Trials / Completed

CompletedNCT02682693

Denosumab as an add-on Neoadjuvant Treatment (GeparX)

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)

Status: Completed
Phase: Phase 2
Study type: Interventional
Enrollment: 780 (actual)

Sponsor: GBG Forschungs GmbH · Academic / Other
Sex: All
Age: 18 Years – 75 Years
Healthy volunteers: Not accepted

Summary

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.

Detailed description

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.

Conditions

Interventions

Type	Name	Description
DRUG	Denosumab	Denosumab 120 mg every 4 weeks for 6 cycles
DRUG	nab-Paclitaxel	nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks)
DRUG	Epirubicin	Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times
DRUG	Cyclophosphamide	Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times
DRUG	Carboplatin	Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel
DRUG	Trastuzumab	Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles
DRUG	Pertuzumab	Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles

Timeline

Start date: 2017-02-13
Primary completion: 2019-12-31
Completion: 2020-12-31
First posted: 2016-02-15
Last updated: 2021-02-02

Locations

1 site across 1 country: Germany

Source: ClinicalTrials.gov record NCT02682693. Inclusion in this directory is not an endorsement.