Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid

Study Overview
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Brief Summary
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The primary objective is, first, the comparison of tamoxifen and anastrozole and, second, the comparison of zoledronate added to standard adjuvant therapy with controls according to disease-free survival (DFS) in premenopausal patients with non-metastatic breast cancer treated with tamoxifen or anastrozole. To assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an antiestrogen or aromatase inhibitor.

Detailed Description
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The trial is conducted as an open multi-center phase III study, in a two-factorial study design and according to Good Clinical Practice (GCP) guidelines. Patients will be randomly assigned to a total of 4 study groups in a 1:1:1:1 assignment ratio. Several stratification criteria will be used in order to ensure balanced distribution of known risk factors. A total of 1.803 patients will be enrolled in 4 arms. Patients will either be treated with anastrozole (1mg daily for 3 years) or tamoxifen (20mg daily for 3 years), and will additionally receive either zoledronate (8mg q4 weeks for 3 years) or no zoledronate (arm A: Nolvadex alone; arm B: Nolvadex plus zoledronate; arm C: Arimidex alone; arm D: Arimidex plus zoledronate). Zoledronate will be administered by i.v. injection at a dose of 4 mg/month for the treatment period of 3 years. Five Bone Mineral Density (BMD) measurements will be performed in a subgroup of patients (404 patients, enrolled in 3 centres).

Official Title
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Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid, in Premenopausal, Hormone Receptor-positive Breast Cancer Patients (Stage I, II)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: tamoxifen
* Drug: anastrozole
* Drug: zoledronic acid
* Other: goserelin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Premenopausal, hormone receptor-positive patient Histologically verified (minimally) invasive breast cancer, local radical treatment 0-9 involved axillary lymph nodes (≥ 10 histologically examined nodes) Tumor stage: pT1b-3, yT0 or yT1a Exclusion Criteria: T1a, T4d, yT4; M1 Previous breast tumor irradiation Previous or concurrent chemotherapy (except for preoperative chemotherapy) Serum creatinine > 1.5 x UNL or creatinine clearance < 60 ml/min

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 59 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: AZ (Arimidex+Zoledronate)<br>Study Drugs Arimidex (Anastrozole), Zometa (Zoledronate; zoledronic acid) | Drug: anastrozole<br>* 1 mg/d<br>* Other names: Arimidex;Drug: zoledronic acid<br>* 4 mg q6m<br>* Other names: Zoledronate, Zometa;Other: goserelin<br>* 3.6 mg goserelin subcutaneously every 28 days<br>|
| Active Comparator: TZ (Tamoxifen+Zoledronate)<br>Study Drugs Nolvadex (Tamoxifen), Zometa (Zoledronate; zoledronic acid) | Drug: tamoxifen<br>* 20 mg/d<br>* Other names: Nolvadex;Drug: zoledronic acid<br>* 4 mg q6m<br>* Other names: Zoledronate, Zometa;Other: goserelin<br>* 3.6 mg goserelin subcutaneously every 28 days<br>|
| Active Comparator: AC (Arimidex Control)<br>Study Drug Arimidex (Anastrozole) | Drug: anastrozole<br>* 1 mg/d<br>* Other names: Arimidex;Other: goserelin<br>* 3.6 mg goserelin subcutaneously every 28 days<br>|
| Active Comparator: TC (Tamoxifen Control)<br>Study Drug Nolvadex (Tamoxifen) | Drug: tamoxifen<br>* 20 mg/d<br>* Other names: Nolvadex;Other: goserelin<br>* 3.6 mg goserelin subcutaneously every 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of anastrozole vs tamoxifen in premenopausal patients with non-metastatic breast cancer with respect to disease-free survival (DFS) | DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause | 9 years after FPI | 
| Comparison of zoledronate vs no zoledronate in premenopausal patients with non-metastatic breast cancer with respect to disease-free survival (DFS) | DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause | 9 years after FPI | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of anastrozole vs tamoxifen in premenopausal patients with non-metastatic breast cancer with respect to recurrence-free survival (RFS) | RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer | 9 years after FPI | 
| Comparison of zoledronate vs no zoledronate in premenopausal patients with non-metastatic breast cancer with respect to recurrence-free survival (RFS) | RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer | 9 years after FPI | 
| Comparison of anastrozole vs tamoxifen in premenopausal patients with non-metastatic breast cancer with respect to overall survival (OS) | OS is defined as time from randomization to death from any cause | 9 years after FPI | 
| Comparison of zoledronate vs no zoledronate in premenopausal patients with non-metastatic breast cancer with respect to overall survival (OS) | OS is defined as time from randomization to death from any cause | 9 years after FPI | 
| Adverse and severe adverse events will be listed for all therapy subgroups anastrozole / zoledronate (AZ), anastrozole / zoledronate control (AC), tamoxifen / zoledronate (TZ), tamoxifen / zoledronate control (TC). | Incidences of adverse and serious adverse events | 9 years after FPI | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stage I, Austrian Breast & Colorectal Cancer Study Group (ABCSG), 12, Phase 3, breast cancer, anastrozole, tamoxifen, zoledronic acid, premenopausal, hormone receptor-positive, Stage II, bone mineral density, BMD, bisphosphonate, zoledronate