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dc.contributor.authorRafii, S
dc.contributor.authorRoda, D
dc.contributor.authorGeuna, E
dc.contributor.authorJimenez, B
dc.contributor.authorRihawi, K
dc.contributor.authorCapelan, M
dc.contributor.authorYap, TA
dc.contributor.authorMolife, LR
dc.contributor.authorKaye, SB
dc.contributor.authorde Bono, JS
dc.contributor.authorBanerji, U
dc.date.accessioned2020-07-28T13:28:27Z
dc.date.issued2015-04
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2015, 21 (8), pp. 1869 - 1876
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3877
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-14-2424
dc.description.abstractPurpose Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown.Experimental design In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies.Results The incidence of all grade infection was significantly higher with all single-agent PI3K-AKT-mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9-9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1-12.4; P = 0.02). Also, the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0-11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0-7.6; P = 0.03) infection when compared with single-agent PI3K-AKT-mTOR inhibitors.Conclusions Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.
dc.formatPrint-Electronic
dc.format.extent1869 - 1876
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectNeoplasm Metastasis
dc.subjectAntineoplastic Agents
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectProtein Kinase Inhibitors
dc.subjectNeoplasm Staging
dc.subjectIncidence
dc.subjectRisk
dc.subjectCase-Control Studies
dc.subjectRetrospective Studies
dc.subjectSignal Transduction
dc.subjectAdolescent
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectClinical Trials, Phase I as Topic
dc.subjectYoung Adult
dc.subjectTOR Serine-Threonine Kinases
dc.subjectBiomarkers
dc.subjectPhosphoinositide-3 Kinase Inhibitors
dc.subjectInfections
dc.titleHigher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials.
dc.typeJournal Article
dcterms.dateAccepted2015-01-28
rioxxterms.versionofrecord10.1158/1078-0432.ccr-14-2424
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2015-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue8
pubs.notesNot known
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Medicine Drug Development Unit (Kaye)
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Medicine Drug Development Unit (Kaye)
pubs.publication-statusPublished
pubs.volume21
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamMedicine Drug Development Unit (Kaye)en_US
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorYap, Timothyen
dc.contributor.icrauthorMolife, Rhodaen
dc.contributor.icrauthorTurner, Lydiaen
dc.contributor.icrauthorKaye, Stanley Bernarden


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