S0226 Anastrozole With or Without Fulvestrant as First-Line Therapy in Postmenopausal Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using drugs such as anastrozole and fulvestrant may fight breast cancer by blocking the use of estrogen. It is not yet known whether anastrozole is more effective with or without fulvestrant in treating breast cancer. PURPOSE: This randomized phase III trial is studying giving anastrozole together with fulvestrant to see how well it works compared to anastrozole alone as first-line therapy in treating postmenopausal women with metastatic breast cancer.

Detailed Description
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OBJECTIVES: Compare the time to tumor progression in postmenopausal women with metastatic breast cancer treated with anastrozole with or without fulvestrant as first-line therapy. Compare the clinical benefit (complete or partial response, confirmed or unconfirmed, or stable disease ≥ 24 weeks) and overall survival of patients treated with these regimens. Compare adverse events in patients treated with these regimens. Determine the prognostic significance of estrogen receptor positivity and HER2/neu status in patients treated with these regimens. Determine parameters of estrogen and clinical pharmacology and estrogen levels in patients treated with these regimens. Compare anastrozole plasma levels at 8, 16, and 24 weeks in patients treated with these regimens (closed as of 4/16/2009). Compare estradiol serum levels at 8, 16, and 24 weeks in patients treated with these regimens (closed as of 4/16/2009). OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior adjuvant tamoxifen therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral anastrozole once daily on days 1-28. Arm II: Patients receive oral anastrozole as in arm I. Patients also receive fulvestrant intramuscularly on days 1, 14, and 28 during course 1 and then on day 28 of the subsequent courses. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients are followed for up to 4 years. PROJECTED ACCRUAL: A total of 690 patients (345 per treatment arm) will be accrued for this study within 3 years.

Official Title
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Phase III Randomized Trial of Anastrozole Versus Anastrozole and Fulvestrant as First Line Therapy for Post Menopausal Women With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: fulvestrant


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed breast cancer meeting 1 of the following criteria: Metastatic disease (M1) Multiple sites of new disease that is clinically obvious metastatic disease (e.g., multiple sites of new osseous disease) Measurable or nonmeasurable disease No known brain or CNS metastases Hormone receptor status: Estrogen-receptor positive* AND/OR Progesterone-receptor positive* NOTE: *Positivity defined as estrogen binding of > 10 fmol/mg cytosol protein by ligand binding assay or positive by immunohistochemistry PATIENT CHARACTERISTICS: Age Not specified Sex Female Menopausal status Postmenopausal, as defined by 1 of the following: Prior bilateral oophorectomy More than 12 months since last menstrual period with no prior hysterectomy At least 55 years of age with prior hysterectomy Under 55 years of age with a prior hysterectomy without oophorectomy and with estradiol and follicle-stimulating hormone levels consistent with menopause Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic No bleeding diathesis (e.g., disseminated intravascular coagulation or clotting factor deficiency) Hepatic INR ≤ 1.6 Renal Not specified Other HIV negative No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy No prior immunotherapy for recurrent or metastatic disease Chemotherapy No prior chemotherapy for recurrent or metastatic disease More than 12 months since prior adjuvant or neoadjuvant chemotherapy No concurrent chemotherapy for malignancy Endocrine therapy Prior adjuvant hormonal therapy allowed At least 12 months since prior adjuvant luteinizing hormone-releasing hormone (LHRH) analogues Menstrual periods must not have resumed since LHRH therapy More than 12 months since prior adjuvant or neoadjuvant aromatase inhibitors (e.g., anastrozole, letrozole, or exemestane) More than 12 months since prior fulvestrant No prior hormonal therapy for recurrent or metastatic disease No other concurrent hormonal therapy for malignancy No concurrent hormone replacement therapy Radiotherapy Not specified Surgery Not specified Other No long-term anticoagulant therapy (except antiplatelet therapy)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive oral anastrozole once daily on days 1-28. | Drug: anastrozole<br>* Given orally<br>|
| Experimental: Arm II<br>Patients receive oral anastrozole as in arm I. Patients also receive fulvestrant intramuscularly on days 1, 14, and 28 during course 1 and then on day 28 of the subsequent courses. | Drug: anastrozole<br>* Given orally<br>Drug: fulvestrant<br>* Given intramuscularly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Tumor Progression | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target measurable lesions over the smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline. Unequivocal progression of non-measurable disease in the opinion of the treating physician. Appearance of any new lesion/site. Death due to disease without prior documentation of progression and without symptomatic deterioration. From date of randomization to time of first documentation of progression, symptomatic deterioration or death due to any cause. Patients last known to be alive and progression free are considered at last date of contact. | Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit (CR, PR, Confirmed or Unconfirmed, or Stable Disease >= 24 Weeks). | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable, Does not qualify for CR, PR, Progression or Symptomatic Deterioration. Clinical Benefit = CR + PR + Stable >= 24 weeks | Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. | 
| Overall Survival | From date of randomization to date of death due to any cause. Patients last known to be alive are censored at last date of contact. | Every 4 weeks while on treatment. Then every 3 months until progression, then six months for two years then annually until four years or until death, which ever occurs first. | 
| Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE version 3.0 terminology. For each patient, worst grade of each event type is reported. Grade3 (Severe), Grade4 (Life-threatening), Grade 5 (Fatal) | Patients were assessed for adverse events after each cycle (1 cycle = 28 days) while on 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