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

项目总结

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.