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

NCT00050011 | Completed Phase 3 Results

• 1 other identifier: CZOL446EUS32
• Study Type: interventional
• Target: 602
• Locations: 2 countries
• Sites: 44

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

Keywords

cancer-treatment related bone loss; postmenopausal women; breast cancer; hormone receptor positive breast cancer; adjuvant therapy; hormonal therapy; bone loss; bisphosphonates; ZFAST; Letrozole; Zoledronic Acid; US32

Outcome Measures

Primary Outcomes (1)

• Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)

  Bone mineral density (BMD) measurements were assessed by dual energy x-ray absorptiometry (DXA). The DXA devices of participating sites were cross-calibrated and the DXA results were compiled and analyzed by a central reader. Percent change = 100\*((BMD at Month 12 - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the last observation carried forward (LOCF) method. Post-baseline non-missing data from month 6 were carried forward to month 12. Data prior to month 6 were not carried forward.

  Baseline, 12 months

Secondary Outcomes (7)

• Percent Change From Baseline in Lumbar Spine (L1-L4) BMD

  Baseline, 2 years, 3 years, 5 years

• Percent Change From Baseline in Total Hip BMD

  Baseline, 12 months, 2 years, 3 years, 5 years

• Percent Change From Baseline in Biochemical Markers of Bone Turnover, Serum N-Telopeptide (sNTX) and Bone-specific Alkaline Phosphatase (BSAP)

  Baseline, 12 months, 2 years, 3 years, 5 years

• Incidence Rate of All Clinical Fractures

  3 years

• Time to Disease Recurrence/Relapse

  over 5 years

Study Arms (2)

Zoledronic Acid upfront

EXPERIMENTAL

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.

Drug: Zoledronic Acid; Drug: Letrozole

Zoledronate delayed-start

EXPERIMENTAL

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.

Drug: Zoledronic Acid; Drug: Letrozole

Interventions

Zoledronic Acid DRUG

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

Also known as: ZOL446, Zoledronate

Zoledronate delayed-start; Zoledronic Acid upfront

Letrozole DRUG

Participants received Letrozole 2.5 mg daily.

Also known as: Femara

Zoledronate delayed-start; Zoledronic Acid upfront

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed informed consent
• 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).
• 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.
• 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.
• Patients with a baseline lumbar spine and total hip BMD T-score at or above -2.0 SD are eligible.
• Patients who will receive adjuvant chemotherapy are eligible for participation. Adjuvant chemotherapy must be completed prior to randomization.
• The date of randomization must not be more than the following:

You may not qualify if:

• Patients with any clinical or radiological evidence of distant spread of their disease at any point before randomization.
• Patients with clinical or radiological evidence of existing fracture in the lumbar spine and/or total hip.
• Patients with a history of fracture with low-intensity or no associated trauma.
• Patients who have started adjuvant hormonal therapy or who have completed adjuvant hormonal therapy prior to randomization.
• 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.
• Patients who have received prior treatment with intravenous bisphosphonates within the past 12 months.
• Patients currently receiving oral bisphosphonates. Oral bisphosphonates must be discontinued within 3 weeks of baseline evaluations.
• 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).
• Patients with prior exposure to anabolic steroids or growth hormone within the past 6 months.
• Patients with prior use of Tibolone within the last 6 months.
• Any prior use of PTH for more than 1 week.
• Prior use of systemic sodium fluoride for \> 3 months during the past 2 years.
• Patients currently treated with any drugs known to affect the skeleton (e.g., calcitonin, mithramycin, or gallium nitrate) within 2 weeks prior to randomization.
• 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.
• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (44)

Highlands Oncology Group

Springdale, Arkansas, 72764, United States

Location

East Valley Hematology & Oncology

Burbank, California, 91505, United States

Location

Louisiana Oncology Associates

Lafayette, California, 70506, United States

Location

Wilshire Oncology Medical Group

LaVerne, California, 91750, United States

Location

Pacific Shores Medical Group

Long Beach, California, 90813, United States

Location

Clinical Trials & Research Associates, Inc.

