Bristol-Myers Squibb Dasatinib Src Inhibition in Endometrial Cancer
Condition: Endometrial Cancer
MeSH terms: Endometrial Neoplasms
Study type: Interventional
Phase: Early Phase 1

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.
    

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.
    

Intervention name(s): Dasatinib; Dasatinib
Intervention type(s): Drug; Drug
Intervention description(s): 100 mg dasatinib, the day before surgery and the day of surgery; 200 mg dasatinib the day before surgery and the day of surgery
Other intervention name(s): Spyricel
Intervention MeSH terms: Dasatinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science