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

Osteoporosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00050011
• Other study ID #: CZOL446EUS32
• Status: Completed
• Phase: Phase 3
• First received: November 18, 2002
• Last updated: February 21, 2014
• Start date: September 2002
• Est. completion date: January 2009

Study information

• Verified date: February 2014
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical 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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 602
• Est. completion date: January 2009
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 85 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Breast Neoplasms
• Osteoporosis

Intervention

Drug:
• Zoledronic Acid
Participants received Zoledronate 4 mg IV 15-minute infusion every 6 months.
• Letrozole
Participants received Letrozole 2.5 mg daily.

Locations

Country	Name	City	State
Puerto Rico	VA Medical Center	San Juan
United States	New Mexico Oncology Hematology, Ltd.	Albuquerque	New Mexico
United States	Hematology-Oncology Centers of the Northern Rockies, PC	Billings	Montana
United States	Odyssey Research Services	Bismarck	North Dakota
United States	Hemoncare PC	Brooklyn	New York
United States	FL Community Cancer Center	Brooksville	Florida
United States	St. Joseph Regional Cancer Center	Bryan	Texas
United States	East Valley Hematology & Oncology	Burbank	California
United States	Nashat Y. Gabrail MD Inc.	Canton	Ohio
United States	Charleston Hematology Oncology	Charleston	South Carolina
United States	Oncology Partners Network	Cincinnati	Ohio
United States	Physician Associates, Inc.	Cincinnati	Ohio
United States	Cancer Specialists of South Texas	Corpus Christi	Texas
United States	Center for Oncology Research & Tx. PA	Dallas	Texas
United States	Dayton Clinical Oncology Program	Dayton	Ohio
United States	Elmhurst Memorial Hospital	Elhurst	Illinois
United States	Northern Virginia Oncology Group	Fairfax	Virginia
United States	Frederick Memorial Hospital Regional Cancer Therapy Center	Frederick	Maryland
United States	Robert R. Carroll, MD, PA	Gainesville	Florida
United States	Cook Research Department at Spectrum Health	Grand Rapids	Michigan
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	Kentuckiana Cancer Institute	Louisville	Kentucky
United States	Oncology Hematology Group of South Florida	Miami	Florida
United States	Clinical Trials & Research Associates, Inc.	Montebello	California
United States	Hematology-Oncology Associates of Northern NJ	Morristown	New Jersey
United States	The Sarah Cannon Cancer Center	Nashville	Tennessee
United States	Pasco Pinellas Cancer Center	New Port Richey	Florida
United States	Eastern Connecticut Hematology/Oncology Associates	Norwich	Connecticut
United States	Ocala Oncology Center	Ocala	Florida
United States	Methodist Cancer Center	Omaha	Nebraska
United States	University of Pittsburgh Cancer Institute/Magee Womens Hospital	Pittsburgh	Pennsylvania
United States	Cancer Research Network, Inc.	Plantation	Florida
United States	Cancer and Blood Institute of the Desert	Rancho Mirage	Colorado
United States	Virginia Physicians, Inc.- Oncology	Richmond	Virginia
United States	Redwood Regional Medical Group	Santa Rosa	California
United States	Swedish Cancer Institute	Seattle	Washington
United States	Rockwood Clinic, PS	Spokane	Washington
United States	Highlands Oncology Group	Springdale	Arkansas
United States	Metro Minnesota CCOP	St. Louis Park	Minnesota
United States	Bay Area Oncology	Tampa	Florida
United States	Space Coast Medical	Titusville	Florida
United States	New England Hematology/Oncology Associates	Wellesley	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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.	Baseline, 2 years, 3 years, 5 years	No
Secondary	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.	Baseline, 12 months, 2 years, 3 years, 5 years	No
Secondary	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.	Baseline, 12 months, 2 years, 3 years, 5 years	No
Secondary	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.	3 years	No
Secondary	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.	over 5 years	No
Secondary	Rate of Change From Baseline in Lumbar Spine (L1-L4) BMD	The rate of change from baseline in BMD was assessed.	Baseline, 5 years	No
Secondary	Rate of Change From Baseline in Total Hip BMD	The rate of change from baseline in BMD was assessed.	Baseline, 5 years	No