TY - JOUR
T1 - Phase i dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
AU - Gardner, Sharon L.
AU - Tarapore, Rohinton S.
AU - Allen, Jeffrey
AU - McGovern, Susan L.
AU - Zaky, Wafik
AU - Odia, Yazmin
AU - Daghistani, Doured
AU - Diaz, Zuanel
AU - Hall, Matthew D.
AU - Khatib, Ziad
AU - Koschmann, Carl
AU - Cantor, Evan
AU - Kurokawa, Ryo
AU - Macdonald, Tobey J.
AU - Aguilera, Dolly
AU - Vitanza, Nicholas A.
AU - Mueller, Sabine
AU - Kline, Cassie
AU - Lu, Guangrong
AU - Allen, Joshua E.
AU - Khatua, Soumen
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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: T1/2, 8.4 h; Tmax, 2.1 h; Cmax, 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.
AB - 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: T1/2, 8.4 h; Tmax, 2.1 h; Cmax, 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.
KW - diffuse intrinsic pontine glioma (DIPG)
KW - diffuse midline glioma
KW - H3 K27M-mutant glioma (DMG)
KW - ONC201
UR - http://www.scopus.com/inward/record.url?scp=85145405626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85145405626&partnerID=8YFLogxK
U2 - 10.1093/noajnl/vdac143
DO - 10.1093/noajnl/vdac143
M3 - Article
C2 - 36382108
AN - SCOPUS:85145405626
SN - 2632-2498
VL - 4
JO - Neuro-Oncology Advances
JF - Neuro-Oncology Advances
IS - 1
M1 - vdac143
ER -