fold for the one evaluable patient sellekchem in the 100 mg dose group. Determination of Cmin throughout the study period showed that steady state exposure was achieved from day 15 onwards. The fraction of vandetanib unbound on day 2 was approximately 0. 065 for both doses and, Inhibitors,Modulators,Libraries based on the 300 mg cohort, this was unaltered at the higher levels observed at steady state. A population pharmacokinetic pharmacodynamic analysis showed lit tle evidence of any correlation between the DCE MRI var iables and either the plasma concentration, daily exposure or total exposure to free or total vandetanib. Soluble markers of angiogenesis tumor activity Higher plasma levels of VEGF were detected at both van detanib doses following multiple dosing, although large variability was observed. There was no suggestion of a dose effect.
No consistent time or dose related changes from baseline were observed for the other markers evaluated. Efficacy There were no RECIST defined objective responses as assessed by contrast enhanced CT. Among the 21 evalua ble patients, five Inhibitors,Modulators,Libraries patients in the 300 mg group had a best response of stable disease 8 weeks and the remaining 16 patients experienced progressive disease. One patient in the 300 mg group had no post baseline measurements and was therefore not evaluable. A waterfall plot of the best percentage change from baseline in the size of target lesions is presented in Fig. 6. Median PFS was 62 days in the 300 mg group and 34 days in the 100 mg group. Safety and tolerability Both vandetanib doses were generally well tolerated.
The most frequently reported adverse events, irrespective of causality, were fatigue, diarrhea, dry mouth and nausea. More adverse Inhibitors,Modulators,Libraries events were reported in the 300 mg group compared with the 100 mg group, which is con sistent with the greater number of days on treatment for the 300 mg group. The majority of adverse events were CTCAE grade 1 or 2, including all cases of diarrhea. The Inhibitors,Modulators,Libraries increases in blood pressure were considered by the inves tigator to be related to vandetanib. Discussion This randomized, open label study used DCE MRI to investigate the effect of once daily oral dosing with vande tanib on tumor perfusion and vascu lar permeability in 22 patients with advanced colorectal cancer and liver metastases. The primary DCE MRI varia bles of iAUC60 and Ktrans did not show any statistically sig nificant changes from baseline for either treatment group.
Therefore, the study did not support the hypothesis that most common adverse events considered by the investiga tor to be related to vandetanib were dry mouth, dyspho nia, diarrhea, fatigue, acne, dry skin and hypertension. Four of these adverse events Inhibitors,Modulators,Libraries were CTCAE grade 3 allergic dermatitis, fatigue, photosensitivity reaction and hypertension. No grade 4 events were Tubacin buy reported. Adverse events that were considered by the investigator to be related to study treatment were mostly manageable by dose reductions or interruptions.