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Groundbreaking FOCUS4 clinical trials report their findings at ASCO

As FOCUS4 prepares to report findings at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021, the NIHR have taken a historical look at how this groundbreaking trial has helped shape the future of clinical trial delivery in the UK. Professor Tim Maughan of the Department of Oncology at the University of Oxford and co-Principal Investigator of the FOCUS4 studies, explores how experience gained from delivering FOCUS4 has helped the UK to rapidly answer questions of global importance about the treatment of COVID-19.

FOCUS4, one of the UK’s flagship precision medicine cancer trials, opened back in 2014. It is a randomised trial investigating treatments for colorectal cancer using a complex adaptive methodology which is known as Multi-Arm, Multi-Stage (MAMS) design. Such trials, also called umbrella or platform trials, allow for multiple treatments to be tested simultaneously against the standard of care (the control). However, FOCUS4 has the added complexity of stratified medicine, which requires that all eligible patients undergo genome sequencing to identify genetic biomarkers relating to their cancer. Patients are then matched to the trial arm/treatment to which they are most likely to respond.

This new way of working emerged following a rapid increase in the number of new cancer treatments being developed by life science companies which needed a systematic approach to quickly understand which treatments worked against which cancers. Professor Maughan explains:

“The adaptive, multi-arm, multi-stage approach was pioneered by the MRC Clinical Trials Unit at UCL and it provides a more efficient way of working compared to traditional back-to-back randomised clinical trials which only test one treatment at a time. Not only does it avoid the delays and costs of setting up a new trial for each new drug candidate, it also makes the screening process more efficient. Patients are screened for a match to all the drugs being trialled and have a higher probability of being able to join the trial and access a cutting-edge treatment. But more importantly – and this is where the adaptive bit comes in – new arms can be added to the trial platform as new drugs become available. Equally, where drugs are showing no benefit, that arm of the trial can be closed and another trial can be opened in the part of the trial.”

The FOCUS4 trial design was considered groundbreaking when it opened in 2014 as it was one of the first large-scale, molecularly stratified, MAMS cancer trials in the UK. It successfully enrolled 1,434 patients from 88 hospitals. Prior to this the FOCUS3 study, opening in February 2010, sought to establish the feasibility of this approach, recruiting 240 patients at 24 centres.

However, the UK’s experience of MAMS trials can be tracked back further to the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) Trial which opened in the UK in 2005. This trial is ongoing, has recruited almost 12,000 participants, and has produced practice-changing results in the treatment of prostate cancer. Although STAMPEDE commenced much earlier than FOCUS3 or FOCUS4, Professor Maughan says it is important to note:

“Although very challenging in other ways, STAMPEDE does not currently involve molecular stratification and this is a significant difference in the complexity of the trial delivery and why trials like FOCUS4 and the National Lung Matrix are world-renowned, despite opening a number of years after STAMPEDE.”

Fast forward to 2020 and the COVID-19 pandemic. The emergency situation necessitated a systematic approach to quickly understand which treatments worked against the novel coronavirus. Sound familiar?

Collaborative research culture

Speed and agility are imperative in a pandemic situation. This caused a seismic shift in attitudes towards developing new ways of working in areas such as streamlining the trial approval process.

Rapid trial set-up and delivery are also crucial. Thankfully, as we’ve established, the UK already had experience and understanding of implementing large scale, adaptive multi-arm, multi-stage clinical trials. This existing knowledge and ability to collaborate on a national scale certainly seems to have underpinned our rapid COVID-19 research response seen in trials like RECOVERY (Randomised Evaluation of COVID-19 Therapy). Professor Maughan said:

“FOCUS4 lies in this historic development of complex innovative designs. It builds first of all on the establishment of the research infrastructure through the Clinical Research Network, which is integral to the support of all these major UK national trials. Secondly, it builds on the adaptive statistical methodology, which was first developed in STAMPEDE – the multi-arm, multi-stage design approach.

“The RECOVERY trial is built on the same adaptive statistical model and also the fact that there was this fantastic research delivery infrastructure in the UK, which enabled it to move very fast and recruit these huge numbers of patients in a very short period of time. The success of RECOVERY and other MAMS trials in recent years is testament to the 20 years of investment in clinical research delivery culture in the NHS and the collaborative working across the industry in the UK.”

