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

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-...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639395/
https://www.ncbi.nlm.nih.gov/pubmed/36382108
http://dx.doi.org/10.1093/noajnl/vdac143
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author 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
author_facet 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
author_sort Gardner, Sharon L
collection PubMed
description 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.
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spelling pubmed-96393952022-11-14 Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy 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 Neurooncol Adv Clinical Investigations 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. Oxford University Press 2022-09-13 /pmc/articles/PMC9639395/ /pubmed/36382108 http://dx.doi.org/10.1093/noajnl/vdac143 Text en © The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Clinical Investigations
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
Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title_full Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title_fullStr Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title_full_unstemmed Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title_short Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy
title_sort phase i dose escalation and expansion trial of single agent onc201 in pediatric diffuse midline gliomas following radiotherapy
topic Clinical Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9639395/
https://www.ncbi.nlm.nih.gov/pubmed/36382108
http://dx.doi.org/10.1093/noajnl/vdac143
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