NCRI Brain Tumour Clinical Studies Group

Annual Report 2012/2013

Data

Section # Indicator Lowest Highest

Disease 1 Incidence of disease (UK) 4753 2,232 48,988

2 Mortality of disease UK) 3750 71 35,042

Members 3 Number of Scientific Members on CSG 22 14 264 Number of Subgroups 5 0 75 Number of Taskgroups 0 0 2

6 Number of Consumers involved in CSG, Subgroup and Taskgroup activities 1 1 4

Portfolio 7 Total number of academic/industry sponsored portfolio studies opening in year 4/1 1/2 24/138 Number of academic/industry sponsored portfolio studies open 15/1 1/1 93/299 Total number of portfolio studies(academic and industry sponsored) closing in year 4 1 21

10 Number of studies conducted internationally (outside UK) open 5 1 3911 Number of Industry Alliance Studies open in year 1 1 3

12 Participation in International Rare Cancer Initiative (IRCI) Yes

Portfolio Delivery 13 Total number of participants recruited (All CSG portfolio studies) 1762 269 3219714 Total number of cancer patients recruited (All CSG portfolio studies) 1095 64 1374815 Proportion of cancer patients recruited by disease 23 3.1 72.216 Proportion of cancer patients recruited to interventional studies (where applicable - all CSG portfolio studies) 3.5 1.1 23.517 Number of non cancer participants recruited to studies (All CSG portfolio studies) 667 0 1844918 Total number of participants recruited to industry sponsored studies (All CSG portfolio studies) 2 2 65819 Proportion of CSG industry sponsored studies closing in year and delivered to time & target 100% 0, 1 100, 320 Proportion of other CSG academic studies closing in years and delivered to time & target 67% 17, 6 100, 1

21 Number of Local Research Networks active in delivering portfolio 38 11 40

Output 22 Number of peer review publications directly associated with CSG portfolio studies 5 0 52

23 Awareness raising/educational events Yes

Progress Review 24 Date of last Progress Review Dec-10

25 Date of next Progress Review Dec-13

NCRI Brain Tumour Clinical Studies Group

National comparison

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NCRI Brain Tumour CSG Annual Report 2012/13

1. Executive Summary The Brain CSG has continued to develop its trial portfolio. GALA-5 has successfully completed, OPARATIC has moved to stage 2 (dose escalation) of the trial and the HCQ trial has opened to recruitment. The number of patients recruited into trials has continued to rise. Recruitment into observational/non-RCT studies, especially the NBT study, is robust and includes many centres that are not recruiting into interventional or RCT trials. Our project officers are working to identify barriers to participation & recruitment by new centres and have successfully improved recruitment in several existing centres. The CSG is developing closer links to the EORTC Brain group and we are looking to establish a national network of trial competent centres incorporating existing UK EORTC brain centres. This is progressing and now needs to identify a clinical trial to pilot this initiative. The CTU at UCL have agreed to act as a hub trials unit for this in order to establish closer links with R&D departments in individual units. It is hoped that by doing so we will reduce the bureaucratic delays and open multiple centres to recruitment more efficiently. We have addressed many of the priorities identified in the 2012 report. The project officers have gathered data relating to barriers to recruitment, which will be presented at the annual BNOS meeting. We have promoted metastatic disease at the NCRI 2012 meeting and through two successfully funded trials and our closer engagement with the EORTC is developing. Major challenges going forward include developing routine collection of standardised high-quality datasets and developing trials for the many patients for whom there is currently no opportunity to participate.

2. Top three achievements in the year The Group’s top 3 achievements this year are:

GALA-5 (http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=9566): this phase I/II feasibility study evaluating the combination of fluorescence-guided resection with intraoperative chemotherapy has completed recruitment. This was the first surgical trial in patients with brain cancer in the UK. It completed recruitment 2 months ahead of schedule. Data analysis is ongoing and a follow-on phase II/III study is being developed.

OPARATIC trial (http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=10482) completed stage 1 which involved the use of a neo-adjuvant approach followed by surgery to confirm appropriate drug penetration of the tumour before proceeding to stage 2 (dose escalation). This is the first time this approach has been successfully deployed in brain cancer in the UK. It is also the first study of a PARPP inhibitor in glioma.

