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Peer-reviewedCC BY-NC-ND 4.0International journal of radiation oncology, biology, physics

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

  • Christopher T. Chen1
  • Michael F. Gensheimer2
  • Tona M. Gilmer3
  • Jennifer Stanley4
  • Deborah Smith5
  • Lei Fang6
  • Michael B. Kastan7
  • Quynh-Thu Le2
  • Simon N. Powell8
  • David G. Kirsch9,10
  • Steven H. Lin11
  • Jonathan T. Yang8
1 more authors
  • Paul B. Romesser12,13
13 affiliations
  1. 1Division of Oncology, Department of Medicine, Stanford University School of Medicine, Palo Alto, California
  2. 2Department of Radiation Oncology, Stanford University School of Medicine, Palo Alto, California
  3. 3XRad Therapeutics, Orlando, Florida
  4. 4PRolific Research Consulting, Punta Gorda, Florida
  5. 5ClinPharm Advantage, Durham, North Carolina
  6. 6PharStat Inc, Raleigh, North Carolina
  7. 7Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina
  8. 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  9. 9Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
  10. 10Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
  11. 11Department of Thoracic Radiation Oncology, Division of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas
  12. 12Department of Radiation Oncology, Colorectal and Anal Cancer Service, Memorial Sloan Kettering Cancer Center, New York, New York
  13. 13Department of Medicine, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, New York, New York
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{chen2026phase,
  title = {{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}},
  author = {Christopher T. Chen and Michael F. Gensheimer and Tona M. Gilmer and Jennifer Stanley and Deborah Smith and Lei Fang and Michael B. Kastan and Quynh-Thu Le and Simon N. Powell and David G. Kirsch and Steven H. Lin and Jonathan T. Yang and Paul B. Romesser},
  journal = {International journal of radiation oncology, biology, physics},
  year = {2026},
  month = sep,
  doi = {10.1016/j.ijrobp.2026.08.069},
  url = {https://doi.org/10.1016/j.ijrobp.2026.08.069},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - 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
AU  - Christopher T. Chen
AU  - Michael F. Gensheimer
AU  - Tona M. Gilmer
AU  - Jennifer Stanley
AU  - Deborah Smith
AU  - Lei Fang
AU  - Michael B. Kastan
AU  - Quynh-Thu Le
AU  - Simon N. Powell
AU  - David G. Kirsch
AU  - Steven H. Lin
AU  - Jonathan T. Yang
AU  - Paul B. Romesser
PY  - 2026
DA  - 2026/09/11
JO  - International journal of radiation oncology, biology, physics
DO  - 10.1016/j.ijrobp.2026.08.069
UR  - https://doi.org/10.1016/j.ijrobp.2026.08.069
AB  - 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.
SN  - 0360-3016
SN  - 1879-355X
ER  -