Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.

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ICR Authors

Dillon, Magnus
 Nenclares, Pablo
 Corbett, Anna
 Swales, Karen
 Banerji, Udai
 Harrington, Kevin

Authors

Dillon, MT
Guevara, J
Mohammed, K
Patin, EC
Smith, SA
Dean, E
Jones, GN
Willis, SE
Petrone, M
Silva, C
Thway, K
Bunce, C
Roxanis, I
Nenclares, P
Wilkins, A
McLaughlin, M
Jayme-Laiche, A
Benafif, S
Nintos, G
Kwatra, V
Grove, L
Mansfield, D
Proszek, P
Martin, P
Moore, L
Swales, KE
Banerji, U
Saunders, MP
Spicer, J
Forster, MD
Harrington, KJ

Document Type

Journal Article

Date

2024-01-16

Date Accepted

2023-11-07

Abstract

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

Citation

Journal of Clinical Investigation, 2023, pp. e175369 -

DOI

10.1172/JCI175369
10.1172/JCI175369

URI

https://repository.icr.ac.uk/handle/internal/6056

Rights

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

Source Title

Journal of Clinical Investigation

Publisher

AMER SOC CLINICAL INVESTIGATION INC

ISSN

0021-9738

eISSN

1558-8238
1558-8238

Collections

Cell and Molecular Biology

Research Team

Targeted Therapy
Clin PD Biomarker Group
Clinical Pharmacology

Notes