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

NCT ID: NCT00127205

Last Updated: 2021-07-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 6097 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-07-31
• Study Completion Date: 2021-03-29

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.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

zoledronic acid

Intervention Type: DRUG

Given IV

Arm II

Patients receive oral clodronate once daily for 35 months.

Group Type: ACTIVE_COMPARATOR

clodronate disodium

Intervention Type: DRUG

Given orally

Arm III

Patients receive oral ibandronate once daily for 35 months.

Group Type: EXPERIMENTAL

ibandronate sodium

Intervention Type: DRUG

Given orally

Interventions

clodronate disodium

Given orally

Intervention Type: DRUG

ibandronate sodium

Given orally

Intervention Type: DRUG

zoledronic acid

Given IV

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

North Central Cancer Treatment Group

NETWORK

Sponsor Role: collaborator

Eastern Cooperative Oncology Group

NETWORK

Sponsor Role: collaborator

NSABP Foundation Inc

NETWORK

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Julie R. Gralow, MD

Role: STUDY_CHAIR

Seattle Cancer Care Alliance

Robert B. Livingston, MD

Role: STUDY_CHAIR

University of Arizona

James N. Ingle, MD

Role: STUDY_CHAIR

Mayo Clinic

Carla I. Falkson, MD

Role: STUDY_CHAIR

University of Alabama at Birmingham

Alexander H Paterson, MD, FRCP

Role: STUDY_CHAIR

Tom Baker Cancer Centre - Calgary

Elizabeth C. Dees, MD

Role: STUDY_CHAIR

UNC Lineberger Comprehensive Cancer Center

Mark J. Clemons, MD

Role: STUDY_CHAIR

Toronto Sunnybrook Regional Cancer Centre

References

Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

Reference Type: DERIVED

PMID: 38979716 (View on PubMed)

Kizub DA, Miao J, Schubert MM, Paterson AHG, Clemons M, Dees EC, Ingle JN, Falkson CI, Barlow WE, Hortobagyi GN, Gralow JR. Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307). Support Care Cancer. 2021 May;29(5):2509-2517. doi: 10.1007/s00520-020-05748-8. Epub 2020 Sep 15.

Reference Type: DERIVED

PMID: 32929540 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Related Links

https://nctn-data-archive.nci.nih.gov/

Data Available: Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Other Identifiers

S0307

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000437061

Identifier Type: -

Identifier Source: org_study_id