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. 2017 May 12;8(45):79298-79304.
doi: 10.18632/oncotarget.17837. eCollection 2017 Oct 3.

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

Isabel Arrillaga-Romany  1 , Andrew S Chi  2 , Joshua E Allen  3 , Wolfgang Oster  3 , Patrick Y Wen  4 , Tracy T Batchelor  1
Affiliations

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

Isabel Arrillaga-Romany et al. Oncotarget. .

Abstract

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.

Keywords: GPCR; Imipridone; ONC201; glioblastoma; glioma.

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Conflict of interest statement

CONFLICTS OF INTEREST J.E.A. and W.O. are employees and shareholders of Oncoceutics.

Figures

Figure 1
Figure 1. Kaplan–Meier curve for (A) progression-free survival and (B) overall survival
Figure 2
Figure 2. Objective response in a patient with recurrent glioblastoma
T1- post contrast brain MRI reveals two enhancing lesions at baseline (left top and bottom panels), which are decreased in size following 12 cycles of therapy (36 weeks; right top and bottom panels).
Figure 3
Figure 3. Correlative assays in peripheral blood
Left panel shows plasma concentrations of ONC201 at 2 hours following the first dose of ONC201. The dashed line indicates the target therapeutic threshold. Right panel shows serum prolactin levels at baseline and one day following ONC201 treatment.
See this image and copyright information in PMC

Comment in

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