Sorafenib and Fulvestrant in Treating Patients With Locally Advanced or Metastatic Breast Cancer That Did Not Respond to Aromatase Inhibitor Therapy

Study Overview
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Brief Summary
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RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. Giving sorafenib together with fulvestrant may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving sorafenib together with fulvestrant works in treating patients with locally advanced or metastatic breast cancer that did not respond to aromatase inhibitor therapy.

Detailed Description
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OBJECTIVES: Primary To investigate the clinical activity of sorafenib tosylate and fulvestrant, as determined by a 4-month progression-free survival rate, in patients with hormone receptor-positive locally advanced or metastatic breast cancer that progressed after prior treatment with an aromatase inhibitor. Secondary To determine the objective response rate in patients treated with this regimen. To determine the median time to progression in patients treated with this regimen. To determine the progression-free survival of patients treated with this regimen. To determine the overall survival of patients treated with this regimen. To establish the safety and tolerability profile of this regimen in these patients. OUTLINE: Patients receive oral sorafenib tosylate twice daily on days 1-28. Patients also receive fulvestrant intramuscularly on days 1 and 15 of course 1 and on day 1 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed at 28-56 days.

Official Title
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A Phase II Open-Label Study of Sorafenib Plus Fulvestrant as Salvage Therapy for Hormone Receptor Positive Metastatic Breast Cancer Failing Prior Aromatase Inhibitor Treatment

Conditions
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Breast Cancer

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of incurable breast cancer Locally advanced or metastatic disease Measurable or evaluable disease Measurable disease is defined as ≥ 1 uni-dimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral computed tomography(CT) scan Bone-only metastases that can be imaged with bone scan AND magnetic resonance imaging (MRI) or bone scan AND plain x-ray is considered measurable disease Tumor lesions that are situated in a previously irradiated area are considered measurable only if they are progressing at the time of study entry Evaluable disease includes unresectable skin/chest wall metastases that can be photographed and whose size can be measured with a ruler Bone-only metastases that can only be imaged using bone scan or malignant pleural effusion(s) only are not considered evaluable disease Previously treated with a third-generation aromatase inhibitor (e.g., letrozole, anastrazole, or exemestane) AND meets one of the following criteria: Progressed during palliative aromatase inhibitor therapy Recurred during adjuvant aromatase inhibitor therapy Recurred within 12 months of completing adjuvant aromatase inhibitor therapy Human Epidermal growth factor Receptor 2(HER2/neu)-negative tumor No Human Epidermal growth factor Receptor 2(HER2/neu) overexpression (i.e., tumor staining 3+ by immunohistochemistry [IHC] or gene amplified by Fluorescence In Situ Hybridization [FISH]) Hormone receptor status: Estrogen receptor and/or progesterone receptor positive, defined as ≥ 10% of malignant cells with positive nuclear staining PATIENT CHARACTERISTICS: Postmenopausal Eastern Cooperative Group(ECOG) performance status 0-1 Life expectancy ≥ 16 weeks Neutrophil count ≥ 1,500/mm^³ Platelet count ≥ 100,000/mm^³ Hemoglobin ≥ 9.0 g/dL Creatinine < 2 mg/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase(AST) ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement) International Normalized Ratio(INR) < 1.5 OR Prothrombin time/ partial thromboplastin time (PT/PTT) normal Left ventricular ejection fraction(LVEF) normal by Multiple Gated Acquisition(MUGA) or ECHO No known allergy to sorafenib tosylate or fulvestrant No cardiac disease, including any of the following: New York Heart Association(NYHA) class III-IV congestive heart failure Unstable angina (anginal symptoms at rest) or new-onset angina (within the past 3 months) Myocardial infarction within the past 6 months Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy No uncontrolled hypertension, defined as systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg despite optimal medical management No thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attacks), within the past 6 months No known HIV infection or chronic hepatitis B or C infection No infection that requires IV antibiotics or produces a fever > 100°F within the past 72 hours No pulmonary hemorrhage/bleeding event ≥ Common terminology criteria for adverse events(CTCAE) grade 2 within the past 4 weeks No other hemorrhage/bleeding event ≥ CTCAE grade 3 within the past 4 weeks No evidence or history of bleeding diathesis or coagulopathy No significant traumatic injury within the past 2 weeks No serious, nonhealing wound, ulcer, or bone fracture No condition that impairs the patient's ability to swallow whole pills No malabsorption problem No second malignancy within the past 5 years, except adequately treated and cured basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No underlying medical condition that, in the principal investigator's opinion, will make the administration of study drug hazardous or would obscure the interpretation of adverse events PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy for metastatic or unresectable locally advanced breast cancer No prior sorafenib tosylate or other Vascular endothelial growth factor(VEGF)-targeting therapies More than 2 weeks since prior major surgery or open biopsy No concurrent anticoagulation with warfarin or heparin No concurrent Hypericum perforatum (St. John wort) or rifampin No other concurrent anticancer agents, including chemotherapy or biological therapy No other concurrent investigational drugs Concurrent bisphosphonates allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

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: Fulvestrant/ Sorafenib<br>Fulvestrant: A loading dose will be administered intramuscularly to all subjects during cycle 1 of treatment as follows: 500 mg IM on Day 1 250 mg IM on Day 15 Upon completion of the loading dose, a fixed dose of Fulvestrant 250 mg IM will be administered on day 1 of the next 28 day cycle and every consecutive cycle until tumor progression or unacceptable toxicity occurs requiring discontinuation. Sorafenib: Subjects will take Sorafenib 800 mg/day administered as 400 mg bid (twice daily)each morning and evening approximately 12 hours apart. Treatment will begin on Day 1 of the study and continue daily until tumor progression or until unacceptable toxicity occurs. | Drug: fulvestrant<br>* Loading dose for cycle 1: 500 mg intramuscular(IM) on Day 1;250 mg IM on Day 15 Upon completion of the loading dose, a fixed dose of fulvestrant 250 mg IM will be administered on day 1 of the next 28 day cycle and every consecutive cycle until tumor progression or until unacceptable toxicity occurs requiring discontinuation of study therapy<br>Drug: sorafenib tosylate<br>* Subjects will take sorafenib 800 mg/day administered as 400 mg bid (twice daily) each morning and evening approximately 12 hours apart. Treatment will begin on Day 1 of the study and continue daily until tumor progression or until an unacceptable toxicity occurs which would require delay, modification or discontinuation of study therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Progression-free Survival at 4 Months | Progression-free survival rate is defined as the proportion of subjects who are progression free (CR, PR and SD) at 4 months after initiating treatment with sorafenib plus fulvestrant. Complete Response (CR):Disappearance of all target (both measurable and evaluable)lesions. Partial Response (PR):At least a 30% decrease in the sum of the longest diameter (LD) of both measurable and evaluable target lesions. Stable Disease (SD):Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease(PD). | 4 months after initiating treatment with sorafenib plus fulvestrant. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate |  | Every 8 weeks (two cycles) while receiving study therapy. | 
| Time to Progression |  | Start of treatment to time of progression. | 
| Progression-free Survival |  | Start of treatment to time of progression or death, whichever comes first. | 
| Overall Survival |  | 28 to 56 days after discontinuation of study therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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male breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer, stage IV breast cancer, recurrent breast cancer