship of trial committees........................................................................................... 112 23.4 Trial Management Group..................................................................................................... 112 23.5 Trial Steering Committee ..................................................................................................... 112 23.6 Data Monitoring Committee................................................................................................. 112 23.7 Finance ................................................................................................................................ 113 23.8 NIHR CRN Portfolio ............................................................................................................. 113 24 Ethical Considerations ................................................................................................................ 113 25 Confidentiality and Data Protection ........................................................................................... 114 26 Insurance and Indemnity ............................................................................................................. 115 27 Publication Policy ........................................................................................................................ 116 28 Reference List............................................................................................................................... 117 Appendix 1 – WMA Declaration of Helsinki .................................................................................... 124 Appendix 2 - Definition of Adverse Events ..................................................................................... 127 Appendix 3 - Common Toxicity Criteria Grading ........................................................................... 129 Appendix 4 – RECIST Criteria 1.1 .................................................................................................... 130 Appendix 5 – Tumor Response at Metastatic Soft Tissue and Bone Sites (Park et al. 2017) ... 133 Appendix 6 - CURIE & SIOPEN scoring methods for neuroblastoma ......................................... 134 Appendix 7 – Temozolomide Dosing............................................................................................... 136 BEACON-Neuroblastoma Protocol_vn 8.0_vd _07Mar2023 Page 20 of 157 BEACON-Neuroblastoma Trial Protocol Appendix 8 – Blood Pressure Levels by Age and Height Percentile for Children and Adolescents ....................................................................................................................................... 139 Appendix 9 – Height for Age Chart - Girls ...................................................................................... 144 Appendix 10 – Height for Age Chart - Boys.................................................................................... 149 Appendix 11 – Lansky and Karnofsky/ECOG Scales .................................................................... 154 Appendix 12 – Tanner Staging ......................................................................................................... 156 Appendix 13 – Clinical studies of anti-GD2 therapies in combination with chemotherapy ...... 157 LIST OF TABLES Table 1 - Second line chemotherapy regimens tested in phase II in relapsed or refractory neuroblastoma since 2000 ..........
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