Testing the Addition of an Anti-Cancer Drug, AZD1390, During Radiation Therapy for Newly Diagnosed High Grade Glioma, Diffuse Midline Glioma, or Diffuse Intrinsic Pontine Glioma

PRIMARY OBJECTIVES: I. To define the recommended phase 2 dose of ATM Kinase Inhibitor AZD1390 (AZD1390) when given in combination with radiation for pediatric supratentorial high-grade gliomas. II. To define the recommended phase 2 dose of AZD1390 when given in combination with radiation for pediatric infratentorial high-grade gliomas. III. To define the toxicities and characterize the safety profile of AZD1390 when given in combination with radiation for pediatric supratentorial high-grade gliomas. IV. To define the toxicities and characterize the safety profile of AZD1390 when given in combination with radiation for pediatric infratentorial high-grade gliomas. V. To characterize the pharmacokinetic profile of AZD1390 when given in combination with radiation to pediatric patients for pediatric supratentorial and infratentorial high-grade gliomas. SECONDARY OBJECTIVES: I. To evaluate preliminary efficacy when AZD1390 is given in combination with radiation to pediatric patients with supratentorial high-grade gliomas as determined via progression free survival (PFS), overall survival (OS) and overall radiographic response (ORR) within the confines of a phase 1 trial. II. To evaluate preliminary efficacy when AZD1390 is given in combination with radiation to pediatric patients with infratentorial high-grade gliomas as determined via PFS, OS and ORR within the confines of a phase 1 trial. III. To obtain preliminary data on neurological function of patients with supratentorial and infratentorial high-grade gliomas receiving AZD1390 and focal radiation via the pediatric neurologic assessment in neuro-oncology (NANO) scale. EXPLORATORY OBJECTIVES: I. To evaluate changes in neurocognitive function from baseline (within 2 weeks of enrollment) to end of protocol directed therapy (completion of AZD1390), at 22 weeks (5.5 months) and at 44 weeks (11.5 months) after completion of radiation. II. To evaluate changes in patient reported outcomes utilizing Patient Reported Outcomes Measurement Information System (PROMIS) from baseline (within 2 weeks of enrollment) and at the time of imaging assessments. III. To evaluate the alternative lengthening of telomeres (ALT) phenotype in archival tumor and cell-free deoxyribonucleic acid (cfDNA) in patients with high grade glioma (HGG) undergoing AZD1390 and radiation therapy. IV. To evaluate the correlation of genomic, transcriptomic, proteomic, and cytokine markers, including homologous recombination deficiency (HRD) and associated mutational signatures and TP53/related DNA repair gene mutational status, with response to AZD1390 and radiation therapy. V. Evaluate differences in radiation dosimetry to organs at risk and target volumes by radiation technique and modality and its correlation with toxicity and response and survival. VI. Evaluate cfDNA in plasma and cerebrospinal fluid (CSF) (when obtained) and pharmacodynamic markers of peripheral blood mononuclear cells (PBMCs) prior, during and after therapy to better understand its correlation with treatment response. OUTLINE: This is a dose-escalation study of AZD1390 in combination with radiation. Patients receive AZD1390 orally (PO) once within 5 days prior to radiation therapy. Patients then receive AZD1390 PO once daily (QD), 5 days per week, Monday through Friday, and also receive radiation therapy on the same days for approximately 6 weeks. Patients then receive AZD1390 on days 1-14 after radiation in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) and blood sample collection and may optionally undergo cerebrospinal fluid collection throughout the study. After completion of study treatment, patients are followed up at 30 days and then every 8 weeks until progression or 2 years after the last dose of AZD1390 as well as at 22 and 44 weeks after completion of radiation therapy. From progression, patients will be followed every 6 months until year 4 from the last dose of AZD1390 then yearly until year 5.