Patient must be ≥ 18 years of age.

Patient must have a Karnofsky Performance Status ≥ 60%.

Patient must have newly diagnosed GBM (must be IDH wild type), with pathologic proof, based on World Health Organization (WHO) 2021 criteria.

Patient must be planning to receive standard-of-care treatment for newly diagnosed glioblastoma.
* NOTE: Patients who are planning to receive radiotherapy: protons, stereotactic radiosurgery, or abbreviated hypofractionated regimens are not eligible and will be unevaluable if treated with these approaches after enrollment. A portable document format (PDF) of the radiation treatment (RT) treatment plan must be uploaded to RAVE.

Patient must have completed an MRI prior to the diagnostic surgery for GBM and have images available for upload into Transfer of Images and Data (TRIAD).

Patient must have diagnostic surgery for GBM within 7 weeks prior to registration.

Patient must not have any additional planned surgery for GBM prior to initiating RT/temozolomide (TMZ)

Patient must have O6-Methylguanine-DNA Methyltransferase (MGMT) methylation status ordered at time of registration.

Patient must have a post-operative (op) MRI completed within 3 weeks after diagnostic surgery for GBM and have images available for upload into TRIAD.

Patient must have no contraindications to MRI, including injection of gadolinium-based contrast agents, and demonstrated ability to tolerate MRI on pre-surgical imaging.

Patient must have no allergies to agents that may potentially be used for non-standard of care imaging (18F-fluciclovine, MR contrast).

Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the interventions being used.
* All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
* A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

PRIMARY OBJECTIVE:
I. For each biomarker (dynamic susceptibility contrast-enhanced MR Imaging, fluciclovine F18 [18F-fluciclovine] PET, MR spectroscopy), to evaluate whether the biomarker can stratify patients with newly diagnosed glioblastoma (GBM) that have progressive enhancement within 12 weeks post-radiation therapy (XRT) into risk groups based on overall survival.

SECONDARY OBJECTIVES:
I. To evaluate whether each biomarker (dynamic susceptibility contrast-enhanced MR Imaging, 18F-fluciclovine PET, MR spectroscopy) can predict final determination of pseudo-progression (PsP) versus (vs.) true progression on follow-up MR imaging as evaluated by a semi-automated central reading process and by institutional radiologist readings.
II. To evaluate whether a prediction model that incorporates multiple biomarkers can discriminate patients with progressive enhancement within 12 weeks post-XRT into high and low risk groups for overall survival.
III. To evaluate whether clinical and imaging biomarkers are predictive of overall and progression-free survival in patients who do not show progressive enhancement within 12 weeks post-XRT.

EXPLORATORY OBJECTIVE:
I. To determine how different methods of defining PsP vs. true progression on imaging relate to patient survival.

OUTLINE:
Patients receive a gadolinium-based contrast agent and undergo DSC-MRI scans at 4 and 8 weeks after completion of standard of care (SOC) radiation therapy. Patients with evidence of disease progression then undergo MR spectroscopy or receive fluciclovine F18 intravenously (IV) and undergo PET scan within 12 weeks of SOC radiation therapy completion.

After completion of study intervention, patients are followed up every 8 weeks for 1 year followed by every 12 weeks for 5 years.