Phase I Dose-Finding Trial of Letrozole in Postmenopausal Women at High Risk for Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- letrozole
- Conditions
- Healthy, no Evidence of Disease
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 112
- Locations
- 3
- Primary Endpoint
- Percentage of serum estradiol suppression in postmenopausal women at high risk for breast cancer
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This randomized phase I trial studies the side effects and the best dose of letrozole in preventing breast cancer in healthy postmenopausal women at high risk for breast cancer. Chemoprevention is the use of drugs to keep breast cancer from forming or coming back. The use of letrozole may keep cancer from forming in healthy postmenopausal women at high risk for breast cancer.
Detailed Description
PRIMARY OBJECTIVES: I. Compare the effect of lower and intermittent doses of letrozole to standard letrozole therapy on estrogen suppression in postmenopausal women at high risk for developing breast cancer. SECONDARY OBJECTIVES: I. Comparison of the effect of lower and intermittent doses of letrozole to standard therapy on signs and symptoms of estrogen deficiency, including menopausal symptoms, serum lipid profile, and serum marker of bone turnover. II. Comparison of the effect of lower and intermittent doses of letrozole to standard therapy on nuclear chromatin abnormality of breast epithelial cells collected by random periareolar fine needle aspiration (RPFNA). TERTIARY OBJECTIVES: I. Determine the prevalence of breast cancer stem cells in the fine needle breast aspirates and explore the potential intervention effect on the prevalence of breast cancer stem cells. OUTLINE: Patients are randomized to 1 of 4 treatment arms. ARM I: Patients receive 2.5 mg of letrozole orally (PO) thrice weekly for 6 months. ARM II: Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months. ARM III: Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months. ARM IV: Patients receive 2.5 mg of letrozole PO once daily for 6 months. After completion of study treatment, patients are followed up at week 30.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy postmenopausal women at "high risk" for breast cancer will be eligible for the study; definition of menopause will be:
- •Amenorrhea for at least 12 months, or
- •History of hysterectomy and bilateral salpingo-oophorectomy, or
- •At least 55 years of age with prior hysterectomy with or without oophorectomy, or
- •Age 35 to 54 with a prior hysterectomy without oophorectomy OR with a status of ovaries unknown with documented follicle-stimulating hormone level demonstrating elevation in postmenopausal range
- •"High risk" for breast cancer will be defined as:
- •Prior histologically confirmed lobular carcinoma in situ (LCIS) treated by local excision only, or
- •At least 1.66% probability of invasive breast cancer within 5 years using the Breast Cancer Risk Assessment Tool
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; Karnofsky 80% or above
- •Leukocytes \>= 3,000/uL
Exclusion Criteria
- •Women diagnosed with osteoporosis (previously or on screening dual-energy X-ray absorptiometry \[DEXA\] for this study) and not on a stable dose of long or short-acting bisphosphonates therapy for at least 3 months will be excluded from the study; women diagnosed with osteoporosis and on raloxifene (Evista) therapy will be excluded from the study; use of calcium and/or vitamin D for osteoporosis prevention or treatment is allowed; women with osteopenia will be allowed to participate in this study
- •Have had invasive cancer within the past five years except non-melanoma skin cancer
- •Evidence of suspicious of malignant disease on bilateral mammogram within the past year unless ruled out by further evaluation
- •History of prior invasive breast cancer or intraductal carcinoma in situ, or history of prior radiation therapy to the chest or breast
- •Participants may not be receiving any other investigational agents; participants may not be concurrently enrolled in another breast cancer prevention intervention trial
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to letrozole
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Within 3 months since prior estrogen or progesterone replacement therapy, oral contraceptives, androgens, luteinizing hormone-releasing hormone analogs, prolactin inhibitors, or antiandrogens
- •Within 3 months since prior tamoxifen, raloxifene, or other selective estrogen-receptor modulators
- •Within 3 months since regular use (more than 2 times a week) of prior estrogenic supplements or herbal remedies
Arms & Interventions
Arm I (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO thrice weekly for 6 months.
Intervention: letrozole
Arm I (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO thrice weekly for 6 months.
Intervention: quality-of-life assessment
Arm I (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO thrice weekly for 6 months.
Intervention: laboratory biomarker analysis
Arm II (1.0 mg letrozole)
Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months.
Intervention: letrozole
Arm II (1.0 mg letrozole)
Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months.
Intervention: quality-of-life assessment
Arm II (1.0 mg letrozole)
Patients receive 1.0 mg of letrozole PO thrice weekly for 6 months.
Intervention: laboratory biomarker analysis
Arm III (0.25 mg letrozole)
Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months.
Intervention: letrozole
Arm III (0.25 mg letrozole)
Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months.
Intervention: quality-of-life assessment
Arm III (0.25 mg letrozole)
Patients receive 0.25 mg of letrozole PO thrice weekly for 6 months.
Intervention: laboratory biomarker analysis
Arm IV (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO once daily for 6 months.
Intervention: letrozole
Arm IV (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO once daily for 6 months.
Intervention: quality-of-life assessment
Arm IV (2.5 mg letrozole)
Patients receive 2.5 mg of letrozole PO once daily for 6 months.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Percentage of serum estradiol suppression in postmenopausal women at high risk for breast cancer
Time Frame: Baseline to week 30
Three one-sided two-sample t-tests will be conducted on the ratios of the mean percentage of suppression simultaneously to test for non-inferiority. A multivariate t-distribution is used to derive the critical value and the power.
Secondary Outcomes
- Menopausal symptoms as assessed by quality of life measures, as assessed by Medical Outcomes Study 36-item Short Form Health Survey (SF-36) and Menopause Specific Quality of Life Questionnaire (MENQOL)(Up to week 30)
- Nuclear chromatin abnormality as assessed by karyometry(Up to week 30)
- Change in serum estrone levels(Baseline to week 30)
- Change in serum testosterone levels(Baseline to week 30)