Atovaquone + Radiation for Pediatric Brain Cancer

(AflacBT2303 Trial)

Recruiting at 1 trial location

Overseen By Tobey MacDonald, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Emory University

Disqualifiers: Chronic illness, Metastatic tumor, Uncontrolled seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment that combines atovaquone, a medication, with standard radiation therapy to assess its safety and tolerability in children recently diagnosed with aggressive brain cancers such as high-grade glioma and diffuse midline glioma. For those whose cancer has returned or worsened, the trial examines the extended use of atovaquone. Children diagnosed with these specific brain cancers and stable conditions, like controlled seizures, might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients must have recovered from prior treatments and that certain time periods must pass after previous therapies before enrolling. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study found atovaquone to be safe and well tolerated in children. This medicine, typically used to treat certain types of pneumonia, has been administered to children once a day without major issues. Although specific safety information for using atovaquone with radiation in treating children's brain cancer is lacking, its use in other conditions suggests it is generally well tolerated. Since this trial is in the early stages, it primarily focuses on assessing the safety of atovaquone when combined with radiation. Its approval for other uses in children suggests it could be a safe option. However, always consult a healthcare provider about potential risks and benefits before joining a trial. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pediatric brain cancer?

Unlike the standard treatments for pediatric brain cancer, which typically include surgery, chemotherapy, and radiation, atovaquone offers a unique approach. Researchers are excited about atovaquone because it targets cancer cells differently by potentially interfering with their energy production, which could make them more vulnerable to treatment. It's also noteworthy that atovaquone is an oral medication, which can be less invasive and easier to administer compared to traditional chemotherapy. This novel mechanism and ease of administration are what make atovaquone a promising option worth exploring further.

What evidence suggests that atovaquone combined with radiation might be an effective treatment for pediatric brain cancer?

Research has shown that combining atovaquone with radiation therapy may help treat brain tumors in children. Early studies suggest this combination can shrink tumors and improve survival chances. In this trial, participants in Stratum 1, who are newly diagnosed, will receive atovaquone followed by atovaquone combined with radiotherapy. Meanwhile, Stratum 2 participants, who either have relapsed or have not progressed after radiation, will receive atovaquone for up to 6 months. One study found that 76.6% of patients did not see their cancer worsen for two years, and 80.9% were still alive after two years. These results are hopeful, especially for challenging cases like diffuse midline glioma (DMG), which usually have poor outcomes. Atovaquone might enhance radiation therapy by boosting its effects on tumor cells. ^{1 2 6 7 8}

Who Is on the Research Team?

Tobey MacDonald, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

This trial is for children with newly diagnosed high-grade brain tumors, including diffuse intrinsic pontine glioma and medulloblastoma. Participants must meet specific health criteria to be eligible. The full list of inclusion and exclusion criteria was not provided.

Inclusion Criteria

Stratum 1: Weight > 10kg

Stratum 2: Weight > 10kg

My seizures are under control.

Exclusion Criteria

I have not had cancer treatment other than radiation.

I have bleeding in my tumor, which causes symptoms or is large.

Stratum 1: Chronic systemic concurrent illness

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Initial Atovaquone Treatment

Newly diagnosed patients receive atovaquone for 2 weeks before starting combination therapy with radiation

2 weeks

Combination Treatment

Participants receive atovaquone in combination with radiation therapy

6 weeks

Extended Atovaquone Treatment

Participants in Stratum 2 receive atovaquone for up to 6 months in the absence of toxicity, intolerance, or tumor progression

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Atovaquone

Trial Overview

The study tests the safety of atovaquone when used with standard radiation therapy in treating pediatric brain tumors. It also looks at how well patients tolerate long-term atovaquone treatment after radiation therapy.

How Is the Trial Designed?

Group I: Stratum 2 Experimental Treatment 2 Interventions

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.

Group II: Stratum 1: Experimental Treatment 2 Interventions

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

Atovaquone is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as Mepron for:

• Pneumocystis jirovecii pneumonia (PCP)
• Plasmodium falciparum malaria

Approved in European Union as Malarone for:

• Plasmodium falciparum malaria
• Pneumocystis jirovecii pneumonia (PCP)

Approved in United Kingdom as Wellvone for:

• Pneumocystis jirovecii pneumonia (PCP)
• Plasmodium falciparum malaria

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Morningside Foundation/Peach Bowl LegACy Fund

Collaborator

Trials

1

Recruited

20+

Published Research Related to This Trial

In a Phase II study involving 53 children with high-risk medulloblastoma, oral etoposide was found to be tolerable and effective when administered during radiotherapy, leading to a high response rate with 40.4% achieving complete response and 51.1% partial response.

The study reported promising survival rates, with 2-year progression-free survival (PFS) at 76.6% and overall survival (OS) at 80.9%, indicating that this treatment regimen could improve outcomes for children with this aggressive form of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II feasibility study of oral etoposide given concurrently with radiotherapy followed by dose intensive adjuvant chemotherapy for children with newly diagnosed high-risk medulloblastoma (protocol POG 9631): A report from the Children's Oncology Group. Esbenshade, AJ., Kocak, M., Hershon, L., et al.[2018]

In a phase 2 trial involving 92 children with recurrent central nervous system tumors, the combination of bevacizumab (BVZ) and irinotecan (CPT-11) was generally well-tolerated, with most severe toxicities being rare and manageable.

The most common adverse effects associated with BVZ included hypertension (38%), fatigue (30%), epistaxis (24%), and proteinuria (22%), with 24% of patients discontinuing therapy due to toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022). Fangusaro, J., Gururangan, S., Poussaint, TY., et al.[2021]

In a case series of four patients treated with bevacizumab after radiotherapy for CNS conditions, there were unexpected occurrences of late radiation-induced neurotoxicity, including three cases of optic neuropathy and one case of Brown-Séquard syndrome.

The authors suggest that bevacizumab may inhibit the repair of normal neural tissue by blocking vascular endothelial growth factor, potentially increasing the risk of neurotoxicity after radiation therapy, highlighting the need for further safety data in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpected late radiation neurotoxicity following bevacizumab use: a case series. Kelly, PJ., Dinkin, MJ., Drappatz, J., et al.[2021]

The maximum tolerated dose (MTD) of etanidazole for children undergoing hyperfractionated radiation therapy for brainstem glioma was determined to be 42 g/m², with cutaneous rash identified as the primary dose-limiting toxicity.

In this Phase I trial involving 18 patients, the study found that children experienced different toxicity profiles compared to adults, as adults had a lower MTD of 34 g/m² limited by peripheral neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma. Marcus, KJ., Dutton, SC., Barnes, P., et al.[2022]

A 3-year-old boy with cerebral radiation necrosis showed significant improvement in mobility after receiving 60 sessions of hyperbaric oxygen therapy, following initial treatment with corticosteroids and bevacizumab that did not yield results.

This case suggests that hyperbaric oxygen therapy can be an effective treatment option for pediatric patients with cerebral radiation necrosis, alongside traditional pharmacologic therapies, while emphasizing the importance of careful treatment planning to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of pediatric cerebral radiation necrosis using hyperbaric oxygenation. Johnson-Arbor, K.[2023]

Chemotherapy for pediatric brain tumor patients is generally well-tolerated and can be more effective after major surgical resection, especially with agents like cisplatin and cyclophosphamide that require hydration.

New supportive care measures, such as mesna and antiemetics like ondansetron, have significantly improved the tolerance of chemotherapy, reducing side effects like hemorrhagic cystitis and neutropenia, which enhances overall treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications of chemotherapy in patients with brain and spinal cord tumors. Allen, JC.[2018]

ImuVert, a biologic response modifier derived from Serratia marcescens, has been granted orphan drug status by the FDA and is currently being tested in a multicenter clinical trial for recurrent malignant astrocytoma, a type of brain tumor with a poor prognosis.

In phase I and II trials, ImuVert showed manageable toxicities, including mild local reactions and some cases of hypotension, indicating that while it has potential as a treatment, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ImuVert therapy in the treatment of recurrent malignant astrocytomas: nursing implications. Cress, NB., Owens, BM., Hill, FH.[2019]

In a pilot study involving 7 children aged 1 to 25 years with radiation-induced necrosis, 83% were able to reduce or stop corticosteroid use, indicating that bevacizumab may effectively manage symptoms associated with radiation injury.

All patients showed improvements in MRI imaging, with a decrease in enhancement and FLAIR signal, suggesting that bevacizumab not only helps with clinical symptoms but also positively affects the underlying imaging characteristics of radiation necrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab in the treatment of radiation injury for children with central nervous system tumors. Dahl, NA., Liu, AK., Foreman, NK., et al.[2020]

Citations

1.

cancer.gov

cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-07762

Atovaquone Alone or Combined with Radiation for the ...

This phase I trial tests the safety and side effects of atovaquone alone or in combination with radiation in treating children with malignant brain tumors.

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06624371

NCT06624371 | Atovaquone Combined With Radiation in ...

In animal studies and early clinical trials, Atovaquone has shown promise in reducing tumor size and improving survival rates. For pediatric brain tumors, which ...

3.

withpower.com

withpower.com/trial/phase-1-glioma-9-2024-a06e7

Atovaquone + Radiation for Pediatric Brain Cancer

The study reported promising survival rates, with 2-year progression-free survival (PFS) at 76.6% and overall survival (OS) at 80.9%, indicating that this ...

4.

clinconnect.io

clinconnect.io/trials/NCT06624371

Atovaquone Combined With Radiation in Children With - ClinConnect

This clinical trial is studying the use of a medication called atovaquone combined with standard radiation therapy to treat children with certain types of ...

5.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10259914/

DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE ...

Diffuse Midline Glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC105594/

Phase I Safety and Pharmacokinetics Study of Micronized ...

The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for ...

7.

mayoclinic.org

mayoclinic.org/drugs-supplements/atovaquone-oral-route/description/drg-20062055

Atovaquone (oral route) - Side effects & dosage

Atovaquone is used to prevent and treat Pneumocystis jiroveci pneumonia (PCP) in adults and children 13 years of age and older who cannot tolerate other ...

8.

cdc.gov

cdc.gov/malaria/resources/pdf/fsp/drugs_2017/atovaquoneproguanil_2017.pdf

Atovaquone-Proguanil (Malarone™)

The list below shows the daily dose for children based on their weight: 5–8 kg children should take a 1/2 pediatric tablet daily,. > 8–10 kg: 3/4 pediatric ...