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Breast NeoplasmsPhase 3NCT00050011

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

A Phase 3 study testing Zoledronic Acid and Letrozole in people with Breast Neoplasms and Osteoporosis, run by Novartis Pharmaceuticals at 44 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 to 85 years, women only
Conditions the study is for
Breast Neoplasms, Osteoporosis
What is being tested?
Zoledronic Acid and Letrozole
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
602 participants
Where
44 sitesin 2 countries
Study dates
Sep 2002to Jan 2009
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 85 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
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  • 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:
  • 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.
  • Patients who have undergone neoadjuvant chemotherapy are eligible.
  • No prior treatment with Femara.

Who cannot join

  • 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.
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  • 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.
  • Uncontrolled seizure disorders associated with falls.
  • Patients with abnormal renal function as evidenced by a serum creatinine equal to or greater than 3 mg/dL (265.2 mmol/L).
  • 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.
  • Patients with baseline lumber spine or total hip BMD T-score below -2.0 SD.
  • 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.
  • Additional Exclusion Criteria: (for Spine DXA)
  • 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.
  • Additional protocol-defined inclusion/exclusion criteria may apply.

Trial locations and contacts

44 sites in 2 countries.

44 sites in 2 countries

United States43 sites

  • New Mexico Oncology Hematology, Ltd.

    Albuquerque, New Mexico, 87109

  • Hematology-Oncology Centers of the Northern Rockies, PC

    Billings, Montana, 59101

  • Odyssey Research Services

    Bismarck, North Dakota, 58501

  • Hemoncare PC

    Brooklyn, New York, 11235

  • FL Community Cancer Center

    Brooksville, Florida, 34613

  • St. Joseph Regional Cancer Center

    Bryan, Texas, 77802

  • East Valley Hematology & Oncology

    Burbank, California, 91505

  • Nashat Y. Gabrail MD Inc.

    Canton, Ohio, 44718

  • Charleston Hematology Oncology

    Charleston, South Carolina, 29403

  • Oncology Partners Network

    Cincinnati, Ohio, 45238

  • Physician Associates, Inc.

    Cincinnati, Ohio, 45238

  • Cancer Specialists of South Texas

    Corpus Christi, Texas, 78412

  • Center for Oncology Research & Tx. PA

    Dallas, Texas, 75230

  • Dayton Clinical Oncology Program

    Dayton, Ohio, 45420

  • Elmhurst Memorial Hospital

    Elhurst, Illinois, 60126

  • Northern Virginia Oncology Group

    Fairfax, Virginia, 22031

  • Frederick Memorial Hospital Regional Cancer Therapy Center

    Frederick, Maryland, 21701

  • Robert R. Carroll, MD, PA

    Gainesville, Florida, 32605

  • Cook Research Department at Spectrum Health

    Grand Rapids, Michigan, 49503

  • Louisiana Oncology Associates

    Lafayette, California, 70506

  • Wilshire Oncology Medical Group

    LaVerne, California, 91750

  • Pacific Shores Medical Group

    Long Beach, California, 90813

  • Kentuckiana Cancer Institute

    Louisville, Kentucky, 40202

  • Oncology Hematology Group of South Florida

    Miami, Florida, 33176

  • Clinical Trials & Research Associates, Inc.

    Montebello, California, 90640

  • Hematology-Oncology Associates of Northern NJ

    Morristown, New Jersey, 07962

  • The Sarah Cannon Cancer Center

    Nashville, Tennessee, 37203

  • Pasco Pinellas Cancer Center

    New Port Richey, Florida, 34652

  • Eastern Connecticut Hematology/Oncology Associates

    Norwich, Connecticut, 06360

  • Ocala Oncology Center

    Ocala, Florida, 33479

  • Methodist Cancer Center

    Omaha, Nebraska, 68114

  • University of Pittsburgh Cancer Institute/Magee Womens Hospital

    Pittsburgh, Pennsylvania, 15213

  • Cancer Research Network, Inc.