The world-leading RECOVERY trial does, indeed, use the MAMS trial design to test emerging treatments for the novel coronavirus and was established during the early stage of the pandemic when there were no proven treatments available. Within three months, it generated clinical evidence resulting in dexamethasone becoming the world’s first proven drug to reduce mortality for the most seriously ill patients. It also showed that hydroxychloroquine, once considered a promising therapeutic candidate for COVID-19, has no clinical benefit for hospitalised patients and this arm of the trial ceased immediately.

The PRINCIPLE (Platform Randomised trial of INterventions against Covid-19 In older peoPLE) and REMAP-CAP (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia) trials also utilise an adaptive platform approach. These flagship trials, building on the foundations of STAMPEDE, FOCUS4 and Lung Matrix, are likely to accelerate uptake and acceptance of the adaptive platform approach in clinical trial delivery in future years as the global drive for faster and more efficient clinical trials intensifies.

Forthcoming findings

It seems quite pertinent then for FOCUS4 to be on the cusp of publishing new findings in the wake of the pandemic. Professor Maughan looks back at some of the previously published results of the trial:

“Our first molecular cohort showed comprehensive negative results, and we were able to close it after only 32 patients had been accrued to FOCUS4-D – one arm of the FOCUS4 trial. That was published back in 2017 and you’ll see in many platform designs that a number of negative results come out. That’s important because we’re showing that things don’t work as well as the things that do work.

“The trial has now closed to recruitment in October 2020, after conducting three molecularly targeted sub-trials and one non-molecularly stratified trial in six years, and has generated some interesting results. Prof Richard Adams will be presenting some of these at the ASCO (American Society of Clinical Oncology) Annual Meeting on 4-8 June 2021 and we are in conversation with journals about publications.

“When we embarked on FOCUS4 we knew it would be a challenge, and we have learnt a huge amount along the way. It’s really important now that we share this learning and continue to improve the way we do clinical trials in the future.”

Professor Maughan also recognises that complex trials like FOCUS4 require the right ingredients to enable successful delivery. He emphasises the importance of the UK’s unique clinical research landscape:

“The whole complex research ecosystem of the UK presents an unparalleled opportunity for complex and innovative trials. We have the NHS as a single health care provider, the NIHR Clinical Research Network as a coordinated research delivery organisation, collaborative laboratory scientists delivering the sequencing, the collective work of the funders, forward-thinking regulators, and the National Cancer Research Institute. All this facilitates a really collaborative clinical research culture within the UK where organisations don’t have to compete with each other for patients, for example. Not a lot of countries in the world that can replicate that same environment.

“We have also shown that our research infrastructure can be adapted to an emergency situation and this is thanks to the NIHR Clinical Research Network and the trained research workforce who are based in every hospital and primary care setting in the UK. I think the real challenge now is ensuring that we learn from the COVID-19 crisis to improve the way we do things normally, in the clinical research setting, outside of the pandemic.”

 

Oxford spin out influencing patient care world wide

Optellum, a lung health company aiming to redefine early diagnosis and treatment of lung disease, today announced it received FDA clearance for its “Virtual Nodule Clinic”.

Optellum was co-founded by Oxford cancer researcher Prof. Sir Michael Brady with the mission of seeing every lung disease patient diagnosed and treated at the earliest possible stage, and cured.

Optellum’s initial product is the Virtual Nodule Clinic, the first AI-powered Clinical Decision Support software for lung cancer management. Their platform helps clinicians identify and track at-risk patients and speed up decisions for those with cancer while reducing unnecessary procedures.

Lung cancer kills more people than any other cancer. The current five-year survival rate is an abysmal 20%, primarily due to the majority of patients being diagnosed after symptoms have appeared and the disease has progressed to an advanced stage. This much-needed platform is the first such application of AI decision support for early lung cancer diagnosis cleared by the FDA.

Physician use of Virtual Nodule Clinic is shown to improve diagnostic accuracy and clinical decision-making. A clinical study, which underpinned the FDA clearance for the Virtual Nodule Clinic, engaged pulmonologists and radiologists to assess the accuracy for diagnosing lung nodules when using the Optellum software.

Dr Václav Potěšil, co-founder and CEO of Optellum says:

“This clearance will ensure clinicians have the clinical decision support they need to diagnose and treat lung cancer at the earliest possible stage, harnessing the power of physicians and AI working together – to the benefit of patients.

