Zoledronic Acid - Letrozole Adjuvant Synergy Trial (ZFAST) - Cancer Treatment Related Bone Loss in Postmenopausal Women With Estrogen Receptor Positive and/or Progesterone Receptor Positive Breast Cancer Receiving Adjuvant Hormonal Therapy

NCT ID: NCT00050011

Last Updated: 2014-03-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 602 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2002-09-30
• Study Completion Date: 2009-01-31

Brief Summary

This protocol is designed to compare the effect on bone of Zoledronic Acid 4 mg every 6 months when given upfront versus delayed start (based on a post-baseline BMD T- Score below -2.0 SD at either the lumbar spine or total hip, or any clinical fracture unrelated to trauma, or an asymptomatic fracture discovered at the month 36 scheduled visit) in stage I-IIIb postmenopausal women with hormone receptor positive breast cancer who will receive Letrozole 2.5 mg daily as an adjuvant therapy.

Conditions

Breast Neoplasms; Osteoporosis

Study Design

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

Study Groups

Zoledronic Acid upfront

Participants in the upfront arm received zoledronate 4 mg i.v. on Day 1 and every 6 months until disease progression (recurrence) or the end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.

Letrozole

Intervention Type: DRUG

Participants received Letrozole 2.5 mg daily.

Zoledronate delayed-start

In lieu of a placebo arm, which was considered unethical for this trial, a delayed start arm was used. Participants who met certain clinical criteria indicating risk of lumbar spine or total hip fracture, or experienced clinical fracture unrelated to trauma or any asymptomatic fracture discovered at the Month 36 scheduled visit, were started on zoledronate 4 mg i.v. and for every 6 months until disease progression (recurrence) or end of study. Participants also received Letrozole 2.5 daily plus calcium (1000-1200 mg) and vitamin D (400-800 IU) daily.

Group Type: EXPERIMENTAL

Zoledronic Acid

Intervention Type: DRUG

Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.

Letrozole

Intervention Type: DRUG

Participants received Letrozole 2.5 mg daily.

Interventions

Zoledronic Acid

Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.

Intervention Type: DRUG

Letrozole

Participants received Letrozole 2.5 mg daily.

Intervention Type: DRUG

Other Intervention Names

ZOL446; Zoledronate; Femara

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent

2. Postmenopausal status defined by one of the following :

• women equal to or greater than 55 years with cessation of menses
• spontaneous cessation of menses within the past 1 year, but amenorrheic in women less than or equal to 55 years (e.g., spontaneous or secondary to hysterectomy), and with postmenopausal gonadotrophin levels (follicle stimulating hormone levels >40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved
• bilateral oophorectomy (prior to the diagnosis of breast cancer).

3. Adequately diagnosed and treated breast cancer defined as:

• Patients with breast cancer whose tumor can be removed by an appropriate surgical procedure such as mastectomy or breast conserving surgery and who receive appropriate additional local treatments such as radiotherapy according to best practice.
• Patients must be at the end of their local treatment without evidence of local residual disease.
• Patients must have no clinical or radiological evidence of distant metastasis.

4. Hormone receptor positive defined as:

• ER and/or PR greater than or equal to1 0 fmol/mg cytosol protein; or greater than or equal to 10% of the tumor cells positive by
• immunohistochemical evaluation.

5. Patients with a baseline lumbar spine and total hip BMD T-score at or above -2.0 SD are eligible.

6. Patients who will receive adjuvant chemotherapy are eligible for participation. Adjuvant chemotherapy must be completed prior to randomization.

7. The date of randomization must not be more than the following:

• 12 weeks from completion of surgery;
• 12 weeks after completion of adjuvant chemotherapy;
• 12 weeks after completion of surgery and radiation therapy; however the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.
• 12 weeks after completion of chemotherapy and radiation therapy; however, the patient may be randomized while receiving radiation therapy - this decision is at the Investigator's discretion.

8. Patients who have undergone neoadjuvant chemotherapy are eligible.

9. No prior treatment with Femara.

Exclusion Criteria

1. Patients with any clinical or radiological evidence of distant spread of their disease at any point before randomization.

2. Patients with clinical or radiological evidence of existing fracture in the lumbar spine and/or total hip.

3. Patients with a history of fracture with low-intensity or no associated trauma.

4. Patients who have started adjuvant hormonal therapy or who have completed adjuvant hormonal therapy prior to randomization.

5. Patients who have received any endocrine therapy within the past 12 months (other than neoadjuvant tamoxifen or toremifene, insulin and/or oral anti-diabetic medications, and thyroid hormone replacement). Hormone replacement therapy must be discontinued prior to randomization.

6. Patients who have received prior treatment with intravenous bisphosphonates within the past 12 months.

7. Patients currently receiving oral bisphosphonates. Oral bisphosphonates must be discontinued within 3 weeks of baseline evaluations.

8. Patients who have received prior treatment with systemic corticosteroids within the past 12 months (short term corticosteroid therapy, e.g. to prevent/treat chemotherapy-induced nausea/vomiting, is acceptable).

9. Patients with prior exposure to anabolic steroids or growth hormone within the past 6 months.

10. Patients with prior use of Tibolone within the last 6 months.

11. Any prior use of PTH for more than 1 week.

12. Prior use of systemic sodium fluoride for > 3 months during the past 2 years.

13. Patients currently treated with any drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate) within 2 weeks prior to randomization.

14. Patients with previous or concomitant malignancy (not breast cancer) within the past 5 years EXCEPT adequately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix. Patients who have had a previous other malignancy must have been disease free for five years.

15. Patients with other non-malignant systemic diseases including uncontrolled infections, uncontrolled type 2 diabetes mellitus, uncontrolled thyroid dysfunction, cardiovascular, renal, hepatic, and lung diseases which would prevent prolonged follow-up. Patients with previous history of thrombosis or thromboembolism can be included only if medically suitable. Patients with a known history of HIV are excluded.

16. Uncontrolled seizure disorders associated with falls.

17. Patients with abnormal renal function as evidenced by a serum creatinine equal to or greater than 3 mg/dL (265.2 mmol/L).

18. History of diseases with influence on bone metabolism, such as Paget's disease, Osteogenesis Imperfecta, and primary or secondary hyperthyroidism within 12 months prior to study entry.

19. Patients with baseline lumber spine or total hip BMD T-score below -2.0 SD.

20. Patients treated with systemic investigational drug(s) and/or device(s) within the past 30 days or topical investigational drugs within the past 7 days.

• History of surgery at the lumbosacral spine, with or without implantable devices.
• Scoliosis with a Cobb angle >15 degree at the lumbar spine.
• Immobility, hyperostosis or sclerotic changes at the lumbar spine, or evidence of sclerotic abdominal aorta sufficient to interfere with DXA scan.
• Any disease of the spine that would preclude the proper acquisition of a lumbar spine DXA.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals, MD

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Highlands Oncology Group

Springdale, Arkansas, United States

East Valley Hematology & Oncology

Burbank, California, United States

Louisiana Oncology Associates

Lafayette, California, United States

Wilshire Oncology Medical Group

LaVerne, California, United States

Pacific Shores Medical Group

Long Beach, California, United States

Clinical Trials & Research Associates, Inc.

Montebello, California, United States

Redwood Regional Medical Group

Santa Rosa, California, United States

Cancer and Blood Institute of the Desert

Rancho Mirage, Colorado, United States

Eastern Connecticut Hematology/Oncology Associates

Norwich, Connecticut, United States

FL Community Cancer Center

Brooksville, Florida, United States

Robert R. Carroll, MD, PA

Gainesville, Florida, United States

Oncology Hematology Group of South Florida

Miami, Florida, United States

Pasco Pinellas Cancer Center

New Port Richey, Florida, United States

Ocala Oncology Center

Ocala, Florida, United States

Cancer Research Network, Inc.

Plantation, Florida, United States

Bay Area Oncology

Tampa, Florida, United States

Space Coast Medical

Titusville, Florida, United States

Elmhurst Memorial Hospital

Elhurst, Illinois, United States

Kentuckiana Cancer Institute

Louisville, Kentucky, United States

Frederick Memorial Hospital Regional Cancer Therapy Center

Frederick, Maryland, United States

New England Hematology/Oncology Associates

Wellesley, Massachusetts, United States

Cook Research Department at Spectrum Health

Grand Rapids, Michigan, United States

Metro Minnesota CCOP

Saint Louis Park, Minnesota, United States

Hematology-Oncology Centers of the Northern Rockies, PC

Billings, Montana, United States

Methodist Cancer Center

Omaha, Nebraska, United States

Hematology-Oncology Associates of Northern NJ

Morristown, New Jersey, United States

New Mexico Oncology Hematology, Ltd.

Albuquerque, New Mexico, United States

Hemoncare PC

Brooklyn, New York, United States

Odyssey Research Services

Bismarck, North Dakota, United States

Nashat Y. Gabrail MD Inc.

Canton, Ohio, United States

Oncology Partners Network

Cincinnati, Ohio, United States

Physician Associates, Inc.

Cincinnati, Ohio, United States

Dayton Clinical Oncology Program

Dayton, Ohio, United States

University of Pittsburgh Cancer Institute/Magee Womens Hospital

Pittsburgh, Pennsylvania, United States

Charleston Hematology Oncology

Charleston, South Carolina, United States

The Sarah Cannon Cancer Center

Nashville, Tennessee, United States

St. Joseph Regional Cancer Center

Bryan, Texas, United States

Cancer Specialists of South Texas

Corpus Christi, Texas, United States

Center for Oncology Research & Tx. PA

Dallas, Texas, United States

Northern Virginia Oncology Group

Fairfax, Virginia, United States

Virginia Physicians, Inc.- Oncology

Richmond, Virginia, United States

Swedish Cancer Institute

Seattle, Washington, United States

Rockwood Clinic, PS

Spokane, Washington, United States

VA Medical Center

San Juan, , Puerto Rico

Countries

United States; Puerto Rico

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)

Other Identifiers

CZOL446EUS32

Identifier Type: -

Identifier Source: org_study_id