- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01426880
Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer (GeparSixto)
A Randomized Phase II Trial Investigating the Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Anthracycline/taxane based combination chemotherapy of at least 18 weeks represents the standard of care in the neoadjuvant setting. In HER2-positive disease trastuzumab is given simultaneously to chemotherapy. Recent data from the Neo-Altto and Neosphere trials suggest that a dual blockage of the HER2 receptor with e.g. trastuzumab and lapatinib reach significantly higher pCR rates than trastuzumab alone and should therefore represent the treatment back-bone of new neoadjuvant trials. A preplanned subgroup analysis of the GeparQuinto study demonstrated that in TNBC the addition of bevacizumab resulted in a significant increase of pCR rates (HR 1.4).
Having a better cardiac tolerability profile compared to conventional anthracyclines, the non-pegylated liposomal encapsulated doxorubicin (NPLD) Myocet® might provide the possibility to combine taxane, anthracycline, platinum salt as well with targeted agents as double HER2 blockage or bevacizumab.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Heidelberg, Germany
- NCT Heidelberg
-
-
Brandenburg
-
Fürstenwalde, Brandenburg, Germany, 15517
- Praxis Dr. Heinrich
-
-
Nordrhein-Westfalen
-
Düsseldorf, Nordrhein-Westfalen, Germany, 40235
- Luisenkrankenhaus
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 1.Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
- 2.Complete baseline documentation must be submitted via Medcodes® and approved by GBG Forschungs GmbH.
- 3.Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration 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.
- 4.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 of inflammatory disease, the extent of inflammation can be used as measurable lesion.
- 5.Patients should be in the following stages of disease: cT2 - cT4a-d or cT1c and cN+ or pNSLN+
- 6.In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
- 7.Centrally confirmed ER/PR/HER-2 and Ki-67 status detected on core biopsy. ER/PR positive is defined as >1% stained cells and HER2-positive is defined as HercepTest IHC 3+ or FISH ratio ≥ 2.2. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
- 8.Age ≥ 18 years.
- 9.Karnofsky Performance status index ≥ 80%.
- 10.Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. LVEF must be above 55%.
- 11.Laboratory requirements: Hematology
- Absolute neutrophil count (ANC) ≥ 2.0 x 109 / L and
- Platelets ≥ 100 x 109 / L and
- Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function
- Total bilirubin < 1.5x UNL and
- ASAT (SGOT) and ALAT (SGPT) ≤ 1.5x UNL and
- Alkaline phosphatase ≤ 2.5x UNL. Renal function
- Creatinine ≤ 175 µmol/L (2 mg/dL) < 1.5x UNL
- Proteinuria: Urine dipstick for proteinuria < 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. If creatinine is between 140 - 175 umol/L (1.6-2.0 mg/dL), the creatinine clearance (calculated or measured) should be ≥ 45 mL/min.
- 12.Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
- 13.Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (≤ 21 days), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray (or CT or MRI) is mandatory. Other tests may be performed as clinically indicated.
- 14.Patients must be available and compliant for central diagnostics, treatment and follow-up.
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 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).
- 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 >160 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
- Previous thromboembolic event (except when thrombophily screening is negative).
- Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.
- History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
- Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 by NCI-CTC criteria v 4.0.
- Currently active infection.
- Active peptic ulcer.
- Incomplete wound healing or unhealed bone fracture.
- Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome, resection of the stomach or small bowel, ulcerative colitis.
- History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.
- Severe pulmonary condition / illness.
- Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment with bevacizumab. Minor surgeries including insertion of an indwelling catheter or sentinel lymph node biopsy within 24 h prior to chemotherapy.
- Definite contraindications for the use of corticosteroids except inhalative corticoids.
- Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol;
Concurrent treatment with:
- chronic corticosteroids unless initiated > 6 months prior to study entry and at low dose (≤ 10 mg methylprednisolone or equivalent).
- sex hormones. Prior treatment must be stopped before study entry.
- virostatic agents like sorivudine or analogs like brivudine, concurrent treatment with aminoglycosides.
- anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a dose of > 325 mg/day or clopidogrel at a dose of > 75 mg/day.
