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Updated: Feb 19, 2026
Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma
Published on: October 27, 2014
A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three
Isabel Arrillaga-Romany1, Andrew S Chi2, Joshua E Allen3
1Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.
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.
Insights
ONC201 shows promise as a well-tolerated oral treatment for recurrent glioblastoma. This drug demonstrated significant survival benefits and tumor regression in a Phase II study, suggesting potential single-agent activity.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Glioblastoma is an aggressive brain cancer with limited treatment options.
- Recurrent glioblastoma, particularly IDH1/2 WT, presents significant therapeutic challenges.
- ONC201 targets DRD2 and induces tumor cell apoptosis through novel mechanisms.
Purpose of the Study:
- To evaluate the safety and efficacy of ONC201 in patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma.
- To assess overall survival (OS) and progression-free survival (PFS) in this patient cohort.
- To investigate ONC201's pharmacokinetic profile and target engagement markers.
Main Methods:
- A Phase II clinical trial was conducted with 17 eligible patients.
- Patients received oral ONC201 at 625mg every three weeks.
- Outcomes including OS, PFS, objective response, safety, and pharmacokinetics were assessed.
Main Results:
- Median OS was 41.6 weeks; OS6 was 71% and OS9 was 53%.
- Two patients remained on study for over 12 months, one with a durable objective response.
- ONC201 was well-tolerated with no drug-related serious adverse events or treatment discontinuations due to toxicity.
Conclusions:
- ONC201 is a well-tolerated oral agent with potential single-agent activity in recurrent glioblastoma.
- Observed survival benefits and tumor regression warrant further investigation.
- DRD2 expression in tumors supports ONC201's mechanism of action.
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