S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.

Study Overview
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Brief Summary
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RATIONALE: Zoledronate, clodronate, or ibandronate may delay or prevent bone metastases in patients with nonmetastatic breast cancer. It is not yet known whether zoledronate is more effective than clodronate or ibandronate in treating breast cancer. PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to clodronate or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer.

Detailed Description
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OBJECTIVES: Compare disease-free survival and overall survival of women with resected primary stage I-III adenocarcinoma of the breast treated with adjuvant zoledronate vs clodronate vs ibandronate. Compare the distributions of sites of first disease recurrence in patients treated with these drugs. Compare adverse events in patients treated with these drugs. Correlate parathyroid hormone related protein status and N-telopeptide levels at baseline with disease-free survival and sites of first recurrence in patients treated with these drugs. Investigate whether there is an association between inherited germ-line single nucleotide polymorphisms (SNP, rs2297480) in farnesyl diphosphate synthase (FDPS) and the adverse event of acute phase reactions in these patients. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 3 treatment arms. Arm I: Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. Arm II: Patients receive oral clodronate once daily for 35 months. Arm III: Patients receive oral ibandronate once daily for 35 months. Treatment in all arms continues in the absence of disease recurrence or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months until disease recurrence and then annually for up to 10 years. PROJECTED ACCRUAL: A total of 5,400 will be accrued for this study.

Official Title
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Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: clodronate disodium
* Drug: ibandronate sodium
* Drug: zoledronic acid


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed primary adenocarcinoma of the breast Stage I-III disease No evidence of metastatic disease Must have undergone lumpectomy or total mastectomy for primary disease within the past 12 weeks, or have completed chemotherapy within the past 8 weeks Axillary evaluation per institutional standards Currently receiving or planning to receive standard adjuvant systemic therapy comprising chemotherapy, hormonal therapy, or combined chemotherapy/hormonal therapy for breast cancer Patients who are at low risk for disease recurrence and for whom adjuvant systemic therapy will not be prescribed are not eligible Patients who receive biologic agents only or local radiotherapy only (without chemotherapy and/or hormone therapy) are not eligible Additional therapies are allowed including radiotherapy and biologic agents (e.g., trastuzumab [Herceptin^®], bevacizumab, or hematopoietic growth factors) Neoadjuvant therapy or hormonal therapy alone is allowed provided study entry occurs ≥ 12 weeks after completion of surgery Patients with skeletal pain are eligible provided bone scan and/or roentgenological exam are negative for metastatic disease Suspicious findings must be confirmed as benign by x-ray, MRI, or biopsy Hormone receptor status: Not specified PATIENT CHARACTERISTICS: Age 18 and over Sex Female Menopausal status Not specified Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Creatinine ≤ 2 times upper limit of normal Creatinine clearance ≥ 30 mL/min No renal failure Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No history of esophageal stricture or motility disorders Gastroesophageal reflux disorder allowed 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 in complete remission PRIOR CONCURRENT THERAPY: Biologic therapy Prior or concurrent hematopoietic growth factors allowed HER-2-targeted therapies allowed Antiangiogenics allowed Chemotherapy See Disease Characteristics Endocrine therapy See Disease Characteristics Radiotherapy Concurrent radiotherapy to the breast, chest wall, or lymph node group allowed at the discretion of the treating physician Surgery See Disease Characteristics Other Prior neoadjuvant therapy allowed Prior bisphosphonates for bone density allowed No other concurrent bisphosphonates as adjuvant therapy or for treatment of osteoporosis No concurrent enrollment in clinical trials with bone density as an endpoint Concurrent enrollment on any other locoregional or systemic therapy breast cancer study (including cooperative group studies) allowed

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 |
| --- | --- |
| Experimental: Arm I<br>Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years. | Drug: zoledronic acid<br>* Given IV<br>|
| Active Comparator: Arm II<br>Patients receive oral clodronate once daily for 35 months. | Drug: clodronate disodium<br>* Given orally<br>|
| Experimental: Arm III<br>Patients receive oral ibandronate once daily for 35 months. | Drug: ibandronate sodium<br>* Given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival | Time from date of registration to date of first observation of recurrence or death due to any cause. Patients last known to be alive who have not experienced recurrence of disease are censored at their last contact date. The outcome for the disease-free survival will be presented as 5 year survival rate. | Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from date of registration to date of death due to any cause. Patients last known to be alive are censored at their last contact date. The outcome for overall survival will be presented as 5 year overall survival rate. | follow up completed every 6 months for 5 years and then annually for 5 years or until death | 
| Distributions of Sites of First Recurrence on the Three Arms. | All sites of invasive disease documented within 30 days of first documentation of invasive recurrence. | Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence | 
| Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I breast cancer, stage II breast cancer, stage IIIA breast cancer, stage IIIB breast cancer, stage IIIC breast cancer