Investigating Denosumab as an add-on to neoadjuvant chemotherapy in RANK/L-positive or RANK/L-negative primary breast cancer and two different nab-Paclitaxel schedules in a 2x2 factorial design
EudraCT No.: 2015-001755-72
A trial of AGO Breast und der German Breast Group (GBG)
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 hormonedependent 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) we could demonstrate that elevated expression of RANK (immunohistochemical score > 8.5 using the N-1H8 antibody by Amgen) was found in 14.5% of patients overall.
The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity. Moreover denosumab showed a trend in improvement of 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 primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome overall and in relation to the expression of RANK/L.
The backbone chemotherapy consists of nab-Paclitaxel because the pCR rate in the GeparSepto study could be increased by using nabPaclitaxel instead of sb paclitaxel. Two different nab-Paclitaxel regimen will be compared
Trial is recruting.
This is a multicenter, prospective, 2x2 randomized, open-label phase IIb study to compare neoadjuvant treatment with and without denosumab in patients with untreated breast cancer and two different nab-paclitaxel schedules.
Patients will be first randomized (using Pocock minimization) to one of the following two treatments in addition to neoadjuvant therapy:
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