Development of the brain penetrant ATM inhibitor WSD0628 in combination with radiation for recurrent high grade glioma

项目说明/摘要 胶质母细胞瘤和其他高级别胶质瘤的患者预后很差，而且 迫切需要开发更有效的疗法，以满足尚未得到满足的医疗需求。结合最大手术 手术切除，放射治疗是这些患者治疗的基石。虽然焦点放射治疗 显著改善了肿瘤控制，大约80%的肿瘤在照射体积内进展。而当 辐射剂量的增加对这种局部失效模式没有明显的影响，有一个令人信服的 开发新的药理策略以提高高级别放射治疗疗效的理论基础 神经胶质瘤。这项应用的重点是对一种高度有效的脑渗透剂进行首次临床评估。 ATM抑制剂(WSD0628)联合放射治疗高级别胶质瘤。我们已经发展出了重要的 临床前数据显示，在细胞培养和原位脑瘤患者中具有强大的放射增敏效应- WSD0628衍生异种移植物(PDX)。重要的是，一项长期生存研究没有证据表明 当WSD0628与高剂量的单次辐射联合使用时，中枢神经系统的毒性增强。这是在 与上皮组织(皮肤、口腔和肠粘膜)显著增强的辐射毒性形成对比 用这种药。与大多数与各种上皮组织密切相邻的其他外围肿瘤相比， 在高级别胶质瘤治疗中，最低风险的上皮组织会受到显著的辐射剂量，而这 可以通过使用限制性的放射治疗计划限制来进一步限制。虽然这提供了一个 WSD0628联合放射治疗新诊断或复发胶质瘤的理论基础 首个人的研究将仅限于预后特别可怕的复发患者，这些患者有较高的 受益比例在临床上是合适的。作为了解生物有效的肿瘤组织的第一步 ，我们将使用多个原位GBM PDX来建立PK→PD→疗效模型，以 描述与强大的ATM抑制相关的总药物和自由药物WSD0628的血浆和肿瘤浓度 和辐射增敏作用。然后，此模型将用于解释收集的系统PK数据，作为 WSD0628剂量递增和剂量扩展I期临床试验。此外，有六名患者需要 手术将在同一天与WSD0628、放射外科和外科手术切除治疗。小心地 结合临床前和临床数据，这项研究将提供一个生物知情的推荐阶段 2WSD0628治疗复发性高级别胶质瘤有效放射增敏的剂量方案。

PROJECT DESCRIPTION/ABSTRACT Patients with glioblastoma and other high-grade gliomas have a dismal prognosis, and there is a compelling unmet medical need to develop more effective therapies. In conjunction with maximal surgical resection, radiation therapy is a cornerstone of treatment for these patients. While focal radiation therapy significantly improves tumor control, approximately 80% of tumors progress within the irradiated volume. While radiation dose escalation has not appreciably impacted this pattern of local failure, there is a compelling rationale to develop novel pharmacologic strategies to enhance the efficacy of radiation therapy in high-grade gliomas. The focus of this application is the first-in-man clinical evaluation of a highly potent, brain penetrant ATM inhibitor (WSD0628) in combination with radiation in high-grade gliomas. We have developed significant pre-clinical data demonstrating robust radiosensitizing effects in cell culture and orthotopic brain tumor patient- derived xenografts (PDXs) with WSD0628. Importantly, a long-term survival study demonstrated no evidence of enhanced CNS toxicity when WSD0628 was combined with a high, single dose of radiation. This is in contrast to significantly enhanced radiation toxicities in epithelial tissues (skin, oral and gut mucosa) observed with this drug. In contrast to most other peripheral tumors with intimate adjacency to various epithelial tissues, minimal ‘at-risk’ epithelial tissues receive significant radiation dose with high-grade glioma treatment, and this can be further limited by using restrictive radiation therapy planning constraints. While this provides a theoretical rationale to combine WSD0628 with radiation in either newly diagnosed or recurrent gliomas, this first-in-man study will be limited to recurrent patients with an especially dire prognosis where a higher risk to benefit ratio is clinically appropriate. As a first step towards understanding a biologically effective tumor tissue concentration in humans, we will use multiple orthotopic GBM PDXs to develop a PK→PD→efficacy model to describe total and free-drug WSD0628 plasma and tumor concentrations associated with robust ATM inhibition and radiosensitizing effects. This model then will be used to interpret the systemic PK data collected as part of a WSD0628 dose-escalation and dose-expansion Phase I clinical trial. In addition, six patients requiring surgery will be treated on the same day with WSD0628, radiosurgery, and surgical resection. By carefully integrating the pre-clinical and clinical data, this study will provide a biologically-informed recommended Phase 2 dosing regimen for effective radiosensitization by WSD0628 for treatment of recurrent high-grade glioma.