Phase 1a clinical trial of XRD-0394, a first-in-class dual ATM/DNA-PK inhibitor, in combination with palliative radiotherapy.

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.