ONC206 + Radiation Therapy for Brain Tumor

(PNOC023 Trial)

Recruiting at 5 trial locations

Overseen By PNOC Operations

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Sabine Mueller, MD, PhD

Must not be taking: Investigational drugs, Anti-cancer agents

Disqualifiers: Immune disorders, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12-24 months

208 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment called ONC206 for brain tumors, specifically diffuse midline gliomas and other malignant CNS tumors. The researchers aim to determine if ONC206 alone or combined with radiation therapy can effectively stop tumor growth by triggering a "stress response" that kills cancer cells without harming normal cells. Different groups in this trial test ONC206 with or without radiation in patients who are newly diagnosed or have recurrent tumors. This trial may suit children and young adults with specific brain tumors who have had prior treatments like radiation but are not currently receiving other cancer therapies. As a Phase 1 trial, this research focuses on understanding how ONC206 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 requires that participants stop taking certain medications before starting the study. Specifically, you must wait a certain period after taking investigational agents, cytotoxic therapy, antibodies, and biologic or small molecule agents. If you are on strong inhibitors or inducers of specific enzymes (CYP3A4, 2D6, 1A2, 2C9, and 2C19), you must stop them at least 14 days before and throughout the study.

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

Research shows that ONC206 is a promising treatment. Lab tests have demonstrated its ability to kill brain tumor cells without harming normal cells. Studies suggest that ONC206 is generally well-tolerated and likely has few side effects, as observed in cell and animal studies.

One study found that ONC206 can cross the protective barrier around the brain, which is crucial for treating brain tumors. This ability allows the drug to effectively reach tumor cells.

When combined with radiation therapy, ONC206 might be safe and effective. Although specific safety data from human trials is limited at this early stage, its progression to this phase indicates some confidence in its safety. Further testing will help confirm how well people tolerate ONC206. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ONC206 for brain tumors because it targets tumors differently compared to standard treatments like surgery, chemotherapy, and radiation. ONC206 is a new drug that works by targeting specific pathways in cancer cells, potentially offering a more precise attack on tumor cells while sparing healthy tissue. This could lead to fewer side effects and improved outcomes for patients with primary malignant CNS tumors and diffuse midline gliomas. Additionally, ONC206 can be used alongside radiation therapy for certain patient groups, which may enhance the effectiveness of the radiation treatment. These unique features make ONC206 a promising option for patients who have limited treatment choices.

What evidence suggests that this trial's treatments could be effective for brain tumors?

Research has shown that ONC206 may help treat certain brain tumors. Studies have found that ONC206 can induce stress in tumor cells, causing them to die without harming healthy cells. In lab tests, ONC206 reduced the number of tumor cells and improved survival rates in animals. In this trial, some participants will receive ONC206 alone, while others will receive it combined with radiation therapy. When used with radiation therapy, ONC206 may also enhance treatment for diffuse midline gliomas, a very aggressive type of brain tumor. Early results suggest it might be effective against both new and recurring tumors in the central nervous system. These findings strongly support further research on ONC206 in clinical trials. ^{1 4 6 7 8}

Who Is on the Research Team?

Sabine Mueller, MD, PhD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for children and adults with newly diagnosed or recurrent diffuse midline gliomas (DMG) and other malignant CNS tumors. Participants must have stable vital signs, not be pregnant or breastfeeding, agree to use contraception if applicable, and cannot be on certain medications that affect ONC206 absorption or immune system disorders.

Inclusion Criteria

I have been on a stable or decreasing dose of steroids for at least 3 days before my baseline MRI scan.

Agreement to use adequate contraception for females of child-bearing potential and males

My child has a recurring brain tumor that has progressed but hasn't been treated for this progression.

Exclusion Criteria

I have an immune system disorder like HIV, hepatitis B or C, or an autoimmune disease.

I do not have any infections that are currently uncontrolled.

Participants currently receiving another investigational drug

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ONC206 orally up to six times per week, with cycles repeating every 28 days for up to 12 months. Radiation therapy is included for certain arms.

