# Adaptive Clinical Efficacy Evaluation of ONC201 in Recurrent High Grade Glioma

> **NIH NIH R44** · ONCOCEUTICS, INC. · 2020 · $999,250

## Abstract

Project Summary
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.

## Key facts

- **NIH application ID:** 9990714
- **Project number:** 5R44CA192427-06
- **Recipient organization:** ONCOCEUTICS, INC.
- **Principal Investigator:** Joshua E. Allen
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $999,250
- **Award type:** 5
- **Project period:** 2015-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990714

## Citation

> US National Institutes of Health, RePORTER application 9990714, Adaptive Clinical Efficacy Evaluation of ONC201 in Recurrent High Grade Glioma (5R44CA192427-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9990714. Licensed CC0.

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