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

Phase 3
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

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


- 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

- 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.

Inclusion Criteria


- 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



- 18 and over


- Female

Menopausal status

- Not specified

Performance status

- Zubrod 0-2

Life expectancy

- Not specified


- Not specified


- Not specified


- Creatinine ≤ 2 times upper limit of normal

- Creatinine clearance ≥ 30 mL/min

- No renal failure


- 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


Biologic therapy

- Prior or concurrent hematopoietic growth factors allowed

- HER-2-targeted therapies allowed

- Antiangiogenics allowed


- See Disease Characteristics

Endocrine therapy

- See Disease Characteristics


- Concurrent radiotherapy to the breast, chest wall, or lymph node group allowed at the
discretion of the treating physician


- See Disease Characteristics


- Prior neoadjuvant therapy allowed

- Prior bisphosphonates for bone density allowed

- No other concurrent bisphosphonates as adjuvant therapy or for treatment of

- 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

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Histologic confirmation of disease recurrence

Outcome Time Frame:

scans or biopsy at recurrence

Safety Issue:


Principal Investigator

Julie R. Gralow, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Seattle Cancer Care Alliance


United States: Federal Government

Study ID:




Start Date:

July 2005

Completion Date:

May 2020

Related Keywords:

  • Breast Cancer
  • stage I breast cancer
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • Breast Neoplasms