ONC201 for Brain Tumor

No longer recruiting at 4 trial locations

Overseen By Ramage, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Jazz Pharmaceuticals

Must not be taking: CYP3A4/5 inhibitors, inducers

Disqualifiers: HIV, Cardiac arrhythmias, Bevacizumab, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 9

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of a drug called ONC201 in treating various aggressive brain tumors. Researchers aim to determine if ONC201 can prevent these tumors from worsening over six months. The trial includes six groups, each with specific tumor types, such as recurrent glioblastoma and diffuse midline glioma. Individuals with a recurring brain tumor, like glioblastoma, may be suitable candidates for this study. As a Phase 2 trial, this research focuses on assessing the treatment's efficacy in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention that you cannot use certain drugs that affect liver enzymes (CYP3A4/5 inhibitors and inducers) during the study and shortly before starting it. It's best to discuss your current medications with the study team to see if any adjustments are needed.

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

Research has shown that ONC201, also known as dordaviprone, is generally safe for people. In studies involving patients with certain brain tumors, the treatment was well-tolerated, and no major safety issues emerged. Some patients experienced mild side effects, but these were not serious.

Additional reports from real-life use and special access programs support these findings. They indicate that ONC201 is safe for individuals with specific types of brain tumors, including those with the H3 K27M mutation. Overall, the evidence suggests that ONC201 is safe enough to warrant further studies on treating brain tumors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about ONC201 because it offers a novel approach to treating aggressive brain tumors like glioblastoma, which are typically hard to manage with existing treatments such as surgery, radiation, and chemotherapy. ONC201 stands out due to its unique mechanism of action, targeting the dopamine receptor D2 (DRD2) pathway, which is not the focus of current standard treatments. This targeted action could potentially lead to more effective outcomes with fewer side effects. Additionally, ONC201 is administered orally, making it a more convenient option compared to traditional intravenous therapies.

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

Research has shown that ONC201 (dordaviprone) may help treat certain brain tumors. In studies, this treatment has demonstrated effectiveness against tumors, particularly in the challenging type of brain cancer known as H3 K27M-mutant gliomas. In this trial, participants will receive ONC201 in different treatment arms, including those with tumors in the thalamus, where ONC201 has been linked to better outcomes compared to other treatments. Data indicates that patients using ONC201 had a median progression-free survival of about 9 months, meaning their cancer did not worsen during this period. While researchers continue to study ONC201, these findings suggest it could be a promising option for individuals with certain recurring brain tumors. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

Inclusion Criteria

Unequivocal evidence of progressive disease on contrast-enhanced brain computerized tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Assessment in Neuro-Oncology Criteria (RANO), or have documented recurrent glioblastoma on diagnostic biopsy.

Previous first line therapy with at least radiotherapy and temozolomide. For Arms D, E, and F, previous first line therapy with at least radiotherapy

Male or Female age ≥16 years.

Exclusion Criteria

Pregnant women because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be discontinued if the mother is treated with ONC201.

Known HIV-positive test on combination antiretroviral therapy.

Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia. Receiving therapeutic agents known to prolong QT interval will be excluded. History of CHF, or MI or stroke in the last 3 months will be excluded.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 625 mg oral dordaviprone (ONC201) every 1 or 3 weeks depending on the arm, with clinical evaluations after each cycle

6 months

Every 1 or 3 weeks (in-person)

Neuroimaging

Neuroimaging studies are performed at baseline, 8 weeks from treatment initiation, and then every 8 weeks thereafter

8 weeks

Baseline, 8 weeks, then every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ONC201

How Is the Trial Designed?

Group I: Arm F Experimental Treatment 1 Intervention

Patients had diffuse midline glioma involving the brainstem, thalamus, or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Group II: Arm E Experimental Treatment 1 Intervention

Patients had clinical and/or radiographic evidence of midline glioma (recurrent disease was not required) and were eligible for salvage surgical resection. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle). Surgical resection was performed approximately 24 hours after at least the second dose of dordaviprone (ONC201).

Group III: Arm D Experimental Treatment 1 Intervention

Patients had confirmed World Health Organization Grade IV glioma with H3 K27M mutation (any number of recurrences were allowed). Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Group IV: Arm C Experimental Treatment 1 Intervention

Patients had clinical and/or radiographic evidence of first recurrence of histologically confirmed World Health Organization Grade IV glioblastoma and were eligible for salvage surgical resection. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle). Surgical resection was performed approximately 24 hours after at least the second dose of ONC201.

Group V: Arm B Experimental Treatment 1 Intervention

Patients had first recurrence histologically confirmed World Health Organization Grade IV glioma. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Group VI: Arm A Experimental Treatment 1 Intervention

Patients had histologically confirmed World Health Organization Grade IV glioblastoma with any number of recurrences. Patients received 625 mg dordaviprone (ONC201) once every 3 weeks.

Who Is Running the Clinical Trial?

Jazz Pharmaceuticals

Lead 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

Chimerix

Lead Sponsor

Trials

42

Recruited

4,100+

Oncoceutics, Inc.

