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Bristol-Myers Squibb Dasatinib Src Inhibition in Endometrial Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01482728
Recruitment Status : Completed
First Posted : November 30, 2011
Last Update Posted : May 13, 2016
Information provided by (Responsible Party):
Linda R Duska, University of Virginia

Brief Summary:
The purpose of this study is to see if the investigators can measure inhibition of a protein, Src (named for Sarcoma), in tissue and blood in patients with a diagnosis of endometrial cancer. Dasatinib is a drug that blocks the activity of an important protein in cancer cells called Src. The investigators can measure the blocking of Src in the bloodstream. However, the investigators do not know if measures in the bloodstream reflect blockage of Src in cancer tissue. The investigators are doing this study to try and see if the investigators can match what the investigators see in cancer tissue to what the investigators see in the bloodstream. the investigators hope that in the future, the investigators can use blood to measure protein inhibition by dasatinib instead of asking patients to undergo repeat biopsies.

Condition or disease Intervention/treatment Phase
Endometrial Cancer Drug: Dasatinib Early Phase 1

Detailed Description:

Endometrial cancer is the most common of the gynecologic malignancies; affecting 42,160 women in the US in 2009.1 In addition it is often a hormonally driven tumor, expressing in many cases both estrogen receptor (ER) and progesterone receptor (PR). While most endometrial cancers are treated successfully with surgery, there is still a need for new agents in the treatment of advanced or recurrent disease. One potential agent is dasatinib, since its target, Src Family Kinases (SFKs), has been implicated in the genesis of the disease. Although not extensive, increasing evidence indicates a link between SFKs and endometrial cancer. In addition one study in breast cancer presented at the American Society of Clinical Oncology (ASCO) in 2009 demonstrated that patients with ER positive breast tumors have a higher response rate to dasatinib, suggesting perhaps a synergy between hormonal therapy and dasatinib. Because of its high efficacy for inhibiting SFKs and growth of the tumor vasculature, as well as a possible effects on the ER, dasatinib is an exciting new possibility for treatment of endometrial cancers.

Questions regarding the ability of dasatinib to inhibit its primary target in tumor tissue (regardless of cancer type) and the relationship between inhibition of SFKs in tissue vs. SFKs in blood cells are also unresolved, as few correlative studies have accompanied the plethora of clinical trials assessing the efficacy of the drug in patients. Furthermore, the effect of dasatinib on the stability of the estrogen receptor in those tissues expressing the receptor (uterine and breast, particularly) is also unknown. Src kinase has been shown to physically associate with the ER and to mediate some of its rapid signaling effects in the presence of estrogen.6 If this physical association also stabilizes the receptor (which is normally degraded upon estrogen stimulation), dasatinib could affect estrogen receptor signaling in an indirect manner. In the Mayer study, all 9 controlled tumors were ER/PR+, suggesting a possible relationship between ER expression and dasatinib response.33 These are questions unexplored in patients. The goals of this study, therefore, are to address these questions and to provide insights for all appropriate cancer types into the action of dasatinib on SFK alone and on the ER in patient samples exposed to the drug. Furthermore, if inhibition of SFKs in blood cells correlates with that in tissue, future studies can utilize blood samples instead of or in addition to tissue to monitor dasatinib activity, obviating the need for extra biopsies or surgical samples for such analyses. The investigators therefore propose a Phase 0 study of dasatinib in patients with endometrial cancer who are undergoing planned hysterectomy. The purpose of this trial will not be therapeutic; the endpoints will be translational as per the Phase 0 design. Due to the potential relationship with ER expression, only endometrioid tumors will be studied, as they most frequently express this receptor (as opposed to clear cell or serous histologies, which most often do not express ER and are not estrogen related).

Given the extensive safety data now available for dasatinib the investigators plan to allow dosing up to the accepted Maximum Tolerated Dose(MTD) which is being used across the dasatinib program. Based on the preliminary data from the Blackwell trial in breast cancer34, adequate inhibition of src family kinases is questionable at doses even higher than 100 mg (although this study was done at steady-state after 4 weeks of treatment); thus it is unlikely that doses less than 100 mg will have any value. The investigators therefore plan to begin at 100 mg to demonstrate safety (and perhaps measurable src inhibition) and then escalate to 200 mg (which is more likely to result in measurable levels of interest) assuming safety. If feasible the investigators would anticipate the ability to demonstrate a dose response of our assay in both tissue and blood, which also requires testing two doses.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: A Phase 0 Pharmacodynamic Study of Dasatinib in Women With Newly Diagnosed Endometrial Cancer
Study Start Date : January 2012
Actual Primary Completion Date : May 2015
Actual Study Completion Date : December 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Dasatinib

Intervention Details:
  • Drug: Dasatinib
    100 mg dasatinib, the day before surgery and the day of surgery
    Other Name: Spyricel
  • Drug: Dasatinib
    200 mg dasatinib the day before surgery and the day of surgery

Primary Outcome Measures :
  1. Changes in levels of SFK protein activity in a) endometrial tumor tissue and b) blood induced within two different doses of dasatinib treatment. [ Time Frame: 1 year ]
    In this study the change in levels of SFK protein activity in both tissue and blood will represent the measured pharmacodynamic response.

Secondary Outcome Measures :
  1. Changes in levels of SFK protein activity in blood correlates with changes in levels of SFK protein activity in endometrial tumor tissue induced by two different doses of dasatinib treatment. [ Time Frame: 1 year ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Women age 18 and older
  • Newly diagnosed primary histologically documented endometrioid adenocarcinoma of the endometrium that is being treated surgically with hysterectomy and BSO
  • Performance status 0-1
  • Agree to pre operative biopsy
  • Adequate organ function
  • Ability to take oral medication
  • Negative serum pregnancy test

Exclusion Criteria:

  • Prior therapy with dasatinib or any other anti-src drug
  • Women with positive pregnancy test
  • Any concurrent chemotherapy not indicated in the study protocol or any other investigational agent(s)
  • Prisoners or subjects who are involuntarily incarcerated
  • Histologic subtypes of endometrial cancer other than endometrioid
  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
  • History of significant bleeding disorder unrelated to cancer
  • No previous history of malignancy which required radiotherapy or systemic treatment within the past 5 years
  • Pleural or pericardial effusion of any grade
  • Cardiac symptoms including but not limited to angina, prolonged QTc interval, significant ventricular arrhythmia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01482728

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United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
University of Virginia
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Principal Investigator: Linda R Duska, MD University of Virginia
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Responsible Party: Linda R Duska, Attending, University of Virginia Identifier: NCT01482728    
Other Study ID Numbers: 15809
First Posted: November 30, 2011    Key Record Dates
Last Update Posted: May 13, 2016
Last Verified: May 2016
Additional relevant MeSH terms:
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Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action