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,Patrick Y Wen,Andrew S Chi,Tracy T Batchelor,Joshua E Allen,Wolfgang Oster

doi:10.18632/oncotarget.17837

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.

Highlights

Glioblastoma is the most frequent adult primary malignant brain tumor
The study did not achieve the primary endpoint, single agent ONC201 showed signs of antitumor activity in this pilot study of recurrent glioblastoma patients that was enriched for several poor prognosis features: unmethylated MGMT, age >50, subtotal resections, and baseline corticosteroid use
While progression-free survival did not achieve the primary endpoint in this small cohort, the durable objective response observed and overall survival results are encouraging with a single agent with infrequent dosing

Summary

Introduction

Glioblastoma is the most frequent adult primary malignant brain tumor. FDA-approved treatment options remain few and the prognosis remains dismal with a median survival of 14.6 months [1] and a 5-year-survival rate of 9.8% [2]. Standard treatment of glioblastoma includes surgery followed by concomitant radiation and temozolomide followed by maintenance temozolomide for 6 months. This regimen can be associated with toxicity that is problematic for elderly patients who frequently experience neurotoxicity and Grade 3-4 hematological toxicities [3]. Recurrent glioblastoma has no approved therapy that has been shown to prolong survival in a prospective study. New therapies are needed for patients with recurrent glioblastoma

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