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

June 8, 2021 updated by: Southwest Oncology Group

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

6097

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

DISEASE CHARACTERISTICS:

  • 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

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Sex

  • Female

Menopausal status

  • Not specified

Performance status

  • Zubrod 0-2

Life expectancy

  • Not specified

Hematopoietic

  • Not specified

Hepatic

  • Not specified

Renal

  • Creatinine ≤ 2 times upper limit of normal
  • Creatinine clearance ≥ 30 mL/min
  • No renal failure

Other

  • 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • Prior or concurrent hematopoietic growth factors allowed
  • HER-2-targeted therapies allowed
  • Antiangiogenics allowed

Chemotherapy

  • See Disease Characteristics

Endocrine therapy

  • See Disease Characteristics

Radiotherapy

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

Surgery

  • See Disease Characteristics

Other

  • Prior neoadjuvant therapy allowed
  • Prior bisphosphonates for bone density allowed
  • No other concurrent bisphosphonates as adjuvant therapy or for treatment of osteoporosis

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: zoledronic acid
Given IV
Active Comparator: Arm II
Patients receive oral clodronate once daily for 35 months.
Drug: clodronate disodium
Given orally
Experimental: Arm III
Patients receive oral ibandronate once daily for 35 months.
Drug: ibandronate sodium
Given orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease-free Survival
Time Frame: 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.
Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: 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.
follow up completed every 6 months for 5 years and then annually for 5 years or until death
Distributions of Sites of First Recurrence on the Three Arms.
Time Frame: 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.
Disease assessments are completed every 6 months for 5 years then annually for 5 years or until death or recurrence
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Time Frame: 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.
Toxicity assessment is repeated every 2 months for the first 6 months, then every 3 months until 3 years or end of treatment.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Southwest Oncology Group

Collaborators

National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
NCIC Clinical Trials Group
Cancer and Leukemia Group B
North Central Cancer Treatment Group
NSABP Foundation Inc

Investigators

  • Study Chair: Julie R. Gralow, MD, Seattle Cancer Care Alliance
  • Study Chair: Robert B. Livingston, MD, University of Arizona
  • Study Chair: Carla I. Falkson, MD, University of Alabama at Birmingham
  • Study Chair: Alexander H Paterson, MD, FRCP, Tom Baker Cancer Centre - Calgary
  • Study Chair: Elizabeth C. Dees, MD, UNC Lineberger Comprehensive Cancer Center
  • Study Chair: Mark J. Clemons, MD, Toronto Sunnybrook Regional Cancer Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2005

Primary Completion (Actual)

December 1, 2017

Study Completion (Actual)

March 29, 2021

Study Registration Dates

First Submitted

August 3, 2005

First Submitted That Met QC Criteria

August 3, 2005

First Posted (Estimate)

August 5, 2005

Study Record Updates

Last Update Posted (Actual)

July 2, 2021

Last Update Submitted That Met QC Criteria

June 8, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CDR0000437061
  • S0307 (Other Identifier: SWOG)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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