12-24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 30 days and then every 3 months for up to 5 years.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• ONC206
• Standard of Care Radiation Therapy

Trial Overview The trial is testing the effectiveness of a new drug called ONC206 alone or combined with standard radiation therapy. The goal is to find the best dose that can stop tumor growth by triggering a stress response in cancer cells without harming normal cells.

How Is the Trial Designed?

Group I: Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression Experimental Treatment 2 Interventions

Participants receive ONC206 PO once a day (QD) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Group II: Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated Experimental Treatment 3 Interventions

Participants undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Group III: Arm B: ONC206 + radiation therapy for newly diagnosed participants Experimental Treatment 3 Interventions

Participants undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Group IV: Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy Experimental Treatment 2 Interventions

Participants receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Who Is Running the Clinical Trial?

Sabine Mueller, MD, PhD

Lead Sponsor

Trials

9

Recruited

440+

Dana-Farber Cancer Institute

Collaborator

Trials

1,128

Recruited

382,000+

Jazz Pharmaceuticals

Industry Sponsor

Trials

252

Recruited

35,100+

Bruce C. Cozadd

Jazz Pharmaceuticals

Chief Executive Officer since 2009

BA in Economics from Yale University, MBA from Stanford University

Dr. Austin

Jazz Pharmaceuticals

Chief Medical Officer since 2023

MD from the Royal College of Surgeons in Ireland

The ChadTough Defeat DIPG Foundation

Collaborator

Trials

1

Recruited

210+

Storm the Heavens Fund

Collaborator

Trials

2

Recruited

570+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Chimerix

Industry Sponsor

Trials

42

Recruited

4,100+

Mithil Prasad Foundation

Collaborator

Trials

2

Recruited

570+

Published Research Related to This Trial

In a phase II clinical trial involving 87 patients, fractionated lesional radiotherapy (60 Gy in 10 fractions) showed a median overall survival of 5.4 months, which was not significantly worse than historical controls, indicating its potential as a viable treatment for brain oligometastases.

The six-month intracranial lesion control rate was 89%, demonstrating non-inferiority compared to previous studies, while only two patients experienced suspected asymptomatic radionecrosis, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases. Rodrigues, G., Yartsev, S., Roberge, D., et al.[2020]

The BRAF V600E inhibitor PLX4720 significantly enhances the effectiveness of radiation therapy (RT) in treating high-grade gliomas (HGGs) with the BRAF V600E mutation, leading to greater anti-tumor effects compared to either treatment alone.

In both in vitro and in vivo studies, combining PLX4720 with RT resulted in increased apoptosis and prolonged survival in mouse models of BRAF V600E HGG, suggesting a promising strategy for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. Dasgupta, T., Olow, AK., Yang, X., et al.[2019]

In a study involving 18 patients with high-grade gliomas, simultaneous teleradiotherapy and anti-EGFR radioimmunotherapy did not show any improvement in disease-free or overall survival compared to teleradiotherapy alone.

The treatment was well-tolerated with no immediate side effects observed, but the findings suggest that combining these therapies may not provide additional benefits in the adjuvant treatment of high-grade gliomas after neurosurgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of monoclonal anti-EGFR antibody in the radioimmunotherapy of malignant gliomas in the context of EGFR expression in grade III and IV tumors. Wygoda, Z., Kula, D., Bierzyńska-Macyszyn, G., et al.[2021]

Combining different treatment approaches for brain metastases can significantly improve treatment efficacy, potentially extending median overall survival to 6 months.

The study highlights the importance of using maximum combinations of therapies, suggesting that this strategy may lead to better outcomes for patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Brain metastasis in breast cancer]. Korytova, LI., Meshechkin, AV., Zhabuna, RM., et al.[2018]

Patients with non-small cell lung cancer (NSCLC) often develop brain metastases, making effective treatment crucial, especially for those with specific genetic mutations like EGFR and ALK.

While radiotherapy is the standard treatment for brain metastases, recent studies suggest that combining it with targeted therapies, such as tyrosine kinase inhibitors, may enhance treatment effectiveness, although more high-quality clinical evidence is needed to support this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. Khalifa, J., Amini, A., Popat, S., et al.[2022]

Radiation therapy for high-grade malignant gliomas (grade III and IV) provides a modest survival benefit of about 3-4 months compared to supportive care or chemotherapy, but curative treatment remains unavailable.

