Combining Atovaquone with Radiation for Treating Children's Brain Tumors

Atovaquone Combined With Radiation in Children With Malignant Brain Tumors

This study is testing if adding atovaquone to radiation therapy can help children with aggressive brain tumors feel better and improve their treatment outcomes.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 18 (estimated)
• Ages: 2 Years to 25 Years
• Sex: All
• Sponsor: Emory University (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation
• Locations: 2 sites (Atlanta, Georgia and 1 other locations)
• Trial ID: NCT06624371 on ClinicalTrials.gov

What this trial studies

This interventional study aims to evaluate the safety and tolerability of atovaquone when used alongside standard radiation therapy in pediatric patients diagnosed with high-grade gliomas and diffuse midline gliomas. Atovaquone, an FDA-approved drug, is being repurposed for cancer treatment due to its ability to inhibit cancer cell survival mechanisms. The study also investigates the long-term use of atovaquone for patients with relapsed or progressed brain tumors after radiation therapy. By potentially enhancing the effectiveness of radiation, this approach could offer new hope for children facing these challenging cancers.

Who should consider this trial

Good fit: Ideal candidates include pediatric patients with newly diagnosed high-grade gliomas or diffuse midline gliomas who meet specific health criteria.

Not a fit: Patients with non-cancerous conditions or those who do not meet the eligibility criteria will not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve survival rates and progression-free survival for children with aggressive brain tumors.

How similar studies have performed: While atovaquone has shown promise in early studies for cancer treatment, this specific combination with radiation therapy is novel and under investigation.

Eligibility criteria

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.

Where this trial is running

Atlanta, Georgia and 1 other locations

• Arthur M Blank Hospital — Atlanta, Georgia, United States (Recruiting)
• Children's Healthcare of Atlanta: Scottish Rite — Atlanta, Georgia, United States (Recruiting)

Study contacts

• Principal investigator: Tobey MacDonald, MD — Emory University
• Study coordinator: Tobey MacDonald, MD

Conditions High-grade Glioma; Medulloblastoma; Diffuse Intrinsic Pontine Glioma; Diffuse Midline Glioma, H3 K27M-Mutant; Atovaquone; Progression-free survival