Denosumab as an add-on Neoadjuvant Treatment (GeparX)
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)
1 other identifier
interventional
780
1 country
1
Brief 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Feb 2017
Typical duration for phase_2
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 27, 2016
CompletedFirst Posted
Study publicly available on registry
February 15, 2016
CompletedStudy Start
First participant enrolled
February 13, 2017
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2019
CompletedStudy Completion
Last participant's last visit for all outcomes
December 31, 2020
CompletedFebruary 2, 2021
February 1, 2021
2.9 years
January 27, 2016
February 1, 2021
Conditions
Outcome Measures
Primary Outcomes (2)
pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.
24 weeks
pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks
12 weeks
Secondary Outcomes (2)
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
Study Arms (4)
Denosumab
EXPERIMENTALDenosumab every 4 weeks for 6 cycles.
nab-Paclitaxel weekly
EXPERIMENTALnab-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.
nab-paclitaxel 2 of 3 weeks
EXPERIMENTALnab-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.
EC every two weeks or every three weeks
EXPERIMENTALEpirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.
Interventions
Denosumab 120 mg every 4 weeks for 6 cycles
nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks)
Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times
Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times
Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel
Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles
Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles
Eligibility Criteria
You may qualify if:
- 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.
You may not qualify if:
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- GBG Forschungs GmbHlead
- Amgencollaborator
- Celgene Corporationcollaborator
Study Sites (1)
Charité Campus Mitte
Berlin, 10113, Germany
Related Publications (3)
Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.
PMID: 38979716DERIVEDBlohmer JU, Link T, Reinisch M, Just M, Untch M, Stotzer O, Fasching PA, Schneeweiss A, Wimberger P, Seiler S, Huober J, Thill M, Jackisch C, Rhiem K, Solbach C, Hanusch C, Seither F, Denkert C, Engels K, Nekljudova V, Loibl S; GBG and AGO-B. Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer: The GeparX 2 x 2 Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1010-1018. doi: 10.1001/jamaoncol.2022.1059.
PMID: 35588050DERIVEDDenkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, Wimberger P, Forberger A, Tesch H, Jackisch C, Schmatloch S, Reinisch M, Solomayer EF, Schmitt WD, Hanusch C, Fasching PA, Lubbe K, Solbach C, Huober J, Rhiem K, Marme F, Reimer T, Schmidt M, Sinn BV, Janni W, Stickeler E, Michel L, Stotzer O, Hahnen E, Furlanetto J, Seiler S, Nekljudova V, Untch M, Loibl S. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021 Aug;22(8):1151-1161. doi: 10.1016/S1470-2045(21)00301-6. Epub 2021 Jul 9.
PMID: 34252375DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Jens Uwe Blohmer, MD
Charite Campus Mitte
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- FACTORIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 27, 2016
First Posted
February 15, 2016
Study Start
February 13, 2017
Primary Completion
December 31, 2019
Study Completion
December 31, 2020
Last Updated
February 2, 2021
Record last verified: 2021-02
Data Sharing
- IPD Sharing
- Will not share