We propose a two-arm adaptive Phase II clinical trial to evaluate ONC201, a selective antagonist of the G protein-coupled receptor (GPCR) dopamine receptor domain 2 (DRD2), in recurrent glioblastoma (GBM) and diffuse midline glioma associated with very poor prognoses and limited treatment options. DRD2 is overexpressed in high grade gliomas and controls Akt/ERK signaling pathways. Downstream of target engagement, ONC201 causes activation of the integrated stress response and inactivation of Akt/ERK signaling in tumors. The small molecule is orally active, penetrates the intact blood-brain-barrier, and induces p53-independent apoptosis in newly diagnosed and recurrent GBM as a single agent and synergistically with bevacizumab to produce survival benefit in mouse models. In clinical trials, ONC201 has been exceptional well tolerated, possessed a therapeutic pharmacokinetic profile, and exhibited sustained pharmacodynamics and anti-cancer activity in advanced cancer patients. No Grade>1 drug-related adverse events were observed in the first-in-human trial, despite achieving therapeutic blood levels and demonstrating signs of biological activity at, and below, its recommended Phase II dose of 625mg PO. In a Phase II pilot cohort of recurrent GBM, a 22-year-old patient with a thalamic H3.3 K27M glioma achieved an objective response with an 92% regression that has remained durable. This patient remains on study for >14 months without drug-related adverse events. Immunohistochemical analyses revealed that this patient?s tumor does not express DRD5, a dopamine receptor family member that opposes DRD2 signaling. Low DRD5 expression is significantly correlated with improved ONC201 preclinical efficacy. Further investigation revealed that H3.3 K27M appears to epigenetically suppress DRD5 expression, rendering tumors sensitive to ONC201. This mutation is a defining feature of diffuse midline gliomas that are often inoperable brainstem tumors. In support of our biomarker hypothesis, gliomas that harbor this H3 K27M mutation are significantly more sensitive to ONC201 in vitro than those that harbor the wildtype H3 gene or that harbor the K3 G34R mutation. The results derived from this proposal are intended to enable the design of a registration trial for ONC201 in a specific indication within high grade glioma.
Aim 1 : Evaluate GBM and H3 K27M diffuse midline glioma cohorts for trial expansion. The first arm of the study will evaluate overall survival among recurrent GBM patients treated with the combination of ONC201 and bevacizumab. The second, independent arm of the study will evaluate the overall response rate of single agent ONC201 in recurrent H3.3 K27M diffuse midline glioma.
Aim 2 : Perform molecular correlative studies and subgroup analyses to specify candidate indication for registration trial. This proposal seeks to provide a safe and durable treatment for patients with a disease that has few treatment options and a dismal prognosis.

Public Health Relevance

This proposal seeks to develop a new cancer drug, ONC201, with a novel biochemical interaction that targets a wide-reaching family of cellular receptors, for patients who have been diagnosed with recurrent glioblastoma and high-grade glioma with limited treatment options and very poor prognoses. In a previous expanded trial group of recurrent glioblastoma patients, ONC201 demonstrated few side effects and robust anti- tumor activity including tumor shrinkage and prolonged survival. The proposed clinical trial is intended to further validate these findings and enable the design of a trial that supports FDA approval for ONC201 with a specific biological indicator within high-grade glioma.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZCA1)
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Franca-Koh, Jonathan C
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Oncoceutics, Inc.
United States
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