    Plantation, Florida, 33324

  • Cancer and Blood Institute of the Desert

    Rancho Mirage, Colorado, 92270

  • Virginia Physicians, Inc.- Oncology

    Richmond, Virginia, 23294

  • Metro Minnesota CCOP

    Saint Louis Park, Minnesota, 55416

  • Redwood Regional Medical Group

    Santa Rosa, California, 95403

  • Swedish Cancer Institute

    Seattle, Washington, 98122

  • Rockwood Clinic, PS

    Spokane, Washington, 99220

  • Highlands Oncology Group

    Springdale, Arkansas, 72764

  • Bay Area Oncology

    Tampa, Florida, 33607

  • Space Coast Medical

    Titusville, Florida, 32796

  • New England Hematology/Oncology Associates

    Wellesley, Massachusetts, 02481

Other trials in United States

Puerto Rico1 site

  • VA Medical Center

    San Juan, 00927

Other trials in Puerto Rico

About this study

Official title: An Open-Label, Randomized, Multicenter Study to Evaluate the Use of Zoledronic Acid in the Prevention of Cancer Treatment-Related Bone Loss in Postmenopausal Women With Estrogen Receptor Positive and/or Progesterone Receptor Positive Breast Cancer Receiving Letrozole as Adjuvant Therapy

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.

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
Medical subject headings
Breast Neoplasms, Osteoporosis, Bone Diseases, Metabolic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Zoledronic AcidDrug

    Also called ZOL446, Zoledronate

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

  • LetrozoleDrug

    Also called Femara

    Participants received Letrozole 2.5 mg daily.

Study groups in NCT00050011
Study groupRoleWhat they receive
Zoledronic Acid upfrontExperimentalParticipants 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.
Receives: Drug: Zoledronic Acid; Drug: Letrozole
Zoledronate delayed-startExperimentalIn 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.
Receives: Drug: Zoledronic Acid; Drug: Letrozole

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Baseline, 12 months

Secondary outcomes (7)

  1. Percent Change From Baseline in Lumbar Spine (L1-L4) 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 Time Frame - Baseline BMD)/Baseline BMD)). Missing data beyond month 12 were not imputed by LOCF.

    Measured: Baseline, 2 years, 3 years, 5 years

  2. Percent Change From Baseline in Total Hip 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 Time Frame - Baseline BMD)/Baseline BMD)). Missing data at month 12 were imputed by using the 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.

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

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

    Blood samples from a subset of participants (231 participants in total) were collected to measure the sNTX and BSAP. Missing data at month 12 were imputed by using the LOCF method. Post-baseline non-missing data from months 6 and 9 were carried forward to month 12. Data prior to month 6 were not carried forward. Missing data beyond month 12 were not imputed by LOCF.

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

  4. Incidence Rate of All Clinical Fractures

    The number of participants who experienced a clinical fracture at month 36 was assessed. Initial x-ray (both AP and lateral views) of the lumbar and thoracic spine were performed at baseline to exclude participants with evidence of fracture. In addition, repeated bone scan and/or x-ray were performed at the Principal Investigator's discretion during the course of the study to confirm evidence of clinical fracture, or at month 36 if there was no evidence of clinical fracture (lumbar and thoracic spine - lateral view). X-ray films were sent to a central reader.

    Measured: 3 years

  5. Time to Disease Recurrence/Relapse

    The median time to disease progression was assessed by Kaplan-Meier analysis. The Principal Investigator assessed each participant for disease recurrence at each visit. Further testing was performed at the discretion of the Principal Investigator and as clinically indicated. Disease progression was defined as chest wall and/or regional recurrence confirmed by positive cytology or biopsy, and/or distance recurrence of the 1) skin, subcutaneous tissue, and lymph nodes (other than local or regional), 2) bone marrow, 3) lung, 4) skeleton 5) liver and 6) central nervous system confirmed by positive cytology, biopsy, aspirate or radiology as appropriate.

    Measured: over 5 years

  6. Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD

    The rate of change from baseline in BMD was assessed.

    Measured: Baseline, 5 years

  7. Rate of Change From Baseline in Total Hip BMD

    The rate of change from baseline in BMD was assessed.

    Measured: Baseline, 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Nov 2002 (estimated)
  2. Study startSep 2002
  3. Primary completionJan 2009
  4. Study completionJan 2009

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
602 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00050011
Sponsor's protocol ID
CZOL446EUS32
Status last verified
Feb 2014
First submitted
18 Nov 2002
Last updated
21 Mar 2014
Data monitoring committee
No

Publications

  • 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.

    PubMed 38979716

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Zoledronic Acid and Letrozole in people with Breast Neoplasms and Osteoporosis, run by Novartis Pharmaceuticals at 44 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Mar 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 44 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Jan 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD) (time frame: Baseline, 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00050011, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Mar 2014.

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