Our goal at Optellum is to redefine early diagnosis and treatment of lung cancer, and this FDA clearance is the first step on that journey. We look forward to empowering clinicians in every hospital, from our current customers at academic medical centers to local community hospitals, to offer patients with lung cancer and other deadly lung diseases the most optimal diagnosis and treatment.”

New partnership enables access to state-of-the-art radiotherapy machine

The first NHS patient has received treatment on the cutting-edge ViewRay MRIdian technology, thanks to a new partnership between the University of Oxford, Oxford University Hospitals (OUH) NHS Foundation Trust and GenesisCare.

The partners, with the support of the John Black Charitable Foundation, have collaborated to establish a ten-year programme of clinical treatment for NHS patients, with further research into improving cancer treatment using the Viewray MRIdian.

Due to the natural, unavoidable movement of soft tissue inside the body, normal tissue around the cancer can be exposed to radiotherapy treatment, particularly when targeting soft-tissue tumours deep within the body. It can be challenging to visualise these organs during radiotherapy with routine radiotherapy delivery.

The ViewRay MRIdian machine is the only one of its kind in the UK, with only 41 machines worldwide. It allows doctors to see the normal soft tissue and the tumour in real time by combining MRI scanning with targeted radiotherapy. Incorporating MRI scans will allow doctors to then tailor doses in real time to the specific internal anatomy of the patient on the day of treatment.

MRIdian technology also minimises the damage to surrounding healthy tissues by switching off when tumour tissue moves outside of the targeted beam. This could mean less side effects for patients and increased dosage of treatment delivered directly to the tumour.

GenesisCare, the University of Oxford and OUH will also partner in research collaborations to develop real-world evidence which will inform future utilisation of the MRIdian technology in hard-to-reach tumours, such as pancreatic cancers. The research partnership will assess the benefits of the MRIdian technology in terms of improved cancer outcomes and reduced toxicity.

Elizabeth Rapple, from South Oxfordshire, is the first patient to use the machine to treat her renal cancer, as part of the new partnership. She says:

“I feel very fortunate to be able to access this machine as part of a new Oxford-wide partnership. Any operation to remove my tumour would have been highly invasive, so it’s lucky that my cancer was suitable for MRIdian radiotherapy. I am so grateful that this unique machine has been made accessible through the NHS, and that I can be the first of many to benefit from this partnership going forward.”

Project leader Professor Tim Maughan, from the University of Oxford, said:

“Treating patients on the MRIdian is like a surgeon putting on their spectacles for an operation – for the first time we can see exactly what the cancer is doing during treatment and adapt to change accordingly.  This accuracy allows us to reduce side effects and we hope to improve cancer outcomes in hard-to-treat cancers.”

Dr James Good, Clinical Oncologist at GenesisCare, said:

“The MRIdian machine is at the cutting-edge of what is possible in radiotherapy technology. The ability to visualise the tumour more accurately, to follow it while it’s being treated and to adapt the plan every day means we can deliver the best possible outcomes.

“This collaboration with the University of Oxford and Oxford University Hospitals will be truly beneficial for cancer patients in the UK. Not only will it provide patients who otherwise would have limited, or sadly, no options with a really viable treatment option, but we can also help demonstrate the effectiveness of this treatment, with the ambition to make it available for all NHS patients in the future.”

Carol Scott, Lead Therapeutic Radiographer & Deputy Clinical Director at Oxford University Hospitals , said:

“OUH are excited to be part of this collaboration offering NHS patients the opportunity to take part in these clinical trials. The use of daily advanced imaging that clearly shows us the tumour and normal soft tissue around it will enable us to take the next step in making our treatments even more personalised and effective”

Prof Andi Roy receives new award for immune-cell research

Co-funded by Cancer Research UK and Children with Cancer UK, Andi is one of 5 to receive £1 million each to investigate children’s and young people’s cancers.

Oxford Cancer Centre appoints Prof. Tim Elliott as new co-director

The CRUK Oxford Centre is pleased to announce the appointment of Professor Tim Elliott as its new co-Director. Tim will work alongside Professor Mark Middleton who has filled the role since 2017, to develop and deliver the research strategy for the Oxford Centre.

Professor Tim Elliott is taking over from Professor Xin Lu, who is stepping down after over 3 successful years in the post. During her tenure, Xin has led a step change in the coordination and integration of research efforts across the city. Under Xin’s leadership, a collaborative network of early cancer detection researchers across Oxford has been established and supported through the formation of the Oxford Centre for Early Cancer Detection (OxCODE). As well as providing a forum to stimulate and catalyse research in this critically important research field, significant programmatic funding has been obtained, including for liver (DeLIVER – Prof. Ellie Barnes) and lung (DART – Prof. Fergus Gleeson) cancers, along with numerous seed and project external funding awards in early detection. Xin will continue to play a major role in directing and supporting the CRUK Oxford Centre strategy in her continuing positions as OxCODE Director, NIHR Oxford BRC Cancer Theme Co-Lead and Director of the Ludwig Institute for Cancer Research, Oxford Branch.

Tim has recently joined the Nuffield Department of Medicine and Oriel College as the Kidani Professor of Immuno-Oncology. He re-joins the Oxford community from Southampton University, having previously completed his undergraduate degree in Biochemistry at Balliol and subsequently holding a Professorial post at the Weatherall Institute for Molecular Medicine. Tim brings with him a wealth of expertise and experience in leading international collaborative multidisciplinary research; and he helped lead the campaign for the Southampton Centre for Cancer Immunology which opened in 2018 and where he was Director until his appointment in Oxford. He is ideally placed to help lead the Oxford Centre in its efforts to ensure that cancer research across the city continues to drive improvements in cancer patient care through enhancing our fundamental understanding of the disease.

Professor Tim Elliott, Cancer Research UK Oxford Centre Co-director and Kidani Professor of Immuno-Oncology at the Nuffield Department of Medicine, University of Oxford, said:

“This is a great time to be joining Oxford.  Recent events have demonstrated how effectively Oxford researchers can come together to generate the new knowledge needed to drive life-saving treatments for a new pathogen.  There is every sign that we can focus that collegiality on beating cancer too.

“I am excited by the prospect of helping multidisciplinary teams to converge on difficult problems that will ultimately lead to better clinical outcomes for people diagnosed with cancer.  I am also really looking forward to working with Mark, whose clinical and translational expertise and great leadership will be key to pulling our discovery science through into the clinic.”

 

Professor Mark Middleton, Cancer Research UK Oxford Centre Co-director and Head of Department of Oncology at the University of Oxford, said:

“I am delighted that Tim will help lead our diverse research community. His successful approach to delivering internationally recognised multi-disciplinary immunology research makes him an exciting addition to Oxford. Tim joins us a fascinating time, with more opportunities than ever for ensuring that cancer patients benefit from the world-leading research being carried out across Oxford. His track record of bringing together fundamental, translational and clinical researchers that span traditional research boundaries will be critical in building on our recent progress exploiting Oxford’s cancer research ecosystem to improve patient care worldwide.

“The leadership Xin has provided to the Cancer Centre over the last 3 years has been transformative. There are many clinical trials and early detection programmes that would not have taken place without her, and this is testament to both her strategic vision and the time and effort she has put into the Centre during her tenure. I’d like to thank Xin on behalf of all the researchers across Oxford who have benefited from her leadership. I look forward to continuing to work with her on delivering the Centre’s goals in her capacity as OxCODE Director, NIHR Oxford BRC Cancer Theme Co-Lead, and Director of the Oxford Branch of the Ludwig Institute for Cancer Research.”

 

A very warm welcome to Professor Tim Elliott from the CRUK Oxford Centre team and wider cancer research community here in Oxford.

Professor Tim Elliot Biography

Professor Tim Elliott left the University of Oxford with a first in Biochemistry in 1983, received a PhD from the University of Southampton in 1986 and completed his postdoctoral training at MIT. He held a lectureship and later a professorship in immunology (Weatherall Institute for Molecular Medicine and Balliol College, University of Oxford) between 1990-2000 before being appointed to the Chair of Experimental Oncology, School of Medicine, University of Southampton.

He was Associate Dean (Research) for the Faculty of Medicine between 2005 and 2015. He’s held appointments on Scientific Advisory boards at the Wellcome Trust, the Association of International Cancer Research, Leukaemia and Lymphoma Research, Symphogen, and Avviity Therapeutics; chairs the CRUK Expert Review Group for Cancer Immunology and sits on the CRUK Discovery Science Research Committee. He has published over 130 papers in the field of molecular immunology; was visiting lecturer of the Alberta Heritage Foundation for Medical Research, University of Edmonton, Alberta in 1999; and recently held a visiting Professorship at the Netherlands Cancer Institute, Amsterdam. He is a fellow of the Royal Society of Biology and in 2014 he was elected to the Academy of Medical Sciences.

