Breast Cancer
Conditions
Keywords
breast cancer
Brief summary
RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development or recurrence of cancer. The use of LY353381 may be an effective way to prevent the development of breast cancer in women who have hyperplasia. PURPOSE: Randomized phase II trial to study the effectiveness of LY353381 in preventing breast cancer in women who have hyperplasia.
Detailed description
OBJECTIVES: * Determine if LY353381 hydrochloride improves baseline cytology in women at high risk for breast cancer. * Determine if this drug modulates other potential surrogate endpoint biomarkers or drug effect biomarkers. * Determine if cytologic improvement is associated with initial presentation of the various stratification factors. * Determine whether cytology is correlated with other potential surrogate endpoint biomarkers or drug effect biomarkers and whether change in cytology is correlated with change in the other biomarkers. * Monitor the effects of this drug in terms of quality of life and women's health. OUTLINE: This is a randomized, double-blind, multicenter study followed by an open-label study for both arms. Patients are stratified according to cytologic status (hyperplasia with atypia vs hyperplasia without atypia), mutation status (known carrier for BRCA1 or BRCA2 genes vs known not to be a carrier of mutant genes), menopausal status (premenopausal vs postmenopausal), estrogen-receptor status, and participating center. Patients are randomized to one of two treatment arms. * Arm I: Patients receive oral LY353381 hydrochloride once daily for 6 months. * Arm II: Patients receive oral placebo once daily for 6 months. Patients in both arms then receive oral LY353381 hydrochloride for an additional 6 months. Quality of life is assessed at baseline and then at 6 and 12 months. Patients are followed at 2 weeks and then annually for 5 years. PROJECTED ACCRUAL: A total of 210-220 patients will be accrued for this study within 2.5-3 years.
Interventions
DRUGarzoxifene
one tablet daily
DRUGPlacebo
matched tablet dialy
Sponsors
National Cancer Institute (NCI)
University of Kansas Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
DISEASE CHARACTERISTICS: * Current random fine needle breast aspiration (FNA) evidence of 1 of the following: * Hyperplasia with atypia * Hyperplasia without atypia but with a 10-year modified Gail risk of at least 4% * Hyperplasia without atypia but with a BRCAPRO risk of at least 25% * Hyperplasia without atypia but with a known mutation in BRCA1 or BRCA2 * Hyperplasia without atypia but with a history of contralateral ductal carcinoma in situ or invasive breast cancer * FNA must have been taken during days 1-14 of the menstrual cycle for premenopausal women * Classified as ACR class I-III on mammogram with stepwedge within past 6 months If intact uterus and/or ovaries, must have color doppler transvaginal pelvic sonogram within past 6 months showing endometrial thickening no greater than 13 mm premenopausal or no greater than 8 mm postmenopausal * No ovarian cysts felt to be possibly or probably non-physiologic that have not resolved to gynecologist's satisfaction on repeat sonogram * Must agree to have or have had genetic counseling and genetic testing performed for BRCA1 and BRCA2 * No active cancer (e.g., detectable disease) * Hormone receptor status: * Not specified PATIENT CHARACTERISTICS: Age: * 18 and over Sex: * Female Menopausal status: * Any Performance status: * Not specified Life expectancy: * At least 12 months Hematopoietic: * Hemoglobin greater than 10 g/dL * Granulocyte count greater than 1,000/mm\^3 * No deficiencies in protein C, protein S, or antithrombin III * No activated protein C resistance Hepatic: * Albumin greater than 3.0 g/dL * Bilirubin less than 1.5 mg/dL * AST less than 100 U/L * Alkaline phosphatase less than 200 U/L Renal: * Creatinine less than 1.5 mg/dL Cardiovascular: * No history of deep venous thrombosis not related to trauma or pregnancy * No severe coronary artery disease * No history of prior stroke Other: * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after study * No other active cancer * No retinal vein thrombosis * No concurrent severe poorly controlled migraine * No factor V Leiden mutation carrier PRIOR CONCURRENT THERAPY: Biologic therapy: * At least 12 months since prior immunotherapy Chemotherapy: * At least 3 months between completion of prior KUMC phase II difluoromethylornithine (DFMO) study and baseline aspiration * At least 12 months since prior chemotherapy Endocrine therapy: * Must not have started or stopped hormone replacement therapy or oral contraceptives within 6 months of baseline aspiration * Must continue all hormone replacement therapy and/or oral contraceptives that were being taken at time of baseline aspiration * At least 12 months since prior tamoxifen, raloxifene, or other antihormonal therapy Radiotherapy: * At least 3 months since prior radiotherapy Surgery: * At least 6 months between prior oophorectomy and baseline aspiration Other: * At least 2 weeks since the start of other new medication that would be ingested for 1 or more months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Masood Score | Baseline to 6 months | Change in the semi-quantitative score assigned by the designated cytopathologist. Range 6-24. Score represents increasing abnormality (i.e., worse appearance) Sum composite of 6 cytomorphological features, each scored as 1-4. |
| Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months | Baseline to 6 months | Change (improvement) in categorical descriptor of cytologic abnormality as assigned by the primary cytopathologist. Categories include: normal (non-proliferative), epithelial hyperplasia, epithelial hyperplasia with atypia. |
Countries
United States
Participant flow
Recruitment details
Screen by random periareolar fine needle aspiration for presence of hyperplasia or hyperplasia with atypia.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo
Placebo: matched tablet dialy | 101 |
| Arzoxifene LY353381, 20 mg daily
arzoxifene: one tablet daily | 98 |
| Total | 199 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 8 | 10 |
Baseline characteristics
| Characteristic | Total | Placebo | Arzoxifene |
|---|---|---|---|
| Age at First Live Birth | 20.4 years STANDARD_DEVIATION 11.2 | 20.6 years STANDARD_DEVIATION 10.4 | 20.2 years STANDARD_DEVIATION 12.1 |
| Age at Menarche | 12.79 years STANDARD_DEVIATION 1.43 | 12.78 years STANDARD_DEVIATION 1.42 | 12.82 years STANDARD_DEVIATION 1.45 |
| Age, Continuous | 46.6 years STANDARD_DEVIATION 6.9 | 46.5 years STANDARD_DEVIATION 7.1 | 46.7 years STANDARD_DEVIATION 6.6 |
| BMI | 26.1 kg/m^2 STANDARD_DEVIATION 5.6 | 26.3 kg/m^2 STANDARD_DEVIATION 5.5 | 26.0 kg/m^2 STANDARD_DEVIATION 5.8 |
| Height | 65.0 inches STANDARD_DEVIATION 2.5 | 64.8 inches STANDARD_DEVIATION 2.6 | 65.1 inches STANDARD_DEVIATION 2.4 |
| Hormone Use None | 135 Participants | 66 Participants | 69 Participants |
| Hormone Use OC or HRT Use | 64 Participants | 35 Participants | 29 Participants |
| Menopause Status Post | 96 Participants | 49 Participants | 47 Participants |
| Menopause Status Pre | 103 Participants | 52 Participants | 51 Participants |
| Number relatives with Breast Cancer 0 Relatives | 50 Participants | 23 Participants | 27 Participants |
| Number relatives with Breast Cancer 1 Relative | 105 Participants | 53 Participants | 52 Participants |
| Number relatives with Breast Cancer 2 Relatives | 40 Participants | 23 Participants | 17 Participants |
| Number relatives with Breast Cancer 3 Relatives | 4 Participants | 2 Participants | 2 Participants |
| Prior Biopsy | 34 Participants | 17 Participants | 17 Participants |
| Region of Enrollment United States | 199 participants | 101 participants | 98 participants |
| Sex: Female, Male Female | 199 Participants | 101 Participants | 98 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 156 lb STANDARD_DEVIATION 36 | 156 lb STANDARD_DEVIATION 32 | 157 lb STANDARD_DEVIATION 40 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 100 / 101 | 97 / 98 |
| serious Total, serious adverse events | 5 / 101 | 9 / 98 |
Outcome results
Primary
Change in Masood Score
Change in the semi-quantitative score assigned by the designated cytopathologist. Range 6-24. Score represents increasing abnormality (i.e., worse appearance) Sum composite of 6 cytomorphological features, each scored as 1-4.
Time frame: Baseline to 6 months
Population: Analysis is restricted to subjects that complete the initial 6-month portion of the trial, have a repeat random periareolar fine needle aspiration, and are thus evaluable for change in Masood score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Masood Score | -1.1 units on a scale | Standard Deviation 1.9 |
| Arzoxifene | Change in Masood Score | -0.8 units on a scale | Standard Deviation 2.1 |
Primary
Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months
Change (improvement) in categorical descriptor of cytologic abnormality as assigned by the primary cytopathologist. Categories include: normal (non-proliferative), epithelial hyperplasia, epithelial hyperplasia with atypia.
Time frame: Baseline to 6 months
Population: Analysis is restricted to subjects that complete the initial 6-month portion of the trial, have a repeat random periareolar fine needle aspiration, and are thus evaluable for change in cytomorphology category.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months | No Improvement | 53 Participants |
| Placebo | Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months | Improvement | 31 Participants |
| Arzoxifene | Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months | No Improvement | 52 Participants |
| Arzoxifene | Number of Participants With Improvement From Baseline in Cytomorphologic Abnormality at 6 Months | Improvement | 30 Participants |