Phase 1a clinical trial of XRD-0394, a first-in-class dual ATM/DNA-PK inhibitor, in combination with palliative radiotherapy.
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2026-09-11
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PURPOSE: XRD-0394 is a dual ATM/DNA-PK inhibitor designed to increase tumor radiosensitivity. We evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single-dose XRD-0394 administered with palliative radiotherapy (RT) in a first-in-human trial. PATIENTS AND METHODS: In an open-label, multicenter phase 1a dose-escalation study, XRD-0394 (40, 80, or 160 mg) was given once, 90±30 minutes prior to fraction 2 of palliative RT. Primary endpoints were dose-limiting toxicities (DLTs) and tolerability; a co-primary objective was achieving a prespecified plasma exposure target (≥530 ng/mL [1 µM] at 1-4 hours post-dose). Exploratory PD activity was assessed by pKAP1 immunohistochemistry in tumor biopsies. RESULTS: Twelve participants were treated. No DLTs occurred and the maximum tolerated dose was not reached. Treatment-related adverse events were limited to grade 1 nausea and diarrhea (n=2), with no treatment-related serious adverse events. At 160 mg, exposures met the prespecified target and supported selection for further development. CONCLUSION: Single-dose XRD-0394 can be safely combined with palliative RT at plasma exposures that exceeded the pre-specified target threshold, supporting fractionated multi-dose studies.
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Chen, Christopher T, Michael F Gensheimer, Tona M Gilmer, Jennifer Stanley, Deborah Smith, Lei Fang, Michael B Kastan, Quynh-Thu Le, et al. (2026). Phase 1a clinical trial of XRD-0394, a first-in-class dual ATM/DNA-PK inhibitor, in combination with palliative radiotherapy. Int J Radiat Oncol Biol Phys. 10.1016/j.ijrobp.2026.08.069 Retrieved from https://hdl.handle.net/10161/35813.
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Michael Barry Kastan
Dr. Kastan earned his M.D./Ph.D. from Washington University School of Medicine and did his clinical training in Pediatrics and Pediatric Hematology-Oncology at Johns Hopkins. He was a Professor of Oncology at Johns Hopkins prior to becoming Chair of the Hematology-Oncology Department and later Cancer Center Director at St. Jude Children’s Research Hospital, before moving to Duke in 2011, where he currently serves as the Executive Director of the Duke Cancer Institute and is the William and Jane Shingleton Professor of Pharmacology and Cancer Biology. His laboratory research has focused on cellular responses to DNA damage, including many highly cited publications reporting the roles of p53 and ATM in DNA damage signaling. Among his numerous honors are election to the National Academy of Sciences, National Academy of Medicine, and the American Academy of Arts and Sciences, and receipt of the AACR-G.H.A. Clowes Memorial Award and Failla Award from the Radiation Research Society. He has served as Chair of the Board of Scientific Counselors of the National Cancer Institute (NCI), on the Boards of Directors of the American Association for Cancer Research (AACR) and the American Association of Cancer Institutes (AACI), and as Editor-in-Chief of the journal Molecular Cancer Research. His lab continues to study molecular and biochemical controls of cellular stress responses, particularly those related to DNA damage, and has spun out two companies focused on novel anti-cancer therapeutics.
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