Targeted Pediatric High-Grade Glioma Therapy

Inclusion Criteria:

1. Age: Patients must be ≥12 months and ≤39 years of age at the time of enrollment ontothis screening protocol.

2. Diagnosis: Patients with newly diagnosed HGG, including DIPG are eligible. Diagnosismust have histologic confirmation from biopsy or resection. The diagnosis of HGGmust have been confirmed by pathology review at the local site. For the diagnosis ofDIPG, patients must have a tumor with pontine epicenter and diffuse involvement ofat least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4glioma (eg, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altereddiffuse 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 areeligible.

• Patients with metastatic/disseminated or multifocal disease or gliomatosiscerebri 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 ofavastin/bevacizumab is allowed (individual treatment arms have different washoutperiod requirements, check individual arm eligibility). No other prior anticancertherapy for HGG will be allowed.

• Participants screening for assignment to TarGeT-L may not have receivedradiation. Timing from surgery to start of RT: For patients who have started RT, radiation musthave started <42 days from definitive surgery or biopsy, however it is stronglyrecommended patients start RT within 31 days from definitive surgery (if patient hadtwo surgeries, radiation must have started within 31 days from second surgery).

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

• If a patient screens through OPTION #1, tumor sample in addition to normalcomparator tissue (peripheral blood, saliva, or buccal swab) must be submittedfor comprehensive molecular screening at the time of screening enrollment.

• If a patient screens through OPTIONS #2 or #3, results from previouslyperformed molecular profiling must be submitted following enrollment. It ishighly recommended that results be uploaded within 7 days of enrollment (ifresults are available at time of enrollment) or within 7 days of resultsbecoming available (if pending at time of enrollment) to allow adequate timefor central review.

6. Informed Consent: All patients and/or their parents or legally authorizedrepresentatives must sign a written informed consent. Assent, when appropriate, willbe obtained according to institutional guidelines.

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

• Patients screening through OPTION #1 are eligible to enroll anytime betweendiagnosis and 10 days post RT (if completing RT).

• Patients screening through OPTIONS #2 or #3 are eligible to enroll anytimebetween diagnosis and 21 days post RT (if completing RT).

• Participants screening for TarGeT-L (lorlatinib) are eligible to enroll onTarGeT-SCR anytime between diagnosis and 31 days post definitive surgery (toallow time for molecular review).

However, it is important to note the following:

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

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

#SCREENING OPTIONS

• OPTION1: Molecular screening through CONNECT TarGeT Clinical Testing Laboratories

• OPTION2: Molecular screening through a national comprehensive tumor profilingprogram

• OPTION3: Clinically validated targeted sequencing or focused profiling

Exclusion Criteria:

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