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

Inclusion Criteria:

• COHORT A and COHORT B: For the dose escalation phase, patients must be ≥ 12 monthsand < 18 years of age at the time of study enrollment

• COHORT C and COHORT D: For the disease expansion phase, patients must be ≥ 12 monthsand < 22 years of age at the time of study enrollment

• Patients with newly diagnosed primary high-grade glioma (HGG), diffuse midlineglioma (DMG) (excluding primary spinal tumors), or diffuse intrinsic pontine glioma (DIPG) who are eligible to receive 54-59.4 Gray (Gy) fractionated radiation at 1.8Gy/day. Patients must have had histologic verification of malignancy at originaldiagnosis except in patients with DIPG as defined below.

• COHORTS A AND C (SUPRATENTORIAL TUMORS):

• HGG and non-pontine DMG:

• Patients with newly diagnosed HGG (including diffuse hemisphericglioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma,H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; orglioblastoma, IDH-wildtype): or non-pontine DMG (including diffusemidline glioma, H3 K27-altered; diffuse pediatric-type high-gradeglioma, H3-wildtype and IDH-wildtype; astrocytoma; IDH-mutant; orglioblastoma, IDH-wildtype) require histologic diagnosis.

• COHORT B AND D (INFRATENTORIAL TUMORS):

• DIPG/pontine DMG or infratentorial HGG or DMG:

• Patients with newly diagnosed typical DIPG, defined as tumors with apontine epicenter and diffuse involvement of at least 2/3 of the ponson at least 1 axial T2-weighted image, are eligible. No histologicconfirmation is required.

• Patients with infratentorial tumors that do not meet radiographiccriteria for typical DIPG (e.g., focal tumors or those involving lessthan 2/3 of the pontine cross-sectional area with or withoutextrapontine extension) are eligible if the tumors are biopsied andproven to be high-grade gliomas (including diffuse midline glioma H3K27-altered; diffuse pediatric-type high-grade glioma, H3-wildtypeand IDH-wildtype; astrocytoma; IDH-mutant; or glioblastoma,IDH-wildtype) by institutional diagnosis.

• Protocol Definitions

• Supratentorial tumors are defined as tumors with an epicenter in thecerebral hemispheres, basal ganglia, thalamus, hypothalamus, or pituitarygland.

• Infratentorial tumors are defined as tumors with an epicenter in thebrainstem, cerebellum

• Patients with measurable or non-measurable (following a gross total resection)disease

• Karnofsky ≥ 50% for patients > 16 year of age and Lansky ≥ 50% for patients ≤ 16years of age.

• Note: Patients who are unable to walk because of paralysis, but who are in awheelchair, will be considered ambulatory for the purpose of assessing theperformance score

• Prior therapy for any cancer diagnosis (including radiation) is not allowed with theexception of surgery and/or corticosteroids. If receiving corticosteroids, dose mustremain stable or decrease after enrollment

• Peripheral absolute neutrophil count (ANC) ≥ 1000/uL (must be performed within 7days prior to enrollment unless otherwise indicated)

≥ 100,000/uL (transfusion independent, defined as not receivingplatelet transfusions for at least 7 days prior to enrollment) (must be performedwithin 7 days prior to enrollment unless otherwise indicated)

• Hemoglobin ≥ 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions) (must be performed within 7 days prior to enrollment unless otherwise indicated)

• A creatinine based on age/sex as follows (must be performed within 7 days prior toenrollment unless otherwise indicated):

• 1 to < 2 years: Maximum serum creatinine 0.6 mg/dL (male), 0.6 mg/dL (female)

• 2 to < 6 years: Maximum serum creatinine 0.8 mg/dL (male), 0.8 mg/dL (female)

• 6 to < 10 years: Maximum serum creatinine 1 mg/dL (male), 1 mg/dL (female)

• 10 to < 13 years: Maximum serum creatinine 1.2 mg/dL (male), 1.2 mg/dL (female)

• 13 to < 16 years: Maximum serum creatinine 1.5 mg/dL (male), 1.4 mg/dL (female)

• >= 16 years: Maximum serum creatinine 1.7 mg/dL (male),1.4 mg/dL (female) OR a 24 hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 OR a glomerularfiltration rate (GFR) ≥ 70 mL/min/1.73 m^2. GFR must be performed using directmeasurement with a nuclear blood sampling method OR direct small moleculeclearance method (iothalamate or other molecule per institutional standard).

Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates are not acceptable for determining eligibility

• Note: The threshold creatinine values in this Table were derived from the Schwartzformula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing childlength and stature data published by the CDC.

