Official Title: “A Phase III Randomized, Placebo-Controlled, Double-Blind Trial Of Risedronate (Actonel) For Prevention Of Bone Loss In Premenopausal Women Undergoing Chemotherapy For Primary Breast Carcinoma”

RATIONALE: Preventing bone loss in patients who are receiving chemotherapy for breast cancer may decrease the risk of fractures and may help patients live more comfortably. It is not yet known whether calcium is more effective with or without risedronate in preventing bone loss.

PURPOSE: This randomized phase III trial is studying two forms of calcium with or without risedronate to compare how well they work in preventing bone loss in premenopausal women who are receiving chemotherapy for primary stage I, stage II, stage IIIA, or stage IIIB breast cancer.

Study Type: Interventional

Study Design: Supportive Care, Randomized, Double-Blind, Placebo Control

OBJECTIVES: - Compare the effectiveness of risedronate vs placebo in the prevention of bone loss in premenopausal women undergoing adjuvant or neoadjuvant chemotherapy for primary breast cancer. - Compare the degree of bone loss over 1 year in these women according to menopausal status after 1 year of therapy. - Determine the relationship of current climacteric symptoms, menstrual and reproductive history, and chemotherapy regimen with ovarian failure (permanent cessation of menses) in these women. - Determine the relationship of baseline serum estradiol levels with ovarian failure in these women.

OUTLINE: This is a randomized, placebo-controlled, double-blind study. Patients are stratified according to planned tamoxifen therapy (yes vs no vs undecided), planned taxane therapy (yes vs no vs undecided), time from last menses (1-3 months vs longer than 3 months to 6 months), and age (under 40 vs 40 to 49 vs 50 and over). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive oral calcium and oral cholecalciferol daily and oral risedronate once weekly. - Arm II: Patients receive calcium and cholecalciferol as in arm I and oral placebo once weekly.

In both arms, treatment begins during the first month of chemotherapy and continues for 1 year in the absence of unacceptable toxicity.

Questionnaires about cessation of menses, ovarian failure, and menopausal symptoms are completed at baseline, monthly during chemotherapy, at 6 months, and then at 1 and 2 years.

Patients are followed for 1 year.

PROJECTED ACCRUAL: A total of 220 patients (110 per treatment arm) will be accrued for this study within 11 months.

Intervention(s) in this Clinical Trial

• Drug: calcium carbonate
• Drug: cholecalciferol
• Drug: risedronate sodium

Primary Measures

• Average intra-patient change in lumbar spine (L2-L4, PA) bone mineral density (BMD) from baseline to one year after study entry

Secondary Measures

• Average intra-patient change in femoral neck and total hip BMD from baseline to one year after study entry
• Incidence of osteopenia in the risedronate vs placebo groups at one year after study entry
• Incidence of osteoporosis in the risedronate vs placebo groups at one year after study entry
• Incidence of a 5% difference in intra-patient BMD scores at baseline
• Serum and urine N-telopeptide and serum alkaline phosphatase at baseline and 6 months
• Frequency and severity of toxicity as measured by NCI CTC version 2.0
• Menopausal symptoms as measured by the Greene Climacteric Scale (GCS) at baseline, monthly during chemotherapy, at 6 months, 1 year, and 2 years after study entry
• Association of baseline serum estradiol levels with permanent cessation of menses
• Relationship between the subscales of the GCS (psychological, vasomotor, somatic and sexual) with type of chemotherapy, duration of chemotherapy, and menstrual cycle changes

DISEASE CHARACTERISTICS:

• Resectable primary breast cancer
• Stage I-IIIB disease
• Scheduled to undergo adjuvant or neoadjuvant chemotherapy
• No hypercalcemia (calcium level greater than 1 mg/dL above upper limit of normal within the past 6 months)
• No hypocalcemia (calcium level greater than 0.5 mg/dL below lower limit of normal within the past 6 months)
• No diseases affecting bone metabolism (i.e., hyperparathyroidism, hyperthyroidism, and hypercortisolism)
• Bone mineral density T score of -2.0 or greater at the hip or spine (T score of -2.1 or less is ineligible)

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Sex
• Female
• Menopausal status
• Premenopausal meeting the following criteria:
• No more than 6 months since last menstrual period
• No prior bilateral oophorectomy
• Not on estrogen replacement therapy
• If total abdominal hysterectomy performed, then must have at least 1 intact ovary
• If more than 3 months since last menstrual period, then must have premenopausal estrogen levels within 1 month of study entry
• Performance status
• ECOG 0-1
• Life expectancy
• Not specified
• Hematopoietic
• Not specified
• Hepatic
• Not specified
• Renal
• Creatinine no greater than 2.0 mg/dL
• No history of severe renal impairment
• Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception
• Able to stand or sit upright for at least 30 minutes
• No known swallowing disorder
• No history of vertebral compression fracture
• Traumatic fracture of the coccyx allowed
• No malabsorption syndrome

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• Not specified
• Chemotherapy
• See Disease Characteristics
• Endocrine therapy
• No concurrent estrogen
• No concurrent estrogen receptor modulators except tamoxifen
• No corticosteroid dose of prednisone or equivalent greater than 5 mg daily for more than 2 weeks within the past 6 months
• No concurrent estrogen replacement therapy
• No concurrent oral contraceptives
• Radiotherapy
• Not specified
• Surgery
• More than 3 months since prior and no concurrent dental extraction, root canal, or dental implants
• No prior bilateral oophorectomy
• Other
• No prior bisphosphonates
• No other concurrent bisphosphonates

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: North Central Cancer Treatment Group

Overall Clinical Trial Officials and Contacts

Stephanie Hines, MD Study Chair Mayo Clinic  

Information obtained from ClinicalTrials.gov on August 28, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00054418

Study ID Number: CDR0000270449

ClinicalTrials.gov Identifier: NCT00054418

Health Authority: United States: Federal Government

Clinical trial summary from the National Cancer Institute's PDQ® database