3 months, Baseline plasma levels of these proteins did not

[jy9202]

The median age was 60 years, and 55 patients had clear cell histology, The objective response rate, the primary endpoint of the study, was 40% Patients achieved and maintained steady state trough plasma concentrations of sunitinib and its active metabolite throughout the dosing periods for multiple cycles. The median total drug Ctrough at purchase ASA404 steady state in all patients was 84. 3 ng mL, which is greater than the 50 n shown to inhibit target RTKs in preclinical models, Drug concentrations increased during the on drug periods and decreased during the off periods, with no accumula tion observed, across dosing cycles. Plasma Levels of VEGF, sVEGFR 2, and PlGF: Baseline Levels and Changes During Sunitinib Treatment Significant changes in the mean plasma lev els of VEGF, sVEGFR 2 and PlGF were noted within each dose cycle, as reported in brief elsewhere and as sum marized in Table 1 for the first treatment cycle.

Baseline values for VEGF and sVEGFR 2 were in the assay detection range for all cases; however, in the case of PlGF, only 17 baseline readings were measured as above the lower limit of quantitation for the buy AZD1480 PlGF ELISA assay cases were in the detectable range Due to the prevalence of readings below the level of quantitation for PlGF, for all subse quent data analysis such readings were assigned a value equal to the lowest detectable concentration standard, At the end of the first cycle, VEGF and PlGF levels increased greater than 3 fold relative to baseline in 24 of 54 cases and 22 of 55 cases, respectively.

Levels of sVEGFR 2 were decreased by at least 30% in 50 of 55 cases during the same time frame, and by at least 20% in all cases. For each supplier AZD2281 of these markers, levels tended to return to near baseline after the 2 week off treatment period between cycles. This suggests a drug dependent effect, as illustrated by the patterns of mean and median ratios to baseline as shown for VEGF and sVEGFR 2, Similarly, the results for PlGF clearly indicate a pharmacodynamic effect of sunitinib treatment, and suggest that PlGF is a biomarker of interest for this agent; however, since most baseline samples were below the lower limit of quantification, pre cise calculation of ratios to baseline was not feasible in most cases. Changes in Plasma Levels of sVEGFR 3 In addition to the three angiogenesis related proteins described above, we also assessed the plasma levels of sVEGFR 3, an apparent circulating variant of VEGFR 3.

Assessment of sVEGFR 3 via ELISA was initially selected based on a result of proteomic screening of plasma sam ples, using an antibody microarray based multiplex assay in which sVEGFR 3 was identified as a potentia pharmacodynamic marker of sunitinib activity, Con firmatory ELISA assessments revealed that significant changes in the mean plasma levels of sVEGFR 3 were noted within each dose cycle, Baseline values for sVEGFR 3 were in the assay detection range for all cases; however, at day 28 of the first cycle, sVEGFR 3 levels were reduced to less that the lower limit of quantitation in 12 of 56 cases, Readings below the quantitation limit were frequently observed at day 28 of subsequent cycles as well.