- other experimental drugs or any other anti-cancer therapy.
- drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A, e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin, Erythromycin, Verapamil, Diltiazem within the last 5 days or the expected need for these treatments during study participation.
- Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
- Male patients.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Carboplatin + background treatment
Carboplatin AUC 2 min/mL weekly, infusion will be used as Add-on to the background therapy (same as comparator arm)
|
Carboplatin, AUC, 2 min/mL weekly, infusion
Other Names:
background treatment according to standards fpr triple negative and Her2pos breast cancer patients Paclitaxel: 80 mg/m² i.v. given weekly on day 1 q day 8 for 18 weeks. NPLD (Myocet®): 20 mg/m² weekly on day 1 q day 8 for 18 weeks Trastuzumab (only for HER2-positive patients): Loading dose: 8 mg/kg, Maintenance dose: 6 mg/kg, day 1 q day 22 for 6 cycles. Post-surgery: up to a total duration of 1 year according to current AGO guidelines Lapatinib 750 mg/day p.o. continuously for 18 weeks; in case of good tolerability (no CTC grade II toxicity except alopecia and nausea/vomiting) during the first cycle the dose may be escalated to 1000 mg. Bevacizumab: 15 mg/kg i.v., day 1 q day 22 for 6 cycles (only in TNBC patients).
Other Names:
|
Active Comparator: background treatment only
background treatment with NLPD (Myocet), Paclitaxel, Herceptin (Trastuzumab fpr Her2 pos), Tyverb (Lapatinib for Her2 pos), Avastin (Bevacizumab for triple negative) agents are used according to marketed formulation via normal procedures at each site and applied according to recommendations of the manufacturers.
|
background treatment according to standards fpr triple negative and Her2pos breast cancer patients Paclitaxel: 80 mg/m² i.v. given weekly on day 1 q day 8 for 18 weeks. NPLD (Myocet®): 20 mg/m² weekly on day 1 q day 8 for 18 weeks Trastuzumab (only for HER2-positive patients): Loading dose: 8 mg/kg, Maintenance dose: 6 mg/kg, day 1 q day 22 for 6 cycles. Post-surgery: up to a total duration of 1 year according to current AGO guidelines Lapatinib 750 mg/day p.o. continuously for 18 weeks; in case of good tolerability (no CTC grade II toxicity except alopecia and nausea/vomiting) during the first cycle the dose may be escalated to 1000 mg. Bevacizumab: 15 mg/kg i.v., day 1 q day 22 for 6 cycles (only in TNBC patients).
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pathological complete response of breast and lymph nodes (ypT0 ypN0; primary endpoint)
Time Frame: 24 weeks (time window -3 weeks)
|
Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries.
Surgery takes place shortly after the 18 weeks (six 3-week cycles) chemotherapy treatment.
No microscopic evidence of residual viable tumor cells in all resected specimens of the breast and axilla meets the primary endpoint.
|
24 weeks (time window -3 weeks)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacogenetic substudy
Time Frame: Baseline
|
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
|
Baseline
|
1.ypT0/is ypN0; ypT0; ypT0/is; ypN0, and regression grades
Time Frame: 24 weeks (time window -3 weeks)
|
24 weeks (time window -3 weeks)
|
|
Clinical and imaging response
Time Frame: 24 weeks (time window -3 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 both arms.
|
24 weeks (time window -3 weeks)
|
loco-regional invasive recurrence free survival (LRRFS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), distant-disease- free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS)
Time Frame: 5 years
|
LRRFS, RRFS, LRFS, DDFS, IDFS and OS are defined as the time period between registration and first event and will be analyzed after the end of the study by referring to data from GBG patient's registry.
|
5 years
|
Tolerability and Safety
Time Frame: during treatment 18 weeks
|
Tolerability and Safety: Descriptive statistics for the 4 treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped
|
during treatment 18 weeks
|
pCR rates per arm
Time Frame: 24 weeks (time window -3 weeks)
|
• To assess the pCR rates per arm separately in patients with triple-negative tumors and HER2-positive tumors.
