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

Active Project Grant Awarded Last action

Award ID
R01CA266596
Recipient
Awarding agency
Obligated
$4,155,293

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date 69% complete
Originally
Place of performance
San Francisco, CA 94143, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $499,535
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Amendment $9,000
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Amendment -$14,010
Amendment $36,720
Amendment $45,321
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Amendment $664,049
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Original award $664,049
Show all 22

Subawards

Subrecipient Amount Awarded
University Of Zurich Aim 1: Establish the safety and RP2D of ONC206 as a single agent and in combination with radiotherapy in children and young adults with DMG and other… $90,750
Emory University Diffuse mid-line gliomas (DMG, including DIPG, and relapsed malignant brain tumors are invariably fatal, and thus in critical need of novel therapeutic… $99,593
Emory University Statement of Work- Emory Diffuse mid-line gliomas (DMG, including DIPG, and relapsed malignant brain tumors are invariably fatal, and thus in critical need of… $70,400
University Of Zurich Aim 1: Establish the safety and RP2D of ONC206 as a single agent and in combination with radiotherapy in children and young adults with DMG and other… $155,889
Regents Of The University Of Michigan Specific Aim 1 To establish the safety and recommended phase 2 dose (RP2D) of ONC206 in patients with DMG and recurrent primary malignant brain tumors (age… $294,487

Quick answers

Who received award R01CA266596?

R01CA266596 was awarded to The Regents Of The University Of California. San Francisco by National Cancer Institute (National Institutes of Health) on September 7, 2022.

How much is award R01CA266596 worth?

$4,155,293 has been obligated on R01CA266596.

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