Tumor control and immune activation through palliative irradiation and ATR inhibition, PATRIOT Part C: a phase Ib trial

Magnus T. Dillon (), Emmanuel C. Patin, Kabir Mohammed, Jeane Guevara, Simon A. Smith, Emma Dean, Heba Soliman, Pablo Nenclares, Motoko Ryugenji, Davina Northcote, Neel Shah, Lorna Grove, Christopher J. Lord, Stephen Pettit, Matt Tall, Karen E. Swales, Udai Banerji, Alan A. Melcher, Mark Saunders, Martin D. Forster and Kevin J. Harrington
Additional contact information
Magnus T. Dillon: The Institute of Cancer Research
Emmanuel C. Patin: The Institute of Cancer Research
Kabir Mohammed: The Royal Marsden NHS Foundation Trust
Jeane Guevara: The Royal Marsden NHS Foundation Trust
Simon A. Smith: AstraZeneca
Emma Dean: AstraZeneca
Heba Soliman: The Royal Marsden NHS Foundation Trust
Pablo Nenclares: The Institute of Cancer Research
Motoko Ryugenji: The Royal Marsden NHS Foundation Trust
Davina Northcote: The Royal Marsden NHS Foundation Trust
Neel Shah: AstraZeneca
Lorna Grove: The Institute of Cancer Research
Christopher J. Lord: The Institute of Cancer Research
Stephen Pettit: The Institute of Cancer Research
Matt Tall: The Institute of Cancer Research
Karen E. Swales: The Institute of Cancer Research
Udai Banerji: The Institute of Cancer Research
Alan A. Melcher: The Institute of Cancer Research
Mark Saunders: The Christie NHS Foundation Trust
Martin D. Forster: UCL Cancer Institute and University College London Hospital NHS Foundation Trust
Kevin J. Harrington: The Institute of Cancer Research

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Ataxia telangiectasia and Rad3-related kinase (ATR) is a rational radiosensitization target. In this study, we explore the combination of the ATR inhibitor, ceralasertib, and palliative radiotherapy, with primary endpoint the identification of maximum tolerated dose, and secondary endpoints the determination of adverse event causality, pharmacokinetics (PK) and anti-tumor activity. Twenty-seven patients were dosed in escalating dose cohorts from 20 to 80 mg twice daily (BD) with concomitant radiation, 20 Gy in 10 fractions or 30 Gy in 15 fractions. Patients were assessed for acute and late toxicities and response after therapy. A non-tolerated dose was not reached. Maximum administered dose was 80 mg BD ceralasertib over 3 weeks with 30 Gy in 15 fractions, at which 1/6 evaluable patients had dose-limiting toxicities (radiation dermatitis and mucositis). PK was comparable to monotherapy. Of 23 efficacy-evaluable participants, 2 (9%) had complete response (CR), 6 (26%) partial response (PR), 13 (57%) stable disease (SD) and 2 (9%) progressive disease (PD) as best response in irradiated tumors. Response was not clearly linked to genomic aberrations. Increased T and natural killer cell activation as observed in peripheral blood as treatment progressed.

Date: 2025
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DOI: 10.1038/s41467-025-62249-0

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