- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02685059
Addition of PD-L1 Antibody MEDI4736 to a Taxane-anthracycline Chemotherapy in Triple Negative Breast Cancer (GeparNuevo)
A Randomized Phase II Study to Investigate the Addition of PD-L1 Antibody MEDI4736 to a Taxane-anthracycline Containing Chemotherapy in Triple Negative Breast Cancer (GeparNuevo)
To date no targeted agents are available to treat TNBC. Therefore chemotherapy is the only treatment option. TNBC often has a high amount of tumour infiltrating lymphocytes. Stimulating the immune cells of TNBC might therefore be an option for these patients to increase the pathological complete response. pCR is highly correlated with outcome in TNBC.
Therefore the addition of a checkpoint inhibitor in addition to chemotherapy might be an additional option for these patients.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
To date no targeted agents are available to treat TNBC. Therefore chemotherapy is the only treatment option. TNBC often has a high amount of tumour infiltrating lymphocytes. Stimulating the immune cells of TNBC might therefore be an option for these patients to increase the pathological complete response. pCR is highly correlated with outcome in TNBC.
Therefore the addition of a checkpoint inhibitor in addition to chemotherapy might be an additional option for these patients.
The primary objective therefore is to compare the pathological complete response (pCR= ypT0 ypN0) rates of neoadjuvant treatment of sequential, nab-Paclitaxel followed by EC +/- the PD-L1 antibody MEDI4736 in patients with early triple negative breast cancer.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Hessen
-
Frankfurt, Hessen, Germany, 60389
- Centrum für Hämatologie und Onkologie am Bethanien-Krankenhaus
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Written informed consent for all study according to local regulatory requirements prior to beginning specific protocol procedures.
- Complete baseline documentation must be sent to GBG Forschungs GmbH.
- Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy 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 or the nodes must be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
- Patients must be in the following stages of disease: cT1b - cT4a-d irrespective of nodal involvement.
In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
- Triple negative disease with centrally confirmed ER negative/PR negative/HER-2 negative, and centrally confirmed Ki-67 value. ER negative is defined as <1% stained cells, PR negative is defined as <10% stained and HER2-negative is defined as either IHC 0/1+ or IHC 2+ and in-situ hybridisation (ISH) of either ratio <2.0 or less than 6 copies of HER2 per tumor cell. Stromal TILs will be evaluated in three groups: low immune infiltrate (0-10% stromal TILs) intermediate immune infiltrate (11-59% stromal TILs), LPBC 60-100% stromal TILs. PD-L1 status and other predefined markers will be prospectively assessed during the study. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization.
- Age >=18 years.
- ECOG Performance status 0-1.
- Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution.
- Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: >=60 years old and no menses for >=1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
- Complete staging work-up within 3 months prior to randomization. All patients must have had breast imaging by breast ultrasound plus either bilateral mammography or breast MRI (one of those <= 21 days). All patients must have had chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan (according to guidelines). In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
- Patients must be available and compliant for central diagnostics, treatment and follow-up.
- Laboratory requirements: Hematology, Hepatic function, Renal Function, Thyroid function
Exclusion Criteria:
- Prior chemotherapy for any malignancy.
- Prior radiation therapy for breast cancer.
- Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
- Inadequate general condition (not fit for dose-dense, dose-intensified anthracycline-taxane-targeted agents-based chemotherapy).
- Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
- 6. 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 at maximum two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett's Correction
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
- History of primary immunodeficiency
- History of allogeneic organ transplant
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
- Known history of previous clinical diagnosis of tuberculosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving MEDI4736
- Autoimmune disease and conditions (i.e. inflammatory bowel disease)
- History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Pre-existing motor or sensory neuropathy of a severity >= grade 2 by NCI-CTC criteria v 4.0.
- Currently active infection.
- Incomplete wound healing or unhealed bone fracture.
- Definite contraindications for the use of corticosteroids
- Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol;
- Concurrent treatment with:
- chronic corticosteroids prior to study entry with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.
- other immunosuppressive medication (e.g. low dose MTX)
- sex hormones (including hormonal contraception) prior treatment must be stopped before study entry.
- other experimental drugs or any other anti-cancer therapy.
- Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
- Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736
- Male patients.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: MEDI4736
part 1: MEDI4736 (with half dose as monotherapy for the first two weeks) part 2: MEDI4736 1.5 g total for 20 weeks
|
MEDI4736 1.5g total i.v. every 4 weeks As monotherapy for the first two weeks (0.75g absolute) (part 1) followed by: MEDI4736 in combination with nab-paclitaxel 125 mg/m² every week for 12 weeks (part 2) followed by MEDI4736 in combination with epirubicin 90mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles (part 3).
