Atovaquone Alone or Combined with Radiation for the Treatment of Children with Malignant Brain Tumors

Inclusion Criteria

• STRATUM 1: Newly diagnosed pHGG/DMG/DIPG * Patients must have histologically confirmed pediatric high-grade glioma (pHGG, World Health Organization [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 ** Measurable disease is not necessary for enrollment on study
• STRATUM 1: Age ≥ 2 to 25 years
• STRATUM 1: Weight > 10kg
• STRATUM 1: Karnofsky and Lansky performance score > 50%
• STRATUM 1: Patients with stable seizures (e.g., no seizures for ≥ 7 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible
• STRATUM 1: Total bilirubin ≤ 2 x upper limit of normal (ULN)
• STRATUM 1: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 225 U/L (5 x the ULN). The ULN for AST and ALT will be 45 U/L (< 10 x the ULN if taking steroids)
• STRATUM 1: Absolute neutrophil count ≥ 1,000/mcL
• STRATUM 1: Platelets ≥ 100,000/mcL
• STRATUM 1: Hemoglobin ≥ 8 g/dL
• STRATUM 1: Creatinine within normal institutional limits for age OR creatinine clearance ≥ 60 mL/min/1.73m^2 for patients with creatinine levels above institutional normal
• STRATUM 2: Relapsed, progressive pHGG/DMG/DIPG and medulloblastoma (MB) (Stratum 2a) or pHGG/DMG/DIPG after completion of standard radiation therapy without prior atovaquone exposure and prior to progression (Stratum 2b). Patients with metastatic disease are allowed for Stratum 2 only * Measurable disease is not necessary for enrollment on study
• STRATUM 2: Patients must have previously undergone standard-of-care treatment including surgery, radiation, and/or first line adjuvant chemotherapy prior to the experimental treatment (atovaquone)
• STRATUM 2: 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 for Stratum 2a
• STRATUM 2: Age ≥ 2 to 25 years
• STRATUM 2: Weight > 10 kg
• STRATUM 2: Karnofsky and Lansky performance score > 50%
• STRATUM 2: Patients with stable seizures (e.g., no seizures for ≥ 7 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible
• STRATUM 2: Patients must have normal organ and marrow function as defined for Stratum 1
• STRATUM 2: Total bilirubin ≤ 2 x upper limit of normal (ULN)
• STRATUM 2: AST (SGOT) and ALT (SGPT) ≤ 225 U/L (5 x the ULN). The ULN for AST and ALT will be 45 U/L (< 10 x the ULN if taking steroids)

Exclusion Criteria

• STRATUM 1: Chronic systemic concurrent illness
• STRATUM 1: History of or receiving current anti-cancer therapy. Patients must be eligible to receive concurrent radiation therapy while on study
• STRATUM 1: Patients with metastatic tumor are excluded for Stratum 1 only
• STRATUM 1: Patients with uncontrolled seizures or seizures requiring escalation or addition of anti-epileptic drugs are excluded
• STRATUM 1: Patients must be fully recovered from all acute effects of prior surgical intervention
• STRATUM 1: History of allergic reactions to atovaquone or attributed to compounds of similar chemical or biologic composition to atovaquone
• STRATUM 1: Symptomatic intratumoral hemorrhage, or asymptomatic intratumoral hemorrhage larger than punctate foci, at any time prior to enrollment
• STRATUM 1: Pregnant or breast-feeding women will not be entered on 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: Chronic systemic concurrent illness
• STRATUM 2: For Stratum 2b, patients who have received prior therapy other than standard of care upfront treatment of surgery, radiotherapy, and/or temozolomide will be excluded from study. Patients in this stratum must not have prior investigational agent exposure
• STRATUM 2: Patients enrolling on stratum 2a must have recovered from all prior therapy as follows below. For Stratum 2b, the only applicable criteria below are for myelosuppressive anticancer therapy if they have received prior temozolomide * Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea * Biologic or investigational agent (anti-neoplastic): Patient must have received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment * Antibodies: ≥ 21 days must have elapsed from infusion of 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 prior to enrollment * Immunotherapy: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses. etc.) at least 42 days prior to enrollment * Radiation: Patients must have had their last fraction of: ** Craniospinal irradiation ≥ 3 months prior to enrollment ** Other substantial bone marrow irradiation ≥ 6 weeks prior to enrollment ** Local or palliative radiation external beam radiation therapy (XRT) (small port) ≥ 2 weeks * Stem cell transplant: Patient must be ≥ 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
• STRATUM 2: Patients with uncontrolled seizures or seizures requiring escalation or addition of anti-epileptic drugs are excluded
• STRATUM 2: Patients must be fully recovered from all acute effects of prior surgical intervention
• STRATUM 2: History of allergic reactions to atovaquone or attributed to compounds of similar chemical or biologic composition to atovaquone
• STRATUM 2: Pregnant or breast-feeding women will not be entered on 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