Targeted Pediatric High-Grade Glioma Therapy

Molecularly-Guided Phase II Umbrella Trial for Children, Adolescents, and Young Adults Newly Diagnosed With High-Grade Glioma, Including Diffuse Intrinsic Pontine Glioma

The goal of this study is to perform genetic sequencing on brain tumors from children, adolescents, and young adult patients who have been newly diagnosed with a high-grade glioma. This molecular profiling will decide if patients are eligible to participate in a subsequent treatment-based clinical trial based on the genetic alterations identified in their tumor.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma; Glioblastoma Multiforme; High Grade Glioma; Anaplastic Astrocytoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; WHO Grade III Glioma; Metastatic Brain Tumor; WHO Grade IV Glioma

Detailed Description

A novel, molecularly-guided, multi-arm phase umbrella II trial is proposed in children, adolescents, and young adults with newly diagnosed HGG, including DIPG, in which we will (1) conduct comprehensive molecular screening of tumor tissue using a multi-omic approach (WES/WGS, gene fusion panels/RNASeq, DNA methylation microarray) across international CONNECT genomics cores with rapid return of clinical results, (2) stratify patients to biologically-targeted treatment arms, based on the tumor molecular profile and histopathology, and (3) perform longitudinal evaluation of peripheral blood, cerebrospinal fluid (CSF), and/or tumor tissue as well as advanced neuro-imaging to determine genomic, immune, and radiologic biomarkers predictive of response, recurrence, resistance, and toxicity.

Based on results of the above tumor molecular profiling and pathology-based confirmation of HGG diagnosis, eligible patients will be assigned to one of several biologically guided treatment arms on a phase II trial.

Approximately 300-350 patients will be enrolled on the screening protocol through which biospecimens (paired tumor DNA/RNA and normal comparator samples) will undergo extensive molecular profiling and/or there will be comprehensive central molecular and pathology review of previously obtained molecular results to assess eligibility to any of the therapeutic subprotocols of the phase II study.

• Study Type: Observational
• Enrollment (Estimated): 350

Contacts and Locations

• Study Contact: Name: Kelsey H Troyer, PhD; Phone Number: 16147223284; Email: kelsey.troyer@nationwidechildrens.org

