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A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma

ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-n...

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Autores principales: Arrillaga-Romany, Isabel, Chi, Andrew S., Allen, Joshua E., Oster, Wolfgang, Wen, Patrick Y., Batchelor, Tracy T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668041/
https://www.ncbi.nlm.nih.gov/pubmed/29108308
http://dx.doi.org/10.18632/oncotarget.17837
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author Arrillaga-Romany, Isabel
Chi, Andrew S.
Allen, Joshua E.
Oster, Wolfgang
Wen, Patrick Y.
Batchelor, Tracy T.
author_facet Arrillaga-Romany, Isabel
Chi, Andrew S.
Allen, Joshua E.
Oster, Wolfgang
Wen, Patrick Y.
Batchelor, Tracy T.
author_sort Arrillaga-Romany, Isabel
collection PubMed
description ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients.
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spelling pubmed-56680412017-11-04 A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma Arrillaga-Romany, Isabel Chi, Andrew S. Allen, Joshua E. Oster, Wolfgang Wen, Patrick Y. Batchelor, Tracy T. Oncotarget Clinical Research Paper ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months. One of these patients had a durable objective response with a secondary glioblastoma possessing a H3.3 K27M mutation, exhibiting regression by 85% in one lesion and 76% in the second lesion. The second patient who continues to receive ONC201 for >12 months remains disease-free after enrolling on this trial following a re-resection. No drug-related SAEs or treatment discontinuation due to toxicity occurred. Plasma PK at 2 hours post-dose was 2.6 ug/mL, serum prolactin induction was observed as a surrogate marker of target engagement, and DRD2 was expressed in all evaluated archival tumor specimens. In summary, ONC201 is well tolerated and may have single agent activity in recurrent glioblastoma patients. Impact Journals LLC 2017-05-12 /pmc/articles/PMC5668041/ /pubmed/29108308 http://dx.doi.org/10.18632/oncotarget.17837 Text en Copyright: © 2017 Arrillaga-Romany et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Clinical Research Paper
Arrillaga-Romany, Isabel
Chi, Andrew S.
Allen, Joshua E.
Oster, Wolfgang
Wen, Patrick Y.
Batchelor, Tracy T.
A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title_full A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title_fullStr A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title_full_unstemmed A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title_short A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
title_sort phase 2 study of the first imipridone onc201, a selective drd2 antagonist for oncology, administered every three weeks in recurrent glioblastoma
topic Clinical Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668041/
https://www.ncbi.nlm.nih.gov/pubmed/29108308
http://dx.doi.org/10.18632/oncotarget.17837
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