Overseen ByByram Ozer, MD
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Chimerix
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.
12345Eligibility 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 am over 18 and have a confirmed brain tumor that has come back.
My organ and bone marrow functions are normal.
My cancer has returned and can be measured, with no further standard treatments available.
I am mostly able to care for myself.
I haven't had experimental or standard chemotherapy recently.
All my side effects from previous treatments have resolved.
I can swallow pills or liquids without difficulty.
I can provide a sample of my tumor from a previous surgery or biopsy.
I can undergo an MRI with contrast.
Exclusion Criteria
I have a heart condition that is currently causing symptoms.
I am HIV-positive and on combination anti-retroviral therapy.
I have a stomach or intestine condition that affects how my body absorbs medicine.
I have a history of heart problems.
I have not taken strong medication affecting liver enzymes in the last 14 days.
I am not pregnant or breastfeeding.
I have had a stroke in the past 3 months.
I have epilepsy that doesn't respond to treatment or I've had recent seizures.
I am currently on blood thinners like warfarin.
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: ONC206Experimental Treatment1 Intervention
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
National Institutes of HealthBethesda, MD
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Who is running the clinical trial?
ChimerixLead Sponsor
National Institutes of Health (NIH)Collaborator
References
ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma. [2023]Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG. However, further work is needed to identify the mechanisms of response of DIPGs to ONC201 treatment and to determine whether recurring genomic features influence response. Using a systems-biological approach, we showed that ONC201 elicits potent agonism of the mitochondrial protease ClpP to drive proteolysis of electron transport chain and tricarboxylic acid cycle proteins. DIPGs harboring PIK3CA-mutations showed increased sensitivity to ONC201, while those harboring TP53-mutations were more resistant. Metabolic adaptation and reduced sensitivity to ONC201 was promoted by redox-activated PI3K/Akt signaling, which could be counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib. Together, these discoveries coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib have provided the rationale for the ongoing DIPG/DMG phase II combination clinical trial NCT05009992.
Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma. [2022]Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc.
Phase I trial, pharmacokinetics, and pharmacodynamics of vandetanib and dasatinib in children with newly diagnosed diffuse intrinsic pontine glioma. [2022]Testing of promising drug combinations is crucial in the treatment of diffuse intrinsic pontine glioma (DIPG). As the VEGF and platelet-derived growth factor (PDGF) pathways are critical in gliomas, we evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of vandetanib, a VEGFR-2 inhibitor, combined with dasatinib, a potent PDGFR inhibitor, during and after radiotherapy in children with newly diagnosed DIPG.
Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. [2019]BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors.
Dual inhibition of BRAF and mTOR in BRAFV600E -mutant pediatric, adolescent, and young adult brain tumors. [2021]Although BRAF inhibition has demonstrated activity in BRAFV600 -mutated brain tumors, ultimately these cancers grow resistant to BRAF inhibitor monotherapy. Parallel activation of the phosphatidylinositol 3-kinase-mammalian target of rapamycin pathway has been implicated as a mechanism of primary and secondary resistance to BRAF inhibition. Moreover, it has been shown specifically that mTOR signaling activation occurs in BRAF-mutant brain tumors. We therefore conducted phase 1 trials combining vemurafenib with everolimus, enrolling five pediatric and young adults with BRAFV600 -mutated brain tumors. None of the patients required treatment discontinuation as a result of adverse events. Overall, two patients (40%) had a partial response and one (20%) had 12 mo of stable disease as best response. Co-targeting BRAF and mTOR in molecularly selected brain cancers should be further investigated.
ETV/Pea3 family transcription factor-encoding genes are overexpressed in CIC-mutant oligodendrogliomas. [2020]Oligodendrogliomas with combined loss of chromosome arms 1p and 19q are known to be particularly sensitive to chemotherapy, and the CIC gene located on 19q is known to be mutated in over 50% of the 1p/19q codeleted oligodendrogliomas. However, the role of CIC in the oligodendroglioma pathogenesis is not known. Exome sequencing of 11 oligodendroglial tumors identified 9 tumors with combined loss of 1p and 19q. Somatic mutations were found in the CIC and FUBP1 genes. Recurrent somatic mutations were also identified in the Notch signaling pathway genes NOTCH1 and MAML3, the chromatin modifying gene ARID1A and in KRAS. Comparison of the transcriptome profiles of CIC-mutant and CIC-wild type oligodendrogliomas from the study cohort as well as 65 1p/19q codeleted oligodendrogliomas from the TCGA cohort identified genes encoding the ETV transcription factor family to be significantly upregulated in the CIC-mutant tumors. Upregulation of a number of negative regulators of the receptor tyrosine kinase signaling pathway like Sprouty and SPRED family members in the CIC-mutant oligodendrogliomas is likely due to the constitutive activation of the pathway resulting from inactive CIC protein. Higher expression of the oncogenic ETV transcription factors in the CIC-mutant oligodendrogliomas may make these tumors more aggressive than the CIC-wild type tumors.