|
24 weeks (time window -3 weeks)
|
Breast and axilla conservation rate
Time Frame: 24 weeks (time window -3 weeks)
|
To determine the breast and axilla conservation rate after each treatment.
|
24 weeks (time window -3 weeks)
|
pCR rate and local recurrence free survival in correlation to clinical complete response and negative core biopsy before surgery
Time Frame: 5 years
|
To determine the pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy before surgery.
|
5 years
|
Clinical and imaging response
Time Frame: 6 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 both arms.
|
6 weeks
|
PCR rate in patients with a clinical complete response and a negative core biopsy
Time Frame: 24 weeks (time window -3 weeks)
|
To assess the pCR rate in patients with a clinical complete response and a negative core biopsy before surgery.
|
24 weeks (time window -3 weeks)
|
Regional recurrence free survival (RRFS)in patients with initial node-positive axilla
Time Frame: until event occurs - no events for cured patients
|
To assess regional recurrence free survival (RRFS) in patients with initial node-positive axilla converted to negative at surgery and treated with sentinel node biopsy alone.
|
until event occurs - no events for cured patients
|
Examination and comparison of molecular markers
Time Frame: Baseline, 6 weeks and 24 weeks
|
To examine and compare pre-specified molecular markers such as BRCA1-mRNA, P53, ALDH1, p4E-BP1, IL-8 metagene, B-Cell metagene as well as exploratory analyses and lymphocyte infiltration on core biopsies before and surgical tissue after end of chemotherapy.
The aim is to identify potential predictive short and long term parameters.
|
Baseline, 6 weeks and 24 weeks
|
CTC Substudy
Time Frame: Baseline, 6 weeks and 24 weeks
|
To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.
|
Baseline, 6 weeks and 24 weeks
|
Ovarian Substudy
Time Frame: Baseline, 6 months, 12 months, 18 months, 24 months, 30 months
|
To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.
|
Baseline, 6 months, 12 months, 18 months, 24 months, 30 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Gunter von Minckwitz, MD, Prof, ASCO, AACR, ESMO, DKG, DGGG, AGO, DGS, BIG, BCIRG, St. Gallen Consensus Panel
Publications and helpful links
General Publications
- Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Kummel S, Sinn P, Jackisch C, Dietel M, Reimer T, Untch M, Loibl S. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015 Mar 20;33(9):983-91. doi: 10.1200/JCO.2014.58.1967. Epub 2014 Dec 22.
- von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, Blohmer JU, Jackisch C, Paepke S, Gerber B, Zahm DM, Kummel S, Eidtmann H, Klare P, Huober J, Costa S, Tesch H, Hanusch C, Hilfrich J, Khandan F, Fasching PA, Sinn BV, Engels K, Mehta K, Nekljudova V, Untch M. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 2014 Jun;15(7):747-56. doi: 10.1016/S1470-2045(14)70160-3. Epub 2014 Apr 30.
- Loibl S, von Minckwitz G, Schneeweiss A, Paepke S, Lehmann A, Rezai M, Zahm DM, Sinn P, Khandan F, Eidtmann H, Dohnal K, Heinrichs C, Huober J, Pfitzner B, Fasching PA, Andre F, Lindner JL, Sotiriou C, Dykgers A, Guo S, Gade S, Nekljudova V, Loi S, Untch M, Denkert C. PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J Clin Oncol. 2014 Oct 10;32(29):3212-20. doi: 10.1200/JCO.2014.55.7876. Epub 2014 Sep 8.
- Hahnen E, Lederer B, Hauke J, Loibl S, Krober S, Schneeweiss A, Denkert C, Fasching PA, Blohmer JU, Jackisch C, Paepke S, Gerber B, Kummel S, Schem C, Neidhardt G, Huober J, Rhiem K, Costa S, Altmuller J, Hanusch C, Thiele H, Muller V, Nurnberg P, Karn T, Nekljudova V, Untch M, von Minckwitz G, Schmutzler RK. Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial. JAMA Oncol. 2017 Oct 1;3(10):1378-1385. doi: 10.1001/jamaoncol.2017.1007.
