Preoperative brain irradiation in glioblastoma (POBIG)

Lead Research Organisation: The University of Manchester
Department Name: School of Medical Sciences

Abstract

"No significant scientific breakthroughs have occurred in the brain tumour sphere for decades", concluded the 2018 All-Party Parliamentary Group on Brain Tumours, which also highlighted the high socioeconomic costs of brain tumours.
Glioblastoma is the most frequent and aggressive type of brain cancer; only 25% of all patients survive >1 year. It affects more than 2500 patients in the UK per year, and the incidence is rising. Current treatment involves surgery followed by (chemo)radiotherapy, and this sequence has not changed or been challenged in decades. Inevitably after surgery, remnant tumour cells are left behind due to its invasive nature and the inability to remove all affected brain tissue. The postoperative radiotherapy regimen targets this remnant tumour contributing to the survival of our patients. Still, numerous efforts focussing on combining radiotherapy with new agents or applying a higher dose of radiotherapy have failed.
Surgery is of both diagnostic and therapeutic value. However, we know that the surgical procedures dramatically influence the tumour landscape as the postoperative tumour microenvironment exhibits increased hypoxia, tumour migration and proliferation. These negative factors directly limit the effectiveness of postoperative treatment and emphasise the clear clinical need for a breakthrough and trialling of preoperative interventions. For this, we need to diagnose glioblastoma without obtaining tissue via surgery. In clinical practice, we refer patients likely to suffer from a glioblastoma seen on an MRI scan for neurosurgical resection. Neuro-oncology radiologists are extremely good at diagnosing glioblastoma radiologically using MRI imaging. Moreover, current MRI scan techniques enable the stratification of glioma subtypes. In other words, MRI imaging techniques are paving the road to initiating preoperative interventions in glioblastoma patients.
Following the benefits of preoperative radiotherapy in other cancers, our Preoperative Brain Irradiation in Glioblastoma (POBIG) study will deliver radiotherapy before surgery. POBIG is the first experience worldwide of standalone contemporary preoperative radiotherapy for glioblastoma patients targeting the tumour in its potentially most treatment sensitive (i.e. preoperative) state. As our patients suffer from such a devastating prognosis, this is a disease with a high clinical need. The field needs, therefore, to deliver more than a clinical study with a strong rationale. Hence, we designed POBIG to fully characterise the radiation response in newly diagnosed glioblastoma patients initiating the development of the desperately needed paradigm shift in the treatment of our patients.
In POBIG, we will assess the safe dose and volume we can treat before surgery. In our study, we also collect unique information to study the radiotherapy response in-depth for each patient. To further improve the non-invasive tumour characterisation and response monitoring, we implement our advanced machine learning-based imaging analysis that will identify the regions of the tumour that are responsible for the poor prognosis. We will also collect different types of liquid biopsies to develop non-invasive tumour characterisation and treatment monitoring tools. All this information will be analysed to inform follow on studies and develop strategies to improve the outcomes for each patient.
In summary, POBIG is a high gain, safety and feasibility phase I dose-escalation study. POBIG is the first step towards the necessary paradigm treatment shift for a disease with a high unmet medical need.

Technical Summary

"No significant scientific breakthroughs have occurred in the brain tumour sphere for decades", concluded the 2018 All-Party Parliamentary Group on Brain Tumours, which also highlighted the high socio-economic costs of brain tumours.
Glioblastoma is the most frequent and aggressive type of brain cancer, and only 25% of all patients survive >1 year. It affects more than 2500 patients in the UK annually, and the incidence is rising. Current treatment involves surgery followed by (chemo)radiotherapy, and this sequence has not been changed in decades. Inevitably after surgery, remnant tumour cells are left behind due to its invasive nature and the inability to remove all affected brain tissue. Furthermore, the surgical procedure dramatically influences the tumour landscape as the postoperative microenvironment exhibits increased hypoxia, tumour migration and proliferation. These factors emphasize the clear clinical need for a breakthrough and trialling of preoperative interventions in the tumour's potentially most treatment-sensitive state to improve treatment outcomes for glioblastoma patients. Following the benefits of preoperative radiotherapy in other cancers, our Preoperative Brain Irradiation in Glioblastoma (POBIG) study delivers for the first time single fraction radiotherapy before routine surgery and postoperative (chemo)radiotherapy.
As the field needs more than a clinical strategy with a strong rationale, we collect novel, unique and clinically relevant information at the individual patient level (e.g. sampling of paired irradiated and unirradiated tumour tissue, liquid biopsies and habitat-based imaging analysis). POBIG is a safety and feasibility phase I radiotherapy dose-escalation study. The innovative design of POBIG will contribute to personalized medicine and the necessary paradigm treatment shift for a disease with a high unmet need.

