• Clinical benefit rate [ Designated as safety issue: No ]
  

• Toxicity as assessed by NCI CTCAE version 3.0 [ Designated as safety issue: Yes ]
  
• Tumor marker analysis [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Determine the clinical benefit rate of sorafenib in combination with anastrazole in women with estrogen receptor- and/or progesterone receptor-positive metastatic breast cancer.
• Determine the recommended phase II dose of sorafenib when administered with anastrozole in these patients.

Secondary

• Determine the toxic effects of this regimen in these patients.
• Determine the changes in Raf-MAPK and VEGF-signaling pathways in tumor tissue and stroma before and after treatment with this regimen in these patients.

OUTLINE: This is a multicenter, dose-escalation study of sorafenib.

• Phase I: Patients receive oral sorafenib twice daily and oral anastrozole once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. A minimum of 6 patients are treated at the MTD.

• Phase II: Patients receive sorafenib at the MTD and anastrozole as in phase I. After completion of study treatment, patients are followed every 4-8 weeks.

PROJECTED ACCRUAL: A total of 15-50 patients will be accrued for this study within 2-3 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed breast cancer

  • Metastatic disease

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion, including ≥ 1 of the following:

  • Lesion ≥ 10 mm on CT scan (5 mm sections)
  • Lesion ≥ 20 mm on CT scan or MRI (10 mm sections)
  • Bone disease that is ≥ 10 mm on MRI
  • Lytic bone lesions that are ≥ 10 mm on CT scan (with 5 mm sections) OR ≥ 20 mm on plain film or CT scan (with 10 mm sections)
  • Lesion ≥ 10 mm on physical exam
• Patients must have received ≥ 1 prior aromatase inhibitor in either the adjuvant or metastatic setting and must have had either disease recurrence or disease progression on a prior aromatase inhibitor therapy
• No brain metastases diagnosed within the past 6 months OR previously untreated brain metastases

• Hormone receptor status:

  • Estrogen receptor-positive and/or progesterone receptor-positive, defined as > 1% staining by immunohistochemistry or > 10 fmol/mg of protein by radio-ligand dextran-coated steroid binding assay

PATIENT CHARACTERISTICS:

Age

• 18 and over

Sex

• Female

Menopausal status

• Postmenopausal, as defined by 1 of the following:

  • Prior bilateral oophorectomy
  • No menses for ≥ 12 months in patients with an intact uterus
  • Follicle-stimulating hormone (FSH) in postmenopausal range in patients < 60 years of age who have had a prior hysterectomy or have been amenorrheic for ≥ 3 months
  • Age ≥ 60 years
• Pre- or perimenopausal patients receiving monthly injections of goserelin at a dose of 3.6 mg are eligible

Performance status

• ECOG 0-2

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• No bleeding diathesis

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• Systolic blood pressure (BP) < 150 mm Hg and diastolic BP < 100 mm Hg on at least one reading prior to study entry
• No uncontrolled hypertension

• None of the following within the past 6 months:

  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Myocardial infarction
  • Cardiac arrhythmia with hemodynamic compromise

Other

• Not pregnant or nursing
• Able to swallow oral medication
• No known HIV positivity
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other active invasive malignancy within the past 5 years except nonmelanoma skin cancer or treated carcinoma in situ of the cervix
• No other uncontrolled illness

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• More than 4 weeks since prior chemotherapy
• No more than 2 prior chemotherapy regimens for metastatic disease

Endocrine therapy

• See Disease Characteristics
• At least 8 weeks since prior anastrozole therapy
• Concurrent steroids allowed if dose is stable

Radiotherapy

• More than 4 weeks since prior radiotherapy

Surgery

• More than 4 weeks since prior major surgery

Other

• Recovered from prior therapy
• No prior sorafenib

• No concurrent therapeutic anticoagulation

  • Concurrent prophylactic anticoagulation (i.e., low-dose warfarin) for venous or arterial access devices allowed provided PT and PTT are ≤ 1.5 times ULN

• No concurrent agents that may interact with sorafenib, including any of the following:

  • Hypericum perforatum (St. John's wort)
  • Rifampin
  • P450 CYP3A4 enzyme-inducing anticonvulsants (e.g., phenytoin, carbamazepine, or phenobarbital)
• No other concurrent investigational agents