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Strategy day & engagement with EORTC: The Brain CSG strategy day was successful in developing a forward-looking programme in line with the future plans outlined in the 2011/12 annual report. Two productive CSG meetings have been held to establish closer links and develop a national network of trial competent centres. This initiative is now looking to develop a trial to pilot this initiative in the UK.

3. Structure of the Group Good progress has been made towards organic restructuring of the subgroups. The merger of the Novel Agents Subgroup with the Translational Subgroup has been effectively made by organising the meetings on the same day with a 1 hour overlap for both groups to be together. The current membership of the subgroups can be found in Appendix 1. Merger of the Technology and Imaging Subgroups is ongoing with joint, overlapping, meetings envisioned for 2013/14. The main CSG has lost several members (Professor Siow Ming Lee, Professor Neil Burnet, Dr Paul Mulholland, Dr Paul Sanghera, Dr Swethajit Biswas and Ms Naomi Crosby) due to “retirement” while retaining several experienced people. We have also recruited a new, young and active member with interests in cerebral metastatic disease (Dr Gillian Whitfield), a clinical trials statistician (Dr Wendy Qian) and neuropathologist (Dr Kathreena Kurian). The current membership of the CSG can be found in Appendix 1.

4. Achievements and challenges of the subgroups Novel Agents & Translational Subgroup The main development this year is that meetings are now being held in collaboration with the Translational Subgroup, with the aims of improving communication between the two original subgroups, identifying promising new agents arising from translational laboratories and enabling early biomarker input into clinical trial design. A model was piloted at the 23rd March 2013 meeting whereby the Translational Subgroup met for two hours followed by a two hour meeting of the Novel Agents Subgroup, with Professor Anthony Chalmers and other Novel Agent Subgroup members joining the second hour of the first meeting and Professor Peter Collins joining the first hour of the second meeting. This arrangement worked well and will be continued for future meetings. Dr Mazhar Ajaz presented a strategy for classifying and prioritising potential novel agents for testing in GBM at the 23rd March 2013 meeting. This stimulated a proposal for a one day workshop devoted to this topic, which was subsequently presented and approved by the Brain Tumour CSG. The Project Officers would supply project support and Dr Ajaz and Professor Chalmers would identify a date and venue, create an agenda and draw up an invitation list. The following study that was developed with input from the subgroup and is actively recruiting:

OPARATIC study – phase I study of olaparib and temozolomide in recurrent glioblastoma, CI Anthony Chalmers. Funded and managed by CRUK DDO. This trial is now open in 7 UK sites (Glasgow, Manchester, Marsden, Edinburgh, Cambridge, Birmingham, Bristol). Recruitment to Stage 1 was completed at 3 patients and the primary endpoint met. 3 patients have now been recruited to the first cohort of Stage 2.

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The following studies are under development:

LDE225 (Smoothened inhibitor) in relapsed medulloblastoma – commercial phase I study in paediatric patients is complete and Novartis are planning to extend to phase II in both paediatric and adult populations; projected to open in May 2013. Two adult sites in the UK sought.

Pegylated Arginine Deaminase (ADI-SS PEG) in recurrent glioblastoma, CI Professor Peter Schmid. The study was rejected by CTAAC and an appeal unsuccessful. Following additional statistical review and discussions with the PI, this study had been taken off the Novel Agents Subgroup agenda but there was strong interest from the Translational Subgroup for such a biomarker driven study so Professor Schmid (CI) has been contacted for an update.

PARADIGM – short course radiotherapy plus olaparib in newly diagnosed glioblastoma patients ineligible for radical treatment, CI Professor Chalmers. The study had been on hold pending AZ olaparib review. The Olaparib programme has now been re-activated and this study invited for presentation at the AZ-NCRN Combinations Alliance Workshop on 8-9 May.

Chemocentryx study – a phase I study of a CXCR7 inhibitor in GBM had been submitted to NAC in response to a DDO call for expressions of interest, with Professor Chalmers as CI. Its rating was preliminary so it will be resubmitted with additional pre-clinical data. The Novel Agents Subgroup discussed a novel phase I ‘first in human’ study design that would enable the compound to be tested in the appropriate patient population.

As indicated previously, the Translational Subgroup met with the New Agents Subgroup in March. The translational studies previously discussed and being carried out by members of the subgroup includes one on meningiomas that has resulted in a publication (Reuss et al, Acta Neuropathologica, 125, 351-8, 2013) describing the unique mutation pattern found in secretory meningiomas. The bolt on translational study to BR12 is being prepared for publication. Issues relating to EQA in diagnostic molecular neuropathology and national standards for tissue banking were discussed with a document “Tumour collection guidelines for CNS tumours” being planned. The overlap of the meeting with the New Agents group was very successful, the aim being to integrate translational research at an early stage into all trials and it was agreed that this should be continued for all future subgroup meetings. Subgroup membership was reviewed and a number of new members will be invited to join. Technology Subgroup The Technology Subgroup (TSG) has continued to prosper. We have continued to strengthen links with clinical oncology, promote fluorescence-guided surgical technology and establish the phase 0 approach to drug development. The TSG has supported Dr Paul Sanghera and Dr Gillian Whitfield who have continued to develop a study titled “A randomized phase II trial of Hippocampal Sparing versus Conventional Whole Brain after surgical resection or radiosurgery in favourable prognosis patients with 1-4 brain metastases”. This has been submitted to CTAAC for consideration and a decision is imminent. The TSG has also supported Dr Richard Baird in developing a clinical trial investigating the role of

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radiotherapy in enhancing drug penetration in patients with cerebral breast metastases. The study is titled “A randomised phase 2 trial of afatinib (BIBW-2992) penetration into cerebral metastases following targeted radiotherapy, with safety run-in”. The application to CTAAC has been successful and the trial is now in set-up in Cambridge. These trials reflect progress in several key objectives: the development of advanced radiotherapy research; the development of technologies to improve drug penetration into brain tumours and a focus on cerebral metastatic disease. The TSG has previously supported the development and execution of GALA-5, which completed on schedule. A follow-on phase III study, InGALA, is now under development. Future study development will include a focus on meningiomas. The TSG has already supported the development of the ROAM study that will examine the role of radiotherapy in the management of newly diagnosed atypical meningioma. Funding has been applied for through an NIHR strategic call for research in rare disease. In addition the TSG (and CSG) will be working closely with the EORTC to promote radiotherapy research in atypical meningioma across a wider network. Strategic evolution going forward will be to strengthen links with the Imaging Subgroup (ISG) with a view to merging the two groups. The objective of the merger will be to establish a coherent structure to develop and deploy non-pharmacological technologies within the context of interventional clinical trials and biomarker development. Further plans include the development of stereotactic radiosurgery trials beginning with some preliminary feasibility work in 2013/14. Imaging Subgroup The subgroup main successes of the subgroup have been:

Draft guidelines for minimal imaging dataset for UK clinical trials and the institution of imaging review for CSG reviewed studies

Successful funding of Quantitative diffusion imaging for early treatment response and progression evaluation in adult high grade gliomas; a multicentre study. PI: Adam Waldman, Funder: The Brain Tumour Charity

Palliative Care Subgroup The Palliative Care Subgroup (PSG), following discussions at the 2012 Brain CSG Strategy Day, has actively promoted links with the palliative care community as well as those with neuropsychological and neuro-psychosocial expertise. Dr Angela Costello has completed her study on Social Cognitive Dysfunction Following Brain Tumour: Patients and Relatives Perspective and this has been submitted to the Journal of Neuro Oncology and BNOS conference 2013. Dr Helen Bulbeck has set up a meeting at BNOS 2013 to help promote collaborative research into neuropsychosocial care for people and carers who are living with a brain tumour diagnosis. Dr Lucy Brazil has been working with Dr Anthony Byrne and his team at the Marie Curie Research Centre, Wales Cancer Trials Unit on a phase II/III trial of early palliative care for patients with GBM. Progress has been made with refining the protocol as well as defining the statistical and financial aspects.

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Dr Jane Neerkin has been running a study of Advanced Care Planning in brain tumour patients. Using funding from the National Brain Appeal, a qualitative interview study has opened that is exploring health care professional’s attitudes towards advance care planning. Seven interviews have been conducted so far and have already highlighted the difficulties in knowing when to approach patients, the lack of proper documentation as well as a need to shift focus to advanced care planning being about the patient needing to make the decision. The second part of this work will be to investigate the attitudes of patients and carers towards advanced care planning using similar methodology. Funding is still needed for this part of the project. Strategically over the next year with an expanded subgroup we anticipate new trial ideas whilst consolidating work on existing trials in progress.

5. Task groups/Working parties The Group had no task groups or working parties during the reporting year.

6. Patient recruitment summary for last 5 years There has been a gradual increase in the number of patients being recruited into portfolio studies. However, the majority of patients are entering non-interventional & non-RCT studies. Improving recruitment into interventional and RCT studies remains a significant challenge for the CSG.

Table 1 Summary of patient recruitment over 5 years by RCT/Non-RCT

Year All subjects Cancer patients only % of cancer patients relative to incidence

Non-RCT RCT Non-RCT RCT Non-RCT RCT

2007/2008 - 106 - 106 - 2.5

2008/2009 6 33 6 33 0.1 0.8

2009/2010 89 35 89 35 2.1 0.8

2010/2011 410 45 410 45 9.7 1.1

2011/2012 560 77 534 77 12.7 1.8

Table 2 Summary of patient recruitment by Interventional/Non-interventional

Year All participants Cancer patients only % of cancer patients relative to incidence

Non-interventional

Interventional Non-interventional

Interventional Non-interventional

Interventional

2012/2013 1594 168 927 168 19.5 3.5

7. Links to other CSGs and international groups The Brain CSG is continuing to develop a strengthening relationship with other CSGs, in particular Breast & Lung, through engagement and support for trials in cerebral metastatic disease. The Brain CSG is also successfully developing a randomised phase II study of WBRT vs. radiosurgery in patients with cerebral metastases.

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The Brain CSG is actively pursuing closer links with the EORTC. Two meetings have been held at the EORTC AGM and at ASCO between the CSG Chair and representatives of the EORTC. This has resulted in agreement to develop a national network of trial competent centres in the UK based on the existing EORTC centres. The UCL CTC has agreed to act as a central hub to establish stronger links with individual R&D departments in each centre. It is hoped that this will reduce bureaucratic delays in opening centres to new trials. We are now seeking an appropriate clinical trial to pilot this strategic initiative.

8. Funding applications in last year The following studies were submitted for funding: Table 3 Successful funding applications for the year

Title Acronym CI Funding body

Randomised phase 2 study of afatinib penetration into cerebral metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy

CamBMT1 Dr Richard Baird CTAAC

A randomized phase II trial of hippocampal sparing versus conventional whole brain radiotherapy after surgical resection or radiosurgery in favourable prognosis patients with 1-4 brain metastases *

Dr Gillian Whitfield

CTAAC

*Study deemed fundable, but deferred until June 2013 meeting due to lack of funds

Table 4 Unsuccessful funding applications for the year

Title Acronym CI Funding body

Are anti-depressants safe in cerebral glioma and would a RCT be feasible?

Dr R Grant, Dr A Rooney, Dr A Carson

CTAAC

There were no outline submissions made.

9. Industry sponsored trials portfolio Currently NCRN 396 is on going (http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=12071). Additional studies reviewed include:

NCRN605: A double-blind, placebo-controlled, randomized, Phase IIIb trial evaluating the efficacy and safety of standard of care (SOC) +/-continuous bevacizumab treatment following progression of disease (PD) in patients with glioblastoma (GBM) after first (1st)-line treatment with radiotherapy, temozolomide and bevacizumab

NCRN592: Phase III clinical trial evaluating DCVax®-L, autologous dendritic cells (DC) pulsed with tumor lysate antigen for the treatment of glioblastoma multiforme (GBM)

NCRN614: Double-Blind, Randomized, Multicenter Comparative Trial to Evaluate Two Doses of Intratumoral 131I-chTNT-1/B mAb (Cotara®) for the Treatment of Recurrent Glioblastoma Multiforme (GBM)

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NCRN631: An International, Randomized, Double-Blind, Controlled Study of Rindopepimut/GM-CSF with Adjuvant Temozolomide in Patients with Newly Diagnosed, Surgically Resected, EGFRvIII-positive Glioblastoma

The process by which sites are chosen requires greater transparency. The CSG should have greater say in where these trials are opened in the interests of promoting participation & recruitment.