Industry Sponsor

Trials

10

Recruited

500+

Published Research Related to This Trial

In a case series of 4 patients with BRAF V600E primary brain tumors, dual therapy with dabrafenib and trametinib led to near-complete or complete clinical responses in three patients after 8 weeks, demonstrating significant efficacy.

The combination therapy not only showed greater effectiveness than dabrafenib alone but also helped reduce skin-related side effects, such as keratosis, highlighting its potential to improve patient tolerability during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual BRAF/MEK therapy in BRAF V600E-mutated primary brain tumors: a case series showing dramatic clinical and radiographic responses and a reduction in cutaneous toxicity. Bernstein, A., Mrowczynski, OD., Greene, A., et al.[2023]

A nine-year-old male patient with anaplastic astrocytoma progressed to an epithelioid glioblastoma, and mutational analysis revealed a BRAF V600E mutation, suggesting this mutation as a potential therapeutic target in glioma.

Treatment with the BRAF inhibitor dabrafenib resulted in clinical stability and 'Stable Disease' for ten months, indicating that targeted therapy may be a promising salvage option for younger patients with gliomas harboring this mutation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. Ceccon, G., Werner, JM., Dunkl, V., et al.[2022]

The INTERCEPT H3 trial is investigating the safety and immunogenicity of the H3K27M-vac vaccine in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab in 15 adult patients with newly diagnosed diffuse midline gliomas (DMG) carrying the H3K27M mutation.

Preliminary results from earlier studies suggest that the H3K27M-vac vaccine can induce specific immune responses that may help suppress tumor growth, making it a promising treatment strategy for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas. Grassl, N., Sahm, K., Süße, H., et al.[2023]

A study of 159 patients with grade II/III gliomas revealed significant over-expression of specific tumor-associated antigens (BCAN, CSPG4, IGF2BP3, PTPRZ1, and TNC) at both mRNA and protein levels, indicating their potential as targets for immunotherapy.

In a smaller group of 27 patients, spontaneous T cell responses to the IMA950 antigens were detected in all grade II patients and 71% of grade III patients, suggesting that these antigens are relevant for effective tumor targeting and could enhance the efficacy of immunotherapy when combined with other peptides.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma. Dutoit, V., Migliorini, D., Ranzanici, G., et al.[2021]

The phase I trial involving 33 patients with IDH1(R132H)+ astrocytomas demonstrated that the IDH1-specific peptide vaccine was safe, with only grade 1 adverse events reported, and induced immune responses in 93.3% of participants.

Patients who developed immune responses to the vaccine had significantly better outcomes, with a two-year progression-free rate of 0.82, compared to those without immune responses, highlighting the vaccine's potential efficacy in treating this specific type of glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A vaccine targeting mutant IDH1 in newly diagnosed glioma. Platten, M., Bunse, L., Wick, A., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11066938/

ACTION: a randomized phase 3 study of ONC201 ... ONC201 (dordaviprone) has demonstrated antitumor efficacy in preclinical and clinical evaluations of H3 K27M-mutant glioma. ONC201 is a first-in-class small- ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39700833/

Real life data of ONC201 (dordaviprone) in pediatric and ... Our real-life data support a better outcome for patients with thalamic tumors treated with ONC201. We demonstrated furthermore the feasibility of a successful ...

3. braintumor.org braintumor.org/news/first-treatment-approved-for-rare-pediatric-and-adult-brain-tumor-type-fda-grants-accelerated-approval-to-dordaviprone-modeyso/

First Treatment Approved for Rare Pediatric and Adult ... Patients with this type of glioma often face an extremely poor prognosis, with limited therapeutic options and very low survival rates following ...

4. ejcancer.com ejcancer.com/article/S0959-8049(24)01772-6/fulltext

Real life data of ONC201 (dordaviprone) in pediatric and ... Median OS after ONC201 start was 143 days or 4,7 mo (1–711 days) for the whole cohort. Univariate and multivariable analysis identified site ( ...

5. academic.oup.com academic.oup.com/noa/article/7/Supplement_3/iii1/8244874

6 ONC201 (DORDAVIPRONE) IN THE TREATMENT OF ... Median progression free survival (PFS) and median overall survival (OS) from initial diagnosis in the ONC201 vs. non-ONC201 patients was 9.05 ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.10017

Efficacy and safety of dordaviprone (ONC201) in ... Dordaviprone (ONC201), a first in class imipridone, has demonstrated safety and efficacy in an integrated analysis of patients with recurrent H3 K27M-mutant ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0959804924017726

Real life data of ONC201 (dordaviprone) in pediatric and ... When the ONC201 compassionate use project was launched, preliminary efficacy and safety data of ONC201 in diffuse midline gliomas in adults and ...

8. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii225/7890111

NCOG-07. SAFETY OF ONC201 TREATMENT IN PATIENTS ... The present analysis reports safety data from ONC028, a compassionate use program (CUP) for patients with previously treated H3 K27M-mutant ...