Investigating Denosumab as an add-on Neoadjuvant Treatment for RANK-positive or RANK-negative Primary Breast Cancer and Two Different Nab-Paclitaxel Schedules ; 2x2 Factorial Design (GeparX)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 780
- 试验地点
- 1
- 主要终点
- pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.
研究概览
简要总结
Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models.
In a retrospective analysis it could be demonstrated that elevated expression of RANK was found in 14.5% of patients overall, with a significant predominance in patients with hormone-receptor-negative disease. Expression of RANK was associated with a higher pathological complete response rate but with a shorter disease-free and overall survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity.
It appears therefore reasonable to test denosumab, a clinically available antibody against RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation to the expression of RANK.
详细描述
RANK ligand (RANKL), a key factor for bone remodeling and metastasis, is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mouse and human mammary epithelium via its receptor RANK and has a role in ovarian hormone-dependent expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models.
In a retrospective analysis of 601 patients treated in the GeparTrio study with chemotherapy (TAC) it could be demonstrated that elevated expression of RANK (immunohistochemical score > 8.5 using the N-1H8 antibody by Amgen) was found in 14.5% of patients overall, with a significant predominance in patients with hormone-receptor-negative disease (33.7% vs 6.4% tumors positive for RANK). Expression of RANK was associated with a higher pathological complete response rate (pCR) (23.0% vs 12.6%) but with a shorter disease-free and overall survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity. Moreover denosumab improves disease-free survival in postmenopausal woman with hormone receptor positive breast cancer.
It appears therefore reasonable to test denosumab, a clinically available antibody against RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation to the expression of RANK.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Denosumab
Denosumab every 4 weeks for 6 cycles.
干预措施: Denosumab (Drug)
nab-Paclitaxel weekly
nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel.
干预措施: nab-Paclitaxel (Drug)
nab-Paclitaxel weekly
nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel.
干预措施: Carboplatin (Drug)
nab-Paclitaxel weekly
nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel.
干预措施: Trastuzumab (Drug)
nab-Paclitaxel weekly
nab-Paclitaxel weekly for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin in parallel to nab-paclitaxel.
干预措施: Pertuzumab (Drug)
nab-paclitaxel 2 of 3 weeks
nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel.
干预措施: nab-Paclitaxel (Drug)
nab-paclitaxel 2 of 3 weeks
nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel.
干预措施: Carboplatin (Drug)
nab-paclitaxel 2 of 3 weeks
nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel.
干预措施: Trastuzumab (Drug)
nab-paclitaxel 2 of 3 weeks
nab-Paclitaxel day 1,8 q22 for 12 weeks. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab. Patients with triple-negative tumors receive Carboplatin weekly in parallel to nab-paclitaxel.
干预措施: Pertuzumab (Drug)
EC every two weeks or every three weeks
Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
干预措施: Epirubicin (Drug)
EC every two weeks or every three weeks
Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
干预措施: Cyclophosphamide (Drug)
EC every two weeks or every three weeks
Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
干预措施: Trastuzumab (Drug)
EC every two weeks or every three weeks
Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
干预措施: Pertuzumab (Drug)
结局指标
主要结局
pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.
时间窗: 24 weeks
pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks
时间窗: 12 weeks
次要结局
- To test for interaction of denosumab treatment with RANK expression.(24 weeks)
- To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+ tumors.(24 weeks)