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

开发脑渗透性 ATM 抑制剂 WSD0628 联合放射治疗复发性高级别胶质瘤

• 批准号: 10730230
• 负责人: Jann N. Sarkaria
• 金额: $ 64.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730230
• 关键词: Development; brain; penetrant; ATM; inhibitor

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.

项目描述/摘要 胶质母细胞瘤和其他高级别胶质瘤患者的预后很差，并且存在 迫切需要开发更有效的治疗方法并结合最大程度的手术来满足未满足的医疗需求。 切除、放射治疗是这些患者治疗的基石，而局部放射治疗。 显着改善肿瘤控制，大约 80% 的肿瘤在照射体积内进展。 辐射剂量的增加并没有明显影响这种局部失效的模式，有一个令人信服的事实 开发新的药理学策略以提高高级别放射治疗的疗效的理由 该应用的重点是对高效脑渗透剂的首次人体临床评估。 ATM 抑制剂 (WSD0628) 与放射治疗联合治疗高级神经胶质瘤我们已经取得了显着进展。 临床前数据证明细胞培养物和原位脑肿瘤患者具有强大的放射增敏作用 重要的是，长期生存研究没有证明任何证据。 当 WSD0628 与高单剂量放射结合时，中枢神经系统毒性增强。 与观察到的上皮组织（皮肤、口腔和肠粘膜）显着增强的辐射毒性相反 与大多数其他与各种上皮组织紧密相邻的外周肿瘤相比， 在高级神经胶质瘤治疗中，最小的“高危”上皮组织会接受显着的辐射剂量，这 可以通过使用限制性放射治疗计划约束来进一步限制，但这提供了一个限制。 将 WSD0628 与放射治疗新诊断或复发性神经胶质瘤相结合的理论依据 首次人体研究将仅限于预后特别糟糕的复发患者，这些患者的风险较高 效益比在临床上是适当的，作为了解生物学有效的肿瘤组织的第一步。 人体浓度，我们将使用多个原位 GBM PDX 开发 PK→PD→功效模型 描述与强大的 ATM 抑制相关的总和游离药物 WSD0628 血浆和肿瘤浓度 然后，该模型将用于解释作为一部分收集的全身 PK 数据。 一项WSD0628剂量递增和剂量扩展I期临床试验另外，有6名患者需要进行。 手术当天将使用WSD0628、放射外科和手术切除进行仔细治疗。 整合临床前和临床数据，本研究将提供一个基于生物学的推荐阶段 WSD0628 的有效放射增敏治疗复发性高级别神经胶质瘤的 2 种给药方案。