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Recruiting
      • Sydney Children's Hospital
      • Contact: David Ziegler, MBBS; Phone Number: +61293821730; Email: d.ziegler@unsw.edu.au
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Recruiting
      • Queensland Children's Hospital
      • Contact: Tim Hassall, MBBS; Phone Number: +61730683593; Email: tim.hassall@health.qld.gov.au
  • Victoria
    • Melbourne, Victoria, Australia, 3052
      • Recruiting
      • Royal Children's Hospital
      • Contact: David Eisenstat, MD MA FRCPC FRACP; Phone Number: +61 3 9345 5479; Email: David.Eisenstat@rch.org.au
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Recruiting
      • Perth Children's Hospital
      • Contact: Nick Gottardo, MBChB, FRACP, PhD; Phone Number: +61864560241; Email: nick.gottardo@health.wa.gov.au
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • Not yet recruiting
      • The Hospital for Sick Children (SickKids)
      • Contact: Eric Bouffet, MD; Phone Number: 4168137457; Email: eric.bouffet@sickkids.ca
  • Quebec
    • Montreal, Quebec, Canada, H4A3J1
      • Not yet recruiting
      • Montreal Children's Hospital
      • Contact: Genevieve Legault, MD; Phone Number: 60497 5144124400; Email: Genevieve.legault4@mcgill.ca
• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • Not yet recruiting
      • Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
      • Contact: Olaf Witt, MD; Phone Number: 0496221423570; Email: o.witt@kitz-heidelberg.de
• Netherlands
  • Utrecht, Netherlands, 3720
    • Not yet recruiting
    • Princess Máxima Center
    • Contact: Jasper van der Lugt, MD, PhD; Phone Number: 31 6 18559694; Email: J.vanderLugt@prinsesmaximacentrum.nl
• New Zealand
  • Grafton
    • Auckland, Grafton, New Zealand, 1023
      • Not yet recruiting
      • Starship Children's Hospital
      • Contact: Sarah Hunter, MB ChB; Phone Number: +64 9 367 0000; Email: SHunter@adhb.govt.nz
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Not yet recruiting
    • Great Ormond Street Hospital
    • Contact: Darren Hargrave, MD; Phone Number: 02078138525; Email: darren.hargrave@nhs.net
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Not yet recruiting
      • Children's Hospital Colorado
      • Contact: Holly Lindsay, MD; Phone Number: 720-777-8314; Email: holly.lindsay@childrenscolorado.org
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center
      • Contact: Eugene M Hwang, MD; Phone Number: 2024765046; Email: ehwang@childrensnational.org
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Ann & Robert H. Lurie Children's Hospital of Chicago
      • Contact: Ashley Plant, MD; Phone Number: 3122274090; Email: Aplant@luriechildrens.org
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Not yet recruiting
      • Dana-Farber Cancer Institute
      • Contact: Susan C Chi, MD; Phone Number: 6176324386; Email: Susan_chi@dfci.harvard.edu
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • C.S. Mott Children's Hospital
      • Contact: Santhosh Upadhyaya, MD; Phone Number: 866-909-4449; Email: saupadhy@med.umich.edu
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Recruiting
      • Duke University Health System
      • Contact: Daniel Landi, MD; Phone Number: 19196813824; Email: daniel.landi@duke.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: Peter M de Blank, MD; Phone Number: 5135172068; Email: Peter.deBlank@cchmc.org
    • Columbus, Ohio, United States, 43205
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Maryam Fouladi; Phone Number: 6147225758; Email: Maryam.fouladi@nationwidechildrens.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Not yet recruiting
      • Children's Hospital of Philadelphia
      • Contact: Michael J Fisher, MD; Phone Number: 12155905188; Email: fisherm@email.chop.edu
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Texas Children's Hospital
      • Contact: Patricia Baxter, MD; Phone Number: 8328244681; Email: pabaxter@txch.org
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Erin Crotty, MD; Phone Number: 206-987-2106; Email: erin.crotty@seattlechildrens.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Pediatric and young adult patients new diagnosed with High Grade Glioma including Diffuse Intrinsic Pontine Glioma (per 2021 WHO CNS tumor classification)

Description

Inclusion Criteria:

1. Age: Patients must be ≥12 months and ≤39 years of age at the time of enrollment onto this screening protocol.
2. Diagnosis: Patients with newly diagnosed HGG, including DIPG are eligible. Diagnosis must have histologic confirmation from biopsy or resection. The diagnosis of HGG must have been confirmed by pathology review at the local site. For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (eg, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma). For all other tumors, histologic grade must be WHO grade 3-4.

3. Disease Status: There are no disease status requirements for enrollment.

   • Measurable disease is not required. Patients without measurable disease are eligible.
   • Patients with metastatic/disseminated or multifocal disease or gliomatosis cerebri are eligible.
   • Patients with a primary spinal tumor are eligible.
   • Patients with secondary, radiation related HGG are eligible.

4. Prior Therapy for HGG: Surgery, radiation, and/or dexamethasone are permissible. Temozolomide concurrent with radiation is permissible. Prior administration of avastin/bevacizumab is allowed (individual treatment arms have different washout period requirements, check individual arm eligibility). No other prior anticancer therapy for HGG will be allowed.

   • Participants screening for assignment to TarGeT-L may not have received radiation.

   Timing from surgery to start of RT: For patients who have started RT, radiation must have started <42 days from definitive surgery or biopsy, however it is strongly recommended patients start RT within 31 days from definitive surgery (if patient had two surgeries, radiation must have started within 31 days from second surgery).

5. Tumor Sample Availability OR results from previous molecular profiling/targeted sequencing

   • If a patient screens through OPTION #1, tumor sample in addition to normal comparator tissue (peripheral blood, saliva, or buccal swab) must be submitted for comprehensive molecular screening at the time of screening enrollment.
   • If a patient screens through OPTIONS #2 or #3, results from previously performed molecular profiling must be submitted following enrollment. It is highly recommended that results be uploaded within 7 days of enrollment (if results are available at time of enrollment) or within 7 days of results becoming available (if pending at time of enrollment) to allow adequate time for central review.
6. Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.

