ONC206 for Brain Cancer

Overseen by Byram Ozer, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Chimerix

Must not be taking: Warfarin, Strong CYP inhibitors

Disqualifiers: Cardiac disease, Stroke, Epilepsy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests ONC206, a new oral drug, in patients whose brain or spinal cord tumors have returned. The goal is to find the highest safe dose by increasing the amount given over time and monitoring for side effects.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong inhibitors or inducers of specific liver enzymes (CYP3A4, 2D6, 1A2, 2C9, and 2C19) within 14 days before starting the study drug and throughout the study. It's best to discuss your current medications with the study team.

What data supports the effectiveness of the drug ONC206 for brain cancer?

Research on a similar drug, ONC201, shows it has potential effectiveness in treating diffuse midline gliomas, a type of brain cancer, by targeting specific proteins in cancer cells. This suggests that ONC206 might also be effective, but more research is needed to confirm this. ^{1 2 3 4 5}

What makes the drug ONC206 unique for treating brain cancer?

The research provided does not contain specific information about ONC206, so I cannot determine what makes it unique for treating brain cancer. ^{6 7 8 9 10}

Research Team

Byram Ozer, MD

Principal Investigator

National Institutes of Health (NIH)

Eligibility Criteria

Adults over 18 with recurrent brain tumors, who are in good physical condition (KPS ≥70), have normal organ/marrow function, and haven't had recent chemotherapy or major surgery. They must be able to swallow pills or liquids, consent to the study, test negative for COVID-19, provide a tumor sample, undergo MRI with contrast, and have measurable disease. Pregnant women and those on certain drugs or with specific medical conditions can't participate.

Inclusion Criteria

I haven't had major surgery in the last 4 weeks and have fully recovered from any past surgeries.

I am over 18 and have a confirmed brain tumor that has come back.

Patients must have a negative COVID-19 test within 72 hours of the first dose of study drug

Exclusion Criteria

I have a heart condition that is currently causing symptoms.

I am HIV-positive and on combination anti-retroviral therapy.

Patients with alcohol or substance abuse which would interfere with compliance or safety

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Participants receive escalating doses of ONC206 to determine the maximum tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs)

28 days per cycle

Weekly visits for safety evaluation

Safety Evaluation

Safety and tolerability are monitored through physical examinations, laboratory assessments, and collection of adverse events

Ongoing throughout the trial

Every visit includes safety assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• ONC206 (Small Molecule)

Trial Overview The trial is testing ONC206's safety at different doses for treating various types of recurring brain tumors. It's an early-stage study where patients take oral ONC206 either once weekly or multiple times a week to find the highest dose they can tolerate without severe side effects.

Participant Groups

Group I: ONC206 Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Chimerix

Lead Sponsor

Trials

42

Recruited

4,100+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Dr. Jeanne Marrazzo

National Institutes of Health (NIH)

Chief Medical Officer

MD from University of California, Los Angeles

Dr. Jay Bhattacharya

National Institutes of Health (NIH)

Chief Executive Officer

MD, PhD from Stanford University

Findings from Research

ONC201, a drug that targets specific pathways in cancer cells, has shown promising preclinical and emerging clinical efficacy against diffuse midline gliomas (DMG), including DIPGs, which are highly lethal childhood cancers.

DIPGs with PIK3CA mutations are more sensitive to ONC201 treatment, while those with TP53 mutations are resistant; this suggests that genetic profiling could help tailor treatments, and combining ONC201 with the PI3K/Akt inhibitor paxalisib may enhance effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma. Jackson, ER., Duchatel, RJ., Staudt, DE., et al.[2023]

GsONC201, a locally produced version of ONC201, was confirmed to have an authentic structure and showed similar efficacy to the original ONC201 in both in vitro and in vivo studies, indicating it can be a viable treatment option for DIPG.

Patients with H3K27M-mutant DIPG treated with GsONC201 had a median overall survival of 18 months, which improved to 22 months for those who also received reirradiation, suggesting that GsONC201 may enhance survival outcomes when combined with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma. Duchatel, RJ., Mannan, A., Woldu, AS., et al.[2022]

In a study involving 25 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG), the combination of vandetanib and dasatinib was found to be well tolerated, with a maximum tolerated dose of 65 mg/m² for each drug, and the most significant side effect being diarrhea.

The treatment showed promising pharmacokinetics, with the plasma levels of dasatinib remaining comparable to those seen in adults, and a decrease in phosphorylated 70S6K in blood cells, indicating effective target inhibition during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. Broniscer, A., Baker, SD., Wetmore, C., et al.[2022]

Two cases of malignant brain tumors with BRAF V600E mutations showed promising responses to targeted treatment with BRAF and MEK inhibitors, dabrafenib and trametinib, despite previous resistance to radiation and temozolomide.

One patient had a partial response lasting 14 months, while the other maintained stable disease for 16 months, highlighting the potential of this combination therapy in treating aggressive brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. Schreck, KC., Guajardo, A., Lin, DDM., et al.[2019]

In a phase 1 trial involving five pediatric and young adult patients with BRAFV600-mutated brain tumors, the combination of vemurafenib (a BRAF inhibitor) and everolimus (an mTOR inhibitor) showed promising results, with 40% of patients achieving a partial response and 20% maintaining stable disease for 12 months.

No patients experienced treatment discontinuation due to adverse events, suggesting that this combination therapy is safe and warrants further investigation for treating BRAF-mutant brain cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. Sen, S., Tanaka, R., Khatua, S., et al.[2021]

Oligodendrogliomas with the combined loss of chromosome arms 1p and 19q are particularly sensitive to chemotherapy, and mutations in the CIC gene are found in over 50% of these tumors, indicating a potential target for treatment.

CIC mutations lead to the upregulation of oncogenic ETV transcription factors and negative regulators of receptor tyrosine kinase signaling, suggesting that CIC-mutant oligodendrogliomas may be more aggressive than those without CIC mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. Padul, V., Epari, S., Moiyadi, A., et al.[2020]

The study found that cadherin-6 (CDH6) expression in gliomas is linked to higher tumor grades and poorer patient prognosis, suggesting it could be a significant biomarker for glioma severity.

CDH6 is primarily expressed in astrocyte-like malignant cells and is associated with immune cell infiltration in the glioma microenvironment, indicating its potential as a new therapeutic target for glioma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas. Meng, M., Zhou, H., He, Y., et al.[2022]

NUP205 is significantly overexpressed in lower-grade glioma (LGG) tissues compared to normal brain tissue, particularly in higher-grade tumors, and is associated with poorer patient survival outcomes based on an analysis of 906 samples.

The study suggests that NUP205 influences LGG progression through pathways like the cell cycle and notch signaling, and its high expression correlates with increased immune cell infiltration, especially M2 macrophages, indicating its potential as a target for immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the relationship between abnormally high expression of NUP205 and the clinicopathological characteristics, immune microenvironment, and prognostic value of lower-grade glioma. Liang, W., Hu, C., Zhu, Q., et al.[2023]

FAM20C plays a crucial oncogenic role in gliomas by promoting cell proliferation and metastasis, as demonstrated through in vitro and in vivo studies.

Blocking FAM20C with neutralizing antibodies led to tumor regression in xenograft models, suggesting that targeting FAM20C could be a promising therapeutic strategy for glioma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma. Gong, B., Liang, Y., Zhang, Q., et al.[2023]

References

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

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma. [2022]

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

Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. [2022]

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

Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. [2019]

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

Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]

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

ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. [2020]

7. Switzerland pubmed.ncbi.nlm.nih.gov

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Exploring the relationship between abnormally high expression of NUP205 and the clinicopathological characteristics, immune microenvironment, and prognostic value of lower-grade glioma. [2023]

9. China pubmed.ncbi.nlm.nih.gov

Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma. [2023]

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

RP11-552D4.1: a novel m6a-related LncRNA associated with immune status in glioblastoma. [2022]