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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 Kong
  • Jane Minturn
  • Angela Waanders
  • Isabel Arillaga-Romany
  • Tracy Batchelor
  • Patrick Y. Wen
  • Krystal Merdinger
  • Lee Schalop
  • Martin Stogniew
  • Joshua E. Allen
  • Wolfgang Oster
  • Minesh P. MehtaEmail author
Clinical Study

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.

Keywords

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

Notes

Author contribution

MAK has served as a consultant (medical advisory board) to Bayer over the preceding 2 years.

Funding

Research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center. The funding was provided by Oncoceutics.

Compliance with ethical standards

Conflict of interest

RST, KM, LS, MS, JEA and WO have ownership/employment relationships with Oncoceutics that develops ONC201. LS, MS, WO and MPM serves on the Board of Directors of Oncoceutics. MPM has served as a consultant to Varian, Astra-Zeneca, Celgene, Tocagen, and Abbvie.

Supplementary material

11060_2019_3271_MOESM1_ESM.docx (35 kb)
Supplementary file1 (DOCX 35 kb)
11060_2019_3271_MOESM2_ESM.pdf (1.5 mb)
Supplementary file 2 (PDF 1540 kb)
11060_2019_3271_MOESM3_ESM.docx (2.7 mb)
Supplementary file 3 (DOCX 2723 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Andrew S. Chi
    • 1
  • Rohinton S. Tarapore
    • 2
  • Matthew D. Hall
    • 3
    • 4
  • Nicole Shonka
    • 5
  • Sharon Gardner
    • 1
  • Yoshie Umemura
    • 6
  • Ashley Sumrall
    • 7
  • Ziad Khatib
    • 4
  • Sabine Mueller
    • 8
  • Cassie Kline
    • 8
  • Wafik Zaky
    • 9
  • Soumen Khatua
    • 9
  • Shiao-Pei Weathers
    • 9
  • Yazmin Odia
    • 3
  • Toba N. Niazi
    • 4
  • Doured Daghistani
    • 4
  • Irene Cherrick
    • 10
  • David Korones
    • 11
  • Matthias A. Karajannis
    • 12
  • Xiao-Tang Kong
    • 13
  • Jane Minturn
    • 14
  • Angela Waanders
    • 14
  • Isabel Arillaga-Romany
    • 15
  • Tracy Batchelor
    • 15
  • Patrick Y. Wen
    • 16
  • Krystal Merdinger
    • 2
  • Lee Schalop
    • 2
  • Martin Stogniew
    • 2
  • Joshua E. Allen
    • 2
  • Wolfgang Oster
    • 2
  • Minesh P. Mehta
    • 2
    • 3
    Email author
  1. 1.NYU Langone Health and School of MedicineNew YorkUSA
  2. 2.OncoceuticsPhiladelphiaUSA
  3. 3.Radiation OncologyMiami Cancer InstituteMiamiUSA
  4. 4.Nicklaus Children’s HospitalMiamiUSA
  5. 5.University of Nebraska Medical CenterOmahaUSA
  6. 6.University of MichiganAnn ArborUSA
  7. 7.Levine Cancer InstituteCharlotteUSA
  8. 8.University of California, San FranciscoSan FranciscoUSA
  9. 9.M.D. Anderson Cancer CenterHoustonUSA
  10. 10.SUNY Upstate Medical UniversitySyracuseUSA
  11. 11.University of RochesterRochesterUSA
  12. 12.Memorial Sloan Kettering Cancer CenterNew York CityUSA
  13. 13.University of CaliforniaIrvineUSA
  14. 14.Childrens Hospital of PhiladelphiaPhiladelphiaUSA
  15. 15.Massachusetts General HospitalBostonUSA
  16. 16.Dana-Farber/Brigham and Women’s Cancer CenterBostonUSA

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