Study record dates
Study Major Dates
Study Start
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 (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Skin Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Adenocarcinoma
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Breast Diseases
- Neoplasms, Ductal, Lobular, and Medullary
- Carcinoma, Ductal
- Breast Neoplasms
- Inflammatory Breast Neoplasms
- Carcinoma, Ductal, Breast
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Tubulin Modulators
- Antimitotic Agents
- Mitosis Modulators
- Antineoplastic Agents, Phytogenic
- Protein Kinase Inhibitors
- Carboplatin
- Paclitaxel
- Lapatinib
Other Study ID Numbers
- GBG 66
- 2011-000553-23 (EudraCT Number)
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
-
Dana-Farber Cancer InstituteIncyte CorporationActive, not recruitingInflammatory Breast Cancer (IBC)United States
-
NYU Langone HealthCompletedBreast CancerUnited States
-
BerGenBio ASAMerck Sharp & Dohme LLCTerminatedTriple Negative Breast Cancer | Inflammatory Breast Cancer Stage IVSpain, United States, United Kingdom, Norway
-
National Cancer Institute (NCI)TerminatedAnatomic Stage IV Breast Cancer AJCC v8 | Metastatic Triple-Negative Breast Inflammatory CarcinomaUnited States
-
Hoffmann-La RocheActive, not recruitingInflammatory Breast Cancer | Early Breast Cancer | Locally Advanced Breast CancerCanada, Croatia, Spain, Argentina, Mexico, Korea, Republic of, Bosnia and Herzegovina, Brazil, Costa Rica, Turkey, Singapore, Bulgaria, South Africa, India, Peru, Kenya, Chile
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingAnatomic Stage IIIB Breast Cancer AJCC v8 | Anatomic Stage IIIC Breast Cancer AJCC v8 | Prognostic Stage IIIB Breast Cancer AJCC v8 | Prognostic Stage IIIC Breast Cancer AJCC v8 | Breast Inflammatory CarcinomaUnited States
-
Filipa Lynce, MDAstraZeneca; Daiichi Sankyo, Inc.RecruitingBreast Cancer | HER2-positive Breast Cancer | Invasive Breast Cancer | Inflammatory Breast Cancer Stage III | HER2 Low Breast AdenocarcinomaUnited States
-
National Cancer Institute (NCI)CompletedInflammatory Breast Cancer | Stage II Breast Cancer | Stage IIIA Breast Cancer | Stage IIIB Breast Cancer | Stage IIIC Breast CancerUnited States
-
M.D. Anderson Cancer CenterNovartis; Puma Biotechnology, Inc.; Celcuity IncRecruiting
-
Institut Paoli-CalmettesMSD France; OncodistinctRecruitingInflammatory Breast CancerFrance, Belgium
Clinical Trials on Carboplatin
-
Eisai Inc.CompletedCancerUnited States, Austria, India
-
Samyang Biopharmaceuticals CorporationCompleted
-
NHS Greater Glasgow and ClydeCompletedOvarian Cancer | Fallopian Tube Cancer | Primary Peritoneal Cavity CancerUnited Kingdom, Australia, New Zealand
-
Duke UniversityCompletedBrain and Central Nervous System TumorsUnited States, Canada
-
National Cancer Institute (NCI)CompletedBreast Cancer | Ovarian CancerUnited States
-
H. Lee Moffitt Cancer Center and Research InstituteNational Cancer Institute (NCI)CompletedUnspecified Adult Solid Tumor, Protocol SpecificUnited States
-
Eli Lilly and CompanyCompletedLung NeoplasmsUnited States
-
National Cancer Institute (NCI)Children's Oncology GroupCompletedBrain and Central Nervous System TumorsUnited States, Canada, Puerto Rico, Australia, Netherlands, New Zealand, Switzerland
-
All India Institute of Medical Sciences, New DelhiCouncil of Scientific and Industrial Research, IndiaUnknownIntraocular RetinoblastomaIndia
-
MEI Pharma, Inc.CompletedPeritoneal Neoplasms | Ovarian Cancer | Fallopian Tube CancerUnited States, Spain, Belgium, United Kingdom, Australia, Italy, Poland