# Phase 0/1 trial of ONC206 - a novel imipridone for children with diffuse midline gliomas and recurrent malignant brain tumors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $664,049

## Abstract

Project Summary
The aim of this phase 0/1 clinical trial is to assess the safety and preliminary efficacy of the novel, orally available,
blood brain barrier (BBB) penetrant imipridone ONC206 in pediatric patients with malignant brain tumors
including diffuse midline gliomas (DMG). We show that ONC206 exerts its activity in DMGs and medulloblastoma
through activation of the mitochondrial protease ClpP, a serine protease that plays a central role in mitochondrial
protein quality control by degrading misfolded proteins. ClpP activation through ONC206 lead to apoptosis
involving upregulation of ATF4 and C/EBP homologous protein (CHOP) and induction of DR5 and TRAIL. In our
preliminary analyses, we have found that ClpP expression correlates with ONC206 response in vitro and that
ONC206’s effect is completely abrogated in H3K27M models with CRISPR/Cas9 knockout. Our in vivo data
demonstrate that ONC206 leads to significant survival benefit in relevant in vivo model systems. Based upon
this exciting preliminary data, this will be the first study to test the safety and to determine the recommended
phase-2 dose (RP2D) of ONC206 as a single agent in pediatric patients including patients with DMGs and other
recurrent malignant brain tumors. Further, we will test ONC206 as single agent and in combination with radiation
in newly diagnosed and with re-irradiation in relapsed pediatric DMGs. We will assess the safety, PK profile and
preliminary efficacy of ONC206 in four different cohorts: (1) in newly diagnosed DMG, (2) in DMG patients who
completed radiation therapy, (3) in DMG patients at time of recurrence with re-irradiation and (4) other recurrent
malignant brain tumors. Using a Bayesian optimal interval (BOIN) design the maximal sample size will be 3-42
per cohort. All cohorts will be expanded so that 12 patients per cohort have been treated at the RP2D. To
investigate the BBB penetration of ONC206, 40 patients will be treated at the RP2D in a phase 0 component of
the study, stratified by anatomic region since penetrance might differ based on tumor location (pontine, thalamic
vs. other locations). Within the confines of a phase 1 study, we will also assess progression fee and overall
survival. For each patient we will collect tumor tissue, CSF and serum for correlative studies with a focus CLpP
expression as a potential biomarker of response. We will also assess tumor circulating DNA as potential marker
for disease for treatment response. Further, we will assess quality of life and patient reported outcomes, which
is critically important but has not yet been done comprehensively in this patient population. This will be the first
study to comprehensively assess ONC206 in this pediatric patient population and will lay the groundwork for
future combination trials.

## Key facts

- **NIH application ID:** 10519952
- **Project number:** 1R01CA266596-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Sabine Mueller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $664,049
- **Award type:** 1
- **Project period:** 2022-09-07 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519952

## Citation

> US National Institutes of Health, RePORTER application 10519952, Phase 0/1 trial of ONC206 - a novel imipridone for children with diffuse midline gliomas and recurrent malignant brain tumors (1R01CA266596-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10519952. Licensed CC0.

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