Bristol-Myers Squibb Dasatinib Src Inhibition in Endometrial Cancer
| Status: | Completed |
|---|---|
| Conditions: | Cervical Cancer, Cancer, Endometrial Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 7/11/2015 |
| Start Date: | January 2012 |
| End Date: | December 2015 |
| Contact: | Heather L Lothamer, MSN |
| Email: | hll5y@virginia.edu |
| Phone: | 434-924-9924 |
A Phase 0 Pharmacodynamic Study of Dasatinib in Women With Newly Diagnosed Endometrial Cancer
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.
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.
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.
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.
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
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