A Phase II Evaluation of Brivanib (BMS582664), an Oral, Multitargeted Growth Factor Tyrosine Kinase Inhibitor in the Treatment of Recurrent or Persistent Endometrial Carcinoma

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed endometrial carcinoma, including any of the following
epithelial cell types:

- Endometrioid adenocarcinoma

- Serous adenocarcinoma

- Undifferentiated carcinoma

- Clear cell adenocarcinoma

- Mixed epithelial carcinoma

- Adenocarcinoma not otherwise specified

- Mucinous adenocarcinoma

- Squamous cell carcinoma

- Transitional cell carcinoma

- Recurrent or persistent disease that is refractory to curative therapy or established
treatments

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
conventional techniques (e.g., palpation, plain x-ray, CT scan, or MRI) or ≥ 10 mm by
spiral CT scan

- Must have ≥ 1 target lesion to assess response as defined by RECIST criteria

- Tumors within a previously irradiated field will be designated as "non-target"
lesions unless there is documented disease progression or a biopsy is obtained
to confirm persistence ≥ 90 days after completion of radiotherapy

- Must not be eligible for a higher priority GOG protocol, if one exists

- Must have received 1 prior chemotherapeutic regimen for management of endometrial
carcinoma

- Chemotherapy administered in conjunction with primary radiation as a
radio-sensitizer will be counted as a systemic chemotherapy regimen

- One additional cytotoxic regimen for management of recurrent or persistent
disease allowed

- No known brain metastases

PATIENT CHARACTERISTICS:

- GOG performance status (PS) 0-2 (for patients who have received 1 prior regimen) OR
GOG PS 0-1 (for patients who have received 2 prior regimens)

- ANC ≥ 1,500/mcL

- Platelet count ≥ 100,000/mcL

- Hemoglobin > 9 g/dL

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- Urine protein: proteinuria must be ≤ 3+ by dipstick

- Patients with urine protein > 3+ who undergo a 24 hour urine collection and
demonstrate ≤ 3.5 g in 24 h allowed

- Bilirubin ≤ 1.5 times ULN

- AST/ALT ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Albumin ≥ 2.5 g/dL

- PT/INR ≤ 1.5 times ULN

- Baseline serum potassium ≥ 3.5 mmol/L (potassium supplementation allowed)

- QTc ≤ 450 msec by ECG

- LVEF > 50%

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 3 months after
completion of study treatment

- No pre-existing thyroid abnormality with thyroid function that cannot be maintained
in the normal range with medication

- No neuropathy (sensory and motor) > grade 1 (per CTCAE v3.0 criteria)

- No hyponatremia (i.e., sodium < 130 mEq/L)

- No active/known HIV, hepatitis B, or hepatitis C

- No gastrointestinal bleeding or any other hemorrhage/bleeding event ≥ grade 3 (per
CTCAE v3.0 criteria) within the past 30 days

- No poor wound healing, non-healing ulcers, or bone fractures within the past 3 months

- No uncontrolled or significant cardiovascular disease, including any of the
following:

- Myocardial infarction within the past 12 months

- Uncontrolled angina within the past 12 months

- NYHA class III-IV congestive heart failure

- Uncontrolled hypertension, defined as systolic blood pressure (BP) > 150 mm Hg
or diastolic BP > 100 mm Hg, despite optimized antihypertensive therapy

- History of stroke, transient ischemic attack, or other CNS ischemic event

- Cardiac arrhythmias requiring antiarrhythmic therapy, except beta blockers or
digoxin

- Valvular heart disease ≥ grade 2 (per CTCAE v3.0 criteria)

- No active infection requiring antibiotics, except uncomplicated urinary tract
infection

- No inability to swallow tablets or untreated malabsorption syndrome

- No serious uncontrolled medical disorder or active infection that would impair the
ability of the patient to receive study therapy or whose control may be jeopardized
by the complications of this therapy

- No other invasive malignancies within the past 3 years, except nonmelanoma skin
cancer or other specific malignancies

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior surgery, radiotherapy, or chemotherapy

- At least 1 week since prior hormonal therapy directed at the malignant tumor

- At least 3 weeks since prior immunologic agents or other therapy directed at the
malignant tumor

- No prior non-cytotoxic therapy for management of endometrial carcinoma, except
hormonal therapy

- No prior brivanib alaninate or other anti-vascular, anti-PDGFR, or anti-FGFR therapy

- No prior radiotherapy to any portion of the abdominal cavity or pelvis, except for
the treatment of endometrial carcinoma within the past 5 years

- Prior radiotherapy for localized cancer of the breast, head and neck, or skin
allowed provided it was completed > 3 years ago and the patient remains free of
recurrent or metastatic disease

- No prior chemotherapy for any abdominal or pelvic tumor, except for the treatment of
endometrial carcinoma within the past 5 years

- Prior adjuvant chemotherapy for localized breast cancer allowed provided it was
completed > 3 years ago and the patient remains free of recurrent or metastatic
disease

- No prior cancer treatment that would contraindicate study therapy

- No concurrent chronic antiplatelet therapy (e.g., aspirin > 300 mg/day or clopidogrel
≥ 75 mg/day)

- No concurrent warfarin for prophylaxis or treatment of thrombosis allowed

- Low-molecular weight heparin allowed

- Concurrent low molecular weight heparin allowed provided PT/INR ≤ 1.5