Phase 1a Clinical Trial of XRD-0394, a First-in-Class Dual Ataxia-Telangiectasia Mutated and DNA-Dependent Protein Kinase Inhibitor, in Combination With Palliative Radiation Therapy

PURPOSE: XRD-0394 is a dual ataxia-telangiectasia mutated and DNA-dependent protein kinase inhibitor designed to increase tumor radiosensitivity. We evaluated the safety, pharmacokinetics, and pharmacodynamics of single-dose XRD-0394 administered with palliative radiation therapy (RT) in a first-in-human trial. METHODS AND MATERIALS: In an open-label, multicenter phase 1a dose-escalation study, XRD-0394 (40, 80, or 160 mg) was given once, 90 ± 30 minutes before fraction 2 of palliative RT. Primary endpoints were dose-limiting toxicities and tolerability; a coprimary objective was achieving a prespecified plasma exposure target (≥530 ng/mL [1 µM] at 1-4 hours postdose). Exploratory pharmacodynamic activity was assessed by phosphorylated KRAB-associated protein 1 immunohistochemistry in tumor biopsies. RESULTS: Twelve participants were treated. No dose-limiting toxicities 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. CONCLUSIONS: Single-dose XRD-0394 can be safely combined with palliative RT at plasma exposures that exceeded the prespecified target threshold, supporting fractionated multidose studies.