For one patient, the cause of death was unknown. Pharmacokinetics The mean serum concentrations http://www.selleckchem.com/products/MG132.html of AS1402 after the first dose for the 1, 3, 9, and 16 mg kg treatment groups are shown in Figure 1. A multiexponential decline in serum concentrations of AS1402 was observed, and systemic exposure increased with each successive dose escalation. Steady state serum concentrations did not appear to have been reached in the majority of the patients during study treatment. The mean ter minal half life of AS1402 appeared shorter at the higher dose levels. Because the sampling schedule was shorter for the higher dose cohorts, the shorter half life values are likely to represent an earlier phase of the serum concentration time curve, potentially including a partial distribution phase along with a terminal elimination phase.

Although the initial doses were given 21 days apart, the PK data supported a reduction of the dosing interval to 7 days. The calculated noncompartmental pharmacokinetic parame ters are summarized in Table 3. Clearance of AS1402 from serum was consistent Inhibitors,Modulators,Libraries across all dose cohorts, with mean val ues ranging from 0. 34 to 0. 49 ml h kg. The Inhibitors,Modulators,Libraries volume of distribu tion was broadly comparable across the treatment cohorts, with mean values ranging from 50. 3 to 68. 2 ml kg. AS1402 exhibited linear pharmacokinetics with respect to dose across the 1 to 16 mg kg dose range, as demonstrated by the dose Sixteen patients had elevated CA15. 3 levels at screen ing and throughout the study. CEA levels remained relatively unaltered by treatment with AS1402, and no clear trends in correlation between CA27.

29 and exposure to AS1402 were found. Clinical activity Inhibitors,Modulators,Libraries Twenty two patients were evaluable for efficacy. Objective clinical response was assessed according to RECIST. No objective complete or partial responses were recorded during dose escalation, five patients had a best overall response of stable disease, stable disease durations ranged from 80 to 119 days. All these patients Inhibitors,Modulators,Libraries had progressive disease before antibody therapy. The median time to tumor progression by cohort is summarized in Table 4. Discussion These are the first data from a clinical study of a MUC1 target ing naked antibody. In total, 26 evaluable patients were recruited into the study, doses of 1 mg kg, 3 mg kg, 9 mg kg, and 16 mg kg were tested. The 16 mg kg dose was consid ered to be the maximum viable dose.

Repeated i. v. administra tion of AS1402 was well tolerated, with an MTD exceeding 16 mg kg. The majority of drug related AEs were NCI CTC grade 1 or 2. Infusion associated reactions were generally CTC grade Inhibitors,Modulators,Libraries 1. No incidents of patients with positive titers for anti human antibodies were found during the study. Systemic exposure of AS1402 appears to be linear with respect selleck 17-AAG to dose within the 1 to 16 mg kg dose range assessed.