Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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Sorafenib may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. Estradiol can cause the growth of breast cancer. Hormone therapy using anastrozole may fight breast cancer by blocking the use of estradiol by the tumor cells. Sometimes when hormone therapy is given, it does not stop the growth of tumor cells. The tumor is said to be resistant to hormone therapy. Giving sorafenib together with anastrozole may reduce drug resistance and allow the tumor cells to be killed. This phase I/II trial is studying the side effects and best dose of sorafenib when given in combination with anastrozole and to see how well they work in treating postmenopausal women with metastatic breast cancer.

Detailed Description
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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.

Official Title
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A Phase I/II Trial of BAY 43-9006 (Sorafenib) in Combination With Anastrozole in Patients With Metastatic Breast Cancer

Conditions
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Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: anastrozole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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 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. | Drug: sorafenib tosylate<br>* Given orally<br>* Other names: SFN;Drug: anastrozole<br>* Given orally<br>* Other names: ICI-D1033;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response + Partial Response + Stable Disease > 24 Weeks | Clinical Outcome measured using Response Evaluation Criteria In Solid Tumors (RECIST,)V1.0, and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), a tumor that is neither growing nor shrinking. A patient has clinical benefit from treatment if CR + PR + SD > 24 weeks. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Number of patients treated with the sorafenib / anastrozole combination who experienced Grade 1-4 adverse events according to NCI common terminology criteria for adverse events (CTCAE) version 3.0 | 1 year | 
| Tumor Marker Analysis | Number of participants with significant change in the following circulating tumor biomarkers, measured by flow cytometry: cluster designation (CD)146, CD133. Values were normalized by CD45 values(ie CD146+/CD45- and CD133+/CD45-). | 1 year |