Phase I/II and Phase II Clinical Trials of Axitinib for Selected Cancers ...

NCCN Axitinib RFP: 20DEC10Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelialgrowth factor (VEGF) receptors 1, 2 and 3. In kinase assays, axitinib was shown to be apotent and ATP-competitive inhibitor of receptor tyrosine kinases (RTK) of VEGFreceptors 1, 2 and 3 , but not a potent inhibitor of the closely related kinases of FGFR-1,Flt-3, Tie-2 or CSFR-1 and was inactive against most kinases of distant families in thekinome (1, 2).Table 1. Receptor tyrosine kinase affinities and selectivity of axitinib (2)TargetVEGFR-2VEGFR-1VEGFR-3PDGFR-βKITPDGFR-αCSF-1RFGFR-1Flt3Cell potency(IC 50 , nM)0.20.10.1-0.31.61.75.073231>1000Axitinib has no measurable kinase activity against RET, cMet, EGFR, and many otherRTKs at ≥ 1 uM. Key metabolites of axitinib do not have significant activity againstVEGF and PDGF RTKs.2.2 Clinical Pharmacology and Safety Experience in HumansHuman studies have shown that axitinib is absorbed within 4 hours following oral dosingwith a mean absolute bioavailability of 58%. Axitinib is highly protein bound (>99%), withno change in protein binding with hepatic impairment. Both the major human circulatingplasma metabolites (the sulfoxide and glucuronide) are inactive. The elimination ofaxitinib is predominantly hepatobiliary and the drug has a short plasma half-life (2.5-6.1hours) (1, 3).Common adverse events observed in patients treated with axitinib include fatigue,hypertension, proteinuria, hoarseness and diarrhea.CONFIDENTIALPage 2 of 16