10. Collaborative partnership studies with industry In addition to the above, the following studies are run in partnership with industry. RADVAN - XRT +/vandetanib in CNS melanoma- A randomised double blind phase 2 trial of whole brain radiotherapy with or without vandetanib in metastatic melanoma with brain metastases. The C.I. is Professor Mark Middleton & the study is funded by AstraZeneca. LANTERN - A randomised phase II screening trial with functional imaging and patient reported toxicity sub-studies comparing LApatiNib plus capecitabine versus continued Trastuzumab plus capecitabine after local therapy in patients with ERb B2 positive metastatic breast cancer developing brain metastases. The C.I. is Dr David Dodwell & the funder is GSK.

11. Progress towards achieving 3 year strategy Following our strategy day our 3-year strategy has been refined as follows:

Further engagement with EORTC & development of a national network of trial competent centres: The Brain CSG is actively pursuing closer links with the EORTC. Two meetings have been held at the EORTC AGM and at ASCO between the CSG chair and representatives of the EORTC. This has resulted in agreement to develop a national network of trial competent centres in the UK based on the existing EORTC centres. The UCL CTC has agreed to act as a central hub to establish stronger links with individual R&D departments in each centre. It is hoped that this will reduce bureaucratic delays in opening centres to new trials. We are now seeking an appropriate clinical trial to pilot this strategic initiative

Improving recruitment to clinical trials by identifying barriers to centre engagement & participation: The CSG project officers have proven effective at increasing clinical trial recruitment in existing centres and identifying new centres. Qualitative research is begun to identify specific barriers to participation and recruitment. These data will be presented at BNOS 2013 (see appendix 4). The next challenge in this area will be to identify solutions to the problems identified in a cost-effective manner and pilot their application in the context of a clinical trial.

Focus on cerebral metastatic disease: This is an ongoing strategic priority. A second NCRI workshop on cerebral metastases was held at NCRI 2012, which was very well attended. The CSG continues to increase its engagement with other CSGs in the development of their relevant trials and has been active in promoting its own metastatic trials (see Table 3 above).

Standardisation of data collection (clinical, radiological & biological): This is a new initiative to develop high-resolution data collection in the context of routine clinical practice. The objective is to provide a robust standard of care applied to all patients undergoing treatment for a brain tumour.

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12. Impact of clinical trials on routine UK clinical practice Below are examples of how clinical trials within the Brain CSG have impacted on routine UK clinical practice:

BR12: This trial has helped rationalise the management of patients with recurrent GBM in the UK. The use of PCV versus TMZ in the context of early v late relapse respectively has been incorporated into clinical practice.

EORTC 22952: randomised trial examining the role of whole brain radiotherapy after resection or radiosurgery for patients with 1-3 brain metastases. This has influenced the management of patients with cerebral metastases.

EORTC 26052: the role of dose dense TMZ v standard protocols. The data is beginning to emerge suggesting that dose dense regimens do not convey advantage.

13. Consumer involvement Dr Helen Bulbeck has been working with the CSG as a consumer representative to enhance patient empowerment and communication and has established a comprehensive database of UK brain tumour support services. Mr Neil Dickson (Chair of Trustees, The Bain Tumour Charity) has been heavily involved in promoting the issues of research funding for clinical trials, clinical trial recruitment and research in cerebral metastatic disease. He has held meetings with Professor Sir Mike Richards & Dr Harpal Kumar (CEO CRUK). The meetings have encouraged CRUK to establish brain cancer is a strategic cancer to be focused on in CRUK's next five-year plan (2014-2019). TBTC as an organisation is working to improve consumer involvement with regard to disseminating more information about NCRI badged brain tumour clinical trials. The TBTC continues to stage patient information days throughout the UK. This is available to patients and their families (adult and paediatric). It was agreed to include an update on the NCRI brain tumour clinical trials at each support day. This has been a great success and has enabled many more patients and their families to have access to this information. The sessions have been well received and give consumers a feeling that something positive is being done about increasing the number of trials available for brain tumour patients in the UK.

