title: A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors.
abstract: BACKGROUND
  AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD).
  
  
  METHODS
  AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained.
  
  
  RESULTS
  Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2).
  
  
  CONCLUSIONS
  AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.
authors.affiliation: Arizona Cancer Center, Tucson, USA. Electronic address: dmahadevan@azcc.arizona.edu.
authors.forename: D
authors.initials: D
authors.lastname: Mahadevan
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.affiliation: Astex Therapeutics Limited, Cambridge, UK.
authors.forename: M S
authors.initials: MS
authors.lastname: Squires
authors.affiliation: Arizona Cancer Center, Tucson, USA.
authors.forename: D
authors.initials: D
authors.lastname: Rensvold
authors.affiliation: Arizona Cancer Center, Tucson, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kurtin
authors.affiliation: Arizona Cancer Center, Tucson, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pretzinger
authors.affiliation: Arizona Cancer Center, Tucson, USA.
authors.forename: T
authors.initials: T
authors.lastname: Dragovich
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne.
authors.forename: J
authors.initials: J
authors.lastname: Adams
authors.affiliation: Astex Therapeutics Limited, Cambridge, UK.
authors.forename: V
authors.initials: V
authors.lastname: Lock
authors.affiliation: Astex Therapeutics Limited, Cambridge, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: Arizona Cancer Center, Tucson, USA.
authors.forename: D
authors.initials: D
authors.lastname: Von Hoff
authors.affiliation: Northern Centre for Cancer Care, Newcastle upon Tyne.
authors.forename: H
authors.initials: H
authors.lastname: Calvert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C531230:4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide; D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D018844:Cyclin-Dependent Kinases