ONC201 for Brain Tumor

Recruiting at 4 trial locations

Overseen By Ramage, PhD

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Chimerix

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

84 Participants Needed

Trial Summary

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.

What makes the drug ONC201 unique for treating brain tumors?

ONC201 is unique because it targets a specific pathway in cancer cells, potentially offering a new approach for treating brain tumors that are resistant to standard therapies. Unlike other treatments, it may work by inducing stress in tumor cells, leading to their death, and is being explored for its effectiveness in various types of brain tumors. ^{1 2 3 4 5}

What is the purpose of this trial?

This trial tests ONC201, a new type of treatment that has shown promise in fighting various cancers, including a specific type of brain cancer, in patients who have this cancer returning.

Eligibility Criteria

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

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

Treatment Details

Interventions

• ONC201

Participant Groups

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?

Chimerix

Lead Sponsor

Trials

42

Recruited

4,100+

Oncoceutics, Inc.

Industry Sponsor

Trials

10

Recruited

500+

Findings from Research

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]

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]

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]

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]

References

1. United States 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. [2021]

2. United States 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. [2023]

3. England pubmed.ncbi.nlm.nih.gov

A vaccine targeting mutant IDH1 in newly diagnosed glioma. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. [2022]

5. England pubmed.ncbi.nlm.nih.gov

INTERCEPT H3: a multicenter phase I peptide vaccine trial for the treatment of H3-mutated diffuse midline gliomas. [2023]