14. Open meetings / annual trials days The following meetings have been held:

A second workshop on cerebral metastases was held at the NCRI 2012 conference. This was very well attended demonstrating interest & enthusiasm for clinical trials from a broad spectrum of the oncology community.

Additional outreach meetings have been held in Brighton, Coventry, Glasgow, Cardiff, Southampton, London, Newcastle, Oxford and Cambridge. These roadshows have been an ideal opportunity to make patients and their families aware about NCRI involvement in clinical trials. The sessions have been well received and give consumers a feeling that something positive is being done about increasing the number of trials available for brain tumour patients in the UK.

A successful strategy day was held in October 2012 when our 3-year strategy was refined (see above)

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15. Priorities and challenges for the forthcoming year The priorities and challenges for the Group are to:

Continue progress towards a national network of trial competent centres and identify an appropriate clinical trial to pilot the initiative. We will then work to ensure rapid multi-centre deployment and identify barriers and solutions where there are difficulties to rapid uptake of the study.

Work with CR-UK to integrate clinical trial development with strategic research initiatives, including the generation of high-resolution imaging and biological datasets.

Develop a proposal for an imaging study in patients with Low Grade Glioma in response to the NIHR HTA call.

16. Concluding remarks The Brain CSG continues to evolve. It has established a coherent membership structure with appropriate skill sets and is continuing to develop clinical trials successfully. In parallel the Group is improving the national infrastructure for research in brain cancer and identifying barriers and challenges in this area that need to be addressed to deliver real lasting benefit for patients. Wider national engagement is allowing the Group to support other CSGs in developing their trials with involve the brain and as well as develop trials in cerebral metastatic disease of its own. International engagement means that the UK-leading trials will be better positioned to recruit sufficient numbers of patients to deliver clinically valid results. All of these developments are integrated into a 3-year plan for further development.

17. Appendices 1. Membership of main CSG and subgroups 2. Portfolio Maps 3. Publications in previous calendar year 4. Major international presentations in previous year

Dr Colin Watts (Brain CSG Chair)

Appendix 1

CSG and Subgroup membership

CSG Membership

Member Location

Dr Lucy Brazil Middlesex

Dr Helen Bulbeck Isle of Wight

Professor Anthony Chalmers Brighton

Professor Peter Collins Cambridge

Professor Garth Cruickshank Birmingham

Mr Neil Dickson Hampshire

Dr Abigail Evans London

Mr Tom Flannery Belfast

Dr Jane Fleming Waterford, Ireland

Professor Oliver Hanemann Plymouth

Dr Darren Hargrave Surrey

Dr Kirsten Hopkins Bristol

Dr Kathreena Kurian Bristol

Dr Catherine McBain Manchester

Mr Stephen Price Cambridge

Dr Wendi Qian London

Dr Joanne Rickett London

Dr Richard Shaffer Surrey

Professor Susan Short London

Dr Adam Waldman London

Dr Colin Watts Cambridge

Dr Gillian Whitfield Manchester

Subgroup Membership

Palliative Care Subgroup Technology Subgroup Imaging Subgroup

Dr Lucy Brazil (Chair) Dr Colin Watts (Chair) Dr Adam Waldman (Chair)

Dr Sosie Kassab Dr Jagmohan Singh Dr Rolf Jager

Dr Anne Arber Dr Andrew Broadbelt Dr Jeremy Rees

Dr Angela Costello Dr Patrick Mitchell Professor Sebastian Brandner

Ms Emma Townsley Dr Paul Byrne Mr Stephen Price

Dr Jane Neerkin Dr Richard Shaffer Dr David Collins

Dr Jane Fleming Professor Garth Cruickshank Professor Paul Tofts

Ms Vicky Hurwitz Dr Raj Janesh Professor Martin Leach

Dr Paul Sanghera Professor Alan Jackson

Translational Subgroup Professor Susan Short Professor Neil Burnet

Professor Peter Collins (Chair) Dr Chris Clark

Dr Tracy Warr Novel Agents Subgroup Dr Dow-Mu Koh

Dr Willie Stewart Professor Anthony Chalmers (Chair) Dr Jackie Sullivan

Dr Paul Mulholland Dr Mazhar Ajaz

Professor Oliver Hanemann Professor Mike Brada

Dr Kathreena Kurian Dr Swethajit Biswas

Dr Sean Lawler Dr Paul Mullholland

Ms Jo Rickett Dr Darren Hargrave

Dr Catherine McBain

Dr Sarah Jefferies

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BRAIN CSG PORTFOLIO MAP A BRAIN TUMOURS

