Targeted Pediatric High-Grade Glioma Therapy

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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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

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: Patients must be ≥12 months and ≤30 years of age at the time of enrollment onto this screening protocol. 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. 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. 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). 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. 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. 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

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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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 comprehensive molecular characterization across clinical molecular testing laboratories at CONNECT sites and begin treatment on a TarGeT treatment subprotocol within 10 calendar days of starting radiation therapy (RT) (if treatment involves an agent given concurrently with RT) or within 35 days of completion of RT (if treatment involves adjuvant maintenance therapy). | 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 |