Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy. Issue 1 (13th September 2022)

• Record Type: Journal Article
• Authors: Gardner, Sharon L; Tarapore, Rohinton S; Allen, Jeffrey; McGovern, Susan L; Zaky, Wafik; Odia, Yazmin; Daghistani, Doured; Diaz, Zuanel; Hall, Matthew D; Khatib, Ziad; Koschmann, Carl; Cantor, Evan; Kurokawa, Ryo; MacDonald, Tobey J; Aguilera, Dolly; Vitanza, Nicholas A; Mueller, Sabine; Kline, Cassie; Lu, Guangrong; Allen, Joshua E; Khatua, Soumen
• Is Part Of: Neuro-oncology advances. Volume 4:Issue 1(2022)
• Publication Date: 2022-09-13
• Subjects: diffuse midline glioma -- H3 K27M-mutant glioma (DMG) -- diffuse intrinsic pontine glioma (DIPG) -- ONC201; 616.99481
• DOI: 10.1093/noajnl/vdac143
• Languages: English
• ISSNs: 2632-2498

Abstract

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; AUC0-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.