Professor Elliott was amongst the key group of immunologists who developed studies of antigen presentation at the molecular level during the 1990s, undertaking a series of studies to determine and define the immunostimulatory properties of MHC Class I molecules and elucidating the molecular mechanisms of co-factor assisted peptide loading of MHC Class I in antigen presenting cells: work considered to be the foundation of much of the recent work on antigen presentation. The work underpins rational T-cell based vaccine design and continues to fuel translational research where discoveries in the areas of antigen discovery, T cell regulation and immunodominance are making a significant impact on new and ongoing cancer immunotherapy trials.

His mechanistic studies have always benefitted from an active interface with the physical sciences,  mathematics and computer science, nanofabrication and engineering.

What we can learn from cancer survivors

Understanding how an individual survives cancer, and why they respond well to therapy, can be vital in identifying new therapeutic targets. A new project seeks to see why some advanced pancreatic cancer patients overcome the odds and respond positively to treatment.

Oxford Cancer alumni’s biotech success

Scenic Biotech was founded in March 2017 as a spin-out of the University of Oxford and the Netherlands Cancer Institute. The company is based on the Cell-seq technology developed by co-founders Sebastian Nijman and Thijn Brummelkamp in their academic labs.

Cell-seq is a large-scale genetic screening platform that allows the identification of genetic modifiers – or disease suppressors – that act to decrease the severity of a disease. These disease-specific genetic modifiers are difficult to identify by more traditional population genetics approaches, especially in the case of rare genetic diseases. By mapping all the genetic modifiers that can influence the severity of a particular disease, Cell-seq unveils a new class of potential drug targets that can be taken forward for drug development.

In a deal worth $375m, Scenic Biotech has recently entered into a strategic collaboration with Genentech, a member of the Roche Group. This will enable discovery, development and commercialisation of novel therapeutics that target genetic modifiers.

Oxford lymphoid study group established

The new Oxford Lymphoid Disorder Study Group, chaired by Dr Graham Collins, will be launched this September in Blood Cancer Awareness Month

Oxford University and Sichuan University form joint Centre for Gastrointestinal Cancer

The University of Oxford-Sichuan University Huaxi Joint Centre for Gastrointestinal Cancer is a new international collaboration that seeks to develop an integrated gastrointestinal cancer plan through the exchanging of ideas and resources.

NCITA: a new consortium on cancer imaging

Cancer imaging is an umbrella term that defines diagnostic procedures to identify cancer through imaging – such as scans via x-rays, CT scans and ultrasounds. There is no single imaging test that can accurately diagnose cancer, but a variety of imaging tests can be used in the monitoring of cancer and planning of its treatments.

What is NCITA?

NCITA – the UK National Cancer Imaging Translational Accelerator – is a new consortium that brings together world leading medical imaging experts to create an infrastructure for standardising the cancer imaging process, in order to improve its application in clinical cancer treatment.

Research and medical experts from the University of Oxford have come together with UCL, University of Manchester, the Institute of Cancer Research, Imperial, Cambridge University and many more to create this open access platform.

How will NCITA help cancer research?

On top of bringing together leading experts in cancer imaging to share their knowledge, the NCITA consortium will create a variety of systems, software and facilities to help localise and distribute new research and create a centralised location for cancer-image data to be analysed.

NCITA will in include a data repository for imaging, artificial intelligence (AI) tools and training opportunities – all of which will contributing to a revolution in the speed and accuracy of cancer diagnosis, tumour classification and patient response to treatment.

The NCITA network is led by Prof Shonit Punwani, Prof James O’Connor, Prof Eric Aboagye, Prof Geoff Higgins, Prof Evis Sala, Prof Dow Mu Koh, Prof Tony Ng, Prof Hing Leung and Prof Ruth Plummer with up to 49 co-investigators supporting the NCITA initiative.  NCITA is keen to expand and bring in new academic and industrial partnerships as it develops.

Go to the NCITA website to stay up to date of news about cancer imaging research.

For more information on this exciting new initiative, see the media release about the NCITA launch here.