ONC206 + Radiation Therapy for Brain Tumor

(PNOC023 Trial)

Recruiting in Palo Alto (17 mi)

+4 other locations

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Sabine Mueller, MD, PhD

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

Disqualifiers: Immune disorders, Uncontrolled infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial studies the effects of ONC206, a new drug that stresses out cancer cells to kill them, in children and young adults with difficult-to-treat brain tumors. The drug can be used alone or with radiation therapy. ONC206 is related to ONC201, which has shown promise in treating certain types of brain tumors.

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.

What data supports the effectiveness of the treatment ONC206 + Radiation Therapy for brain tumors?

Radiation therapy has been shown to improve survival rates for certain types of brain tumors, such as glioblastomas, for 1-2 years and for other types up to 5-10 years. However, there is no evidence that it prolongs life for low-grade gliomas, though it may help with symptoms. ^{1 2 3 4 5}

How does the drug ONC206 differ from other treatments for brain tumors?

ONC206 is unique because it is combined with radiation therapy specifically for brain tumors, potentially offering a novel approach compared to standard treatments. While the exact mechanism of ONC206 is not detailed in the provided research, the combination with radiation therapy suggests a strategy to enhance treatment efficacy, similar to how other targeted therapies are used to improve outcomes in brain metastases from other cancers. ^{6 7 8 9 10}

Research Team

Sabine Mueller, MD, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

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

I have recovered from all side effects of my previous treatments.

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

Trial Timeline

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

Treatment Details

Interventions

• ONC206 (Stress Response Inducer)
• Standard of Care Radiation Therapy (Radiation)

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.

Participant Groups

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

Patients 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.

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

Patients 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.

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

Patients 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.

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

Patients 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.

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+

Dr. Benjamin L. Ebert

Dana-Farber Cancer Institute

Chief Executive Officer

MD from Harvard Medical School, PhD from Oxford University

Dr. Craig A. Bunnell

Dana-Farber Cancer Institute

Chief Medical Officer since 2012

MD from Harvard Medical School, MPH from Harvard School of Public Health, MBA from MIT Sloan School of Management

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+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Chimerix

Industry Sponsor

Trials

42

Recruited

4,100+

Mithil Prasad Foundation

Collaborator

Trials

2

Recruited

570+

Findings from Research

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 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]

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]

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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

A systematic overview of radiation therapy effects in brain tumours. [2019]

2. United States 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. [2021]

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

Radiation therapy of brain tumors. [2019]

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

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases. [2022]

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

Fractionated stereotactic radiation therapy in the management of primary oligodendroglioma and oligoastrocytoma. [2018]

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

Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. [2019]

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

A Phase II Multi-institutional Clinical Trial Assessing Fractionated Simultaneous In-Field Boost Radiotherapy for Brain Oligometastases. [2020]

8. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Brain metastasis in breast cancer]. [2018]

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

Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. [2022]

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

Interstitial 252Cf neutron therapy for glioblastoma multiforme. [2019]