The goal of this interventional study is to Assess the safety and tolerability of atovaquone in combination with standard radiation therapy (RT) for the treatment of pediatric patients with newly diagnosed pediatric high-grade glioma/diffuse midline glioma/diffuse intrinsic pontine glioma (pHGG/DMG/DIPG).

The secondary aim is to assess the safety and tolerability of longer-term atovaquone treatment for pediatric patients with relapsed or progressed pHGG/DMG/DIPG and medulloblastoma (MB) or pHGG/DMG/DIPG after completion of RT and before progression.

Atovaquone, an FDA-approved antiparasitic drug, is being explored as a potential treatment for certain cancers, particularly leukemia and pediatric brain tumors like high-grade gliomas. Since Atovaquone's safety and dosage are already established, repurposing it for cancer treatment is cost-effective.

Research shows that Atovaquone can inhibit a protein called STAT3, which is involved in cancer cell survival and immune response suppression. By doing this, it may enhance the effectiveness of radiation therapy, especially in tumors with low oxygen levels. In animal studies and early clinical trials, Atovaquone has shown promise in reducing tumor size and improving survival rates.

For pediatric brain tumors, which often resist standard treatments, Atovaquone's ability to cross the blood-brain barrier could make it particularly valuable. Ongoing clinical trials are examining its effects in combination with radiation therapy for treating newly diagnosed high-grade gliomas and relapsed medulloblastomas. Overall, Atovaquone's repurposing could lead to new, effective treatment options for difficult-to-treat cancers in children.

Inclusion Criteria:

-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:

  1. Total bilirubin ≤ 2x upper limit of normal (ULN) and
  2. AST (SGOT) and ALT (SGPT) ≤ 225 U/L (5x the ULN). The ULN for AST and ALT will be 45 U/L.

Exclusion Criteria:

Stratum 1

• Chronic systemic concurrent illness
• Concurrent or history of anti-cancer therapy other than RT
• Patients with metastatic tumor are excluded for Stratum 1 only.
• Patients with uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs are excluded.
• Patients must fully recover from all acute effects of prior surgical intervention.
• History of allergic reactions to atovaquone or attributed to compounds of similar chemical or biological composition to atovaquone.
• Symptomatic intratumoral hemorrhage, or asymptomatic intratumoral hemorrhage larger than punctate foci, at any time prior to enrollment.
• Pregnant or breast-feeding women will not be entered into this study as there may be fetal risks or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment. This should be documented in the electronic medical records as part of the consent discussion.

Stratum 2

• Concurrent illness

• Patients must have recovered from all prior therapy as follows:

  1. Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks before study enrollment or at least six (6) weeks if prior nitrosourea.
  2. Biologic or investigational agent (anti-neoplastic): Patient must have received their last dose of the investigational or biologic agent ≥ 7 days before study enrollment.
  3. Antibodies: ≥ 21 days must have elapsed from an infusion of the last dose of antibody and toxicity related to prior antibody therapy must be recovered to Grade ≤ 1. Agents with prolonged half-lives: At least three half-lives must have elapsed before enrollment.
  4. Immunotherapy: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses. etc.) at least 42 days before enrollment.
  5. Radiation: Patients must have had their last fraction of • Craniospinal irradiation ≥ 3 months before enrollment. • Other substantial bone marrow irradiation ≥ 6 weeks before enrollment • Local or palliative XRT (small port) ≥ 2 weeks.
  6. Stem Cell Transplant: Patient must be ≥ 12 weeks since autologous bone marrow/stem cell transplant before enrollment. Patients with uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs are excluded.

• Patients must fully recover from all acute effects of prior surgical intervention.

• History of allergic reactions to atovaquone or attributed to compounds of similar chemical or biological composition to atovaquone.

• Pregnant or breast-feeding women will not be entered into this study as there may be fetal risks or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during treatment and for 3 months after stopping treatment. This should be documented in the electronic medical records as part of the consent discussion.