Sorafenib and Letrozole, Anastrozole, or Exemestane in Treating Postmenopausal Women With Estrogen Receptor-Positive and/or Progesterone Receptor-Positive Metastatic Breast Cancer

OBJECTIVES:

Primary

- To compare the progression-free survival of postmenopausal women with estrogen
receptor- and/or progesterone receptor-positive metastatic breast cancer treated with
sorafenib tosylate vs placebo and letrozole, anastrozole, or exemestane.

Secondary

- To compare the overall survival and time to treatment failure of patients treated with
these regimens.

- To compare the objective tumor response rate and duration of response in patients
treated with these regimens.

- To assess the adverse event profile of sorafenib tosylate in combination with aromatase
inhibitors in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to prior aromatase
inhibitor therapy (yes vs no) and line of endocrine therapy for metastatic disease
(first-line vs second-line). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive oral sorafenib tosylate twice daily and oral letrozole,
anastrozole, or exemestane once daily on days 1-28.

- Arm II: Patients receive oral placebo twice daily and oral letrozole, anastrozole, or
exemestane once daily on days 1-28.

In both arms, treatment repeats every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study therapy, patients are followed periodically for up to 5 years.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed adenocarcinoma of the breast

- Metastatic disease

- Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by
conventional techniques (i.e., MRI or CT scan of chest, abdomen and pelvis) or ≥ 10
mm by spiral CT scan

- Non-measurable disease allowed, defined as all other lesions (or sites of
disease), including small lesions (longest diameter < 20 mm by conventional
techniques or < 10 mm by spiral CT scan)

- Must have objective evidence of progression within the past 3 months

- No human epidermal growth factor receptor 2 (HER2)/neu overexpression, defined as
gene amplification by fluorescence in situ hybridization or 3+ overexpression by
immunohistochemistry, or unknown HER2/neu status

- No active brain metastases

- Patients with neurological symptoms must undergo a contrast CT scan or MRI of
the brain to exclude active brain metastasis

- Patients with treated brain metastases allowed provided they have no evidence of
disease and have been off definitive therapy (including steroids) for the past 3
months

- Hormone receptor status:

- Estrogen receptor- and/or progesterone receptor-positive disease

PATIENT CHARACTERISTICS:

- Female

- The Eastern Cooperative Oncology Group (ECOG) performance status 0-1

- Postmenopausal

- Hemoglobin ≥ 9.0 g/dL

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement)

- INR ≤ 1.5

- PTT within normal limits

- Creatinine ≤ 1.5 times ULN

- Not nursing, pregnant, or able to become pregnant

- No significant traumatic injury within the past 4 weeks

- No history of bleeding diathesis or uncontrolled coagulopathy

- No serious, nonhealing wound, ulcer, or bone fracture

- No clinically significant cardiac disease, including any of the following:

- New York Heart Association class III-IV congestive heart failure

- Unstable angina (i.e., anginal symptoms at rest) or new-onset angina (i.e.,
began within the past 3 months)

- Myocardial infarction within the past 6 months

- No cardiac ventricular arrhythmias requiring antiarrhythmic therapy

- No uncontrolled hypertension (systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg),
despite optimal medical management

- No thrombolic, embolic, venous, or arterial events (e.g., cerebrovascular accident
including transient ischemic attacks) within the past 6 months

- No pulmonary hemorrhage or bleeding event > grade 2 within the past 4 weeks

- No other hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks

- No active clinically serious infection > grade 2

- No known HIV infection

- No chronic hepatitis B or C infection

- No previous or concurrent cancer that is distinct in primary site or histology from
breast cancer except carcinoma in situ of the cervix, treated basal cell skin cancer,
superficial bladder tumors (i.e., Ta and Tis), or any cancer curatively treated
within the past 5 years

- No known or suspected allergy to sorafenib tosylate or other agents used in this
study

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No major surgery or open biopsy within the past 4 weeks

- No more than 1 prior regimen of endocrine therapy for metastatic breast cancer,
provided that the patient has not received an aromatase inhibitor within the past 12
months

- No more than 1 prior regimen of chemotherapy for metastatic disease

- More than 2 weeks since prior radiotherapy, except if to a non-target lesion only or
single-dose radiotherapy for palliation

- Prior radiotherapy to a target lesion(s) is permitted only if there has been
clear progression of the lesion since radiotherapy was completed

- Concurrent anticoagulation treatment (e.g., warfarin or heparin) allowed

- No concurrent Hypericum perforatum (St. John's wort), rifampin, bevacizumab, or any
other drugs (licensed or investigational) that target vascular endothelial growth
factor (VEGF) or VEGF receptors

- No concurrent cytochrome P450 enzyme-inducing anti-epileptic drugs (e.g., phenytoin,
carbamazepine, or phenobarbital)