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dc.contributor.authorO'Brien, MER
dc.contributor.authorSarker, D
dc.contributor.authorBhosle, J
dc.contributor.authorThillai, K
dc.contributor.authorYap, TA
dc.contributor.authorUttenreuther-Fischer, M
dc.contributor.authorPemberton, K
dc.contributor.authorJin, X
dc.contributor.authorWiebe, S
dc.contributor.authorde Bono, J
dc.contributor.authorSpicer, J
dc.date.accessioned2019-09-16T15:01:49Z
dc.date.issued2018-11
dc.identifier.citationCancer chemotherapy and pharmacology, 2018, 82 (5), pp. 757 - 766
dc.identifier.issn0344-5704
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3333
dc.identifier.eissn1432-0843
dc.identifier.doi10.1007/s00280-018-3661-1
dc.description.abstractPurpose Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy.Methods As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin plus paclitaxel (A/C/P). Starting doses: afatinib 20 mg/day, carboplatin AUC6 (A/C) with paclitaxel 175 mg/m 2 (A/C/P) (chemotherapy: Day 1 of 21-day cycles). The primary objective was to determine the MTDs; safety, pharmacokinetics and antitumor activity were also evaluated.Results Thirty-eight patients received A/C (n = 12) or A/C/P (n = 26). No dose-limiting toxicities (DLTs) were reported with A(20 mg)/C(AUC6). One patient experienced DLT in the A(40 mg)/C(AUC6) cohort (grade 3 acneiform rash); A(40 mg)/C(AUC6) was determined as the recommended phase II dose (RP2D) for A/C. Two patients each had DLTs with A(20 mg/day)/C(AUC6)/P(175 mg/m 2 ): fatigue, infection, diarrhea, small intestine hemorrhage, dehydration, renal impairment, neutropenic sepsis (n = 1), mucositis (n = 1); A(40 mg)/C(AUC5)/P(175 mg/m 2 ): febrile neutropenia (n = 1), mucositis, fatigue (n = 1); and A(30 mg)/C(AUC5)/P(175 mg/m 2 ): stomatitis (n = 1), mucositis (n = 1). No DLT was observed with A(20 mg)/C(AUC5)/P(175 mg/m 2 ), determined as the RP2D for A/C/P. The most frequent drug-related adverse events were (A/C; A/C/P): rash (75%; 73%), fatigue (67%; 69%), and diarrhea (58%; 88%). Drug plasma concentrations were similar between cycles, suggesting no drug-drug interactions. Objective response rates in these heavily pretreated patients were A/C, 3/12 (25%); A/C/P, 5/26 (19%).Conclusions Afatinib 40 mg/day (approved monotherapy dose) with carboplatin AUC6, and afatinib 20 mg/day with carboplatin AUC5 and paclitaxel 175 mg/m 2 demonstrated manageable safety and antitumor activity. Afatinib > 20 mg/day in the triple combination was not well tolerated.
dc.formatPrint-Electronic
dc.format.extent757 - 766
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectPaclitaxel
dc.subjectCarboplatin
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectTreatment Outcome
dc.subjectDrug Administration Schedule
dc.subjectMaximum Tolerated Dose
dc.subjectDose-Response Relationship, Drug
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectAfatinib
dc.titleA phase I study to assess afatinib in combination with carboplatin or with carboplatin plus paclitaxel in patients with advanced solid tumors.
dc.typeJournal Article
dcterms.dateAccepted2018-07-30
rioxxterms.versionofrecord10.1007/s00280-018-3661-1
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-11
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer chemotherapy and pharmacology
pubs.issue5
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/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/Clinical Studies/Treatment of thoracic tumours
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Treatment of thoracic tumours/Treatment of thoracic tumours (hon.)
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/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/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/Clinical Studies/Treatment of thoracic tumours
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Treatment of thoracic tumours/Treatment of thoracic tumours (hon.)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume82
pubs.embargo.termsNot known
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamTreatment of thoracic tumoursen_US
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorO'Brien, Maryen
dc.contributor.icrauthorYap, Timothyen


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