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

Authors

Christopher T Chen, Michael F Gensheimer, Tona M Gilmer, Jennifer Stanley, Deborah Smith, Lei Fang, Michael B Kastan, Quynh-Thu Le, Simon N Powell, David G Kirsch, Steven H Lin, Jonathan T Yang, Paul Romesser

Published in

International journal of radiation oncology, biology, physics. Sep 11, 2026. Epub Sep 11, 2026.

Abstract

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.
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.
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.
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.

PMID:
42727889
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.

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