7. Enrollment timeline: Patients are eligible to enroll on the TarGeT-SCR anytime between diagnosis and the following specific timepoints post completion of RT (if relevant)

   • Patients screening through OPTION #1 are eligible to enroll anytime between diagnosis and 10 days post RT (if completing RT).
   • Patients screening through OPTIONS #2 or #3 are eligible to enroll anytime between diagnosis and 21 days post RT (if completing RT).
   • Participants screening for TarGeT-L (lorlatinib) are eligible to enroll on TarGeT-SCR anytime between diagnosis and 31 days post definitive surgery (to allow time for molecular review).

However, it is important to note the following:

• For treatment protocols that include targeted therapy administered concurrently with RT, patients must start treatment within 10 calendar days of starting RT.

• For treatment protocols that only include maintenance/adjuvant therapy (no systemic therapy given concurrently with radiation), patients must start treatment by 35 days post RT

  #SCREENING OPTIONS

• OPTION1: Molecular screening through CONNECT TarGeT Clinical Testing Laboratories
• OPTION2: Molecular screening through a national comprehensive tumor profiling program
• OPTION3: Clinically validated targeted sequencing or focused profiling

Exclusion Criteria:

-Tumors that do not meet HGG and DIPG diagnoses specified above

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Molecular profiling	Utilize molecular, clinical, and histopathologic data to assess eligibility for specific biologically-guided treatment subprotocols among pediatric, adolescent and young adult patients with newly diagnosed HGG, including DIPG.	4 years
Feasibility of molecular profiling and enrollment to a TarGeT treatment protocol	Determine the percent of pediatric, adolescent, and young adult patients newly diagnosed with HGG, including DIPG, who undergo screening through one of three TarGeT-SCR screening mechanisms and are assigned to a TarGeT treatment arm.	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genomic Research	Increase knowledge of the genomic and immunologic landscape of newly-diagnosed pediatric and young adult HGGs, including DIPG, through comprehensive molecular characterization.	6 years
Germline susceptibility testing	Determine the frequency and spectrum of germline cancer susceptibility mutations in children and young adults with HGG and DIPG and assess the feasibility of return of those results.	4 years
Biobanking	Prospectively collect tumor tissue from diagnostic biopsy/resection as well as baseline peripheral blood and cerebrospinal fluid (CSF) samples for the CONNECT biorepository to be used in correlative research for the present trial as well as future studies.	4 years
Progression Free Survival	Prospectively collect data to estimate the distribution of PFS in HGG and DIPG patients, respectively, who do not enroll on any TarGeT treatment subprotocol.	4 years
Feasibility of Assignment	Determine the percent of pediatric, adolescent, and young adult patients newly diagnosed with HGG, including DIPG, who are assigned to a TarGeT treatment arm through one of the three TarGeT-SCR screening mechanisms, and begin treatment on a TarGeT treatment subprotocol within the required timelines.	4 years
Descriptively analyze patients not assigned	For patients who consent to TarGeT-SCR but do not enroll on a TarGeT treatment subprotocol: Descriptively capture and analyze reasons for lack of treatment arm enrollment.	4 years
Overall Survival	Prospectively collect data to estimate the distribution of OS in HGG and DIPG patients, respectively, who do not enroll on any TarGeT treatment subprotocol.	4 years

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Investigators: Study Director: Margot Lazow, MD, Nationwide Children's Hospital; Study Chair: Maryam Fouladi, MD, Nationwide Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2024
• Primary Completion (Estimated): August 28, 2029
• Study Completion (Estimated): August 28, 2034

Study Registration Dates

• First Submitted: April 20, 2023
• First Submitted That Met QC Criteria: May 1, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): June 10, 2026
• Last Update Submitted That Met QC Criteria: June 8, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioblastoma; Glioma; Brain Neoplasms; Astrocytoma
• Other Study ID Numbers: CONNECT TarGeT-SCR; R01FD008167 (U.S. FDA Grant/Contract); HT9425-23-1-0770 (Other Grant/Funding Number: DoD)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No