A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer

ObjectiveTo determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients.MethodsDasatinib was dosed at 100 or 200mg PO BID at 32 and 8h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8h following the second dose.ResultsTen patients completed the study, 5at each dose level (DL). Average (median, standard deviation, range) 2h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200mg DL, respectively. Average ratio of 8h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of 60%.ConclusionsThis is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.