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

项目摘要 该0/1期临床试验的目的是评估新型口服药物的安全性和初步疗效， 血脑屏障（BBB）渗透剂依米普利酮ONC 206在儿童恶性脑肿瘤中的应用 包括弥漫性中线神经胶质瘤（DMG）。我们发现ONC 206在DMG和髓母细胞瘤中发挥其活性， 通过激活线粒体蛋白酶ClpP，一种在线粒体中起核心作用的丝氨酸蛋白酶， 通过降解错误折叠的蛋白质进行蛋白质质量控制。通过ONC 206激活ClpP导致细胞凋亡 包括ATF 4和C/EBP同源蛋白（CHOP）的上调以及DR 5和TRAIL的诱导。在我们 初步分析，我们发现ClpP表达与体外ONC 206应答相关， ONC 206的作用在CRISPR/Cas9敲除的H3 K27 M模型中完全消除。我们的体内数据 这表明ONC 206在相关的体内模型系统中导致显著的存活益处。基于 这一令人兴奋的初步数据，这将是第一个研究，以测试安全性，并确定推荐的 ONC 206作为单药在儿科患者（包括DMG和其他疾病患者）中的2期剂量（RP 2D） 复发性恶性脑肿瘤此外，我们将测试ONC 206作为单一药剂和与辐射组合 在新诊断的和复发的儿童DMG的再照射。我们将评估安全性、PK特征和 ONC 206在四个不同群组中的初步功效：（1）在新诊断的DMG中，（2）在 完成放射治疗，（3）DMG患者在复发时再次照射，（4）其他复发 恶性脑瘤使用贝叶斯最优区间（BOIN）设计，最大样本量为3-42 每个队列。将扩展所有队列，以便每个队列有12例患者接受RP 2D治疗。到 研究ONC 206的BBB渗透，40名患者将在0期组分中以RP 2D接受治疗， 该研究根据解剖区域分层，因为肿瘤位置（脑桥、丘脑 vs.其他地点）。在1期研究的范围内，我们还将评估进展费用和总体 生存对于每例患者，我们将收集肿瘤组织、CSF和血清用于与病灶CLP相关的研究 表达作为反应的潜在生物标志物。我们还将评估肿瘤循环DNA作为潜在标记物 疾病的治疗反应。此外，我们将评估生活质量和患者报告的结果， 是至关重要的，但尚未在该患者人群中全面实施。这将是第一 这项研究旨在全面评估该儿科患者人群中的ONC 206，并将为 未来的联合试验

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.