Two regimen are currently considered to have highest efficacy for patients with high-risk early stage breast cancer: sequential treatment of high dose epirubicin, taxane, and cyclophosphamide concomitantly with a dual HER2-blockade, and weekly treatment with paclitaxel/non-pegylated liposomal doxorubicin with dual HER2-blockade or carboplatin. The aim of the GeparOcto study is to compare those two regimen/strategies. Both regimens are myelosuppressive with a significant incidence of chemotherapy induced anaemia. The second aim of the GeparOcto study is therefore to compare the use of parental ferric carboxymaltose versus physician's choice for the treatment of chemotherapy-induced anemia in patients with iron deficiency.
Several recent strategies have improved efficacy of systemic treatment for patients with high-risk early stage breast cancer: the addition of a dual HER2-blockade for HER2-positive; the implementation of carboplatin for TNBC and the use of dose-dense or dose-dense, dose escalated chemotherapy in all high-risk subtypes of breast cancer. Two regimen are currently considered to have highest efficacy: sequential treatment of high dose epirubicin, taxane, and cyclophosphamide (ETC) concomitantly with a dual HER2-blockade mainly based on the AGO ETC adjuvant study, and weekly treatment with paclitaxel/non-pegylated liposomal doxorubicin with dual HER2-blockade or carboplatin (PM(Cb)) based on the GeparSixto study. The aim of the GeparOcto study is to compare those two regimen/strategies. Both regimens are myelosuppressive with a significant incidence of chemotherapy induced anaemia. Anemia is often associated with impaired physical and cognitive function and consequently the patients suffer from a reduced quality of life. Surgical complications are higher in anemic patients. The second aim of the GeparOcto study is therefore to compare the use of parental ferric carboxymaltose versus physician's choice for the treatment of chemotherapy-induced anemia in patients with iron deficiency.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
961
20 mg/m2, i.V. 18 times weekly
Carboplatin AUC 1.5 18 times weekly (only in patients with triple-negative breast cancer).
paclitaxel 80mg/m² 18 times weekly
150mg/m² every 2 weeks for 3 cycles.
2000 mg/m² every 2 weeks for 3 cycles.
420 (840) mg every 3 weeks simultaneously to all T and C cycles in the ETC arm and to all cycles in the PM(Cb) arm.
Trastuzumab 6 (8) mg/kg every 3 weeks simultaneously to all T and C cycles in the ETC arm and to all cycles in the PM(Cb) arm.
after first anemia grade ≥2 and in case of randomisation: Ferric carboxymaltose i.V. 1000 mg followed 1 week later by an injection of ferric carboxymaltose i.V. 500 mg (if body weight is \<70 kg) or 1000 mg (if body weight is ≥70 kg). In case body weight is \<50 kg, both dosages will be reduced to 500 mg each.
NTC
Heidelberg, Baden-Wurttemberg, Germany
pathological complete response (pCR= ypT0/is ypN0)
To compare the pathological complete response (pCR= ypT0/is ypN0) rates of neoadjuvant treatment with sequential, dose-dense, dose-intensified ETC(+HP) vs. weekly PM(Cb)(+HP) in patients with high-risk operable or locally advanced breast cancer. Masked role for assessor.
Time frame: 18 weeks (time window + 3 weeks)
Only for those patients randomized for the supportive anemia treatment: frequency of patients reaching hemoglobin (Hb) levels ≥ 11g/dl 6 weeks after treatment start of a first episode of anemia grade ≥2
Only for those patients randomized for the supportive anemia treatment: To compare the frequency of patients reaching hemoglobin (Hb) levels ≥ 11g/dl 6 weeks after treatment start of a first episode of anemia grade ≥2 (Hb \< 10g/dl) between patients receiving supportive treatment for iron deficiency with parental ferric carboxymaltose versus physician's choice (no supportive treatment, oral iron substitution, erythropoiesis-stimulating agent (ESA), or both).
