Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201 Journal Article


Authors: Chi, A. S.; Tarapore, R. S.; Hall, M. D.; Shonka, N.; Gardner, S.; Umemura, Y.; Sumrall, A.; Khatib, Z.; Mueller, S.; Kline, C.; Zaky, W.; Khatua, S.; Weathers, S. P.; Odia, Y.; Niazi, T. N.; Daghistani, D.; Cherrick, I.; Korones, D.; Karajannis, M. A.; Kong, X. T.; Minturn, J.; Waanders, A.; Arillaga-Romany, I.; Batchelor, T.; Wen, P. Y.; Merdinger, K.; Schalop, L.; Stogniew, M.; Allen, J. E.; Oster, W.; Mehta, M. P.
Article Title: Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201
Abstract: Background: 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. Methods: 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. Findings: 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. Interpretation: 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. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.
Keywords: adolescent; adult; child; clinical article; controlled study; human tissue; preschool child; school child; treatment outcome; unclassified drug; gene mutation; overall survival; prednisone; cancer recurrence; case report; bevacizumab; drug safety; cancer adjuvant therapy; cancer radiotherapy; temozolomide; nuclear magnetic resonance imaging; glioma; progression free survival; multiple cycle treatment; radiation; dexamethasone; lomustine; pediatric; glioblastoma; histone h3; drug response; open study; headache; maximum plasma concentration; hydrocortisone; drug half life; hemiparesis; mutant; pontine glioma; human; male; female; article; diffuse intrinsic pontine; diffuse midline glioma; diffuse midline; drd2 antagonist; h3 k27m; onc201; dopamine 2 receptor blocking agent; onc 201; abducens nerve paralysis
Journal Title: Journal of Neuro-Oncology
Volume: 145
Issue: 1
ISSN: 0167-594X
Publisher: Springer  
Date Published: 2019-10-01
Start Page: 97
End Page: 105
Language: English
DOI: 10.1007/s11060-019-03271-3
PUBMED: 31456142
PROVIDER: scopus
PMCID: PMC7241441
DOI/URL:
Notes: Article -- Export Date: 1 November 2019 -- Source: Scopus
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