CDH6 as a prognostic indicator and marker for chemotherapy in gliomas. [2022]Glioma is the most malignant cancer of the central nervous system. There are various therapies for treating gliomas, but their outcomes are not satisfactory. Therefore, new targets for glioma treatment are needed. This study examined the cadherin-6 (CDH6) expression in gliomas using The Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets. CDH6 expression positively correlated with the World Health Organization (WHO) tumor grade and negatively correlated with patient prognosis. A significant decrease in CDH6 promoter methylation was identified with an increase in the WHO grade severity. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses suggested that CDH6 might be involved in cell-cell interactions and immune processes in the glioma microenvironment. Weighted gene co-expression network analysis revealed a correlation between CDH6 and cell adhesion molecules, focal adhesions, phosphatidylinositol 3-kinase-protein kinase B signaling pathways, nuclear division, chromosome segregation, mitotic nuclear division, and immune-related pathways. CDH6 strongly correlated with immunosuppressive cells, including regulatory T cells, monocytes, macrophages, tumor-associated macrophages, and myeloid-derived suppressor cells. It also showed correlations with immune-active cells such as B cells, CD8+ T cells, and dendritic cells. Single-cell analysis showed that CDH6 was expressed mainly in astrocyte (AC)-like malignant cells. Differentially expressed genes of AC-like malignant cells were found to be associated with stress response, membranous processes, viral infections, and several types of cancers. Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy.
Exploring the relationship between abnormally high expression of NUP205 and the clinicopathological characteristics, immune microenvironment, and prognostic value of lower-grade glioma. [2023]Nuclear pore complex (NPC) is a major transport pivot for nucleocytoplasmic molecule exchange. Nucleoporin 205 (NUP205)-a main component of NPC-plays a key regulatory role in tumor cell proliferation; however, few reports document its effect on the pathological progression of lower-grade glioma (LGG). Therefore, we conducted an integrated analysis using 906 samples from multiple public databases to explore the effects of NUP205 on the prognosis, clinicopathological characteristics, regulatory mechanism, and tumor immune microenvironment (TIME) formation in LGG. First, multiple methods consistently showed that the mRNA and protein expression levels of NUP205 were higher in LGG tumor tissue than in normal brain tissue. This increased expression was mainly noted in the higher WHO Grade, IDH-wild type, and 1p19q non-codeleted type. Second, various survival analysis methods showed that the highly expressed NUP205 was an independent risk indicator that led to reduced survival time of patients with LGG. Third, GSEA analysis showed that NUP205 regulated the pathological progress of LGG via the cell cycle, notch signaling pathway, and aminoacyl-tRNA biosynthesis. Ultimately, immune correlation analysis suggested that high NUP205 expression was positively correlated with the infiltration of multiple immune cells, particularly M2 macrophages, and was positively correlated with eight immune checkpoints, particularly PD-L1. Collectively, this study documented the pathogenicity of NUP205 in LGG for the first time, expanding our understanding of its molecular function. Furthermore, this study highlighted the potential value of NUP205 as a target of anti-LGG immunotherapy.
Epigenetic and transcriptional activation of the secretory kinase FAM20C as an oncogene in glioma. [2023]Gliomas are the most prevalent and aggressive malignancies of the nervous system. Previous bioinformatic studies have revealed the crucial role of the secretory pathway kinase FAM20C in the prediction of glioma invasion and malignancy. However, little is known about the pathogenesis of FAM20C in the regulation of glioma. Here, we construct the full-length transcriptome atlas in paired gliomas and observe that 22 genes are upregulated by full-length transcriptome and differential APA analysis. Analysis of ATAC-seq data reveals that both FAM20C and NPTN are the hub genes with chromatin openness and differential expression. Further, in vitro and in vivo studies suggest that FAM20C stimulates the proliferation and metastasis of glioma cells. Meanwhile, NPTN, a novel cancer suppressor gene, counteracts the function of FAM20C by inhibiting both the proliferation and migration of glioma. The blockade of FAM20C by neutralizing antibodies results in the regression of xenograft tumors. Moreover, MAX, BRD4, MYC, and REST are found to be the potential trans-active factors for the regulation of FAM20C. Taken together, our results uncover the oncogenic role of FAM20C in glioma and shed new light on the treatment of glioma by abolishing FAM20C.
RP11-552D4.1: a novel m6a-related LncRNA associated with immune status in glioblastoma. [2022]Glioblastoma (GBM) is the most malignant form of brain cancer in the world. Nevertheless, the survival rate of patients with GBM is extremely low. N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) conduct important biological functions in patients' survival status and the immunotherapeutic response. Here, m6A-related lncRNAs were identified by a co-expression method. Univariate and multivariate Cox regression together with LASSO were applied to establish the risk model. Kaplan-Meier and ROC analysis were applied to evaluate the prediction power of this risk model. Finally, the related immune profiling and chemical sensitivity targets were also investigated. The risk model holding three m6A-related lncRNAs was confirmed as an independent predictor for the prognosis. Furthermore, we found the risk model based on m6A-related lncRNAs is associated with the immune status, immunosuppressive biomarkers, and chemo-sensitivity in GBM patients. The RP11-552D4.1 is found to facilitate neuronal proliferation. This risk model consisted of m6A-related lncRNAs may be available for the clinical interventions in GBM patients.