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

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Active Control

Study Primary Completion Date: May 2011

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.

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 3 years. - Arm III: Patients receive oral ibandronate once daily for 3 years. 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 4,500 will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: clodronate disodium
  • Given orally
• Drug: ibandronate sodium
  • Given orally
• Drug: zoledronic acid
  • Given IV

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 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.
• Active Comparator: Arm II
  • Patients receive oral clodronate once daily for 3 years.
• Experimental: Arm III
  • Patients receive oral ibandronate once daily for 3 years.

Primary Measures

• Histologic confirmation of disease recurrence
  • Safety Issue?: No
• Sites of first disease recurrence
  • Safety Issue?: No
• Disease-free survival
  • Safety Issue?: No
• Overall survival
  • Safety Issue?: No
• Zubrod performance status
  • Safety Issue?: No

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 is allowed provided study entry occurs 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 (i.e., CAN-NCIC-MA27)
• Concurrent enrollment on any other locoregional or systemic therapy breast cancer study (including cooperative group studies) allowed

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Southwest Oncology Group

Overall Clinical Trial Officials and Contacts

Julie R. Gralow, MD  Seattle Cancer Care Alliance  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00127205

Study ID Number: CDR0000437061

ClinicalTrials.gov Identifier: NCT00127205

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database

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