TIP-30. Molecularly-guided phase 2 umbrella trial for children and young adults with newly-diagnosed high-grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG): CONNECT TarGeT (Targeted pediatric HGG therapy) trial in progress 

Children and young adults with HGGs have limited treatment options and a dismal prognosis, underscoring the critical need to develop novel, biologically-rational, and minimally toxic therapies for this vulnerable population. Genome-wide discoveries have provided valuable insight into the underlying biology of pediatric HGG/DIPG, identifying recurrent, actionable somatic alterations within molecularly distinct subgroups. We have developed TarGeT, an international, multi-institutional, multi-arm molecularly-guided phase 2 umbrella trial in children and young adults newly-diagnosed with HGG including DIPG, in which we (1) conduct comprehensive tumor molecular screening using a multi-omic approach (whole exome sequencing, RNA-based fusion panel, DNA methylation array) with rapid return of results and/or rapid review of previously obtained results, (2) stratify patients to biologically-targeted therapy arms to assess efficacy, and (3) perform longitudinal genomic and immune profiling of peripheral blood, cerebrospinal fluid, and tumor tissue plus advanced serial neuro-imaging assessments to determine multimodal biomarkers predictive of response and resistance. More than 300 patients will be enrolled on the overarching screening protocol (TarGeT-SCR [NCT05839379]) through which tumor molecular characterization is performed (or reviewed if previously obtained); all cases undergo central molecular, pathology, and clinical review for eligibility confirmation and arm assignment, based on presence of targetable genetic alterations. The following TarGeT treatment arms (most involving upfront radiotherapy), are open or soon to open, selected based on prevalence of targets in HGG/DIPG, relevant pre-clinical and clinical data, established pediatric safety data, and prioritizing combinations: (A) ribociclib and everolimus (target: cell cycle or PI3K//mTOR pathway alterations) [NCT05843253], (A-2) ribociclib and temozolomide (H3G34 mutation) (B) tovorafenib (MAPK pathway alterations), (D) olutasidenib and temozolomide (IDH1 mutation) [NCT06161974], (F) nivolumab and relatlimab (high tumor mutational burden, mismatch repair deficiency), (L) lorlatinib (+/- chemotherapy or radiation) (ROS1, ALK fusion). Development of additional treatment arms is underway, with possibility of incorporating new arms as supporting data allows.