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

Authors

• Andrew S. Chi, NYU Langone Health and School of Medicine, New York, NY, USA.
• Rohinton S. Tarapore, Oncoceutics, Philadelphia, PA, USA.
• Matthew D. Hall, Radiation Oncology, Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL, 33176, USA.
• Nicole Shonka, University of Nebraska Medical Center, Omaha, NE, USA.
• Sharon Gardner, NYU Langone Health and School of Medicine, New York, NY, USA.
• Yoshie Umemura, University of Michigan, Ann Arbor, MI, USA.
• Ashley Sumrall, Levine Cancer Institute, Charlotte, NC, USA.
• Ziad Khatib, Nicklaus Children's Hospital, Miami, FL, USA.
• Sabine Mueller, University of California, San Francisco, San Francisco, CA, USA.
• Cassie Kline, University of California, San Francisco, San Francisco, CA, USA.
• Wafik Zaky, M.D. Anderson Cancer Center, Houston, TX, USA.
• Soumen Khatua, M.D. Anderson Cancer Center, Houston, TX, USA.
• Shiao-Pei Weathers, M.D. Anderson Cancer Center, Houston, TX, USA.
• Yazmin Odia, Radiation Oncology, Miami Cancer Institute, 8900 N. Kendall Drive, Miami, FL, 33176, USA.
• Toba N. Niazi, Nicklaus Children's Hospital, Miami, FL, USA.
• Doured Daghistani, Nicklaus Children's Hospital, Miami, FL, USA.
• Irene Cherrick, SUNY Upstate Medical University, Syracuse, NY, USA.
• David Korones, University of Rochester, Rochester, NY, USA.
• Matthias A. Karajannis, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.
• Xiao-Tang Kong, University of California, Irvine, CA, USA.
• Jane Minturn, Childrens Hospital of Philadelphia, Philadelphia, PA, USA.
• Angela Waanders, Childrens Hospital of Philadelphia, Philadelphia, PA, USA.
• Isabel Arillaga-Romany, Massachusetts General Hospital, Boston, MA, USA.
• Tracy Batchelor, Massachusetts General Hospital, Boston, MA, USA.
• Patrick Y. Wen, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
• Krystal Merdinger, Oncoceutics, Philadelphia, PA, USA.
• Lee Schalop, Oncoceutics, Philadelphia, PA, USA.
• Martin Stogniew, Oncoceutics, Philadelphia, PA, USA.
• Joshua E. Allen, Oncoceutics, Philadelphia, PA, USA.
• Wolfgang Oster, Oncoceutics, Philadelphia, PA, USA.
• Minesh P. Mehta, Oncoceutics, Philadelphia, PA, USA. MineshM@baptisthealth.net.

Document Type

Article

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.

Medical Subject Headings

Adolescent; Adult; Antineoplastic Agents (therapeutic use); Brain Neoplasms (drug therapy, genetics, pathology); Child; Child, Preschool; Female; Follow-Up Studies; Glioma (drug therapy, genetics, pathology); Heterocyclic Compounds, 4 or More Rings (therapeutic use); Histones (genetics); Humans; Imidazoles; Male; Mutation; Prognosis; Pyridines; Pyrimidines; Receptors, Dopamine D2 (chemistry); Survival Rate; Young Adult

Publication Date

10-1-2019

Publication Title

Journal of neuro-oncology

E-ISSN

1573-7373

Volume

145

Issue

1

First Page

97

Last Page

105

PubMed ID

31456142

Digital Object Identifier (DOI)

10.1007/s11060-019-03271-3

Recommended Citation

Chi, Andrew S.; Tarapore, Rohinton S.; Hall, Matthew D.; Shonka, Nicole; Gardner, Sharon; Umemura, Yoshie; Sumrall, Ashley; Khatib, Ziad; Mueller, Sabine; Kline, Cassie; Zaky, Wafik; Khatua, Soumen; Weathers, Shiao-Pei; Odia, Yazmin; Niazi, Toba N.; Daghistani, Doured; Cherrick, Irene; Korones, David; Karajannis, Matthias A.; Kong, Xiao-Tang; Minturn, Jane; Waanders, Angela; Arillaga-Romany, Isabel; Batchelor, Tracy; Wen, Patrick Y.; Merdinger, Krystal; Schalop, Lee; Stogniew, Martin; Allen, Joshua E.; Oster, Wolfgang; and Mehta, Minesh P., "Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201" (2019). Neurology. 1454.
https://scholar.barrowneuro.org/neurology/1454