Ibandronate or Zoledronate in Treating Patients With Newly Diagnosed Bone Metastases From Breast Cancer

OBJECTIVES:

Primary

* Compare the efficacy, in terms of reducing frequency and timing of skeletal-related events (SREs), of ibandronate vs zoledronate in patients with newly diagnosed bone metastases secondary to breast cancer.

Secondary

* Compare the median time to first SRE in patients treated with these regimens.
* Compare the percentage of patients experiencing a SRE after treatment with these regimens.
* Compare the number of occult vertebral fractures present in patients at the end of treatment with these regimens.
* Compare the pain and analgesic scores and quality of life of patients treated with these regimens.
* Compare the number of patients developing renal dysfunction or hypocalcemia during the study period.
* Compare the number of patients developing osteonecrosis of the jaw during study treatment and follow-up.
* Compare the overall survival of these patients at 96 weeks and at 5 years.
* Compare the health-resource usage of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, parallel-group, controlled, multicenter study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 21* or 28 days for at least 96 weeks (24 or 32 courses) in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients who receive concurrent chemotherapy every 3 weeks receive study treatment every 21 days

* Arm II: Patients receive oral ibandronate once daily on days 1-28. Treatment repeats every 28 days for at least 96 weeks (24 courses) in the absence of disease progression or unacceptable toxicity. Patients with bone pain or hypercalcemia at study entry or those who require IV therapy due to hypercalcemia while on study may receive 1 treatment with ibandronate IV at the discretion of the supervising clinician.

Quality of life and pain are assessed at baseline, after every 3 courses, and at completion of study treatment.

After completion of study treatment, patients are followed annually for up to 3 years.

PROJECTED ACCRUAL: A total of 1,400 patients will be accrued for this study.

• ibandronate sodium (Drug)
• zoledronic acid (Drug)
• Zolendronic Acid (Drug), also known as Zoledronate: Zoledronic acid 4 mg by intravenous infusion every 4 weeks.

Primary outcomes

• Frequency and timing of skeletal-related events (SREs) [96 weeks]

Secondary outcomes

• Time to first SREs [96 Weeks]
• Proportion of patients with SREs [96 Weeks]
• Pain and analgesic score [96 weeks]
• Quality of life [96 weeks]
• Toxicity [96 weeks]
• Survival [5 years]
• Health resource usage and serum bone marker levels [96 weeks]

Sex: All, ages: 18 Years to any

DISEASE CHARACTERISTICS:

* Histologically proven breast cancer

  * Metastatic disease
  * Previous relapsed disease in sites other than bone allowed
* Newly diagnosed multiple bone metastases within the past 3 months, meeting all of the following criteria:

  * Painful or asymptomatic
  * Lytic, mixed, or purely sclerotic type
  * Radiological diagnosis
  * IV bisphosphonate therapy indicated
* No CNS metastases
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Male or female
* Menopausal status not specified
* No known active peptic ulcer
* Not pregnant or nursing
* Fertile patients must use effective contraception
* No active dental problems, including infection of the teeth or jawbone (maxilla or mandible) or dental or fixture trauma
* No prior or current diagnosis of osteonecrosis of the jaw, exposed bone in the mouth, or slow healing after dental procedures
* Creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 x upper limit of normal (ULN)
* AST and ALT ≤ 1.5 times ULN
* No history of bisphosphonate hypersensitivity
* Able to comply with instructions relating to oral study medications
* Able to take oral study medications
* No psychiatric illness or other condition that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

* At least 6 months since prior bisphosphonate therapy
* At least 6 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants)

  * Concurrent unplanned dental extractions allowed provided study medication is discontinued for 8 weeks before and after the surgery
* Concurrent chemotherapy and/or hormone therapy for metastatic disease allowed
* No concurrent medications that affect bone metabolism (e.g., calcitonin or other nontrial bisphosphonates)

• Results publication: Gillespie D, Farewell D, Barrett-Lee P, Casbard A, Hawthorne AB, Hurt C, Murray N, Probert C, Stenson R, Hood K. The use of randomisation-based efficacy estimators in non-inferiority trials. Trials. 2017 Mar 9;18(1):117. doi: 10.1186/s13063-017-1837-3. PMID 28274254
• Results publication: Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, Timmins H, Wheatley D, Grieve R, Griffiths G, Murray N. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014 Jan;15(1):114-22. doi: 10.1016/S1470-2045(13)70539-4. Epub 2013 Dec 11. PMID 24332514

• Peter J. Barrett Lee, MD, Study chair, Velindre NHS Trust