Phase I, Open-Label, Multicentre, Dose-Escalation, Pharmacokinetic and Pharmacodynamic Trial of the Oral Aurora Kinase Inhibitor PF-03814735 in Advanced Solid Tumours

Patrick Schöffski, Suzanne F Jones, Herlinde Dumez, Jeffrey R Infante, Elke Van Mieghem, Camilla Fowst, Paola Gerletti, Huiping Xu, John L Jakubczak, Patricia A English, Kristen J Pierce, Howard A Burris

Eur J Cancer. 2011 Oct;47(15):2256-64.

PMID: 21852114

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP942487163	PF-03814735		942487-16-3	Price