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A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)

Primary Purpose

Tubular Breast Cancer Stage II, Tubular Breast Cancer Stage III, Mucinous Breast Cancer Stage II

Status
Completed
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
non-pegylated liposomal doxorubicin
Carboplatin
Paclitaxel
Epirubicin
Cyclophosphamide
Pertuzumab
Trastuzumab
Ferric carboxymaltose
Sponsored by
German Breast Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tubular Breast Cancer Stage II

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

Patients will be eligible for study participation only if they comply with the following criteria:

  • Written informed consent according to local regulatory requirements prior to beginning specific protocol procedures.
  • Complete baseline documentation must be submitted via MedCODES to GBG Forschungs GmbH.
  • 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 of inflammatory disease, the extent of inflammation can be used as measurable lesion.
  • Patients must have stage cT1c - cT4a-d disease. Patients with HER2- positive or TNBC are eligible irrespective of nodal status (cN0-cN3). Patients with luminal B-like tumors (defined here as ER and/or PgR >1% stained cells, HER2 negative, Ki-67 >20%) only with histologically (sentinel-node biopsy, core- or fine-needle biopsy) involved lymph nodes (pN1-3).
  • In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
  • Centrally confirmed ER, PR and HER2 status. Central pathology includes also assessment of Ki-67 and LPBC 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). 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.
  • Karnofsky Performance status index 90%.
  • Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 4 weeks prior to randomization. LVEF must be above 55%.
  • Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
  • 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 in case of high risk for primary metastasis. In case of a positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
  • Patients must agree with central pathology testing of core biopsy specimen and final pathology specimen and be available and compliant for treatment and follow-up.
  • In addition for patients to be randomized to the two supportive anemia treatment arms:
  • Hemoglobin level <10g/dl.
  • Body weight ≥ 40 kg.
  • No need for immediate red blood cell transfusion.
  • Transferrin saturation (TSAT) ≤20% and serum ferritin <300ng/ml.

Exclusion Criteria:

  • Patients with ER- and/or PR-positive, HER2-negative breast cancer and Ki- 67 <= 20% (any luminal A-like subtype) or luminal B-like (Ki67>20%) subtype without nodal involvement.
  • Patients with stages cT1a, cT1b, or any M1.
  • Patients with pure lobular invasive breast cancer.
  • 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).
  • 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.
  • 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.
  • Incomplete wound healing.
  • 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 unless initiated > 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).
  • sex hormones. 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.
  • Male patients.

In addition for patients to be randomized to the two supportive anemia treatment arms:

  • Iron substitution (oral or IV) or blood transfusions or treatment with r-HuEPO with the last 4 weeks prior to study start.
  • Known hypersensibility or contraindication against ferric carboxymaltose.

Sites / Locations

  • NTC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

PM(Cb)

ETC

Arm Description

PM(Cb): paclitaxel 80mg/m² 18 times weekly simultaneously with NPLD (Myocet®)20mg/m² 18 times weekly simultaneously with carboplatin AUC 1.5 18 times weekly (only in patients with TNBC) Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all cycles.

ETC: epirubicin 150mg/m² every 2 weeks for 3 cycles followed by paclitaxel 225 mg/m² every 2 weeks for 3 cycles followed cyclophosphamide 2000 mg/m² every 2 weeks for 3 cycles. Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all T and C cycles.

Outcomes

Primary Outcome Measures

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.
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).

Secondary Outcome Measures

pcR rates per arm
To assess the pCR rates per arm separately for the stratified subpopulations.
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.
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).
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.
Breast conservation rate
To determine the breast conservation rate after each treatment.
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.
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.
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.
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.
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.
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.
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.
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.
Examination of PIK3CA mutation
To examine PIK3CA mutation in patients with HER2-positive tumor on core biopsies.
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.
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.
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.
Pharmacogenetic substudy
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
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.
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.

Full Information

First Posted
April 22, 2014
Last Updated
July 10, 2017
Sponsor
German Breast Group
Collaborators
Amgen, Roche Pharma AG, Teva Pharmaceuticals USA, Vifor Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT02125344
Brief Title
A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)
Official Title
A Randomized Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2017
Overall Recruitment Status
Completed
Study Start Date
December 2014 (Actual)
Primary Completion Date
November 2016 (Actual)
Study Completion Date
January 30, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
German Breast Group
Collaborators
Amgen, Roche Pharma AG, Teva Pharmaceuticals USA, Vifor Pharma

