It was planned that 24 evaluable patients www.selleckchem.com/products/SB-203580.html would be recruited into the study, with six patients allocated to each treatment group. AS1402 was administered over a 60 minute period for the 1 mg kg and 3 mg kg cohorts. The infusion times were increased to 120 minutes and 180 minutes for the 9 mg kg and 16 mg kg cohorts, respectively. For patients in the 1 mg kg and 3 mg kg cohorts, the first two treatments were given 21 days apart. The half life after the first dose was determined for each patient, Inhibitors,Modulators,Libraries and the dosing intervals for dose 3 onward were set on an individual patient basis to be within 3 days of the half life, in multiples of 7 days. For patients in the 9 mg kg and 16 mg kg cohorts, the dosing interval in multiples of 7 days was determined for the whole cohort, based on PK anal ysis of the data from all previous cohorts.

Patients remained on treatment until they had disease progression Inhibitors,Modulators,Libraries or dose limiting toxicity. Cohort expansion to nine patients occurred if DLT was observed in any cohort. Adverse events were coded according to the National Cancer Institute Common Ter minology Criteria for Adverse Events, version 3. 0. DLT was defined as nonhematologic and hematologic grade 3 or greater, grade 2 or greater allergic reaction, or grade 2 or greater autoimmune reaction. The MTD was defined as the highest dose studied at which the incidence of DLTs was less than 33%. In each cohort, a single patient was treated initially and observed for at least 21 days. If no DLT occurred in the first patient, then two additional patients were treated at the same dose level and observed for 21 days.

If either none or one of the three patients experienced Inhibitors,Modulators,Libraries a DLT, then the cohort was expanded to six patients. If at any given dose level, the first patient experienced a DLT, then one more patient was enrolled at that dose level and observed for 21 days before accrual of additional patients. Analytic methods and pharmacokinetics Inhibitors,Modulators,Libraries Blood samples for pharmacokinetic analysis were drawn before infusion, at the end of infusion, at 4, 6, and 12 h after the start of infusion, and on days 2, 3, 4, 5, 8, 11, and 15. Anal ysis of AS1402 in human serum samples used a two step solid phase enzyme linked immunosorbant assay with bovine serum albumin conjugated to the 20 amino acid pep tide sequence recognized by AS1402 as the bound antigen. The lower limit of detection of this assay was 0.

Inhibitors,Modulators,Libraries 5g ml. Noncompartmental pharmacokinetic parameters were calcu lated from individual patient serum concentration time profiles by using WinNonlin v4. 0. The maximum serum concentration of AS1402 was obtained directly from observed data. The elimination half life was estimated from the terminal selleck products phase of the serum con centration time profile. The area under the serum concentra tion time profile extrapolated to infinity was calculated by using the log linear trapezoidal rule.