Brain Metastases Meningioma

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6

NCRN396: Open-label, phase II study of vemurafenib in patients with BRAF V600 mutation-positive cancersNCRN426: Phase III, randomised, observer-blind, placebo-controlled, multicentre trial to assess the immunogenicity & safety of GSK Biologicals’ herpes zoster HZ/su candidate vaccine in adults

SIO

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BRAIN CSG PORTFOLIO MAP B BRAIN TUMOURS

Low Grade GliomaAnaplastic

Astrocytoma (Grade 3)

AnaplasticOligodendroglioma

(Grade 3)Glioblastoma

NB

T St

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*CODEL/EORTC 26081-22086 currently on holdNCRN396: Open-label, phase II study of vemurafenib in patients with BRAF V600 mutation-positive cancersNCRN417: Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab + bevacizumab vs onartuzumab monotherapy in recurrent glioblastoma

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Appendix 3 Publications arising from the Group’s portfolio

OPARATIC Carruthers, R. and Chalmers, A.J. (2012), “The potential of PARP inhibitors in neuro-oncology,” CNS Oncology. 1(1), pp. 85-97.

EORTC protocol 22042 - 26042

Reuss, D.E., et al., Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7

mutations. Acta neuropathologica, 2013. 125(3): p. 351-8

GALA-5 Trial

Sottoriva, A., et al., Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary

dynamics. Proceedings of the National Academy of Sciences of the United States of America, 2013.

110(10): p. 4009-14

MRI biomarkers of low grade glioma growth and infiltration

Peet, A.C., et al., Functional imaging in adult and paediatric brain tumours. Nature reviews. Clinical

Oncology, 2012. 9(12): p. 700-11

The role of project officers in increasing clinical trial activity for

brain tumour research

A Evans1, J Rickett1, H Bulbeck2, P Smith1, C Watts3 for the NCRI Brain Tumour Clinical Studies Group 1Cancer Research UK and UCL Cancer Trials Centre, London, UK, 2brainstrust/ NCRI Brain CSG Consumer Representative, 3Addenbrooke’s Hospital, Cambridge, UK

• The National Cancer Research Institute (NCRI) Brain Tumour Clinical Studies Group

(CSG) and its sub-groups design and take forward studies as well as provide expert

advice at the early stages of protocol development for the wider neuro-oncology

community

• The CSG identified that clinical trial activity for brain tumours was too low and that

additional support was required to increase the number of trials and levels of

recruitment in the UK. Charity funding was obtained and The Brain Tumour Charity

(TBTC) currently fund two part-time Project Officers to support this activity

• The role of Project Officer 1 is to support the CSG sub-groups in developing new

study ideas and to increase the number of patients being recruited to brain tumour

trials across the NCRN networks. The role of Project Officer 2 is to identify the

barriers to the setting up, running and recruitment to brain tumour trials

Background

Project Officer 1: • Using data provided by the NCRI Secretariat and NCRN, the Project Officer identified

sites that were not recruiting to brain tumour trials and met with key staff to present the

trials on the portfolio and conduct preliminary discussions on barriers to recruitment

• Communication with Network Managers was enhanced by regular email contact to

publicise new trials as they opened and to provide current status updates on trials in

development, in set-up or open to new sites

• Trial activity and recruitment numbers were compared year on year

Project Officer 2: • 34 staff from eight sites across the UK involved in brain tumour trials were interviewed

to gain insight into the local barriers to set up, recruitment and running of studies

• Sites representing a range of experience, trial activity and resource were selected

Staff groups represented:

• People affected by brain tumours (consumers) were invited by email to take part in an

anonymous online survey designed with the assistance of the consumer

representative of the NCRI Brain Tumour CSG

• 197 people participated

Methods

Staff Group Number Interviewed

Research nurse 7

Clinical neuro-oncologist 6

Radiologist 5

Pathologist 4

Neurosurgeon 3

Trials staff (non-clinical) 4

Pharmacist 3

Radiographer 2

R&D department 2

The NCRI Brain CSG Project Officers are supported by The Brain Tumour Charity. The

Project Officers would like to thank all those staff and consumers who contributed

towards the data in this paper.