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tubular Breast Cancer Stage II, Tubular Breast Cancer Stage III, Mucinous Breast Cancer Stage II, Breast Cancer Female NOS, Invasive Ductal Breast Cancer, HER2 Positive Breast Cancer, Inflammatory Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
961 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PM(Cb)
Arm Type
Experimental
Arm Description
PM(Cb): paclitaxel 80mg/m² 18 times weekly simultaneously with NPLD (Myocet®)20mg/m² 18 times weekly simultaneously with carboplatin AUC 1.5 18 times weekly (only in patients with TNBC) Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all cycles.
Arm Title
ETC
Arm Type
Active Comparator
Arm Description
ETC: epirubicin 150mg/m² every 2 weeks for 3 cycles followed by paclitaxel 225 mg/m² every 2 weeks for 3 cycles followed cyclophosphamide 2000 mg/m² every 2 weeks for 3 cycles. Patients with HER2-positive disease will receive trastuzumab 6 (8) mg/kg every 3 weeks and pertuzumab 420 (840) mg every 3 weeks simultaneously to all T and C cycles.
Intervention Type
Drug
Intervention Name(s)
non-pegylated liposomal doxorubicin
Other Intervention Name(s)
Myocet
Intervention Description
20 mg/m2, i.V. 18 times weekly
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Other Intervention Name(s)
Carbomedac
Intervention Description
Carboplatin AUC 1.5 18 times weekly (only in patients with triple-negative breast cancer).
Intervention Type
Drug
Intervention Name(s)
Paclitaxel
Other Intervention Name(s)
var.
Intervention Description
paclitaxel 80mg/m² 18 times weekly
Intervention Type
Drug
Intervention Name(s)
Epirubicin
Other Intervention Name(s)
Farmorubicin
Intervention Description
150mg/m² every 2 weeks for 3 cycles.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Endoxan
Intervention Description
2000 mg/m² every 2 weeks for 3 cycles.
Intervention Type
Drug
Intervention Name(s)
Pertuzumab
Other Intervention Name(s)
Perjeta
Intervention Description
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.
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 T and C cycles in the ETC arm and to all cycles in the PM(Cb) arm.
Intervention Type
Drug
Intervention Name(s)
Ferric carboxymaltose
Other Intervention Name(s)
Ferinject
Intervention Description
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.
Primary Outcome Measure Information:
Title
pathological complete response (pCR= ypT0/is ypN0)
Description
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)
Title
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
Description
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)
Secondary Outcome Measure Information:
Title
pcR rates per arm
Description
To assess the pCR rates per arm separately for the stratified subpopulations.
Time Frame
18 weeks (time frame + 3 weeks)
Title
Clinical and imaging response
Description
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)
Title
Rates of ypT0 ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and the residual cancer burden (RCB) score.
Description
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)
Title
Toxicity and Compliance including incidence of febrile neutropenia
Description
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)
Title
Breast conservation rate
Description
To determine the breast conservation rate after each treatment.
Time Frame
18 weeks (time frame: + 3 weeks)
Title
loco-regional invasive recurrence free survival (LRRFS) in both arms and according to stratified subpopulations
Description
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
Title
distant-disease-free survival (DDFS) in both arms and according to stratified subpopulations.
Description
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
Title
invasive disease-free survival (IDFS) in both arms and according to stratified subpopulations.
Description
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
Title
overall survival (OS) in both arms and according to stratified subpopulations.
Description
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
Title
regional recurrence free survival (RRFS) in patients with initial node-positive axilla
Description
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
Title
pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy
Description
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
Title
Correlation of response
Description
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)
Title
Examination and comparison of molecular markers
Description
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)
Title
Examination of PIK3CA mutation
Description
To examine PIK3CA mutation in patients with HER2-positive tumor on core biopsies.
Time Frame
Baseline and 18 weeks (time frame + 3 weeks)
Title
Only for those patients randomized for the supportive anemia treatment: Quality of life
Description
To compare quality of life using the FACT-An anemia and fatigue questionnaire between the supportive treatment arms.
Time Frame
up to 18 weeks
Title
Only for those patients randomized for the supportive anemia treatment: median time to achieve a hemoglobin level ≥11g/dl
Description
To compare the median time to achieve a hemoglobin level ≥11g/dl between the supportive treatment arms.
Time Frame
up to 18 weeks
Title
Only for those patients randomized for the supportive anemia treatment: frequency of patients with a hemoglobin level ≥11g/dl
Description
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
Title
Pharmacogenetic substudy
Description
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)
Title
GeparPET substudy
Description
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)
Title
Ovarian function
Description
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

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients will be eligible for study participation only if they comply with the following criteria: Written informed consent according to local regulatory requirements prior to beginning specific protocol procedures. Complete baseline documentation must be submitted via MedCODES to GBG Forschungs GmbH. 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 of inflammatory disease, the extent of inflammation can be used as measurable lesion. Patients must have stage cT1c - cT4a-d disease. Patients with HER2- positive or TNBC are eligible irrespective of nodal status (cN0-cN3). Patients with luminal B-like tumors (defined here as ER and/or PgR >1% stained cells, HER2 negative, Ki-67 >20%) only with histologically (sentinel-node biopsy, core- or fine-needle biopsy) involved lymph nodes (pN1-3). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured. Centrally confirmed ER, PR and HER2 status. Central pathology includes also assessment of Ki-67 and LPBC 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). 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. Karnofsky Performance status index 90%. Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 4 weeks prior to randomization. LVEF must be above 55%. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential. 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 in case of high risk for primary metastasis. In case of a positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated. Patients must agree with central pathology testing of core biopsy specimen and final pathology specimen and be available and compliant for treatment and follow-up. In addition for patients to be randomized to the two supportive anemia treatment arms: Hemoglobin level <10g/dl. Body weight ≥ 40 kg. No need for immediate red blood cell transfusion. Transferrin saturation (TSAT) ≤20% and serum ferritin <300ng/ml. Exclusion Criteria: Patients with ER- and/or PR-positive, HER2-negative breast cancer and Ki- 67 <= 20% (any luminal A-like subtype) or luminal B-like (Ki67>20%) subtype without nodal involvement. Patients with stages cT1a, cT1b, or any M1. Patients with pure lobular invasive breast cancer. 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). 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. 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. Incomplete wound healing. 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 unless initiated > 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent). sex hormones. 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. Male patients. In addition for patients to be randomized to the two supportive anemia treatment arms: Iron substitution (oral or IV) or blood transfusions or treatment with r-HuEPO with the last 4 weeks prior to study start. Known hypersensibility or contraindication against ferric carboxymaltose.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andreas Schneeweiss, MD, Prof.
Organizational Affiliation
NTC Heidelberg
Official's Role
Principal Investigator
Facility Information:
Facility Name
NTC
City
Heidelberg
State/Province
Baden-Württemberg
ZIP/Postal Code
69120
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
34801353
Citation
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http://www.germanbreastgroup.de/studien/neoadjuvant
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A Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)

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