Clinical trial NCT00050011: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2002-11-20
Enrollment: 602
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.


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.

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.

Primary outcomes:
measure: Percent Change From Baseline in Lumbar Spine (L1-L4) Bone Mineral Density (BMD)
timeFrame: Baseline, 12 months
Secondary outcomes:
measure: Percent Change From Baseline in Lumbar Spine (L1-L4) BMD
timeFrame: Baseline, 2 years, 3 years, 5 years
measure: Percent Change From Baseline in Total Hip BMD
timeFrame: Baseline, 12 months, 2 years, 3 years, 5 years
measure: Percent Change From Baseline in Biochemical Markers of Bone Turnover, Serum N-Telopeptide (sNTX) and Bone-specific Alkaline Phosphatase (BSAP)
timeFrame: Baseline, 12 months, 2 years, 3 years, 5 years
measure: Incidence Rate of All Clinical Fractures
timeFrame: 3 years
measure: Time to Disease Recurrence/Relapse
timeFrame: over 5 years
measure: Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD
timeFrame: Baseline, 5 years
measure: Rate of Change From Baseline in Total Hip BMD
timeFrame: Baseline, 5 years
Other outcomes:
Locations:
city: Springdale
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Burbank
country: United States
facility: East Valley Hematology & Oncology
state: California
city: Lafayette
country: United States
facility: Louisiana Oncology Associates
state: California
city: LaVerne
country: United States
facility: Wilshire Oncology Medical Group
state: California
city: Long Beach
country: United States
facility: Pacific Shores Medical Group
state: California
city: Montebello
country: United States
facility: Clinical Trials & Research Associates, Inc.
state: California
city: Santa Rosa
country: United States
facility: Redwood Regional Medical Group
state: California
city: Rancho Mirage
country: United States
facility: Cancer and Blood Institute of the Desert
state: Colorado
city: Norwich
country: United States
facility: Eastern Connecticut Hematology/Oncology Associates
state: Connecticut
city: Brooksville
country: United States
facility: FL Community Cancer Center
state: Florida
city: Gainesville
country: United States
facility: Robert R. Carroll, MD, PA
state: Florida
city: Miami
country: United States
facility: Oncology Hematology Group of South Florida
state: Florida
city: New Port Richey
country: United States
facility: Pasco Pinellas Cancer Center
state: Florida
city: Ocala
country: United States
facility: Ocala Oncology Center
state: Florida
city: Plantation
country: United States
facility: Cancer Research Network, Inc.
state: Florida
city: Tampa
country: United States
facility: Bay Area Oncology
state: Florida
city: Titusville
country: United States
facility: Space Coast Medical
state: Florida
city: Elhurst
country: United States
facility: Elmhurst Memorial Hospital
state: Illinois
city: Louisville
country: United States
facility: Kentuckiana Cancer Institute
state: Kentucky
city: Frederick
country: United States
facility: Frederick Memorial Hospital Regional Cancer Therapy Center
state: Maryland
city: Wellesley
country: United States
facility: New England Hematology/Oncology Associates
state: Massachusetts
city: Grand Rapids
country: United States
facility: Cook Research Department at Spectrum Health
state: Michigan
city: St. Louis Park
country: United States
facility: Metro Minnesota CCOP
state: Minnesota
city: Billings
country: United States
facility: Hematology-Oncology Centers of the Northern Rockies, PC
state: Montana
city: Omaha
country: United States
facility: Methodist Cancer Center
state: Nebraska
city: Morristown
country: United States
facility: Hematology-Oncology Associates of Northern NJ
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology, Ltd.
state: New Mexico
city: Brooklyn
country: United States
facility: Hemoncare PC
state: New York
city: Bismarck
country: United States
facility: Odyssey Research Services
state: North Dakota
city: Canton
country: United States
facility: Nashat Y. Gabrail MD Inc.
state: Ohio
city: Cincinnati
country: United States
facility: Oncology Partners Network
state: Ohio
city: Cincinnati
country: United States
facility: Physician Associates, Inc.
state: Ohio
city: Dayton
country: United States
facility: Dayton Clinical Oncology Program
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute/Magee Womens Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston Hematology Oncology
state: South Carolina
city: Nashville
country: United States
facility: The Sarah Cannon Cancer Center
state: Tennessee
city: Bryan
country: United States
facility: St. Joseph Regional Cancer Center
state: Texas
city: Corpus Christi
country: United States
facility: Cancer Specialists of South Texas
state: Texas
city: Dallas
country: United States
facility: Center for Oncology Research & Tx. PA
state: Texas
city: Fairfax
country: United States
facility: Northern Virginia Oncology Group
state: Virginia
city: Richmond
country: United States
facility: Virginia Physicians, Inc.- Oncology
state: Virginia
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Spokane
country: United States
facility: Rockwood Clinic, PS
state: Washington
city: San Juan
country: Puerto Rico
facility: VA Medical Center
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals, MD
role: STUDY_DIRECTOR
References: