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

Andrew S. Chi, Rohinton S. Tarapore, Matthew D. Hall, Nicole Shonka, Sharon Gardner, Yoshie Umemura, Ashley Sumrall, Ziad Khatib, Sabine Mueller, Cassie Kline, Wafik Zaky, Soumen Khatua, Shiao Pei Weathers, Yazmin Odia, Toba N. Niazi, Doured Daghistani, Irene Cherrick, David Korones, Matthias A. Karajannis, Xiao Tang KongJane Minturn, Angela Waanders, Isabel Arillaga-Romany, Tracy Batchelor, Patrick Y. Wen, Krystal Merdinger, Lee Schalop, Martin Stogniew, Joshua E. Allen, Wolfgang Oster, Minesh P. Mehta

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalJournal of Neuro-Oncology
Issue number1
StatePublished - Oct 1 2019


  • Adult
  • DRD2 antagonist
  • Diffuse intrinsic pontine
  • Diffuse midline
  • Glioma
  • H3 K27M
  • ONC201
  • Pediatric
  • Radiation

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research


Dive into the research topics of 'Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201'. Together they form a unique fingerprint.

Cite this