Clinical trial NCT05839379: Targeted Pediatric High-Grade Glioma Therapy
Official title: Molecularly-Guided Phase II Umbrella Trial for Children, Adolescents, and Young Adults Newly Diagnosed With High-Grade Glioma, Including Diffuse Intrinsic Pontine Glioma
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: High Grade Glioma
Diffuse Intrinsic Pontine Glioma
Anaplastic Astrocytoma
Glioblastoma
Glioblastoma Multiforme
Diffuse Midline Glioma, H3 K27M-Mutant
Metastatic Brain Tumor
WHO Grade III Glioma
WHO Grade IV Glioma
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
First posted: 2023-05-03
Enrollment: 450
Sex: ALL
Minimum age (years): 12
Maximum age (years): 39
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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)

Brief summary: 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.

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 400-450 patients will be enrolled on the screening protocol through which biospecimens (paired tumor DNA/RNA and normal comparator samples) will undergo extensive molecular profiling to assess eligibility to any of the therapeutic subprotocols of the phase II study.

Eligibility criteria: 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. The diagnosis of HGG must have been confirmed by local pathology review. 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, but not recommended. No other prior anticancer therapy for HGG will be allowed.

   Timing from surgery to start of RT: For patients who have started RT, radiation must have started within 31 days of definitive surgery or biopsy (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 or saliva) 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

   * Patients screening through OPTION #1 are eligible to enroll anytime between diagnosis and 10 days post RT.
   * Patients screening through OPTIONS #2 or #3 are eligible to enroll anytime between diagnosis and 21 days post RT.

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

Primary outcomes:
measure: Molecular profiling
timeFrame: 4 years
measure: Feasibility of molecular profiling and enrollment to a TarGeT treatment protocol
timeFrame: 4 years
Secondary outcomes:
measure: Genomic Research
timeFrame: 6 years
measure: Germline susceptibility testing
timeFrame: 4 years
measure: Biobanking
timeFrame: 4 years
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Perth
country: Australia
facility: Perth Children's Hospital
state: Western Australia
city: Toronto
country: Canada
facility: The Hospital for Sick Children (SickKids)
state: Ontario
city: Montréal
country: Canada
facility: Montreal Children's Hospital
state: Quebec
city: Heidelberg
country: Germany
facility: Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
state: Baden-Württemberg
city: Utrecht
country: Netherlands
facility: Princess Máxima Center
city: London
country: United Kingdom
facility: Great Ormond Street Hospital
Study officials:
affiliation: Nationwide Children's Hospital
name: Maryam Fouladi, MD
role: STUDY_CHAIR
affiliation: Nationwide Children's Hospital
name: Margot Lazow, MD
role: STUDY_DIRECTOR
References: