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

Trial Summary

What is the purpose of this trial?

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.

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 Atovaquone safe for use in humans?

There is no specific safety data on Atovaquone combined with radiation for pediatric brain cancer in the provided research articles. ^{1 2 3 4 5}

How is the drug Atovaquone unique in treating pediatric brain cancer?

Atovaquone is unique because it is primarily used as an antimalarial and antiparasitic drug, and its use in combination with radiation for pediatric brain cancer is novel, potentially offering a different mechanism of action compared to traditional chemotherapy drugs. ^{2 3 6 7 8}

Research Team

Tobey MacDonald, MD

Principal Investigator

Emory University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

ImuVert therapy in the treatment of recurrent malignant astrocytomas: nursing implications. [2019]

2. Germany pubmed.ncbi.nlm.nih.gov

Bevacizumab in the treatment of radiation injury for children with central nervous system tumors. [2020]

3. Switzerland pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Unexpected late radiation neurotoxicity following bevacizumab use: a case series. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

A phase I trial of etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma. [2022]

6. United States 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. [2018]

7. United States 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). [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Treatment of pediatric cerebral radiation necrosis using hyperbaric oxygenation. [2023]