Publications

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Description NCRI Brain Working Group 
Organisation Brainstrust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Deputy Chair of the Working Group. Contribution to the development of a drug-RT combination study design and funding application using knowledge and experience of the POBIG award.
Collaborator Contribution The NCRI Brain Group's "Building a platform for early phase interventions in glioblastoma patients" Working Group sets out to achieve Priority 2 of the NCRI Brain Group Strategic Priorities: To develop a window of opportunity study, early phase trial or basket study for glioblastoma patients utilising targeted agents, immunotherapy and/or drug-RT combinations
Impact Multi disciplinary grant application submitted - CTU, 7 NHS sites, academic institutions, commercial partners, PPI and brain tumour charities.
Start Year 2022
 
Description NCRI Brain Working Group 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Deputy Chair of the Working Group. Contribution to the development of a drug-RT combination study design and funding application using knowledge and experience of the POBIG award.
Collaborator Contribution The NCRI Brain Group's "Building a platform for early phase interventions in glioblastoma patients" Working Group sets out to achieve Priority 2 of the NCRI Brain Group Strategic Priorities: To develop a window of opportunity study, early phase trial or basket study for glioblastoma patients utilising targeted agents, immunotherapy and/or drug-RT combinations
Impact Multi disciplinary grant application submitted - CTU, 7 NHS sites, academic institutions, commercial partners, PPI and brain tumour charities.
Start Year 2022
 
Description NCRI Brain Working Group 
Organisation University of Sheffield
Department Sheffield Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Deputy Chair of the Working Group. Contribution to the development of a drug-RT combination study design and funding application using knowledge and experience of the POBIG award.
Collaborator Contribution The NCRI Brain Group's "Building a platform for early phase interventions in glioblastoma patients" Working Group sets out to achieve Priority 2 of the NCRI Brain Group Strategic Priorities: To develop a window of opportunity study, early phase trial or basket study for glioblastoma patients utilising targeted agents, immunotherapy and/or drug-RT combinations
Impact Multi disciplinary grant application submitted - CTU, 7 NHS sites, academic institutions, commercial partners, PPI and brain tumour charities.
Start Year 2022
 
Description Translational Analysis 
Organisation Netherlands Cancer Institute (NKI)
Country Netherlands 
Sector Academic/University 
PI Contribution Provision of glioblastoma tissue samples (collected within the POBIG study)
Collaborator Contribution Analysis of the glioblastoma tissue samples
Impact Analysis and publication underway.
Start Year 2022
 
Description Translational Analysis 
Organisation University of Bern
Country Switzerland 
Sector Academic/University 
PI Contribution Planned analysis of glioblastoma tissue samples.
Collaborator Contribution Provision of glioblastoma tissue samples.
Impact Ethics application and analysis expected 2024.
Start Year 2023
 
Title POBIG 
Description Preoperative brain irradiation in glioblastoma. Principle funding source: MRC DPFS and CRUK RadNet Manchester. Study is recruiting. 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2022
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Challenging the current treatment paradigm of glioblastoma patients. 
 
Description Annual POBIG Project Meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact The annual face to face POBIG project meeting took place in Manchester in March 2024. The primary aim was to review study progress against the milestones and obtain feedback on the future plans.

The meeting involved Patient, Sponsor, CTU, Clinical and Research representatives from the different sites. Patient engagement is an ongoing and vital element of the POBIG study: our patient representative attends the monthly POBIG Trial Management Group meetings (virtual). Providing the opportunity for the patient representative to meet the study team in person and to visit the laboratories where translational research takes place provided us with the opportunity to strengthen the working relationship and express our gratitude for their ongoing support and engagement.

The PI (Borst) discussed the next steps for the study, including the development of a future funding bid.
Year(s) Of Engagement Activity 2024
 
Description National News 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Guardian news article summarising the study and progress so far.
Year(s) Of Engagement Activity 2023
URL https://www.theguardian.com/science/2023/feb/02/pioneering-nhs-trial-targets-brain-tumours-before-su...
 
Description Radio article 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact BBC Radio 5 news interview about the progress of the study so far.
Year(s) Of Engagement Activity 2023