Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer

PRIMARY OBJECTIVES:

I. Determine the clinical benefit rate of sorafenib in combination with anastrazole in women with estrogen receptor- and/or progesterone receptor-positive metastatic breast cancer.

II. Determine the recommended phase II dose of sorafenib when administered with anastrozole in these patients.

SECONDARY OBJECTIVES:

I. Determine the toxic effects of this regimen in these patients. II. 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.

Inclusion criteria

• 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
• 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
• 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
• ECOG 0-2
• More than 3 months
• Absolute neutrophil count >= 1,500/mm3 Platelet count >= 100,000/mm3 No bleeding diathesis
• Bilirubin =< 1.5 times upper limit of normal (ULN AST and ALT =< 2.5 times ULN
• 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
• 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
• More than 4 weeks since prior chemotherapy
• No more than 2 prior chemotherapy regimens for metastatic disease
• At least 8 weeks since prior anastrozole therapy
• Concurrent steroids allowed if dose is stable
• More than 4 weeks since prior radiotherapy
• More than 4 weeks since prior major surgery
• 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

Exclusion criteria

• estrogen receptor status unknown
• history of myocardial infarction within 6 months
• performance status 3
• performance status 4
• premenopausal
• progesterone receptor status unknown
• HIV positive