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

Study Overview
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Brief Summary
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RATIONALE: 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. Estrogen can cause the growth of breast cancer cells. Aromatase inhibition therapy using letrozole, anastrozole, or exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether sorafenib is more effective than a placebo when given together with letrozole, anastrozole, or exemestane in treating metastatic breast cancer. PURPOSE: This randomized phase II trial is studying how well sorafenib works compared with a placebo when given together with letrozole, anastrozole, or exemestane in treating postmenopausal women with estrogen receptor-positive and/or progesterone receptor-positive metastatic breast cancer.

Detailed Description
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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.

Official Title
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Phase II Randomized Study of Sorafenib Compared to Placebo When Administered in Combination With Aromatase Inhibitors for Postmenopausal Women With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: exemestane
* Drug: letrozole
* Drug: sorafenib tosylate
* Other: placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral sorafenib tosylate twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: anastrozole<br>* given orally<br>Drug: exemestane<br>* given orally<br>Drug: letrozole<br>* given orally<br>Drug: sorafenib tosylate<br>* given orally<br>|
| Active Comparator: Arm II<br>Patients receive oral placebo twice daily and oral letrozole, anastrozole, or exemestane once daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: anastrozole<br>* given orally<br>Drug: exemestane<br>* given orally<br>Drug: letrozole<br>* given orally<br>Other: placebo<br>* given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as the time from randomization to the earliest date of documentation of disease progression or death due to any cause. In the case of a participant started treatment and then never return for any evaluations, the participant was censored for progression 1 day post-randomization. | Time from randomization to disease progression or death (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival time was defined as the time from randomization to death due to any cause. | Time from randomization to death (up to 5 years) | 
| Time to Treatment Failure | Time to treatment failure was defined as the time from the date of the randomization to the date at which the patient was removed from treatment due to progression, adverse events, or refusal. | Time from randomization to treatment failure (up to 5 years) | 
| Objective Tumor Response Rate | A confirm response was defined as either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluation at least 4 weeks apart. The confirmed response rate was estimated within each treatment group by the number of confirmed responses divided by the total number of participants randomized. | Up to 5 years | 
| Duration of Response | Duration of response was defined for all patients who have achieved a confirmed response as the date at which the patient's earliest best objective status was first noted to be either a CR or PR to the earliest date progression was documented. | Up to 5 years | 
| Adverse Event | Number of participants that experienced adverse events (grade 3 and above) as measured by NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Adverse events were assessed every week during first 6 weeks of therapy, every 4 weeks on months 1 to 6, every 12 weeks on months 7 and beyond and at the end of treatment. | Time from randomization to end of treatment | 

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