A Multicenter, Open-label, Randomized Trial to Evaluate the Anti-cancer Effects of Zoledronic Acid and Circulating Tumor Cell Measurements in Patients With HER2-negative Metastatic Breast Cancer Without Bone Metastasis

Inclusion Criteria:

- Written informed consent

- Female patients (age ≥18 years)

- HER2-negative metastatic breast cancer (stage IV)

- Patients will be receiving chemotherapy or hormonal therapy

- Patients with no bone metastasis and ≤1 prior treatments for metastatic breast
cancer. Patients with newly diagnosed metastatic breast cancer may have received
adjuvant or neoadjuvant chemotherapy as long as treatment was completed ≥12 months
prior to relapse.

- Asymptomatic brain metastasis is permitted if all of the following criteria are met:

1. no sign of clinical progression or known progression of brain metastasis

2. off steroids for at least 2 weeks prior to study enrollment

- Stable renal function: two serum creatinine determinations of <3 mg/dL, obtained no
less than 7 days apart (one value may be obtained within 6 weeks prior to Screening;
the second must be obtained during Screening)

- ECOG performance status of 0 or 1

- Life expectancy of ≥ 6 months

- Negative serum pregnancy test

- Ability and willingness to comply with all study requirements

Exclusion Criteria:

- Known hypersensitivity to zoledronic acid or other bisphosphonates

- Patients with history of another malignancy within the last two years prior to study
enrollment, except cured basal cell carcinoma of the skin or excised carcinoma in
site of the cervix

- Use of concurrent investigational agents is prohibited. Prior use of investigational
agents is permitted if discontinued ≥30 days prior to Screening.

- No prior therapy with an antiresorptive agent

- Patients with active brain metastases or meningeal metastases

- Current or recent (in the six months prior to initial study drug treatment) severe
cardiovascular disease (defined as uncontrolled congestive heart failure),
hypertension refractory to treatment, or poorly controlled Type I/II diabetes
mellitus

- Current active dental problems including dental abscess or infection of the jawbone
(maxilla or mandible) or a current or prior diagnosis of osteonecrosis of the jaw

- Patients who have received radiotherapy ≤ 4 weeks prior to study enrollment or who
have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for
bone lesions ≤ 2 weeks prior to study enrollment is allowed

- Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) ≤ 4 weeks prior to study enrollment or who have not recovered from side
effects of such therapy

- Diminished renal capacity: calculated creatinine clearance (CrCl) <30 mL/min (based
on Cockcroft-Gault formula)

- Corrected (i.e., adjusted for serum albumin) serum calcium of <8.0 mg/dL (2.00
mmol/L) or ≥ 12 mg/dL (3.00 mmol/L)

- Pregnant or breast-feeding females

- Women of child-bearing potential who are not willing/able to use effective methods of
birth control (e.g., abstinence, oral contraceptives or implants, IUD, vaginal
diaphragm or sponge, or condom with spermicide)

- History of non-compliance to medical regimens and/or patients who are considered
unreliable

- History of bone metabolism diseases