dc.contributor.author | Dillon, MT | |
dc.contributor.author | Guevara, J | |
dc.contributor.author | Mohammed, K | |
dc.contributor.author | Patin, EC | |
dc.contributor.author | Smith, SA | |
dc.contributor.author | Dean, E | |
dc.contributor.author | Jones, GN | |
dc.contributor.author | Willis, SE | |
dc.contributor.author | Petrone, M | |
dc.contributor.author | Silva, C | |
dc.contributor.author | Thway, K | |
dc.contributor.author | Bunce, C | |
dc.contributor.author | Roxanis, I | |
dc.contributor.author | Nenclares, P | |
dc.contributor.author | Wilkins, A | |
dc.contributor.author | McLaughlin, M | |
dc.contributor.author | Jayme-Laiche, A | |
dc.contributor.author | Benafif, S | |
dc.contributor.author | Nintos, G | |
dc.contributor.author | Kwatra, V | |
dc.contributor.author | Grove, L | |
dc.contributor.author | Mansfield, D | |
dc.contributor.author | Proszek, P | |
dc.contributor.author | Martin, P | |
dc.contributor.author | Moore, L | |
dc.contributor.author | Swales, KE | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Saunders, MP | |
dc.contributor.author | Spicer, J | |
dc.contributor.author | Forster, MD | |
dc.contributor.author | Harrington, KJ | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-11-14T10:00:06Z | |
dc.date.available | 2023-11-14T10:00:06Z | |
dc.date.issued | 2024-01-16 | |
dc.identifier | 175369 | |
dc.identifier.citation | Journal of Clinical Investigation, 2023, pp. e175369 - | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6056 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/JCI175369 | |
dc.identifier.doi | 10.1172/JCI175369 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | e175369 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | |
dc.relation.ispartof | Journal of Clinical Investigation | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Cancer immunotherapy | |
dc.subject | DNA repair | |
dc.subject | Drug therapy | |
dc.subject | Oncology | |
dc.title | Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2023-11-07 | |
dc.date.updated | 2023-11-14T09:17:01Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1172/JCI175369 | |
rioxxterms.licenseref.startdate | 2023-11-07 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/37934611 | |
pubs.organisational-group | ICR | |
pubs.organisational-group | ICR/Primary Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy | |
pubs.organisational-group | ICR/Students | |
pubs.organisational-group | ICR/Students/PhD and MPhil | |
pubs.organisational-group | ICR/ImmNet | |
pubs.organisational-group | ICR/Students/PhD and MPhil/14/15 Starting Cohort | |
pubs.organisational-group | ICR/Students/PhD and MPhil/13/14 Starting Cohort | |
pubs.publication-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1172/jci175369 | |
icr.researchteam | Targeted Therapy | |
icr.researchteam | Clin PD Biomarker Group | |
icr.researchteam | Clinical Pharmacology | |
dc.contributor.icrauthor | Dillon, Magnus | |
dc.contributor.icrauthor | Nenclares, Pablo | |
dc.contributor.icrauthor | Corbett, Anna | |
dc.contributor.icrauthor | Swales, Karen | |
dc.contributor.icrauthor | Banerji, Udai | |
dc.contributor.icrauthor | Harrington, Kevin | |
icr.provenance | Deposited by Dr Magnus Dillon on 2023-11-14. Deposit type is initial. No. of files: 1. Files: 2023110_PATRIOT_AB_R4_final.pdf | |