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

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.