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.
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.
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.
Parallel
Atovaquone
DrugAtovaquone oral suspension (750 mg/5mL) will be administered with meals on an outpatient basis. Patients 13 years and older will receive atovaquone 750 mg PO BID, the standard pediatric dosing for Pneumocystis Jirovecii Pneumonia (PJP) prevention and treatment. For those aged 2-12 years, atovaquone will be dosed at 30mg/kg once daily. The maximum dose for children under 12 will be 1500 mg.
Radiation Therapy
Radiation54-60 Gy in 1.8 Gy daily fractions of MRI-guided proton radiotherapy using intensity-modulated pencil-beam scanning technology to match the target will be used.
Drug Limiting toxicities (DLT) in Stratum 1
Adverse events that meet definition of DLT and tolerability. The outcome will be evaluated by descriptive statistics. Rates of symptomatic and asymptomatic radiation necrosis will also be estimated for Stratum 1 patients.
Drug Limiting toxicities (DLT) in Stratum 2
Adverse events that meet definition of DLT and tolerability. The outcome will be evaluated by descriptive statistics. Rates of symptomatic and asymptomatic radiation necrosis will also be estimated for Stratum 2 patients.
Progression Free Survival (PFS) in newly diagnosed pediatric high-grade glioma/diffuse midline glioma/diffuse intrinsic pontine glioma (pHGG/DMG/DIPG) patients (Stratum 1)
PFS is defined as the time from initiation of drug treatment to the occurrence of confirmed disease progression. Subjects who are lost to follow-up or withdraw from the study will be treated as censored observations at the last follow-up time point when they are alive.
Progression Free Survival (PFS) in Stratum 2 subjects
PFS is defined as the time from initiation of drug treatment to the occurrence of confirmed disease progression. Subjects that are lost to follow-up or withdraw from the study will be treated as censored observations at the last follow-up time point when they are alive.
Overall survival (OS) in newly diagnosed pHGG/DMG/DIPG patients (Stratum 1)
OS is defined as time from enrollment to death due to any cause. The Kaplan-Meier method will be used to estimate the OS rates over time. Median survival time along with 95% confidence interval (CI) will be calculated
Overall survival in Stratum 2 subjects
OS is defined as time from enrollment to death due to any cause. The Kaplan-Meier method will be used to estimate the OS rates over time. Median survival time along with 95% confidence interval (CI) will be calculated
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Emory University
Lead sponsor
Morningside Foundation/Peach Bowl LegACy Fund
Collaborator
