S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.

Phase 3

Completed

Interventions: Drug: clodronate disodium
Drug: ibandronate sodium
Drug: zoledronic acid

Brief Summary: 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.

Detailed Description: 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.

* 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.

Recruitment & Eligibility

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Arm && Interventions

Group	Intervention	Description
Arm II	clodronate disodium	Patients receive oral clodronate once daily for 35 months.
Arm III	ibandronate sodium	Patients receive oral ibandronate once daily for 35 months.
Arm I	zoledronic acid	Patients receive zoledronate IV over 15 minutes once a month for 6 months and then once every 3 months for 2.5 years.

Primary Outcome Measures

Name	Time	Method
Disease-free Survival	Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence	Time from date of registration to date of first observation of recurrence or death due to any cause. Patients last known to be alive who have not experienced recurrence of disease are censored at their last contact date. The outcome for the disease-free survival will be presented as 5 year survival rate.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs	Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment.	Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Overall Survival	follow up completed every 6 months for 5 years and then annually for 5 years or until death	Time from date of registration to date of death due to any cause. Patients last known to be alive are censored at their last contact date. The outcome for overall survival will be presented as 5 year overall survival rate.
Distributions of Sites of First Recurrence on the Three Arms.	Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence	All sites of invasive disease documented within 30 days of first documentation of invasive recurrence.