Explorative Trial to Identify the Impact of Denosumab on the Systemic Immunity and Local Immunologic Microenvironment in Postmenopausal Patients With HER2 Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 试验地点
- 8
- 主要终点
- Change in intratumoral T-cell (CD4, CD8 and Treg) numbers and function between the baseline biopsy and the surgical specimen.
研究概览
简要总结
The aim of this prospective, randomized, multicenter, open-label, explorative phase II study is to identify the impact of (neo)adjuvant denosumab on the systemic immunity and local immunologic microenvironment in postmenopausal patients with HER2 negative non-metastatic primary breast cancer.
详细描述
In this study, postmenopausal patients with stage T1c + grade 3, stage II or III, HER2-negative breast cancer, which are planned to undergo surgery followed by adjuvant AC-T chemotherapy, are randomized between no denosumab, denosumab low dosing and denosumab high dosing. Denosumab administration will start one week before surgery and continue until the last chemotherapy cycle.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 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
- •Postmenopausal, defined as 1 year without menstrual activity, previous bilateral oophorectomy, age older than 60 years or baseline FSH >20 U/l and estradiol <110 pmol/l.
- •Clinical stage T1c + grade 3, stage II or III breast cancer amenable to adjuvant AC-T combination chemotherapy.
- •Measurable disease (breast and/or lymph nodes).
- •Histological proven HER2-negative breast cancer in the core biopsy material.
- •Adequate bone marrow function (within 4 weeks prior to randomization): WBC≥3.0x109/l, neutrophils ≥1.5 x 109/l, platelets ≥100 x 109/l.
- •Adequate liver function (within 4 weeks prior to randomization): bilirubin ≤1.5 X upper limit of normal (UNL) range, ALAT and/or ASAT ≤2.5 x UNL, Alkaline Phosphatase ≤5 x UNL.
- •Adequate renal function (within 4 weeks prior to randomization): the calculated creatinine clearance should be ≥50 ml/min.
- •Albumin-adjusted serum calcium > 2.0 mmol/L (8.0mg/dL)
- •Accessible for treatment and follow-up.
- •Written informed consent.
排除标准
- •Evidence of distant metastases (M1).
- •History of breast cancer.
- •Prior chemotherapy or radiation therapy.
- •Previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
- •Prior or current bisphosphonate or denosumab usage.
- •Serious other diseases as recent (last 6 months) myocardial infarction, clinical signs of cardiac failure or clinically significant arrhythmias.
- •Current active dental problems including dental abscess or infection of the jawbone (maxilla or mandible), non-healed dental or oral surgery, a current or prior diagnosis of osteonecrosis of the jaw or planned invasive dental procedures for the course of the study.
- •Known hypersensitivity reaction to any of the components of the treatment.
- •Medical or psychological condition which in the opinion of the investigator would not permit the patient to complete the study or sign meaningful informed consent.
研究组 & 干预措施
Denosumab 120 mg
All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are additionally treated with denosumab 120 mg every 3 weeks. First denosumab gift is before surgery, last denosumab gift is together with the last cycle of chemotherapy.
干预措施: Denosumab 120 mg (Drug)
Denosumab 60 mg
All patients undergo surgery followed by adjuvant chemotherapy. Patients in this study arm are additionally treated with denosumab 60 mg every 6 months. First denosumab gift is before surgery, last denosumab gift is together with the last cycle of chemotherapy.
干预措施: Denosumab 60 mg (Drug)
结局指标
主要结局
Change in intratumoral T-cell (CD4, CD8 and Treg) numbers and function between the baseline biopsy and the surgical specimen.
时间窗: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.
The change will be determined by use of IHC and immunofluorescent stainings.
Change in myeloid cell (M1/M2 Macrophage, MDSC, DC) numbers and function between the baseline biopsy and the surgical specimen.
时间窗: The change can be determined after the surgical specimen is obtained, which is around two weeks after enrolment.
The change will be determined by use of IHC and immunofluorescent stainings.
次要结局
- Shift in activated T effector cell levels.(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Shift in regulatory T-cell levels.(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Change in functional response of T-cells.(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Change in mature and immature myeloid cells (M1/M2 macrophage, MDSC, DC).(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Shift in myeloid cell function.(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Change in stimulation capacity APCs.(Measurements will be done in PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Change in serum levels of RANKL and OPG.(Measurements will be done in serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Change in serum cytokine levels (TNF-alpha, interleukines, IFN gamma).(Measurements will be done in serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment.)
- Correlation of tumor measurements with serum measurements.(Measurements will be done in tumor material and serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.)
- Correlation of tumor measurements with PBMCs measurements.(Measurements will be done in tumor material and PBMCs from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.)
- Correlation of serum measurements and PBMCs measurements.(Measurements will be done in PBMCs/serum from before start treatment, day of surgery and 7 days after last chemotherapy administration, which will be around 8 months after enrolment and tumor material from baseline and surgery.)
- Toxicity according to NCI CTCAE v4.03.(Toxicity will be assessed from start treatment up to 30 days following the last dose of treatment.)
- Difference in descriptive event free survival (EFS) at 3 years based on immune response.(EFS will be determined after 3 years.)