title: Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours.
abstract: This phase I study (ClinicalTrials.gov ID: NCT00424632) evaluated the safe dose, pharmacokinetics, and pharmacodynamics of the aurora kinase A and B inhibitor, PF-03814735. Patients with advanced solid tumours received oral, once-daily (QD) PF-03814735 on Schedule A: days 1-5 (5-100mg); or Schedule B: days 1-10 (40-60mg) of 21-day cycles. Fifty-seven patients were treated: 32 and 25 on Schedules A and B, respectively. Dose-limiting toxicities were: febrile neutropenia (Schedule A); and increased levels of aspartate amino transferase, left ventricular dysfunction, and prolonged low-grade neutropenia (Schedule B). Maximum tolerated doses were 80mg QD (Schedule A) and 50mg QD (Schedule B). Common treatment-related adverse events were mainly mild to moderate and included diarrhoea, fatigue, nausea, and vomiting. Nineteen patients achieved stable disease, which was prolonged in four cases. PF-03814735 was rapidly absorbed and demonstrated linear pharmacokinetics up to 100mg QD; mean terminal half-life ranged from 14.4 to 23.6h. Aurora B activity, assessed by histone H3 phosphorylation in mitotic cells, decreased in tumour tissue from 10/12 patients evaluated (range: -70% to -3%). (18)F-fluorodeoxyglucose positron emission tomography demonstrated metabolic responses in only 1/21 patients. PF-03814735 was generally well tolerated with manageable toxicities, and a recommended phase II dose could be established for both schedules. Aurora B activity was inhibited in tumour tissue, but clinical or metabolic antitumour activity was limited.
authors.affiliation: Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Catholic University Leuven, Leuven, Belgium. patrick.schoffski@uz.kuleuven.be
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Elke
authors.initials: E
authors.lastname: Van Mieghem
authors.forename: Camilla
authors.initials: C
authors.lastname: Fowst
authors.forename: Paola
authors.initials: P
authors.lastname: Gerletti
authors.forename: Huiping
authors.initials: H
authors.lastname: Xu
authors.forename: John L
authors.initials: JL
authors.lastname: Jakubczak
authors.forename: Patricia A
authors.initials: PA
authors.lastname: English
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Pierce
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000368:Aged; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001530:Belgium; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D005260:Female; D019788:Fluorodeoxyglucose F18; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016014:Linear Models; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals; D013714:Tennessee; D016896:Treatment Outcome
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D006657:Histones; C550549:N-(2-(6-(4-cyclobutylamino-5-trifluoromethylpyrimidine-2-ylamino)-1,2,3,4-tetrahydro-1,4-epiazano-naphthalen-9-yl)-2-oxo-ethyl)acetamide; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C576917:AURKA protein, human; C576921:AURKB protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases