Abstract A045: the 5G (next Generation AGile Genomically Guided Glioma) Platform Trial – A First-in-world Adaptive Clinical Trial for Precision Treatment of Brain Tumours

Abstract Background: The failure of neuro-oncology clinical trials to deliver new and effective therapies for brain tumours has been attributed to the following challenges:Heterogeneity and poor natural history Brain tumours are a heterogenous group, with WHO 2021 classification including over 120 different types and subtypes based on specific molecular alterations. Intratumoural heterogeneity and evolution under treatment pressure complicate the molecular environment landscape.Limited pipeline of novel therapeutics entering early phase trials Most early phase cancer trials exclude patients with brain tumours out of safety concerns. Despite recent efforts to broaden eligibility criteria to safely enrol patients with metastatic intracranial disease, fewer than 1% of global early phase trials enrol patients with brain tumours.Suboptimal trial design Poor-quality historical data informing statistical models and trial designs contributes to delayed accrual, under-enrolment and over-optimistic predictions of therapy’s effect. Highly selected patient populations not representative of real-world (RW) data, risk overlooking therapies that may be effective for some cohorts of patients.Traditional fixed-arm trials are inefficient for testing multiple targeted therapies, underscoring the need for innovative designs incorporating real-time data and genomic profiling. Methods: The 5G platform trial is a multi-center, multi-arm adaptive,early phase hypotheses testing study sponsored by The Institute of Cancer Research (London). All participants undergo whole genome and transcriptome sequencing at baseline via the Minderoo Precision Brain Tumour programme (MPBTP-University of Cambridge). This analysis identifies molecular subtypes to define the appropriate biomarker for stratification into trial subprotocols. Adaptive design integrating real time data integration at pre-specified interim analyses, enables refinement of the selection biomarker, seamless addition of combination arms, allowing an agile transition from recurrent to frontline minimal residual disease setting post radical chemo-radiotherapy. Promising arms will advance to randomised later phase testing using synthetic controls derived from contemporaneous genomically matched datasets provided by the MPBTP. Results: Trial recruitment was initiated in October 2024 with 3 sub-protocols open (5G-RUBY, 5G-EMERALD and 5G-PEARL). Early enrolment data indicate high feasibility of genomic-guided allocation, with >95% of sequenced tumours yielding potentially actionable mutations. Conclusions: The 5G platform trial represents the world's first fully adaptive, genomics-driven platform for brain tumours, with the potential to revolutionize brain tumour treatment by embedding precision medicine and RW adaptability into trial execution. By evaluating multiple therapies in parallel, it addresses longstanding barriers to innovation and paves the way for paradigm-shifting treatments. Results will inform global standards for adaptive oncology trials for brain tumour patients. Citation Format: Juanita Lopez, Diogo Silva, Marieke Thompson, Liam Welsh, Antonia Creak, Cristina Boixareu, Ching Leung, Paul Hart, Philip Benjami, Nina Tunariu, Mihaela Rata, Ana Prim Padilha, Anna Zachariou, Toby Prout, Mona Parmar, Bindu Rao Baikady, Xiaoran Lai, Holly Tovey, Christina Yap, Adam Sharp, Alec Paschalis, Anna Minchom, Udai Banerji, Johann De Bono, Igor Vivanco, Bristi Basu, Richard Mair. The 5G (Next Generation AGile Genomically Guided Glioma) Platform Trial – A First-in-world Adaptive Clinical Trial for Precision Treatment of Brain Tumours [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A045.