A Randomized Window of Opportunity Study of Preoperative Letrozole and Simvastatin Versus Letrozole Alone in Stage I-III Hormone Receptor Positive, HER2 Negative Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 40
- 试验地点
- 4
- 主要终点
- Mean percentage change in Ki-67
研究概览
简要总结
This early phase I trial tests whether letrozole with simvastatin works better than letrozole alone to stop tumor cell proliferation in patients with stage I-III hormone receptor positive, HER2 negative invasive breast cancer. Letrozole and simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The addition of simvastatin to letrozole may be more effective at stopping the growth of cancer cells than letrozole alone.
详细描述
PRIMARY OBJECTIVE:
I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in a decrease of Ki67, a biomarker of tumor proliferation, in postmenopausal women with stage I-III, hormone receptor positive, HER2 negative breast cancer following 14 days of pre-surgical therapy.
SECONDARY OBJECTIVES:
I. To determine if the addition of simvastatin to letrozole compared to letrozole alone will result in increased immune activation from pre- to post-treatment, based on the evaluation of the immune subtype composition in the tissue via multiplex immunofluorescence.
II. To determine if changes (from pre- to post-treatment) in immune activation correlate with changes in antiproliferative response, based on Ki-67 (from pre- to post-treatment).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Pathologists are blinded to each other's data and data from earlier analyses of samples.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Age >= 18 years
- •Biopsy proven hormone receptor positive, HER2 negative stage I-III invasive breast cancer
- •Estrogen receptor (ER) and/or progesterone receptor (PR) positivity are defined as >= 10% of cells expressing hormonal receptors via IHC analysis
- •HER2 negativity is defined as either of the following by local laboratory assessment
- •IHC 0, 1+, or 2+ and in situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell)
- •Minimum primary tumor size 5 mm on any breast imaging (mammogram, ultrasound, magnetic resonance imaging [MRI])
- •Baseline Ki-67 IHC expression on tumor tissue >= 10%
- •Post-menopausal women
- •Prior bilateral oophorectomy
- •Age >= 55 years
- •Age < 55 and amenorrheic for 12 months or more in the absence of chemotherapy, endocrine therapy, or ovarian suppression and follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol in the postmenopausal range
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Prior treatment:
- •No systemic therapy (chemotherapy, immunotherapy, endocrine therapy, and/or investigational therapy) within 3 months of trial enrollment
- •No statins, fibrates, or ezetimibe within 3 months of trial enrollment
- •No active liver disease
- •Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to initiation of study treatment)
- •Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth factor support or transfusion) (within 14 days prior to initiation of study treatment)
- •Platelets >= 100,000/mcL (within 14 days prior to initiation of study treatment)
- •Total bilirubin =< 2 institutional upper limit of normal (ULN) (within 14 days prior to initiation of study treatment)
- •Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 institutional ULN (within 14 days prior to initiation of study treatment)
- •Serum creatinine =< 2 mg/dL (or glomerular filtration rate >= 40 mL/min) (within 14 days prior to initiation of study treatment)
- •Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
- •Be willing and able to provide written informed consent for the trial
排除标准
- •Patients who are receiving any other investigational agents or an investigational device within 3 months before administration of first dose of study drugs
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin and/or letrozole
- •Concomitant use of strong CYP3A4 inhibitors (i.e. clarithromycin, erythromycin, itraconazole, ketroconazole, nefazodone, Posaconazole, voriconazole, protease inhibitors [including boceprevir and telaprevir], telithromycin, cobicistat-containing products), cyclosporine, danazol, and gemfibrozil
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, substance abuse disorders, or psychiatric illness/social situations that would limit compliance with study requirements
- •Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; or uncontrolled grade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite antihypertensive therapy
- •Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy
研究组 & 干预措施
Arm I (letrozole, simvastatin)
Patients receive letrozole PO QD and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Simvastatin (Drug)
Arm I (letrozole, simvastatin)
Patients receive letrozole PO QD and simvastatin PO QD for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Letrozole (Drug)
Arm II (letrozole)
Patients receive letrozole PO QD for 14 days in the absence of disease progression or unacceptable toxicity.
干预措施: Letrozole (Drug)
结局指标
主要结局
Mean percentage change in Ki-67
时间窗: From pre-surgical baseline to 14 days following preoperative therapy
Negative change denotes reduction. Ki-67 is a validated surrogate marker for disease-free survival in patients with hormone receptor positive (HR+), HER2- breast cancer. Ki-67 values at 14 days are expressed as geometric mean proportions of the baseline and transformed into percentage change. Geometric mean percentage change of Ki-67 from pre- to post-treatment is calculated and compared between the two treatment arms. A two-sided Mann-Whitney U or Wilcoxon Rank-Sum test is used.
次要结局
- Response per Ki-67(Through study completion, an average of 1 year)
- Change in the level of the following immune biomarkers: Percentage of CD8+ T cells, percentage of FOXp3 Treg cells, ratio of CD8+/Treg ratio(Through study completion, an average of 1 year)
- Incidence of adverse events(Up to 30 days after surgery)
- Patient-Reported Outcomes Measurement Information System (PROMIS) for pain(Up to 30 days after surgery)
研究者
Ruth Sacks
Principal Investigator
Emory University