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

Primary Purpose

Breast Cancer Female NOS, Tubular Breast Cancer Stage II, Mucinous Breast Cancer Stage II

Status

Completed

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Denosumab

nab-Paclitaxel

Epirubicin

Cyclophosphamide

Carboplatin

Trastuzumab

Pertuzumab

About this trial

This is an interventional treatment trial for Breast Cancer Female NOS

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Charité Campus Mitte

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Denosumab

nab-Paclitaxel weekly

nab-paclitaxel 2 of 3 weeks

EC every two weeks or every three weeks

Arm Description

Denosumab every 4 weeks for 6 cycles.

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.

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.

Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.

Outcomes

Primary Outcome Measures

pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.

pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks

Secondary Outcome Measures

To test for interaction of denosumab treatment with RANK expression.

To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+ tumors.

Full Information

NCT ID

NCT02682693

First Posted

January 27, 2016

Last Updated

February 1, 2021

Sponsor

German Breast Group

Collaborators

Amgen, Celgene Corporation

1. Study Identification

Unique Protocol Identification Number

NCT02682693

Brief Title

Denosumab as an add-on Neoadjuvant Treatment (GeparX)

Acronym

GeparX

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

February 2021

Overall Recruitment Status

Completed

Study Start Date

February 13, 2017 (Actual)

Primary Completion Date

December 31, 2019 (Actual)

Study Completion Date

December 31, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

German Breast Group

Collaborators

Amgen, Celgene Corporation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Breast Cancer Female NOS, Tubular Breast Cancer Stage II, Mucinous Breast Cancer Stage II, Invasive Ductal Breast Cancer, HER2 Positive Breast Cancer, Inflammatory Breast Cancer, Tubular Breast Cancer Stage III

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Factorial Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

780 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Denosumab

Arm Type

Experimental

Arm Description

Denosumab every 4 weeks for 6 cycles.

Arm Title

nab-Paclitaxel weekly

Arm Type

Experimental

Arm Description

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.

Arm Title

nab-paclitaxel 2 of 3 weeks

Arm Type

Experimental

Arm Description

Arm Title

EC every two weeks or every three weeks

Arm Type

Experimental

Arm Description

Epirubicin and Cyclophosphamide 600mg/m² for 4 times. Patients with HER2-positive tumors receive Trastuzumab and Pertuzumab.

Intervention Type

Drug

Intervention Name(s)

Denosumab

Other Intervention Name(s)

Human monoclonal IgG2 antibody

Intervention Description

Denosumab 120 mg every 4 weeks for 6 cycles

Intervention Type

Drug

Intervention Name(s)

nab-Paclitaxel

Other Intervention Name(s)

Abraxane

Intervention Description

nab-paclitaxel 125 mg/m² weekly for 12 weeks or at day 1,8 q22 for 4 cycles (12 weeks)

Intervention Type

Drug

Intervention Name(s)

Epirubicin

Other Intervention Name(s)

Farmorubicin

Intervention Description

Epirubicin 90 mg/m² every 2 or 3 weeks for 4 times

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Endoxan

Intervention Description

Cyclophosphamide 600 mg/m² every 2 or 3 weeks for 4 times

Intervention Type

Drug

Intervention Name(s)

Carboplatin

Other Intervention Name(s)

Diamminplatin(II)-cyclobutan-1,1-dicarboxylat

Intervention Description

Carboplatin AUC 2 weekly in parallel to nab-Paclitaxel

Intervention Type

Drug

Intervention Name(s)

Trastuzumab

Other Intervention Name(s)

Herceptin

Intervention Description

Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all chemotherapy cycles

Intervention Type

Drug

Intervention Name(s)

Pertuzumab

Other Intervention Name(s)

Perjeta

Intervention Description

Pertuzumab 420 (840) mg every 3 weeks simultaneously to all chemotherapy cycles

Primary Outcome Measure Information:

Title

pcR rates of neoadjuvant treatment with or without denosumab in addition to nab-paclitaxel and EC.

Time Frame

24 weeks

Title

pcR (ypT0 ypN0) rates of nab-Paclitaxel weekly for 12 weeks or 2 of 3 weeks for 12 weeks

Time Frame

12 weeks

Secondary Outcome Measure Information:

Title

To test for interaction of denosumab treatment with RANK expression.

Time Frame

24 weeks

Title

To assess the pCR rates per arm for both randomizations separately for TNBC and HR-/HER2+ tumors.

Time Frame

24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jens Uwe Blohmer, MD

Organizational Affiliation

Charite Campus Mitte

Official's Role

Principal Investigator

Facility Information:

Facility Name

Charité Campus Mitte

City

Berlin

ZIP/Postal Code

10113

Country

Germany

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

35588050

Citation

Blohmer 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.

Results Reference

derived

PubMed Identifier

34252375

Citation

Denkert 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.

Results Reference

derived

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Denosumab as an add-on Neoadjuvant Treatment (GeparX)

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