Time frame: 18 weeks (time window + 3 weeks)
pcR rates per arm
To assess the pCR rates per arm separately for the stratified subpopulations.
Time frame: 18 weeks (time frame + 3 weeks)
Clinical and imaging response
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.
Time frame: 18 weeks (time window + 3 weeks)
Rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and the residual cancer burden (RCB) score.
Response (by physical examination, imaging response, breast conservation) will also be summarized as rates in each treatment group).
Time frame: 18 weeks (time frame + 3 weeks)
Toxicity and Compliance including incidence of febrile neutropenia
Descriptive statistics for the 5 treatments (ETC +/- anti-HER2-treatment, PM +/- anti-HER2-treatment, PMCb) will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.
Time frame: 18 weeks (time frame + 3 weeks)
Breast conservation rate
To determine the breast conservation rate after each treatment.
Time frame: 18 weeks (time frame: + 3 weeks)
loco-regional invasive recurrence free survival (LRRFS) in both arms and according to stratified subpopulations
LRRFS is 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.
Time frame: 5 years
distant-disease-free survival (DDFS) in both arms and according to stratified subpopulations.
DDFS is 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.
Time frame: 5 years
invasive disease-free survival (IDFS) in both arms and according to stratified subpopulations.
IDFS is 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.
Time frame: 5 years
overall survival (OS) in both arms and according to stratified subpopulations.
OS is 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.
Time frame: 5 years
regional recurrence free survival (RRFS) in patients with initial node-positive axilla
To assess regional recurrence free survival (RRFS) in patients with initial node-positive axilla converted to negative (ypN0) at surgery and treated with sentinel node biopsy alone.
Time frame: until event occurs - no event for cured patients
pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy
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.
Time frame: 5 years
Correlation of response
To correlate response (complete vs. partial vs. no change) measured by best appropriate imaging method after 6 weeks of treatment with pCR.
Time frame: 18 weeks (time frame + 3 weeks)
Examination and comparison of molecular markers
To examine and compare pre-specified molecular and histological markers such as Ki67, stromal TILs, immunologically relevant genes (e.g. CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21, IDO1, PD-1, PDL1, CTLA4, FOXP3, and combinations of these genes) as well as e.g. CD138, CD47, MET and other markers on core biopsies before and eventually also on surgical tissue after end of chemotherapy. The aim is to identify potential predictive short and long term parameters.
Time frame: Baseline and 18 weeks (time frame + 3 weeks)
Examination of PIK3CA mutation
To examine PIK3CA mutation in patients with HER2-positive tumor on core biopsies.
Time frame: Baseline and 18 weeks (time frame + 3 weeks)
Only for those patients randomized for the supportive anemia treatment: Quality of life
To compare quality of life using the FACT-An anemia and fatigue questionnaire between the supportive treatment arms.
Time frame: up to 18 weeks
Only for those patients randomized for the supportive anemia treatment: median time to achieve a hemoglobin level ≥11g/dl
To compare the median time to achieve a hemoglobin level ≥11g/dl between the supportive treatment arms.
Time frame: up to 18 weeks
Only for those patients randomized for the supportive anemia treatment: frequency of patients with a hemoglobin level ≥11g/dl
To compare the frequency of patients with hemoglobin level ≥11g/dl in the week after the end of the last chemotherapy cycle between the supportive treatment arms.
Time frame: up to 18 weeks
Pharmacogenetic substudy
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
Time frame: 18 weeks (time frame + 3 weeks)
GeparPET substudy
To demonstrate that PET-CT before surgery in addition to conventional presurgical staging methods can decrease the mastectomy rate in patients receiving neoadjuvant chemotherapy for breast cancer.
Time frame: 18 weeks (time frame + 3 weeks)
Ovarian function
To assess ovarian function measured by amenorrhea rate in correlation with changes in E2, FSH, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged \<45 years.
Time frame: Baseline until 2 years after EOS
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