CRUK/23/004: 5G: A Next Generation AGile Genomically Guided Glioma Modular Platform for proof-of-concept molecular hypothesis testing in patients with malignant brain tumours

Background Despite of an increased understanding of the molecular landscape of malignant brain tumours, with the majority of glioma patients harbouring potentially actionable mutations, a critical disconnect exists between achieved scientific advances and failure to improve patient outcome.

Patients with malignant brain cancer have historically been excluded from early phase trials, even where potentially actionable targets have been identified.

The reasons for this include 1) limitations of preclinical brain tumour models in reflecting the molecular aberrations, genomic complexity and heterogeneity seen in patients 2) uncertainty surrounding brain penetration of potential novel agents.

Aims and Methods The overall aim of this platform is to overcome the exclusion of brain cancer patients from early phase trials; and accelerate drug development in brain cancer using a rational and efficient adaptive, iterative design.

This 5G platform is a Bayesian multicentre, multi-stage, multi-arm, open-label, iterative, adaptive, seamless early phase hypotheses testing platform trial for patients with malignant brain tumours.

This master protocol is designed to evaluate the safety and preliminary efficacy of genotype matched investigational targeted therapies or combinations for malignant brain tumours.

The modular ‘Lego block’ design allows for subprotocols to be flexibly assembled depending on prior knowledge of each investigational therapy.

Each block is pre-designed utilising a Bayesian adaptive design with linked components to assess the co-primary outcomes of safety and preliminary efficacy.

We aim to use small cohorts of genomically selected patients as their own disease model, learning as much as possible from them, including their genomic heterogeneity to refine biomarker selection for targeted therapies. Iterative learning will allow adaption based on emerging results, finessing the selection biomarker.

We anticipate that the adaptive iterative trial format will improve execution efficiency, allowing for the establishment of a precision medicine strategy for malignant brain tumours.

Impact Our 5G proposal will build for the first time, a platform for hypotheses testing of novel biomarker-based therapies in malignant brain tumours.

With a clear go/no-go/adapt decision algorithm together with planned translational biomarker work in partnership with the Minderoo Precision Brain Tumour Programme, we aim to have a clear path for novel therapies to move towards later stage registration trials.

Planning for success, this platform has the potential to be transformative for patients with malignant brain tumours with accelerated approvals for genotype-matched therapies to become standard of care globally for brain tumours, improving both survival and quality of life for these patients.