Atovaquone Combined With Radiation in Children With Malignant Brain Tumors (AflacBT2303)

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.

Study Overview

• Status: Recruiting
• Conditions: Medulloblastoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; High-grade Glioma
• Intervention / Treatment: Drug: Atovaquone; Radiation: Radiation Therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Tobey MacDonald, MD; Phone Number: 404-727-1447; Email: aflacdevtreferral@choa.org
• Study Contact Backup: Name: Amber Kaminski; Email: aflacdevtreferral@choa.org

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Recruiting
      • Arthur M Blank Hospital
      • Contact: Amber Kaminski; Email: aflacdevtreferral@choa.org
      • Contact: Tobey MacDonald, MD
    • Atlanta, Georgia, United States, 30342
      • Recruiting
      • Children's Healthcare of Atlanta: Scottish Rite
      • Principal Investigator: Tobey MacDonald, MD
      • Contact: Amber Kaminski; Email: aflacdevtreferral@choa.org
      • Contact: Tobey J MacDonald, MD; Phone Number: 404-727-1447; Email: aflacdevtreferral@choa.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stratum 1: Newly diagnosed pHGG/DMG/DIPG patients. New Diagnosis followed by 2 weeks (+/- 7 days) atovaquone followed by approx. 6 weeks Atovaquone + Radiotherapy	Drug: Atovaquone; Atovaquone 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: Radiation Therapy; 54-60 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.; Other Names: Standard of Care
Experimental: Stratum 2; Stratum 2 will be bifurcated into: Stratum 2a (patients with relapse or progression); Stratum 2b (patients without progression after radiation) The same dosing regimen for atovaquone will be used for up to 6 months in the absence of toxicity, intolerance, or tumor progression. Patients will begin therapy between 2-4 weeks after documented relapse or progression of tumor or between 2-4 weeks after completion of standard RT for pHGG/DMG/DIPG patients who have completed standard Radiotherapy without previous atovaquone treatment.	Drug: Atovaquone; Atovaquone 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: Radiation Therapy; 54-60 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.; Other Names: Standard of Care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, end of study (10 weeks)
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.	Baseline, End of study (Month 7)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Month 12
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.	Baseline, Month 12
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	Baseline, end of study (Week 10)
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	Baseline, End of study (Month 7)
Objective Tumor Response Rate (ORR) for Stratum 2	Objective response (PR or CR), observed anytime during treatment and sustained for at least 8 weeks, in patients with relapsed or progressive pHGG, DMG/DIPG, or MB. Complete Response (CR): Complete disappearance on MR of all evaluable tumor and mass effect, on a stable or decreasing dose of corticosteroids (or receiving only adrenal replacement doses),accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. If CSF was positive, it must be negative. Partial Response (PR): Greater than or equal to 50% reduction in tumor size by bi-dimensional measurement, as compared with the baseline measurements, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.	Baseline, End of study (Month 7)

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Morningside Foundation/Peach Bowl LegACy Fund
• Investigators: Principal Investigator: Tobey MacDonald, MD, Emory University

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: October 1, 2024
• First Submitted That Met QC Criteria: October 2, 2024
• First Posted (Actual): October 3, 2024

Study Record Updates

• Last Update Posted (Actual): July 22, 2025
• Last Update Submitted That Met QC Criteria: July 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Progression-free survival; Atovaquone
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neuroectodermal Tumors, Primitive; Central Nervous System Neoplasms; Brain Stem Neoplasms; Infratentorial Neoplasms; Diffuse Intrinsic Pontine Glioma; Glioma; Brain Neoplasms; Medulloblastoma; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Atovaquone
• Other Study ID Numbers: STUDY00007693

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No