onc201 and Glioma

Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis.. We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI).. Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression.. Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Topics: Brain Neoplasms; Child; Circulating Tumor DNA; Glioma; Histones; Humans; Imidazoles; Mutation; Pyridines; Pyrimidines

H3K27 altered pediatric pontine diffuse midline gliomas (pDMG) have a poor prognosis, and conventional treatments offer limited benefits. However, recent advancements in molecular evaluations and targeted therapies have shown promise. The aim of this retrospective analysis was to evaluate the effectiveness of German-sourced ONC201, a selective antagonist of dopamine receptor DRD2, for the treatment of pediatric H3K27 altered pDMGs.. Pediatric patients with H3K27 altered pDMG treated between January 2016 and July 2022 were included in this retrospective analysis. Tissue samples were acquired from all patients via stereotactic biopsy for immunohistochemistry and molecular profiling. All patients received radiation treatment with concurrent temozolomide, and those who could acquire GsONC201 received it as a single agent until progression. Patients who could not obtain GsONC201 received other chemotherapy protocols.. Among 27 patients with a median age of 5.6 years old (range 3.4-17.9), 18 received GsONC201. During the follow-up period, 16 patients (59.3%) had progression, although not statistically significant, the incidence of progression tended to be lower in the GsONC201 group. The median overall survival (OS) of the GsONC201 group was considerably longer than of the non-GsONC201 group (19.9 vs. 10.9 months). Only two patients receiving GsONC201 experienced fatigue as a side effect. 4 out of 18 patients in the GsONC201 group underwent reirradiation after progression.. In conclusion, this study suggests that GsONC201 may improve OS in pediatric H3K27-altered pDMG patients without significant side effects. However, caution is warranted due to retrospective design and biases, highlighting the need for further randomized clinical studies to validate these findings.

Topics: Adolescent; Brain Stem Neoplasms; Child; Child, Preschool; Glioma; Humans; Imidazoles; Pyridines; Retrospective Studies

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction.. The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Topics: Brain Neoplasms; Epigenesis, Genetic; Glioma; Histones; Humans; Mutation; Treatment Outcome

Topics: Circulating Tumor DNA; Glioma; Humans; Imidazoles; Liquid Biopsy; Pyridines; Pyrimidines

Topics: Cell Lineage; Energy Metabolism; Glioma; Humans; Imidazoles; Pyridines; Pyrimidines

H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated.. Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence.. Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms.. The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Female; Follow-Up Studies; Glioma; Heterocyclic Compounds, 4 or More Rings; Histones; Humans; Imidazoles; Male; Mutation; Prognosis; Pyridines; Pyrimidines; Receptors, Dopamine D2; Survival Rate; Young Adult