A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer
To 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.
Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h 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 8 h following the second dose.
Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h 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%.
This 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 8 h 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.
KeywordsDasatinib Endometrial cancer Src inhibition Pharmacodynamics
This study was supported by the UVA Cancer Center through the Women’s Oncology Program, NCI Cancer Center Support Grant, P30 CA44579. Drug was supplied by Bristol-Myers Squibb Company. Pharmacokinetic studies were funded by Bristol-Myers Squibb Company as a Laboratory Service Agreement to University of Pittsburgh, Pittsburgh PA. This part of the project utilized the UPCI Cancer Pharmacokinetics and Pharmacodynamics Facility (CPPF) and was supported in part by award P30-CA47904.
Compliance with ethical standards
Conflict of interest
Linda R. Duska, Gina R. Petroni, Heather Lothamer, William Faust, Susan M. Christner, Anne M. Mills, and Sarah J. Parsons have no financial conflicts of interest. Dr. Duska receives research funding to her department (OB/GYN) for clinical trial research. Jan Beumer reports receiving research funding from BMS to his institute. Dr. Fracasso reports that she became an employee of Bristol-Myers Squibb Company (BMS) as of May 1, 2014, and as such, she has stock with the company. Prior to her employment with BMS, she was a Professor of Medicine and Obstetrics and Gynecology at the University of Virginia where she is now affiliated as a Visiting Professor of Medicine and Obstetrics and Gynecology. This clinical study was done while she was a Professor at the University of Virginia and no activities in this work have any relationship to her work at BMS.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Statement of translational relevance
Window-of-opportunity trials represent a relatively novel trial mechanism designed to ask translational questions about drug mechanism without intention of clinical benefit. In the case of endometrial cancer, the penultimate “biopsy” is the surgical specimen, allowing study of the tumor tissue as well as the adjacent normal endometrium, the endometrial stroma (the microenvironment) and the myometrium. Prior surgical window studies in endometrial cancer have demonstrated the feasibility and acceptability of this trial format. These studies allow investigators to answer complex scientific questions regarding drug mechanism of action in the tumor, as well as pharmacokinetic and pharmacodynamic questions. In the current study, we demonstrated for the first time that dasatinib was measurable and concentrated in tumor tissue 8 hours after dosing. Additionally, we demonstrated drug activity in tumor and normal tissue. These findings will allow further study of dasatinib in solid tumor, as well as inform future trials.
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