Denosumab as an add-on Neoadjuvant Treatment (GeparX) (GeparX)

February 1, 2021 updated by: German Breast Group

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)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

780

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Berlin, Germany, 10113
        • Charité Campus Mitte

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  • Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration from the breast lesion alone is not sufficient. Incisional biopsy or axillary clearance is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
  • Tumor lesion in the breast with a palpable size of 2 cm or a sonographical size of 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case tumor isn't measurable by sonography, then MRI or mammography is sufficient. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
  • Patients must have stage cT1c - cT4a-d disease.
  • In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
  • Centrally confirmed ER-negative and PR-negative status. Central pathology includes also assessment of HER2, Ki-67, TIL and RANK status on core biopsy. ER/PR negative is defined as ≤1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridization (ISH) and according to ASCO-CAP guidelines as of 2013. LPBC (lymphocyte predominant breast cancer) is defined as more than 50% stromal tumour infiltrating lymphocytes. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization.

Exclusion criteria:

  • Patients with stages cT1a, cT1b, or any M1.
  • Prior chemotherapy for any malignancy.
  • Prior radiation therapy for breast cancer.
  • History of disease with influence on bone metabolism, such as osteoporosis, Paget's disease of bone, primary hyperparathyroidism requiring treatment at the time of randomization or considered likely to become necessary within the subsequent six months.
  • Use of bisphosphonates or denosumab within the past 1 year.
  • Significant dental/oral disease, including prior history or current evidence of osteonecrosis/ osteomyelitis of the jaw, active dental or jaw condition which requires oral surgery, non-healed dental/oral surgery, planned invasive dental procedure for the course of the study.
  • Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
  • Known or suspected congestive heart failure (>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >140 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
  • Currently active infection.
  • Incomplete wound healing.
  • Definite contraindications for the use of corticosteroids.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Denosumab
Denosumab every 4 weeks for 6 cycles.
Drug: Denosumab
Denosumab 120 mg every 4 weeks for 6 cycles
Other Names:
  • Human monoclonal IgG2 antibody
Experimental: 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.
Drug: nab-Paclitaxel
nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks)
Other Names:
  • Abraxane
Drug: Carboplatin
Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel
Other Names:
  • Diamminplatin(II)-cyclobutan-1,1-dicarboxylat
Drug: Trastuzumab
Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Herceptin
Drug: Pertuzumab
Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Perjeta
Experimental: 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.
Drug: nab-Paclitaxel
nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks)
Other Names:
  • Abraxane
Drug: Carboplatin
Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel
Other Names:
  • Diamminplatin(II)-cyclobutan-1,1-dicarboxylat
Drug: Trastuzumab
Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Herceptin
Drug: Pertuzumab
Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Perjeta
Experimental: 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.
Drug: Trastuzumab
Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Herceptin
Drug: Pertuzumab
Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles
Other Names:
  • Perjeta
Drug: Epirubicin
Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times
Other Names:
  • Farmorubicin
Drug: Cyclophosphamide
Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times
Other Names:
  • Endoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.
Time Frame: 24 weeks
24 weeks
pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
To test for interaction of denosumab treatment with RANK expression.
Time Frame: 24 weeks
24 weeks
To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+ tumors.
Time Frame: 24 weeks
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

German Breast Group

Collaborators

Celgene Corporation
Amgen

Investigators

  • Principal Investigator: Jens Uwe Blohmer, MD, Charité Campus Mitte

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 13, 2017

Primary Completion (Actual)

December 31, 2019

Study Completion (Actual)

December 31, 2020

Study Registration Dates

First Submitted

January 27, 2016

First Submitted That Met QC Criteria

February 10, 2016

First Posted (Estimate)

February 15, 2016

Study Record Updates

Last Update Posted (Actual)

February 2, 2021

Last Update Submitted That Met QC Criteria

February 1, 2021

Last Verified

February 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GBG 88

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Inflammatory Breast Cancer

Clinical Trials on Denosumab

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in United Kingdom

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe