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Dose interruptions buy ARQ 197 were permitted for no more than 14 days for patients experiencing DLTs in the first cycle or intolerable toxicities in the subsequent cycles, with treat ment resumed at the next lower dose level upon adequate recovery. More than two dose level reductions were not allowed. Patients in the PK extension study and food effect study were also included to evaluate safety further. Evaluation of antitumor activity Antitumor activity was assessed by tumor measurements according to RECIST 1. 0 and performed at 8 week inter vals. The primary efficacy endpoint was progression free survival, which was defined as the time from the first administration until disease progression or death. Overall survival and response rate were also assessed.<br><br> Clinical benefit rate was measured and defined as the pro portion AZD0530 379231-04-6 of patients with complete response, partial re sponse and stable disease 6 months. Pharmacokinetic analysis All PK sampling was performed in the first cycle. Plasma concentrations of AST1306 single day dosing were de termined at the following distinct time pointspre dose, 0. 5 h, 1 h, 1. 5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, and 48 h after the single dose administration in the 400 mg QD and 800 mg QD dose cohorts. For the next five dose cohorts with twice daily administration, the time points of plasma sample collec tion were as followspre dose, 0. 5 h, 1 h, 1. 5 h, 2 h, 3 h, 4 h, 6 h, 8 h, and 12 h after the first dose administration, and pre dose, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 24 h after the second dose administration.<br><br> Three dose cohorts with three times daily administra tion were further investigated with distinct time points for plasma collecting. PK parameters of AST1306 were also determined on days 10, 23, and 24 of conti nuous supplier Alvocidib treatment. The PK sampling schedule for the PK extension phase was totally the same as that for the dose escalation study. PK analysis was conducted using Phoenix WinNonlin software. Standard non compartmental methods were used to calcu late the area under the plasma concentration time curve over the time interval from 0 to 24 h, max imum measured concentration of the analyte in plasma, and terminal half life of the analyte in plasma. Time from dosing to the maximum concentration of the analyte in plasma was reported as a median value.<br><br> The concentration at the trough level was determined using the concentration at 24 h on steady state days. The power model method was used to assess the dose proportionality. The differences between fed and fasting conditions were assessed by ANOVA, and 90% confi dence intervals for ratios were given. Results Patient characteristics From May 2010 to April 2012, a total of 71 patients with advanced solid tumors were recruited into this study. Twelve patients were enrolled in the food effect study at the MTD dose level. The baseline demographic character istics of these patients are provided in Table 1. Patients had a variety of cancer types, with the most common being breast cancer and NSCLC. Patients were heavily pre treated, and 84. 5% of them had received 3 lines of ther apy regimens.