Atovaquone Combined With Radiation in Children With Malignant Brain Tumors

NCT06624371 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: STUDY00007693
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

High-grade Glioma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant

Keywords

Atovaquone; Progression-free survival

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Progression Free Survival (PFS) in newly diagnosed pediatric high-grade glioma/diffuse midline glioma/diffuse intrinsic pontine glioma (pHGG/DMG/DIPG) patients (Stratum 1)

  Baseline, Month 12

• Progression Free Survival (PFS) in Stratum 2 subjects

  Baseline, Month 12

• Overall survival (OS) in newly diagnosed pHGG/DMG/DIPG patients (Stratum 1)

  Baseline, end of study (Week 10)

• Overall survival in Stratum 2 subjects

  Baseline, End of study (Month 7)

• Objective Tumor Response Rate (ORR) for Stratum 2

  Baseline, End of study (Month 7)

Study Arms (2)

Stratum 1:

EXPERIMENTAL

Newly diagnosed pHGG/DMG/DIPG patients. New Diagnosis followed by 2 weeks (+/- 7 days) atovaquone followed by approx. 6 weeks Atovaquone + Radiotherapy

Drug: Atovaquone; Radiation: Radiation Therapy

Stratum 2

EXPERIMENTAL

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; Radiation: Radiation Therapy

Interventions

Atovaquone DRUG

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.

Stratum 1:; Stratum 2

Radiation Therapy RADIATION

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.

Also known as: Standard of Care

Stratum 1:; Stratum 2

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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:
• 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.
• Biologic or investigational agent (anti-neoplastic): Patient must have received their last dose of the investigational or biologic agent ≥ 7 days before study enrollment.
• 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.

Sponsors & Collaborators

• Emory University: lead
• Morningside Foundation/Peach Bowl LegACy Fund: collaborator

Study Sites (2)

Arthur M Blank Hospital

Atlanta, Georgia, 30329, United States

RECRUITING

Children's Healthcare of Atlanta: Scottish Rite

Atlanta, Georgia, 30342, United States

RECRUITING

MeSH Terms

Conditions

Glioma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma

Interventions

Atovaquone; Radiotherapy; Standard of Care

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Naphthoquinones; Quinones; Organic Chemicals; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Therapeutics; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Tobey MacDonald, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tobey MacDonald, MD

CONTACT

404-727-1447; aflacdevtreferral@choa.org

Amber Kaminski

CONTACT

aflacdevtreferral@choa.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: In Stratum 1, six subjects will be enrolled for a Phase I safety evaluation of atovaquone with radiotherapy (RT). Patients will take atovaquone orally once daily for at least 7 days and up to 21 days before starting RT, continuing through RT without interruption. The study will use a Rolling-6 design with no dose escalation. If no more than one dose-limiting toxicity (DLT) or drug discontinuation for over two weeks due to intolerance occurs in the first six subjects, six additional patients will be enrolled to confirm the safety of the combination. If two or more DLTs or unique drug discontinuations are observed among these twelve patients, the regimen will be deemed too toxic. In Stratum 2, six subjects will receive atovaquone daily for six months. Given prior safety in pediatric patients, DLTs are not expected. However, if two or more DLTs or prolonged discontinuations occur, the regimen will also be considered too toxic

Study Record Dates

• First Submitted: October 1, 2024
• First Posted: October 3, 2024
• Study Start: March 28, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027
• Last Updated: July 22, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)