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

Abstract 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.

Authors

Institutions

Publication Details

Journal
Neuro-Oncology
Published
2025-11-01
DOI
https://doi.org/10.1093/neuonc/noaf201.1690
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Michael J. Fisher, Patricia Baxter, Uri Tabori, Darren Hargrave et al.
Neuro-Oncology
Glioma Diagnosis and Treatment
article

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

Michael J. Fisher, Patricia Baxter, Uri Tabori, Darren Hargrave, Hamza Gorsi, Nicholas G. Gottardo, Diana Thomas, Chris Jones, Michael Hubank, Erin Crotty, Joshua D. Palmer, Vera Paulson, Sarah Leary, Anirban Das, David S. Ziegler, Ralph Salloum, Santosh Valvi, Margot Lazow, Elaine R. Mardis, Bonnie Cole, Jason Dyke, Rachid Drissi, Felix Sahm, Christine Fuller, Ashley Plant, Maryam Fouladi, Susan Chi, Cynthia Hawkins, Mark J. Cowley, Thomas Jacques, Kathleen M. Schieffer, Eugene I. Hwang, Anna Harr, David Jones, Thomas Robertson, Michael Rodriguez, Kelsey Troyer
article en

Abstract

Abstract 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.

Neuro-OncologyVol. 27(Supplement_5)
Lurie Children's Hospital (US), Seattle Children's Hospital (US), Nationwide Children's Hospital (US), Children's Hospital of Philadelphia (US), Children's National (US), Institute of Cancer Research (GB), German Cancer Research Center (DE), University of Washington (US), SUNY Upstate Medical University (US), Heidelberg University (DE), Royal Brisbane and Women's Hospital (AU), Royal Perth Hospital (AU), The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US), Great Ormond Street Hospital (GB), Princess Margaret Hospital for Children (AU), Hospital for Sick Children (CA), University Hospital Heidelberg (DE), Prince of Wales Hospital (AU), Children's Cancer Institute Australia (AU), Dana-Farber Cancer Institute (US), Children's Hospital of Michigan (US), Texas Children's Hospital (US), Perth Children's Hospital, University College London (GB), Seattle University (US)
Openalex Percentile: Top 52%
Glioma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.