Refining Tamoxifen Dose for Premenopausal Breast Cancer Risk Reduction (RENAISSANCE): A Phase II Single Arm Trial
概览
- 阶段
- 2 期
- 干预措施
- Biopsy Procedure
- 疾病 / 适应症
- Breast Carcinoma
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 200
- 试验地点
- 19
- 主要终点
- Proportion of women who have a response at any time point
- 状态
- 招募中
- 最后更新
- 19天前
概览
简要总结
This phase II trial evaluates response-guided low-dose tamoxifen for reducing breast density in women who are at higher than average risk for breast cancer. Increasing breast density is a well established risk factor for breast cancer. Tamoxifen is a selective estrogen receptor modulator. It works by blocking the effects of the hormone estrogen in the breast. Tamoxifen has been shown to reduce breast density, even at reduced dosages, and is approved for the prevention of breast cancer.
详细描述
PRIMARY OBJECTIVE: I. To evaluate whether the overall proportion of premenopausal tamoxifen responders (defined by absolute dense area reduction on mammogram of \> 10%) can be increased through a strategy of within-individual dose escalation among non-responders from 5 mg per day to 10 mg per day. SECONDARY OBJECTIVES: I. To assess the association of plasma levels of major tamoxifen metabolites with tamoxifen dose and breast density changes from baseline. II. To evaluate longitudinal change from baseline in serum biomarkers of tamoxifen response at each dose level: sex hormone binding globulin (SHBG), insulin like growth factor 1 (IGF-1) and C-reactive protein (CRP). III. To assess the association of baseline dense area (continuous variable) with tamoxifen response. IV. To evaluate the impact of tamoxifen dose on participant-reported symptoms (Breast Eight Symptom Scale, BESS). V. To evaluate the impact of tamoxifen dose on adherence to final tamoxifen dose. EXPLORATORY OBJECTIVES: I. To evaluate breast tissue-based biomarkers (in research biopsy samples) that associate with tamoxifen response at six months, comparing within-person change in responders and non-responder. II. To assess the association between single nucleotide polymorphisms that overlap between risk of breast cancer and dense are of breasts; and others that relate to efficiency of tamoxifen metabolism. III. To evaluate change in breast cancer risk estimates from baseline to 18 months, as assessed by an AI (artificial intelligence) tool and compare changes by dose group. OUTLINE: This is a within-participant dose-escalation study of tamoxifen. Participants receive tamoxifen 5mg orally (PO) once daily (QD) for 6 months. Participants with absolute dense area reduction (aDAR) \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study. After completion of study intervention, patients are followed up at 4 weeks.
研究者
入排标准
入选标准
- •Premenopausal women at the time of enrollment defined by any of the following:
- •Age under 50 years and regular menstruation (most recent period within the past 3 months)
- •Age under 50 years and continuous hormonal contraception use and at least one intact ovary
- •Women who are not postmenopausal based on serum hormone levels. Women with estradiol =\< 30 pg/mL, follicle-stimulating hormone (FSH) \>= 30 IU/mL are eligible
- •Women with any of the following:
- •A history of unilateral estrogen receptor (ER) positive ductal carcinoma in situ (DCIS) with local therapy completed (as determined by treating physician recommendation and patient acceptance) at least 1 month prior to study entry. (The untreated breast will be the study breast, for both imaging and optional biopsy)
- •Recent or prior lobular carcinoma in situ (LCIS), or any form of epithelial atypia, flat epithelial (FEA), atypical ductal hyperplasia (ADH), or atypical lobular hyperplasia (ALH)
- •Are risk eligible for preventive medication based on a five-year risk of 1.7% or greater, estimated with a validated model: the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool, Tyrer-Cusick, Breast Cancer Surveillance Consortium. If the Tyrer-Cuzick model is used a ten-year risk of 3.4% or greater is acceptable
- •Are tamoxifen-eligible by American Society of Clinical Oncology (ASCO) guidelines (\>= 2-fold increased risk compared to peer if age \>= 45 years, and \>= 4-fold increased risk if age \< 45 years)
- •A history of mantle radiotherapy
排除标准
- •BIRADS breast density category A on most recent mammogram
- •History of selective estrogen receptor modulator (SERM) use within the past 5 years unless:
- •Use was less than 6 months duration in the past 5 years and not used in the 1 year prior to enrollment OR
- •Use was no greater than 2 months duration in the past 1 year and not used in the 6 months prior to enrollment
- •History of invasive breast cancer
- •Prior bilateral mastectomy or breast augmentation surgery including breast implants. Prior bilateral excisional surgical biopsy, mastopexy (breast lift) or mammoplasty (breast reduction) is allowed, as long as \> 1 year has passed since the procedure
- •Women with "mosaic mammographic screening views", i.e., whose larger breast size precludes being imaged within a single mammographic screening view
- •Current use of a strong CYP3A4 inducer or a strong CYP2D6 inhibitor unless willing and able to discontinue use and switch to an alternative medication for the duration of participation, under the advice of their physician. If the physician believes the current medication cannot be replaced, the participant will not be eligible
- •Current use of Warfarin
- •Planning to become pregnant within the next two years. Potential study participants will be questioned about this and excluded if they are planning pregnancy over the next 20 months
研究组 & 干预措施
Prevention (tamoxifen)
Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.
干预措施: Biopsy Procedure
Prevention (tamoxifen)
Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.
干预措施: Biospecimen Collection
Prevention (tamoxifen)
Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.
干预措施: Mammography
Prevention (tamoxifen)
Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.
干预措施: Questionnaire Administration
Prevention (tamoxifen)
Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.
干预措施: Tamoxifen
结局指标
主要结局
Proportion of women who have a response at any time point
时间窗: At 6, 12, and 18 months
Tamoxifen response is defined as absolute dense area reduction (aDAR) of \>= 10% on mammogram compared to baseline mammogram. A one sample exact binomial test for one proportion will be used, and the exact two-sided p-value will be reported. Response rate for the entire study population, as well as for the group of women who were dose-escalated, will be estimated and reported with the corresponding 95% confidence interval. Absolute and relative changes in dense area will be estimated using descriptive statistics (e.g., mean and standard deviation, or median and interquartile range), and, as a sensitivity analysis, a paired t-test or the signed rank test will be used to determine whether there was a reduction in dense area. Similar descriptive statistics will be performed in each dose sequence group for both the response rate and dense area changes.
次要结局
- Plasma levels of major tamoxifen (TAM) metabolites(At 6, 12, and 18 months)
- Longitudinal change in serum biomarkers of tamoxifen response(From baseline up to 18 months)
- Baseline dense area(Up to 18 months)
- Patient-reported symptoms(At baseline, 6, 12, and 18 months)
- Adherence to final tamoxifen dose(Up to 18 months)