Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy and/or Hormone Therapy With or Without Zoledronate in Treating Women With Stage II or Stage III Breast Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 18 and over Other SHEFF-AZURE EU-20315, ISRCTN79831382, BIG-1-04, NCT00072020

Objectives

Primary

1. Compare disease-free survival of women with stage II or III breast cancer at high risk of relapse treated with neoadjuvant or adjuvant chemotherapy and/or hormonal therapy with vs without zoledronate.

Secondary

1. Compare time to bone metastases, as first recurrence, in patients treated with these regimens.
2. Compare time to bone metastases, per se, in patients treated with these regimens.
3. Compare time to distant metastases in patients treated with these regimens.
4. Compare overall survival in patients treated with these regimens.
5. Compare the reduction in skeletal-related events (fractures, spinal cord compression, radiotherapy to the bone, surgery to the bone, and hypercalcemia) before and after the development of bone metastases in patients treated with these regimens.
6. Determine the safety and toxicity of zoledronate in patients treated with these regimens.
7. Correlate prognostic factors, such as estrogen-receptor and progesterone-receptor status, TNM stage, tumor grade, HER2/neu status, and menopausal status with treatment outcome in patients treated with these regimens.
8. Determine more specific prognostic indicators for the development of bone metastases and factors that are able to predict specific benefit from bisphosphonate treatment using proteomics, tissue micro-array, and other modern techniques in these patients.

Entry Criteria

Disease Characteristics:

• Diagnosis of primary breast cancer, meeting 1 of the following staging criteria:
  • Stage II
  • Stage III
  • T stage ≥ T1



• Receiving OR scheduled to receive chemotherapy and/or endocrine therapy
  • For patients receiving neoadjuvant therapy
    • Tumor > 5 cm (T3), features of locally advanced disease (T4), OR biopsy-proven lymph node involvement (N1)
    • Scheduled to proceed to definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant therapy
    • No more than 30 days between initiation of neoadjuvant therapy and start of study drug
  • For patients receiving adjuvant therapy
    • Must have undergone complete primary tumor resection and treatment of axillary lymph nodes*
    • Must have lymph node involvement
    • No prior neoadjuvant therapy**
    • No more than 60 days since prior definitive surgery

   [Note: *Patients whose treatment plan includes further primary tumor resection and/or treatment of the axillary lymph nodes (e.g., clearance or radiotherapy) with curative intent after completion of chemotherapy are eligible provided the treatment is completed within 9 months of study entry ]

   [Note: **Preoperative endocrine therapy with a duration of < 30 days is not considered prior neoadjuvant therapy]




• No evidence of recurrent or metastatic disease



• No history of breast cancer, except ductal carcinoma in situ or lobular carcinoma in situ



• Hormone receptor status:
  • Not specified

Prior/Concurrent Therapy:

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics

Surgery

• See Disease Characteristics
• More than 4 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants)
  • Dental fillings, teeth scaling and polishing, or minor gingival surgery within the past 4 weeks are allowed

Other

• More than 1 year since prior bisphosphonates
• More than 30 days since prior investigational drugs
• No concurrent investigational drugs (i.e., not locally approved for any indication)

Patient Characteristics:

Age

• 18 and over

Sex

• Female

Menopausal status

• Premenopausal or postmenopausal

Performance status

• Karnofsky 80-100%

  OR

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Creatinine ≤ 1.5 times upper limit of normal

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No active dental problems, including dental abscess or infection of the jaw bone (e.g., maxilla or mandible)
• No prior or current diagnosis of osteonecrosis of the jaw
• No other malignancy within the past 5 years (including prior contralateral breast cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix
• No history of disease with influence on bone metabolism, including any of the following:
  • Paget’s disease of the bone
  • Primary hyperparathyroidism
  • Osteoporosis requiring treatment or likely to require treatment within the next 6 months
• No other severe physical or psychological disease that would preclude study compliance
• No known hypersensitivity to bisphosphonates

Expected Enrollment

A total of 3,300 patients (1,650 per treatment arm) will be accrued for this study within 3 years.

Outcomes

Disease-free survival as assessed annually for 10 years

Time to bone metastases as first recurrence assessed annually for 10 years
Time to bone metastases per se as assessed annually for 10 years
Time to distant metastases as assessed annually for 10 years
Overall survival as assessed by final analysis at 10 years
Skeletal-related events prior to development of bone metastases as assessed annually for 10 years
Skeletal-related events following development of bone metastases as assessed annually for 10 years
Safety and toxicity of zoledronic acid as assessed annually for 10 years
Evaluation of the influence of prognostic factors (e.g., estrogen receptor or progesterone receptor [ER/PR] status, TNM stage, tumor grade, HER2/neu, and menopausal status) on treatment outcome
Analysis of tumor-specific mutations, proteomics and gene expression changes in tumor cells

Outline

This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy. Patients also receive concurrent zoledronate IV over 15 minutes every 3-4 weeks for 6 doses, every 3 months for 8 doses, and then every 6 months for 5 doses in the absence of disease progression or unacceptable toxicity.



• Arm II: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy alone.

After completion of study treatment, patients are followed annually for 5 years.

Coleman R, Thorpe H, Cameron D, et al.: Zoledronic acid is well tolerated and can be safely administered with adjuvant chemotherapy first safety data from the AZURE trial (BIG01/04). [Abstract] Breast Cancer Res Treat 100 (Suppl 1): A-2080, S107, 2006.

Trial Contact Information

Trial Lead Organizations

University of Sheffield School of Medicine and Biomedical Sciences

Robert Coleman, MD, FRCP, Study coordinator		Ph: 44-114-226-5213 Email: r.e.coleman@sheffield.ac.uk
Victoria Hiley, Study coordinator		Ph: 44-113-343-1497 Email: v.l.hiley@leeds.ac.uk

Registry Information
Official Title		Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients with High Risk Localized Breast Cancer?
Trial Start Date		2003-08-18
Registered in ClinicalTrials.gov		NCT00072020
Date Submitted to PDQ		2003-09-12
Information Last Verified		2006-01-23

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