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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 | European journal of cancer (Oxford, England : 1990) |
Vol | 47 |
Issue | 15 |
Date | 2011 Oct |
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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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PF-03814735 | PF03814735 | Aurka Inhibitors 24 Aurkb Inhibitors 20 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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Unknown unknown | Advanced Solid Tumor | not applicable | PF-03814735 | Phase I | Actionable | In a Phase I trial, PF-03814735 demonstrated safety and preliminary efficacy in advanced solid tumor patients (PMID: 21852114). | 21852114 |