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

Award Number: R01CA266596
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Phase 0/1 trial of ONC206 - a novel imipridone for children with diffuse midline gliomas and recurrent malignant brain tumors - 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. Background This R01 includes three international sites — Children's Hospital Zurich (Switzerland), Prinses Máxima Center (Netherlands), and École Polytechnique Fédérale de Lausanne (EPFL, Switzerland) — that were approved as part of the original NIH award as well as subsequent progress reports. General Justification: The study addresses diffuse midline glioma (DMG), a rare pediatric malignancy for which the patient population, specialized clinical infrastructure, and relevant scientific expertise are concentrated at a small number of centers worldwide, several of which are outside the United States. The trial has now progressed into enrollment of several expansion cohorts, making high enrolling sites more critical than ever to reaching accrual targets within a feasible timeframe. Removing these three sites at this stage would materially compromise the study's ability to complete expansion-cohort enrollment, would eliminate access to preliminary/foundational data already generated in support of the study's aims, and would remove specialized analytic expertise not readily available domestically. Each site's role is described below. Site 1: Children's Hospital Zurich (Switz


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $600,876 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	002	5	8/27/2026	NON-COMPETING CONTINUATION	$499,535
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	005	5	9/9/2026	SUPPLEMENT FOR EXPANSION	$12,000
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	003	5	9/7/2026	SUPPLEMENT FOR EXPANSION	$46,141
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	004	5	9/8/2026	SUPPLEMENT FOR EXPANSION	$43,200
2026	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	4	8/12/2026	NON-COMPETING CONTINUATION	$0
2026	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	4	4/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $600,876

Issue Date FY: 2025 ( Subtotal = $528,889 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	004	4	9/19/2025	SUPPLEMENT FOR EXPANSION	$9,000
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	002	4	9/18/2025	SUPPLEMENT FOR EXPANSION	$36,720
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	003	4	9/18/2025	SUPPLEMENT FOR EXPANSION	$45,321
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	4	9/18/2025	NON-COMPETING CONTINUATION	-$14,010
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	4	9/9/2025	NON-COMPETING CONTINUATION	$451,858
														Subtotal = $528,889

Issue Date FY: 2024 ( Subtotal = $46,752 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	3	9/20/2024	NON-COMPETING CONTINUATION	$46,752
														Subtotal = $46,752

Issue Date FY: 2023 ( Subtotal = $587,101 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	001	2	8/31/2023	NON-COMPETING CONTINUATION	$587,101
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	5/25/2023	NEW	$0
														Subtotal = $587,101

Issue Date FY: 2022 ( Subtotal = $664,049 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	9/7/2022	NEW	$664,049
														Subtotal = $664,049

Grand Total All Awards = $2,427,667

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

Award Number: R01CA266596

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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