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dc.contributor.authorBautista, F
dc.contributor.authorMoreno, L
dc.contributor.authorMarshall, L
dc.contributor.authorPearson, ADJ
dc.contributor.authorGeoerger, B
dc.contributor.authorPaoletti, X
dc.date.accessioned2018-02-20T12:07:25Z
dc.date.issued2017-11
dc.identifier.citationEuropean journal of cancer (Oxford, England : 1990), 2017, 86 pp. 275 - 284
dc.identifier.issn0959-8049
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1405
dc.identifier.eissn1879-0852
dc.identifier.doi10.1016/j.ejca.2017.09.015
dc.description.abstractDose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children.The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members.Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition.DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials.
dc.formatPrint-Electronic
dc.format.extent275 - 284
dc.languageeng
dc.language.isoeng
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectAntineoplastic Agents
dc.subjectMaximum Tolerated Dose
dc.subjectMedical Oncology
dc.subjectPediatrics
dc.subjectAge Factors
dc.subjectDose-Response Relationship, Drug
dc.subjectModels, Theoretical
dc.subjectResearch Design
dc.subjectAdolescent
dc.subjectAdult
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectInfant
dc.subjectTerminology as Topic
dc.subjectClinical Trials, Phase I as Topic
dc.subjectDrug Dosage Calculations
dc.titleRevisiting the definition of dose-limiting toxicities in paediatric oncology phase I clinical trials: An analysis from the Innovative Therapies for Children with Cancer Consortium.
dc.typeJournal Article
dcterms.dateAccepted2017-09-13
rioxxterms.versionofrecord10.1016/j.ejca.2017.09.015
rioxxterms.licenseref.startdate2017-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEuropean journal of cancer (Oxford, England : 1990)
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume86en_US
pubs.embargo.termsNot known
dc.contributor.icrauthorMarsden,en


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