ATM-Inhibitor WSD0628 in Combination with Radiation Therapy for the Treatment of Recurrent High-Grade Gliomas

Inclusion Criteria

• Age >= 18 years
• Histological confirmation of one of the following: * Glioblastoma, IDH-wildtype * Grade 3 or 4 IDH1/2 mutant astrocytoma (2021 World Health Organization [WHO] classification)
• Measurable disease
• Disease progression after previous treatment for glioma with radiation and chemotherapy
• Minimum life expectancy of >= 3 months
• Group C only (Dose expansion, brain tumor penetration group): Plan for radiosurgery and surgical resection as part of routine clinical care
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
• Hemoglobin >= 9.0 g/dL (obtained =< 15 days prior to registration)
• Leukocytes >= 3.0 x 10^9/L (obtained =< 15 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (or >= 1.5 x 10^9/L) (obtained =< 15 days prior to registration)
• Platelet count >= 100,000/mm^3 or ( >= 100 x 10^9/L) (obtained =< 15 days prior to registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN), or < 3 mg/dL for patients with Gilbert's disease (obtained =< 15 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 15 days prior to registration)
• Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =< 15 days prior to registration)
• Calculated creatinine clearance >= 45 ml/min using the Cockcroft-Gault formula (obtained =< 15 days prior to registration)
• Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
• Willing to take sunlight-protective measures during the study and for two weeks after their last dose of WSD0628
• Provide written informed consent
• Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
• Willingness to provide mandatory blood specimens for correlative research
• Group C (tumor penetrance) only: Willingness to provide mandatory tissue specimens for correlative research

Exclusion Criteria

• Any of the following because this study involves an investigational agent, the genotoxic, mutagenic, and teratogenic effects of which on the developing fetus and newborn are unknown: * Pregnant persons * Nursing persons * Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception
• Uncontrolled intercurrent illness including, but not limited to any of the following conditions: * Ongoing or active infection requiring treatment * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Or psychiatric illness/social situations that would limit compliance with study requirements
• Any of the following cardiac criteria: * Marked baseline prolongation of QT/corrected QT (QTc) interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds [ms]) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fredericia's QT correction formula * History of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) * Use of concomitant medications that prolong the QT/QTc interval * History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Known coagulopathy increasing the risk of bleeding or history of clinically significant hemorrhage, including significant intracranial tumor related hemorrhage
• Any of the following medications: * Enzyme-inducing anticonvulsants =< 14 days prior to registration ** NOTE: Patients can be registered after a change to non-enzyme inducing anticonvulsants) * Patients taking > 8 mg of dexamethasone per day (or equivalent steroid dose) at time of registration
• Any of the following prior therapies: * Radiation therapy =< 26 weeks prior to registration (including gamma tiles) * Chemotherapy, immunotherapy, or any investigational drug =< 4 weeks prior to registration, or carmustine (BCNU) or lomustine (CCNU) =< 6 weeks prior to registration
• Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
• History of hypersensitivity to active or inactive excipients of WSD0628 or drugs with a similar chemical structure or class to WSD0628
• Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of WSD0628
• Uncontrolled hypertension
• History of severe brain-injury or stroke
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm