ID #1132 CONNECT TarGeT-A molecularly-guided phase 2 trial for children and young adults newly diagnosed with high-grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG): (1) Ribociclib and everolimus for HGG/DIPG with cell cycle and/or PI3K/mTOR pathway alterations, and (2) Ribociclib and temozolomide for diffuse hemispheric glioma (DHG), H3G34-mutant

Outcomes for children and young adults with HGG, including DIPG, remain dismal, prompting the unrelenting search for novel, more effective, and minimally toxic treatment paradigms. Next generation sequencing has identified recurring actionable somatic alterations within molecularly distinct subgroups, including high prevalence of cell cycle and PI3K/mTOR pathway aberrations across pediatric HGG/DIPG, as well as H3G34R/V mutations predominantly in adolescent and young adult DHG, with sensitivity to CDK6 inhibition. The CONNECT TarGeT molecularly-guided phase 2 umbrella trial offers a precision medicine approach to pediatric and young adult patients with HGG/DIPG, with targeted treatment arm assignment following central, multidisciplinary, comprehensive molecular, pathology, and clinical screening [NCT05839379]. TarGeT-A [NCT05843253] consists of two oral biologically-targeted combinations with preclinical and clinical rationale: (1) ribociclib and everolimus for HGG/DIPG harboring alterations that activate the cell cycle (CDK4/6, CCND1/2, CDKN2A/B/C) and/or PI3K/mTOR pathway (PTEN, PIK3R1, PIK3CA, TSC1/2), and (2) ribociclib and temozolomide for DHG, H3 G34(R/V)-mutant. TarGeT-A has opened to enrollment across US and international CONNECT sites; at time of abstract submission, the ribociclib and everolimus Part 1 feasibility cohort (incorporating ribociclib powder for oral solution [pfos] formulation) has completed accrual of the first 6 patients (CDK4 amplification [n = 1], loss of CDKN2A/B/C [n = 2] or PTEN [n = 1], and alterations in PIK3CA [n = 1] and TSC1 [n = 1]); preliminary feasibility and pharmacokinetic results will be presented at ISPNO. Part 2 cohorts will soon open, evaluating efficacy of these targeted combinations, defined by progression-free survival (HGG) and overall survival (DIPG) compared to molecularly-stratified, matched historical controls, with additional descriptive strata for thalamic, spinal cord, metastatic, and/or radiation-related HGG, as well as embedded longitudinal multimodal biomarker correlatives. If feasible and effective, TarGeT-A’s precision medicine approach, utilizing identified genomic biomarkers, can be incorporated into treatment of pediatric HGG/DIPG molecular subgroups, with potential to elucidate biologic drivers, expand targeted therapy, and improve prognosis.