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

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ICR Authors

Dillon, Magnus
 Nenclares, Pablo
 Lord, Christopher
 Swales, Karen
 Banerji, Udai
 Melcher, Alan
 Harrington, Kevin

Authors

Dillon, MT
Patin, EC
Mohammed, K
Guevara, J
Smith, SA
Dean, E
Soliman, H
Nenclares, P
Ryugenji, M
Northcote, D
Shah, N
Grove, L
Lord, CJ
Pettit, S
Tall, M
Swales, KE
Banerji, U
Melcher, AA
Saunders, M
Forster, MD
Harrington, KJ

Document Type

Journal Article

Date

2025-08-01

Date Accepted

2025-07-15

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.

Citation

Nature Communications, 2025, 16 (1), pp. 7064 -

DOI

10.1038/s41467-025-62249-0

URI

https://repository.icr.ac.uk/handle/internal/7310

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Nature Communications

Publisher

NATURE PORTFOLIO

ISSN

2041-1723

eISSN

2041-1723

Collections

Cell and Molecular Biology

Research Team

Targeted Therapy

Precision Oncology Lord
Clin PD Biomarker Group
Clinical Pharmacology
Trans Immunotherapy

Notes