Acknowledgements

Results: Project Officer 1

Despite, a significant increase in the number of sites now recruiting to neuro-oncology

research, a key priority for the Project Officers is to increase the number of sites that

recruit to interventional trials. This would be aided by improving the portfolio of trials, to

introduce in particular:

• More interventional trials (phase II and III)

• Trials for a wider range of brain tumour types

• More trials for recurrent tumours

• Trials focussing on brain metastases and palliative care

Project Officers will be key in achieving these aims through:

• The building of better links between sites, charities and research organisations, both

nationally and internationally

• Encouraging and enabling cross-disciplinary relationships within each location to

ensure; (i) that thorough feasibility assessments are undertaken, (ii) the best use of

resources and (iii) patient recruitment is maximised

• Increasing access to new interventional therapies by supporting the work of the CSG

sub-groups

• Increasing the number of Phase III trials by assisting sites in EORTC trial participation

and increasing CSG involvement at an earlier stage of EORTC protocol development

• Addressing exclusion/inclusion criteria issues at an early stage

• Working alongside other national initiatives to ensure sure all patients are told about

research

• Sharing our patient survey data to encourage clinicians to get involved with research

Conclusion

Project Officers have contributed to an increase in recruitment to brain tumour trials in

the UK and the research into the barriers has given insights into how the situation can be

further improved.

Discussion and Conclusion

Barriers How this has been overcome/ could be improved

Resources • Lack of staff: radiologists, RNs, radiographers

• Difficulty in covering costs of e.g.

scans

• Financial incentives for radiologists, RN supported by charity funding

• Ensure that protocols reflect UK standard of

care wherever possible

Patient pathway

• Surgery performed before discussion at MDT

• Timing of when trials are first

mentioned to patients

• Buy-in from all surgeons and pathway adapted to accommodate research

• Trials introduced at pre-assessment clinic

one week after diagnosis

Trials • Lack of trials for specific tumour types • Lack of effective agents

• Increase participation in EORTC trials • Engage with pharma to gain access to new

agents

Opinions of staff involved in trials

• Recurring barriers were identified as well as examples of how these had been

overcome

Results: Project Officer 2

Patient perspective

• The majority of patients did not recall members of their medical team discussing

opportunities for taking part in a trial with them (Fig. 2a)

• 26% of patients wanted to take part in a clinical trial but were unable to

• The most common reasons were lack of a suitable trial (31%) and exclusion/inclusion

criteria (28%) (Fig. 2b)

0 2 4 6 8 10 12

No suitable trials available

Exclusion criteria

Not suggested by medical team

Tumour too advanced/aggressive

Biopsy not performed

Hospital not taking part in trial

Poor cognitive status Fig. 2b

24%

73%

3% Yes

No

Not sure

• There was a year-on-year increase in the number of trials open, the number of sites

recruiting to trials and the number of patients recruited since the Project Officer started

(Fig. 1)

• Positive feedback was given on having a Project Officer as the central point of contact

for all brain trial enquiries

• This had reduced the administrative burden in trial set-up, as well as enabling sites to

have up-to-date knowledge on possible trials for participation and those in the pipeline

0

200

400

600

800

1000

1200

1400

1600

1800

2009-10 2010-11 2011-12 2012-13

No

. o

f p

ati

en

ts r

ecru

ite

d

Project Officer 1

Fig. 1

Fig. 2a

Response of patients

when asked whether trials

had been discussed with

them

Number of responses

Appendix 4 Presentations arising from the Group’s portfolio

There were no presentations directly relating to the Group’s portfolio.