• Stratum 1

⁃ Newly diagnosed pHGG/DMG/DIPG Patients must have histologically confirmed pediatric high-grade glioma (pHGG, WHO Grade 3 or 4) or diffuse midline glioma with altered H3K27 (DMG, WHO Grade 4). Primary pHGG or DMG spinal tumors are eligible. Diffuse intrinsic pontine glioma (DIPG) defined by MRI does not require histological confirmation.

⁃ Weight \> 10kg

⁃ Karnofsky and Lansky performance score \> 50%

⁃ Patients with stable seizures (e.g., no seizures for ≥ 7 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible.

⁃ Adequate liver function defined as:

∙ Total bilirubin ≤ 2x upper limit of normal (ULN) and

‣ AST (SGOT) and ALT (SGPT) ≤ 225 U/L (5x the ULN). The ULN for AST and ALT will be 45 U/L.

⁃ Patients must have normal organ and marrow function as defined below:

∙ absolute neutrophil count \> 1,000/mcL

‣ platelets \> 100,000/mcL

‣ hemoglobin \> 8g/dL

‣ Total bilirubin within normal institutional limits

‣ AST(SGOT)/ALT(SGPT) \< 5 x (\<10 x if taking steroids) the institutional upper limit of normal

‣ creatinine within normal institutional limits for age 2 OR

‣ creatinine clearance \> 60mL/min/1.73 m for patients with creatinine levels above institutional normal

⁃ Stratum 2

⁃ Relapsed, progressive pHGG/DMG/DIPG and medulloblastoma (MB) or pHGG/DMG/DIPG after completion of standard radiation therapy without prior atovaquone exposure and before progression. Patients with metastatic disease are allowed for Stratum 2 only.

‣ -Measurable disease is not necessary for enrollment study.

⁃ Patients must have previously undergone standard-of-care treatment including surgery, radiation, and/or first-line adjuvant chemotherapy before the experimental treatment (atovaquone).

⁃ Patients must have recovered from the acute treatment-related toxicities (defined as \< grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study. There is no upper limit to the number of prior therapies that is allowed.

⁃ Age \> 2 to 25 years

⁃ Weight \> 10kg

⁃ Karnofsky and Lansky performance score \> 50%

⁃ Patients with stable seizures (e.g., no seizures for ≥ 7 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible.

⁃ Patients must have normal organ and marrow function as defined above for Stratum 1

⁃ Adequate liver function is defined as:

• Total bilirubin ≤ 2x upper limit of normal (ULN) and

∙ AST (SGOT) and ALT (SGPT) ≤ 225 U/L (5x the ULN). The ULN for AST and ALT will be 45 U/L.