Through the program pathological evaluation of FFPE specimens of principal

one patient developed a lung infec ARQ 197 価格 tion and the last patient had increased pleural effusions and shortness of breath and both were considered to be unrelated to AST1306. The other five patients experienced SAEs after the first cycle. One of these patients was diag nosed with grade 3 AST1306 related diarrhea. The rest of the SAEs included 1 case of hyperbilirubinemia and 3 deaths within 14 days after the final dose of AST1306 due to disease progression. Pharmacokinetics Additional patients were enrolled up to at least eight pa tients per dose cohort in three dose levels in the PK extension study and food effect study to evaluate PK profiles. Col lected plasma samples were analyzed by dose cohort. The PK analysis population and the geometric mean PK parameters of AST1306 for single day dosing and multiple dosing are summarized in Additional file 2Table S1.<br><br> For single dose evaluation, Cmax was achieved in 1. 83 to 3. 67 hours after oral administration. The plasma levels supplier AZD0530 of AST1306 increased with increasing doses and varied con siderably between patients. Cmax and AUC0 24 h showed a dose dependent increase. The terminal half life of AST1306 ranged between 3. 48 to 5. 56 hours on day 1. For multiple dose evaluation, Cmax and AUC0 24 h showed a dose dependent increase at dose levels of 400 mg QD to 1000 mg TID. Whereas, Cmax and AUC0 24 h increased by a smaller amount at the 1200 mg TID dose level, and showed moderate to high inter individual vari ability. The gMean terminal half life ranged from 3. 33 to 7. 57 h on days 23 24.<br><br> Multiple dose exposure Alvocidib 溶解度 was no more than 3 fold greater than single dose exposure across the entire dose range, as assessed by the mean accumula tion ratio. These results sug gested that there was no major accumulation of AST1306 after repeated daily administration to patients. With the same total daily dose, for example 1500 mg BID vs. 1000 mg TID, the Cavg, AUC0 24h, AUC0 t and AUC0 ∞ of TID administration schedule were higher than those of QD and BID schedules. In addition, the fluctuation index of the TID schedule was lower than that of the BID or QD schedules. In the food effect study, with a fed fasted two way cross over design, a total of 12 patients were enrolled to assess the initial effect of food on the oral bioavailability of AST1306. High fat food intake before a single oral AST1306 dose of 1000 mg significantly altered and increased drug exposure.<br><br> Under fed conditions, mean Tmax was prolonged, Cmax was increased, and AUC0 ∞ was raised. Antitumor activity Fifty five of the 71 patients were evaluable for efficacy. The waterfall plot of best responses in 55 evaluable patients was shown in Figure 1. Of the evaluable patients, 7 pa tients had confirmed PRs. Five of the 17 evaluable breast cancer patients achieved a PR and all responders were HER2 positive. 1 patient had been previously treated with trastuzumab and lapatinib. Among the 12 evaluable NSCLC patients, 1 patient had PR. This patient had failed 3 previous lines of chemotherapy, but was of unknown EGFR mutational status. in addition this patient had not previously received therapy with EGFR inhibitors. One PR was observed in a gastric adenocarcinoma patient who failed 2 lines of chemotherapy and 1 VEGFR2 TKI.