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

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Abstract

Objective

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.

Methods

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.

Results

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%.

Conclusions

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.

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Funding

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.

Author information

Author notes

  1. Co-senior authors: Paula M. Fracasso and Sarah J. Parsons.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Gynecology Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Linda R. Duska & Heather Lothamer

  2. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, USA

    William Faust Jr. & Sarah J. Parsons

  3. Department of Public Health Services, University of Virginia School of Medicine, Charlottesville, VA, USA

    Gina R. Petroni

  4. Cancer Therapeutics Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA

    Jan H. Beumer & Susan M. Christner

  5. Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jan H. Beumer

  6. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Jan H. Beumer

  7. Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA

    Anne M. Mills

  8. Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA

    Paula M. Fracasso

  9. University of Virginia Cancer Center, Charlottesville, VA, USA

    Linda R. Duska, Gina R. Petroni, Heather Lothamer, Paula M. Fracasso & Sarah J. Parsons

Authors
  1. Linda R. Duska
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  2. Gina R. Petroni
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  3. Heather Lothamer
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  4. William Faust Jr.
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  5. Jan H. Beumer
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  6. Susan M. Christner
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  7. Anne M. Mills
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  8. Paula M. Fracasso
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  9. Sarah J. Parsons
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Corresponding author

Correspondence to Linda R. Duska.

Ethics declarations

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.

Ethical approval

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

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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Duska, L.R., Petroni, G.R., Lothamer, H. et al. A window-of-opportunity clinical trial of dasatinib in women with newly diagnosed endometrial cancer. Cancer Chemother Pharmacol 83, 473–482 (2019). https://doi.org/10.1007/s00280-018-3749-7

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  • DOI: https://doi.org/10.1007/s00280-018-3749-7

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