Pilot and Translational Study of Dasatinib (NSC#732517) Paclitaxel and Carboplatin in Women With Advanced Stage and Recurrent Endometrial Cancer
Inclusion Criteria:
- Patients must have measurable stage III, stage IV, or recurrent endometrial carcinoma
whose potential for cure by surgery or radiation therapy alone is poor
- Patients with the following histologic epithelial cell types are eligible:
endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear
cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise
specified (N.O.S.), mucinous adenocarcinoma, squamous cell, transitional cell
carcinoma, and mesonephric carcinoma
- Uterine carcinosarcoma and other sarcomas of the uterus will be excluded
- All patients must have measurable disease defined as at least one lesion that can be
accurately measured in at least one dimension (longest dimension to be recorded)
- Each lesion must be ≥ 20 mm when measured by conventional techniques, including
palpation, plain x-ray, computed tomography (CT), and magnetic resonance imaging
(MRI), or ≥ 10 mm when measured by spiral CT
- Measurable disease lesions must be amenable to pre- and post-treatment biopsy
- Patients must have at least one "target lesion" to be used to assess response on this
protocol as defined by RECIST
- Tumors within a previously irradiated field will be designated as "non-target"
lesions unless progression is documented or a biopsy is obtained to confirm
persistence at least 90 days following completion of radiation therapy
- No patients who have isolated recurrences (vaginal, pelvic, or para-aortic) that are
amenable to potentially curative treatment with radiation therapy or surgery
- No patients who have an active pleural or pericardial effusion of any grade
- No patients with history or evidence upon physical examination of CNS disease
(treated or untreated), including primary brain tumor, seizures not controlled with
standard medical therapy, or any known brain metastases
- GOG performance status of 0 to 2
- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated urinary tract infection [UTI])
- Absolute neutrophil count (ANC) greater than or equal to 1,500/mcL
- Platelets greater than or equal to 100,000/mcL
- Creatinine less than or equal to 1.5 times institutional upper limit normal (ULN)
- Bilirubin less than or equal to 1.5 times ULN
- SGOT and alkaline phosphatase less than or equal to 2.5 times ULN
- PT such that international normalized ratio (INR) is ≤ 1.5 (or an in-range INR,
usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin)
and a PTT ≤ 1.5 times the ULN
- Patients receiving low-molecular weight heparin for the prevention or treatment
of venous thromboembolic disease are eligible if considered clinically stable on
their regimen
- Neuropathy (sensory and motor) less than or equal to CTCAE v4 grade 1
- Oxygen saturation greater than or equal to 88% on room air
- Patients must have a baseline electrocardiogram(EKG) performed prior to enrolling on
study; the EKG must have QTc < 450 msec and must not show evidence of serious
ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation must be
less than 3 beats in a row)
- Cardiac ejection fraction must be within the institutional range of normal as
measured by left ventricular ejection fraction (LVEF) testing
- Patients of childbearing potential must have a negative serum pregnancy test prior to
study entry and be practicing an effective form of contraception during the study and
for at least 6 months after receiving the final treatment of dasatinib
- Patients must be able to swallow whole tablets
- No patients with serious, non-healing wound, ulcer, or bone fracture, including
history of abdominal fistula or gastrointestinal perforation
- Patients with an intra-abdominal abscess within 28 days prior to the first date
of dasatinib therapy are ineligible
- No patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels including:
- Bleeding diathesis, congenital or acquired within one year prior to initiating
protocol therapy (e.g., von Willebrand disease, acquired anti-factor VIII
antibodies)
- Significant gastrointestinal (GI) bleeding within three months prior to
initiating protocol therapy
- No patients with clinically significant cardiovascular disease including:
- Uncontrolled hypertension, defined as systolic > 140 mmHg or diastolic > 90 mm
Hg
- Myocardial infarction or unstable angina within 6 months of the first date of
dasatinib therapy
- New York Heart Association (NYHA) class II or greater congestive heart failure
or serious cardiac arrhythmia requiring medication; this would include women
with atrial fibrillation, who require rate-controlling medication
- CTCAE v.4 grade 2 or greater peripheral vascular disease
- History of cerebrovascular accident (CVA, stroke), transient ischemic attack
(TIA), or subarachnoid hemorrhage within six months of the first date of
dasatinib therapy
- Patients with hypokalemia or hypomagnesemia if it cannot be corrected to within
normal limits prior to dasatinib treatment
- Required use of a concomitant medication that can prolong the QT interval
- No patients who are pregnant or nursing
- HIV-positive patients on combination antiretroviral therapy are ineligible
- Recovered from effects of recent surgery, radiotherapy, or chemotherapy
- Any hormonal therapy directed at the malignant tumor must be discontinued at least
one week prior to registration
- Any other prior therapy directed at the malignant tumor, including immunologic
agents, must be discontinued at least three weeks prior to registration
- Patients should have had NO prior chemotherapy agents for advanced or recurrent
endometrial cancer
- Prior chemotherapy administration in conjunction with primary radiation therapy
as a radiosensitizer would not exclude a patient from participation in this
trial
- Patients who received adjuvant chemotherapy must be disease-free for at least 6
months
- Warfarin is permitted for prophylaxis or treatment of thrombosis
- Low-molecular weight heparin is permitted provided the patient's PT/INR is ≤ 1.5
- Patients may have received prior radiation therapy for treatment of endometrial
carcinoma
- Prior radiation therapy may have included pelvic radiation therapy,
extended-field pelvic/para-aortic radiation therapy, and/or intravaginal
brachytherapy, alone or with chemotherapy as a radiation sensitizer
- All radiation therapy must be completed at least 4 weeks prior to the first date
of study therapy
- Patients may have received prior hormonal therapy for treatment of endometrial
carcinoma
- All hormonal therapy must be discontinued at least one week prior to the first
date of study therapy
- No patients who have previously received dasatinib
- Patients may not be receiving any other investigational agents
- Patients cannot take St. John wort or drink grapefruit juice while on study treatment
(discontinue St. John wort at least five days before starting dasatinib)
- Patients receiving IV bisphosphonates agree that IV bisphosphonates will be withheld
for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia, and may be
restarted only if any hypocalcemia has been corrected
- Patients may not be receiving any prohibited potent CYP3A4 inhibitors; for these
drugs, a washout period of greater than or equal to 7 days is required prior to
starting dasatinib treatment