Other Names:
|
Placebo Comparator: Placebo
part 1: Placebo (for the first two weeks) part 2: Placebo for 20 weeks
|
Placebo i.v. every 4 weeks As monotherapy for the first two weeks (0.75g absolute) (part 1) followed by: Placebo in combination with nab-paclitaxel 125 mg/m² every week for 12 weeks (part 2) followed by MEDI4736/Placebo in combination with epirubicin 90mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for 4 cycles (part 3). |
Active Comparator: Taxane
Nab-Paclitaxel 125 mg/m² weekly for 12 weeks
|
nab-Paclitaxel 125 mg/m² weekly for 12 weeks
Other Names:
|
Active Comparator: Epirubicin
Epirubicin 90 mg/m² 2-weekly for 8 weeks
|
Epirubicin 90 mg/m² 2-weekly for 8 weeks
Other Names:
|
Active Comparator: Cyclophosphamide
Cyclophosphamide 600 mg/m² 2-weekly for 8 weeks
|
Cyclophosphamide 600 mg/m² 2-weekly for 8 weeks
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
pathological complete response (pCR= ypT0 ypN0)
Time Frame: 22 weeks
|
To compare the pathological complete response (pCR= ypT0 ypN0) rates of neoadjuvant treatment of sequential, nab-Paclitaxel followed by EC +/- the PD-L1 antibody MEDI4736 in patients with early triple negative breast cancer.
|
22 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
pCR rates per arm
Time Frame: 22 weeks
|
To assess the pCR rates per arm separately for the stratified subpopulations.
|
22 weeks
|
Rates of ypT0/is ypN0
Time Frame: 22 weeks
|
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in different arms.
|
22 weeks
|
Rates of ypT0/is ypN0/+
Time Frame: 22 weeks
|
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in different arms.
|
22 weeks
|
Rates of ypT(any) ypN0
Time Frame: 22 weeks
|
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in different arms.
|
22 weeks
|
Rates of ypT0 ypN0/+
Time Frame: 22 weeks
|
To determine the response rates of the breast tumor and axillary nodes based on physical examination and imaging tests (sonography, mammography, or MRI) after treatment in different arms.
|
22 weeks
|
Clinical response
Time Frame: 22 weeks
|
To assess clinical response rate after taxane in both groups.
|
22 weeks
|
Breast conservation rate
Time Frame: 22 weeks
|
To determine the breast conservation rate after each treatment.
|
22 weeks
|
Toxicity and compliance as measured by number of participants with treatment-related
Time Frame: 22 weeks
|
Number of participants with treatment-related adverse events CTCAE v4.0
|
22 weeks
|
Molecular markers and gene expression
Time Frame: 22 weeks
|
To examine and compare pre-specified molecular markers and gene expression signatures such as tumor infiltrating lymphocytes, PD-1, PD-L1, Ki-67, etc. on core biopsies before chemotherapy, after the window phase and surgical tissue after end of chemotherapy (in %)
|
22 weeks
|
Survival
Time Frame: 22 weeks
|
To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), event free survival (EFS per FDA definition) and overall survival (OS) in different arms and according to stratified subpopulations (in months)
|
22 weeks
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Sibylle Loibl, Prof. Dr., GBG Forschungs GmbH
Publications and helpful links
General Publications
- Perez-Garcia J, Soberino J, Racca F, Gion M, Stradella A, Cortes J. Atezolizumab in the treatment of metastatic triple-negative breast cancer. Expert Opin Biol Ther. 2020 Sep;20(9):981-989. doi: 10.1080/14712598.2020.1769063. Epub 2020 May 25.
- Massa C, Karn T, Denkert C, Schneeweiss A, Hanusch C, Blohmer JU, Zahm DM, Jackisch C, van Mackelenbergh M, Thomalla J, Marme F, Huober J, Muller V, Schem C, Mueller A, Stickeler E, Biehl K, Fasching PA, Untch M, Loibl S, Weber K, Seliger B. Differential effect on different immune subsets of neoadjuvant chemotherapy in patients with TNBC. J Immunother Cancer. 2020 Nov;8(2):e001261. doi: 10.1136/jitc-2020-001261.
- Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer JU, Grischke EM, Furlanetto J, Tesch H, Hanusch C, Engels K, Rezai M, Jackisch C, Schmitt WD, von Minckwitz G, Thomalla J, Kummel S, Rautenberg B, Fasching PA, Weber K, Rhiem K, Denkert C, Schneeweiss A. A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol. 2019 Aug 1;30(8):1279-1288. doi: 10.1093/annonc/mdz158. Erratum In: Ann Oncol. 2022 Jul;33(7):743-744.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms
- Neoplasms by Site
- Breast Diseases
- Breast Neoplasms
- Triple Negative Breast Neoplasms
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Phytogenic
- Topoisomerase II Inhibitors
- Topoisomerase Inhibitors
- Antineoplastic Agents, Immunological
- Antibiotics, Antineoplastic
- Cyclophosphamide
- Paclitaxel
- Epirubicin
- Durvalumab
Other Study ID Numbers
- GBG89
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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 Breast Cancer
-
Northwestern UniversityEisai Inc.UnknownMale Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Triple-negative Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Estrogen Receptor-negative Breast Cancer | Progesterone Receptor-negative Breast Cancer | HER2-negative...United States
-
Rutgers, The State University of New JerseyNational Cancer Institute (NCI); Rutgers Cancer Institute of New JerseyActive, not recruitingStage IIIA Breast Cancer | Stage IIIB Breast Cancer | Triple-negative Breast Cancer | Stage IIA Breast Cancer | Stage IIB Breast Cancer | Stage IIIC Breast Cancer | Estrogen Receptor-negative Breast Cancer | Progesterone Receptor-negative Breast Cancer | HER2-negative Breast CancerUnited States
-
University of Southern CaliforniaNational Cancer Institute (NCI)TerminatedMale Breast Cancer | Stage IV Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Recurrent Breast CancerUnited States
-
University of Southern CaliforniaNational Cancer Institute (NCI)WithdrawnStage IV Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Triple-negative Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Recurrent Breast Cancer
-
University of WashingtonTerminatedBreast Cancer | Breast Cancer Stage I | Breast Cancer Stage II | Breast Cancer Stage III | Breast Cancer Stage IIB | Breast Cancer Stage IIA | Breast Cancer Stage IIIA | Breast Cancer Stage IIIB | Breast Cancer Stage IIIcUnited States
-
CelgeneCompletedBreast Cancer | Metastatic Breast Cancer | Stage IV Breast Cancer | Triple-negative Breast Cancer | Recurrent Breast Cancer | Breast Tumor | Cancer of the Breast | Triple-negative Metastatic Breast Cancer | Estrogen Receptor- Negative Breast Cancer | HER2- Negative Breast Cancer | Progesterone Receptor- Negative...United States, United Kingdom, Italy, Germany, Spain, Canada, Portugal, Australia, Austria, Greece, Brazil, France
-
University of Southern CaliforniaNational Cancer Institute (NCI)TerminatedHER2-positive Breast Cancer | Stage IV Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Recurrent Breast CancerUnited States
-
University of WashingtonNational Cancer Institute (NCI)CompletedHER2-positive Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Estrogen Receptor-negative Breast Cancer | Estrogen Receptor-positive Breast Cancer | Progesterone Receptor-negative Breast Cancer | Progesterone Receptor-positive Breast...United States
-
University of California, IrvineNational Cancer Institute (NCI); National Institutes of Health (NIH)CompletedBreast Cancer | HER2-positive Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Recurrent Breast Cancer | HER2-negative Breast CancerUnited States
-
University of WashingtonNational Cancer Institute (NCI)CompletedHER2-positive Breast Cancer | Stage IV Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IA Breast Cancer | Stage IB Breast Cancer | Stage IIIC Breast Cancer | Estrogen Receptor-positive Breast CancerUnited States
Clinical Trials on nab-Paclitaxel
-
Fudan UniversityActive, not recruitingTNBC - Triple-Negative Breast CancerChina
-
Shengjing HospitalRecruiting
-
M.D. Anderson Cancer CenterCelgene CorporationCompletedMelanoma | Liver MetastasisUnited States
-
HutchmedNot yet recruiting
-
Peking University Cancer Hospital & InstituteActive, not recruiting
-
Fundacion OncosurCompleted
-
Changhai HospitalRecruiting
-
Trishula Therapeutics, Inc.AbbVieRecruitingPancreatic CancerUnited States
-
CelgeneCompletedColorectal NeoplasmsFrance
-
AIO-Studien-gGmbHCelgene; ClinAssess GmbHCompletedResectable Pancreatic Cancer | Ductal Adenocarcinoma of the PancreasGermany