Reference Detail

Ref Type

Journal Article

PMID

(21852114)

Authors

Schöffski P, Jones SF, Dumez H, Infante JR, Van Mieghem E, Fowst C, Gerletti P, Xu H, Jakubczak JL, English PA, Pierce KJ, Burris HA

Title

Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours.

Journal	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	47	15	2011 Oct	2256-64	Eur J Cancer

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PF-03814735	PF-03814735	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PF-03814735		PF03814735	Aurka Inhibitors 26 Aurkb Inhibitors 21	PF-03814735 is an inhibitor of Aurora kinases A and B, which prevents cell division and proliferation (PMID: 20354118, PMID: 21852114, PMID: 31549911).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References