• Bilirubin (sum of conjugated + unconjugated or total) ≤ 1.5 x upper limit ofnormal (ULN) for age except in patients diagnosed with Gilbert's disease forwhich bilirubin must be ≤ 3.0 × ULN (must be performed within 7 days prior toenrollment unless otherwise indicated)

• Alanine aminotransferase (ALT) ≤ 3 x ULN, unless attributed to tumorinvolvement then ALT ≤ 5 x ULN (must be performed within 7 days prior toenrollment unless otherwise indicated)

• Aspartate aminotransferase (AST) ≤ 3 x ULN, unless attributed to tumorinvolvement then AST ≤ 5 x ULN (must be performed within 7 days prior toenrollment unless otherwise indicated)

• Albumin ≥ 2 g/dL (must be performed within 7 days prior to enrollment unlessotherwise indicated)

• No evidence of dyspnea at rest, no exercise intolerance and a pulse oximetry > 93%

• Patients with seizure disorder may be enrolled if on anticonvulsants and wellcontrolled as evidenced by no increase in seizure frequency in the prior 7days. If needed, evaluate use of enzyme-inducing anticonvulsants

• Serum lipase ≤ 1.5 ULN (must be performed within 7 days prior to enrollmentunless otherwise indicated)

• Prothrombin time (PT)/international normalization rate (INR) < 1.5 x ULN (mustbe performed within 7 days prior to enrollment unless otherwise indicated)

• Patients must have the ability to swallow whole tablets (AZD1390 may not beadministered via nasogastric [NG]/gastric [G]-tubes)

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks offetal and teratogenic adverse events as seen in animal/human studies, OR becausethere is yet no available information regarding human fetal or teratogenictoxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Malesor females of reproductive potential may not participate unless they have agreed touse two effective methods of birth control, including a medically accepted barrieror contraceptive method (eg, male or female condom) for the duration of the study.Abstinence is an acceptable method of birth control. Women of childbearing potentialshould use adequate contraception during study participation and for 6 months afterthe last dose of AZD1390. Male patients with female partners of childbearingpotential should use adequate contraception during study participation and for 16weeks after the last dose of AZD1390

• Investigational Drugs: Patients who are currently receiving another investigationaldrug are not eligible

• Anti-cancer Agents: Patients who are currently receiving other anti-cancer agentsare not eligible with the exception of corticosteroids

• Anti-graft versus host disease (GVHD) agents post-transplant: Patients who arereceiving cyclosporine, tacrolimus or other agents to prevent graft-versus-hostdisease post bone marrow transplant are not eligible for this trial

• CYP-450/Transport Proteins: Patients receiving any medications or substances thatare strong inhibitors or inducers of CYP3A4/5 enzyme are ineligible. Moderateinhibitors and inducers of CYP3A4/5 are permitted but caution should be exercised,and patients monitored closely for possible drug interactions. Strong inhibitors orinducers CYP3A4 should be stopped at least 2 weeks before the first dose of AZD1390 (3 weeks for St John's Wort). As part of the enrollment/informed consent procedures,the patient will be counseled on the risk of interactions with other agents, andwhat to do if new medications need to be prescribed or if the patient is consideringa new over-the-counter medicine or herbal product

• Enzyme-Inducing Anticonvulsants: Patients must not have received enzyme-inducinganticonvulsants within 14 days prior to enrollment

• Patients who have an uncontrolled infection are not eligible

• Patients who have received a prior solid organ transplantation are not eligible

• Patients who in the opinion of the investigator may not be able to comply with thesafety monitoring requirements of the study are not eligible. This includes patientswith rapidly declining neurological status

• Patients must have the ability to swallow whole tablets (AZD1390 may not beadministered via NG/G-tubes). Patients with medical conditions that affect drugabsorption, such as short gut syndrome are not eligible

• Patients with known macular degeneration, uncontrolled glaucoma, or cataracts arenot eligible

• Patients with primary spinal cord high grade gliomas are not eligible

• Patients with metastatic disease are not eligible; Metastatic disease is defined asdistant intracranial or spinal metastasis including leptomeningeal disease, or tumorcells within the CSF. MRI of the spine with and without contrast must be performedif metastatic disease is suspected by the treating physician

• Patients with gliomatosis type growth pattern (or diffuse spread) with involvementof at least 3 lobes of the brain are not eligible with the exception of H3K27M-mutant bithalamic tumors

• Patients with infant-type hemispheric high-grade gliomas are excluded

• Patients with BRAFV600E mutations are excluded

• Patients who are not able to receive protocol specified radiation therapy

• Patients with a history of radiotherapy as part of anti-cancer therapy are excluded

• Presence of myopathy or raised CK > 5 x ULN on 2 occasions at screening will resultin exclusion.

• CK should not be measured following strenuous exercise or in the presence of aplausible alternative cause of CK increase, which may confound interpretationof the results.

• If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatorytest should be carried out within 5 - 7 days.

• If the repeat test confirms a baseline CK >5 x ULN, treatment should not bestarted

• HIV-infected patients on effective anti-retroviral therapy with undetectable viralload within 6 months are eligible as long as they are NOT receiving anti-retroviralagents that are strong inhibitors or inducers of CYP3A4 or substrates of UGT1A1 andUGT1A9

• Evidence of clinically significant cardiac dysfunction or prolonged corrected QTinterval (QTc) (> 450 msec) on baseline electrocardiogram (EKG)

• Patients with known hepatitis B or C with detectable viral load

• Any significant medical condition that in the medical judgement of the investigatorwould compromise the patient's ability to tolerate study drug or participate in thestudy