NCT01864798终止2 期
A Pre-Operative Window Study Evaluating Denosumab, a RANKligand (RANKL) Inhibitor and Its Biological Effects in Young Premenopausal Women Diagnosed With Early Breast Cancer
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 27
- 试验地点
- 6
- 主要终点
- Geometric mean change in tumor Ki67 expression
研究概览
简要总结
This is a prospective, single arm phase IIa trial in which patients with early breast cancer will receive pre-operatively two doses of denosumab 120mg subcutaneously one week apart (maximum 12 days) followed by surgery. Tumor, normal breast tissue and blood samples will be collected at baseline and at surgery. Post-operative treatment will be at the discretion of the investigator.
Primary objective: to determine if a short course of RANKL inhibition with denosumab can induce a decrease in tumor proliferation rates as determined by Ki67 immunohistochemistry (IHC) in newly diagnosed, early stage breast cancer in pre-menopausal women.
Secondary objectives:
- To determine the number of absolute Ki67 responders after a short course of denosumab (defined as <2.7% IHC staining in the post treatment tumor biopsy).
- To determine the effects of a short course of denosumab on serum C-terminal telopeptide levels (CTX).
- To determine the effects of a short course of denosumab on RANK/RANKL gene expression and signaling as assessed by immunohistochemistry (IHC) and RNA sequencing in the tumor.
- To determine the effect of a short course of denosumab on tumor apoptosis rates using IHC
- To determine the effect of a short course of denosumab on modulating the immature mammary epithelial cell populations in the tumor.
- To determine the effect of a short course of denosumab on estrogen signaling pathways in the tumor.
- To determine the effect of a short course of denosumab on various immune
- To determine effect of safety profile of denosumab
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •Female gender
- •Age ≥ 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Premenopausal status defined as the presence of active menstrual cycle or normal menses during the 6 weeks preceding the start of study treatment. Biochemical evidence of phase of menstrual cycle is required (estradiol, FSH and LH). In women previously exposed to hysterectomy,or were using hormonal intrauterine device at the time of enrolment, premenopausal levels of estradiol, FSH and LH are required to be eligible
- •Non-metastatic operable newly diagnosed primary invasive carcinoma of the breast that is:
- •Histologically confirmed
- •Primary tumor size greater than 1.5 cm, measured by any of clinical examination, mammography, ultrasound or magnetic resonance imaging
- •Any clinical nodal status
- •Fully operable and not fixed to chest wall.
- •Known HER2 status
- •Known estrogen receptor (ER) status and progesterone receptor status (PgR)
- •Patient has adequate bone marrow and organ function as shown by:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Platelets ≥ 100 x 109/L
- •Hemoglobin (Hgb) ≥ 9.0 g/dL
- •Serum creatinine ≤ 1.5 x ULN
- •Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
- •AST and ALT ≤ 1.5 x ULN
- •Random blood sugar (RBS) ≤ 200 mg/dL or ≤ 11.1 mmol/L
- •Glycosylated hemoglobin (HbA1c) ≤ 8 %
- •Albumin-adjusted serum calcium ≥ 8.0 mg/dL (≥ 2.0 mmol/L)
- •Women of childbearing potential must agree to use an active local contraception method for the duration of the study and for at least 7 months after the last dose of study treatment
- •Patients must accept to take calcium and vitamin D supplementation until the completion of the study treatment
- •Signed informed consent form (ICF) for all study procedures according to local regulatory requirements prior to beginning of the study
- •Patients must accept to make available tumor and normal tissue samples for submission to central laboratory at the Jules Bordet Institute, Brussels, Belgium, to conduct translational studies as part of this protocol.
排除标准
- •History of any prior (ipsi and/or contralateral) breast cancer
- •Any "clinical" T4 tumor defined by TNM including inflammatory breast cancer
- •History of non-breast malignancies within the 5 years prior to study entry (except carcinoma in situ of the cervix, of the colon, melanoma in situ and basal cell and squamous cell carcinomas of the skin)
- •Prior or planned systemic anti-cancer therapy before definitive surgery
- •Unhealed or planned dental/oral surgery, current or previous osteonecrosis or osteomyelitis of the jaw
- •Pregnant or lactating women or women of childbearing potential without a negative serum or urinary pregnancy test within 7 days prior to starting study treatment; irrespective of the method of contraception used
- •Active Hepatitis-B virus (HBV), Hepatitis-C virus (HCV) or human immunodeficiency virus (HIV) infection
- •Known hypersensitivity to denosumab
- •Bilateral invasive tumors
研究组 & 干预措施
Denosumab
Experimental
干预措施: Denosumab (Drug)
结局指标
主要结局
Geometric mean change in tumor Ki67 expression
时间窗: Baseline and surgery at Day 10
Assessed by immunohistochemistry (IHC) from
次要结局
- TUNEL and caspase-3 apoptosis markers(Baseline and surgery at Day 10)
- Absolute Ki67 responders(Baseline and surgery at Day 10)
- RANK/RANKL gene expression and signalling(Baseline and surgery at Day 10)
- expression of immature mammary epithelial cell population: MaSCs, luminal progenitors , ALDH1(Baseline and surgery at Day 10)
- Safety and tolerability of a short course of denosumab(Day 1, day 8 and surgery Day 10)
- C-terminal telopeptide (CTX) serum levels(Baseline and surgery at Day 10)
- gene expression (AURKA, Ki-67,GGI)(Baseline and surgery at Day 10)
- immune related genes(Baseline and surgery at Day 10)
- Quantity of tumor infiltrating lymphocytes(Baseline and surgery at Day 10)
- gene expression of the estrogen pathways (i.e. ESR1, PgR, BCL2) and estrogen-related gene expression modules (i.e. ESR module)(Baseline and surgery at Day 10)
研究者
研究点 (6)
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