There is no evidence that advanced radiotherapy techniques, such as hyper- and hypofractionation, improve survival compared to conventional radiotherapy for high-grade gliomas, although hypofractionation may offer similar outcomes with shorter treatment times for patients with poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic overview of radiation therapy effects in brain tumours. Berg, G., Blomquist, E., Cavallin-Ståhl, E.[2019]

In early phase I studies, patients undergoing 252Cf brachytherapy combined with whole brain photon beam therapy tolerated the treatment well and showed improvements in performance status and reductions in tumor size as evaluated by CT scans.

The study highlighted the need for individualized treatment plans due to the large size of tumors and significant brain edema, indicating that high-dose external beam irradiation is necessary for effective responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interstitial 252Cf neutron therapy for glioblastoma multiforme. Maruyama, Y., Chin, HW., Young, AB., et al.[2019]

Radiation therapy significantly improves survival rates for various types of brain tumors, especially when used after incomplete surgical resection, with benefits lasting up to 5-10 years for most tumor types.

While glioblastomas showed a survival benefit for only 1-2 years post-treatment, the overall findings suggest that radiation therapy may lead to long-term control of many brain tumors, as many patients remained alive at the time of the review.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy of brain tumors. Sheline, GE.[2019]

Radiosurgery (RS) alone or combined with whole-brain radiotherapy (WBRT) effectively controls brain metastases, achieving a 92% control rate, with a median overall survival of 5.5 months for all patients.

Patients without extracranial disease showed improved median survival (15.4 months) when treated with WBRT in addition to RS compared to those receiving RS alone (8.3 months), suggesting that combining treatments may enhance outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. Pirzkall, A., Debus, J., Lohr, F., et al.[2022]

Fractionated stereotactic radiation therapy (FSRT) was well tolerated by all 56 adult patients with oligodendroglioma or oligoastrocytoma, showing no side effects, and resulted in a median overall survival of 77.5 months from diagnosis.

The treatment demonstrated high local control, with 89% of patients remaining progression-free at one year and 52% at five years, confirming that FSRT effectively targets tumors while sparing healthy brain tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fractionated stereotactic radiation therapy in the management of primary oligodendroglioma and oligoastrocytoma. Combs, SE., Schulz-Ertner, D., Thilmann, C., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04732065

Study Details | NCT04732065 | ONC206 for Treatment of ... ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent ...

2. biorxiv.org biorxiv.org/content/10.1101/2025.09.25.678693v1.full.pdf

ONC206 demonstrates potent anti-tumorigenic activity and ... Our study provides a strong rationale for testing the efficacy of ONC206 in the treatment of patients with medulloblastoma and has set the stage ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11948724/

Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy ... Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and ...

4. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/central-nervous-system-tumor

UCSF Central Nervous System Tumor Clinical Trials for 2025 ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and ...

5. pnoc.us pnoc.us/clinical-trial/pnoc023/

PNOC023 - Clinical Trial We aim to test the tumor penetration and preliminary efficacy of ONC206 within a target validation study in children and young adults with DMGs.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04541082

NCT04541082 | Phase I Study of Oral ONC206 in ... The primary objective of this Phase 1, open-label, dose-escalation, and exploratory study is to evaluate the safety and tolerability profile (establish the ...

7. humanforschung-schweiz.ch humanforschung-schweiz.ch/en/trial-search/study-detail/54254/translate/en/?cHash=4f3c60d95c114adfbfc439a915e1cebb

Assessment of the safety and efficacy of ONC206 ... This drug has been able to significantly reduce tumor cells in cell cultures and animal models and likely has very few side effects. As part of the clinical ...

8. reporter.nih.gov reporter.nih.gov/search/sTFDyY9DoEqeTCbwOKVvOQ/project-details/11196063

Phase 0/1 trial of ONC206 ... ONC206 is safe, crosses the blood brain and blood tumor barrier, and targets mitochondrial ClpP protein. NIH Spending Category. No NIH Spending Category ...