title: Safety, 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.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Boss
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: G K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Departments of Oncology and Clinical Pharmacology, Oxford Radcliffe Hospitals, Oxford.
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire.
authors.forename: D D
authors.initials: DD
authors.lastname: Amakye
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire.
authors.forename: H
authors.initials: H
authors.lastname: Swaisland
authors.affiliation: Departments of Oncology and Clinical Pharmacology, Oxford Radcliffe Hospitals, Oxford.
authors.forename: R S
authors.initials: RS
authors.lastname: Midgley
authors.affiliation: The Derek Crowther Clinical Trials Unit, Christie Hospital NHS Trust, Manchester.
authors.forename: M
authors.initials: M
authors.lastname: Ranson
authors.affiliation: Clinical and Experimental Pharmacology, Paterson Institute for Cancer Research, University of Manchester, Manchester.
authors.forename: S
authors.initials: S
authors.lastname: Danson
authors.affiliation: Medical Oncology, Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, UK.
authors.forename: H
authors.initials: H
authors.lastname: Calvert
authors.affiliation: Medical Oncology, Northern Centre for Cancer Treatment, Newcastle General Hospital, Newcastle upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, Cheshire.
authors.forename: C
authors.initials: C
authors.lastname: Morris
authors.affiliation: Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Carvajal
authors.affiliation: Department of Pathology, Brigham and Women's Hospital; Harvard Medical School.
authors.forename: L R
authors.initials: LR
authors.lastname: Chirieac
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: jhm@nki.nl.
authors.forename: J H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Harvard Medical School; Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: G I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D054316:Biomarkers, Pharmacological / Q000032:analysis; D015331:Cohort Studies; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C521840:AZD5438; D018844:Cyclin-Dependent Kinases