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

• ClinicalTrials.gov Identifier: NCT00127205
• Recruitment Status: Active, not recruiting
• First Posted: August 5, 2005
• Results First Posted: August 28, 2019
• Last Update Posted: August 28, 2020
• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI); North Central Cancer Treatment Group; Eastern Cooperative Oncology Group; NSABP Foundation Inc; Cancer and Leukemia Group B; NCIC Clinical Trials Group
• Information provided by (Responsible Party): Southwest Oncology Group

Tracking Information

• First Submitted Date: August 3, 2005
• First Posted Date: August 5, 2005
• Results First Submitted Date: June 20, 2019
• Results First Posted Date: August 28, 2019
• Last Update Posted Date: August 28, 2020
• Study Start Date: July 2005
• Actual Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 15, 2019)

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: August 15, 2019)

• 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.
• 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.
• 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: S0307 Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer.
• Official Title: Phase III Trial of Bisphosphonates as Adjuvant Therapy for Primary Breast Cancer

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: clodronate disodium
  Given orally
• Drug: ibandronate sodium
  Given orally
• Drug: zoledronic acid
  Given IV

Study Arms

• 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.
  Intervention: Drug: zoledronic acid
• Active Comparator: Arm II
  Patients receive oral clodronate once daily for 35 months.
  Intervention: Drug: clodronate disodium
• Experimental: Arm III
  Patients receive oral ibandronate once daily for 35 months.
  Intervention: Drug: ibandronate sodium

• Publications *: 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. 2020 Sep 15. doi: 10.1007/s00520-020-05748-8. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 15, 2019): 6097
• Original Enrollment: Not Provided
• Estimated Study Completion Date: January 2021
• Actual Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT00127205
• Other Study ID Numbers: CDR0000437061; S0307 ( Other Identifier: SWOG )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Southwest Oncology Group
• Study Sponsor: Southwest Oncology Group

Collaborators

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

Investigators

• Study Chair: Julie R. Gralow, MD; Seattle Cancer Care Alliance
• Study Chair: Robert B. Livingston, MD; University of Arizona
• Study Chair: James N. Ingle, MD; Mayo Clinic
• 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

• PRS Account: Southwest Oncology Group
• Verification Date: August 2020