Can Pha Act

ownloade pose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of al Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy es were taken to investigate the effect of saracatinib on Src activity in tumors. erimental Design: Part A of the study followed a multiple-ascending dose design to establish the um tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and -based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after and multiple dosing. ults: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was ished as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related nemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The nder the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracaccumulated 4to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of g. The half-life was ∼40 hours. clusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reducn tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral tion i dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d.