Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy

Sharon L Gardner; Rohinton S Tarapore; Jeffrey Allen; Susan L McGovern; Wafik Zaky; Yazmin Odia; Doured Daghistani; Zuanel Diaz; Matthew D Hall; Ziad Khatib; Carl Koschmann; Evan Cantor; Ryo Kurokawa; Tobey J MacDonald; Dolly Aguilera; Nicholas A Vitanza; Sabine Mueller; Cassie Kline; Guangrong Lu; Joshua E Allen; Soumen Khatua

doi:10.1093/noajnl/vdac143

Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy

Neurooncol Adv. 2022 Sep 13;4(1):vdac143. doi: 10.1093/noajnl/vdac143. eCollection 2022 Jan-Dec.

Authors

Sharon L Gardner^{1

2

3}, Rohinton S Tarapore^{4

5}, Jeffrey Allen¹, Susan L McGovern³, Wafik Zaky³, Yazmin Odia⁶, Doured Daghistani⁶, Zuanel Diaz⁶, Matthew D Hall^{6

7

8}, Ziad Khatib⁹, Carl Koschmann¹⁰, Evan Cantor^{10

11}, Ryo Kurokawa¹⁰, Tobey J MacDonald¹², Dolly Aguilera¹², Nicholas A Vitanza^{13

14}, Sabine Mueller¹⁵, Cassie Kline^{16

17}, Guangrong Lu⁴, Joshua E Allen^{4

5}, Soumen Khatua¹⁸

Affiliations

¹ NYU Langone Medical Center and School of Medicine, New York, NY, USA.
² Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, USA.
³ The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Clinical Development, Oncoceutics, Philadelphia, PA, USA.
⁵ Clinical Development, Chimerix Inc., Durham, NC, USA.
⁶ Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
⁷ Department of Radiation Oncology, Nicklaus Children's Hospital, Miami, FL, USA.
⁸ Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.
⁹ Department of Neuro-Oncology, Nicklaus Children's Hospital, Miami, FL.
¹⁰ Michigan Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
¹¹ University of Connecticut School of Medicine, Farmington, CT.
¹² Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA.
¹³ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹⁴ Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹⁵ Department of Neurology, Neurosurgery and Pediatrics, University of California San Francisco.
¹⁶ Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA.
¹⁷ Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.

Abstract

Background: ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201.

Methods: This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment.

Results: The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: T _1/2, 8.4 h; T _max, 2.1 h; C _max, 2.3 µg/mL; AUC_0-tlast, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis.

Conclusions: The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.

Keywords: H3 K27M-mutant glioma (DMG); ONC201; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma.