Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.
Date
2024-01-16ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cancer immunotherapy
DNA repair
Drug therapy
Oncology
Research team
Targeted Therapy
Clin PD Biomarker Group
Clinical Pharmacology
Language
eng
Date accepted
2023-11-07
License start date
2023-11-07
Citation
Journal of Clinical Investigation, 2023, pp. e175369 -
Publisher
AMER SOC CLINICAL INVESTIGATION INC