Show simple item record

dc.contributor.authorBoss, D S
dc.contributor.authorSchwartz, G K
dc.contributor.authorMiddleton, M R
dc.contributor.authorAmakye, D D
dc.contributor.authorSwaisland, H
dc.contributor.authorMidgley, R S
dc.contributor.authorRanson, Malcolm R
dc.contributor.authorDanson, Sarah
dc.contributor.authorCalvert, H
dc.contributor.authorPlummer, R
dc.contributor.authorMorris, C
dc.contributor.authorCarvajal, R D
dc.contributor.authorChirieac, L R
dc.contributor.authorSchellens, J H M
dc.contributor.authorShapiro, G I
dc.date.accessioned2010-08-10T12:58:40Z
dc.date.available2010-08-10T12:58:40Z
dc.date.issued2010-04
dc.identifier.citationSafety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. 2010, 21 (4):884-94 Ann Oncolen
dc.identifier.issn1569-8041
dc.identifier.pmid19825886
dc.identifier.doi10.1093/annonc/mdp377
dc.identifier.urihttp://hdl.handle.net/10541/109385
dc.description.abstractBACKGROUND: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. PATIENTS AND METHODS: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. RESULTS: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. CONCLUSIONS: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.
dc.language.isoenen
dc.subjectAnticancerous Agentsen
dc.subjectCanceren
dc.subject.meshAdministration, Oral
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAntineoplastic Agents
dc.subject.meshBiomarkers, Pharmacological
dc.subject.meshCohort Studies
dc.subject.meshCyclin-Dependent Kinases
dc.subject.meshDisease Progression
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshDrug Administration Schedule
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshImidazoles
dc.subject.meshMale
dc.subject.meshNeoplasms
dc.subject.meshProtein Kinase Inhibitors
dc.subject.meshPyrimidines
dc.subject.meshTreatment Outcome
dc.titleSafety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.en
dc.identifier.journalAnnals of Oncologyen
html.description.abstractBACKGROUND: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. PATIENTS AND METHODS: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. RESULTS: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. CONCLUSIONS: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.


This item appears in the following Collection(s)

Show simple item record