Montebello, California, 90640, United States

Location

Redwood Regional Medical Group

Santa Rosa, California, 95403, United States

Location

Cancer and Blood Institute of the Desert

Rancho Mirage, Colorado, 92270, United States

Location

Eastern Connecticut Hematology/Oncology Associates

Norwich, Connecticut, 06360, United States

Location

FL Community Cancer Center

Brooksville, Florida, 34613, United States

Location

Robert R. Carroll, MD, PA

Gainesville, Florida, 32605, United States

Location

Oncology Hematology Group of South Florida

Miami, Florida, 33176, United States

Location

Pasco Pinellas Cancer Center

New Port Richey, Florida, 34652, United States

Location

Ocala Oncology Center

Ocala, Florida, 33479, United States

Location

Cancer Research Network, Inc.

Plantation, Florida, 33324, United States

Location

Bay Area Oncology

Tampa, Florida, 33607, United States

Location

Space Coast Medical

Titusville, Florida, 32796, United States

Location

Elmhurst Memorial Hospital

Elhurst, Illinois, 60126, United States

Location

Kentuckiana Cancer Institute

Louisville, Kentucky, 40202, United States

Location

Frederick Memorial Hospital Regional Cancer Therapy Center

Frederick, Maryland, 21701, United States

Location

New England Hematology/Oncology Associates

Wellesley, Massachusetts, 02481, United States

Location

Cook Research Department at Spectrum Health

Grand Rapids, Michigan, 49503, United States

Location

Metro Minnesota CCOP

Saint Louis Park, Minnesota, 55416, United States

Location

Hematology-Oncology Centers of the Northern Rockies, PC

Billings, Montana, 59101, United States

Location

Methodist Cancer Center

Omaha, Nebraska, 68114, United States

Location

Hematology-Oncology Associates of Northern NJ

Morristown, New Jersey, 07962, United States

Location

New Mexico Oncology Hematology, Ltd.

Albuquerque, New Mexico, 87109, United States

Location

Hemoncare PC

Brooklyn, New York, 11235, United States

Location

Odyssey Research Services

Bismarck, North Dakota, 58501, United States

Location

Nashat Y. Gabrail MD Inc.

Canton, Ohio, 44718, United States

Location

Oncology Partners Network

Cincinnati, Ohio, 45238, United States

Location

Physician Associates, Inc.

Cincinnati, Ohio, 45238, United States

Location

Dayton Clinical Oncology Program

Dayton, Ohio, 45420, United States

Location

University of Pittsburgh Cancer Institute/Magee Womens Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Charleston Hematology Oncology

Charleston, South Carolina, 29403, United States

Location

The Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

St. Joseph Regional Cancer Center

Bryan, Texas, 77802, United States

Location

Cancer Specialists of South Texas

Corpus Christi, Texas, 78412, United States

Location

Center for Oncology Research & Tx. PA

Dallas, Texas, 75230, United States

Location

Northern Virginia Oncology Group

Fairfax, Virginia, 22031, United States

Location

Virginia Physicians, Inc.- Oncology

Richmond, Virginia, 23294, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98122, United States

Location

Rockwood Clinic, PS

Spokane, Washington, 99220, United States

Location

VA Medical Center

San Juan, 00927, Puerto Rico

Location

Related Publications (1)

• 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.

  PMID: 38979716 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Osteoporosis; Bone Diseases, Metabolic

Interventions

Zoledronic Acid; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nitriles; Triazoles

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals, MD

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2002
• First Posted: November 20, 2002
• Study Start: September 1, 2002
• Primary Completion: January 1, 2009
• Study Completion: January 1, 2009
• Last Updated: March 21, 2014
• Results First Posted: January 28, 2014

Record last verified: 2014-02

Locations

US (43); PR (1)