Nanoparticle-based Paclitaxel vs Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Early Breast Cancer (GeparSepto) (GeparSepto)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT01583426

Recruitment Status : Completed

First Posted : April 24, 2012

Last Update Posted : August 6, 2020

View this study on the modernized ClinicalTrials.gov

Sponsor:

Collaborators:

Celgene Corporation

Roche Pharma AG

Information provided by (Responsible Party):

German Breast Group

Tracking Information

First Submitted Date ^ICMJE

April 18, 2012

First Posted Date ^ICMJE

April 24, 2012

Last Update Posted Date

August 6, 2020

Study Start Date ^ICMJE

July 2012

Actual Primary Completion Date

December 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Pathological complete response (pCR=ypT0 ypN0) rates of neoadjuvant treatment of nab-paclitaxel with solvent-based paclitaxel as part of neoadjuvant treatment of operable or locally advanced primary breast cancer. [ Time Frame: 24 weeks (time window + 3 weeks) ]

No microscopic evidence of residual invasive or non-invasive viable tumor cells in all resected specimens of the breast and axilla. Pathological response will be assessed considering all removed breast and lymphatic tissues from all surgeries. The primary endpoint will be summarized as pathological complete remission rate for each treatment group.

Original Primary Outcome Measures ^ICMJE

Same as current

Change History

Current Secondary Outcome Measures ^ICMJE

Rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0, and regression grade [ Time Frame: 24 weeks (time window + 3 weeks) ]
Response (by physical examination, imaging response, breast conservation) will also be summarized as rates in each treatment group.
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.
Tolerability and safety [ Time Frame: during treatment (24 weeks) ]
Descriptive statistics for the 4 treatments (each taxane +/- anti-HER2-treatment) will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.
pCR rates per arm [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess clinical response rate after taxane in both groups.
Breast conservation rate [ Time Frame: 24 weeks (time window + 3 weeks) ]
To determine the breast conservation rate after each treatment.
Onset of grade 3 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess the time of onset of grade 3 neuropathy.
Resolution of grade 3/4 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess the time of resolution of grade 3/4 neuropathy to at least grade 1.
Regional recurrence free survival (RRFS) in patients with initial node-positive axilla [ Time Frame: until event occurs - no event 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.
pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy [ Time Frame: 24 weeks (time frame + 3 weeks) ]
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.
Examination and comparison of molecular markers [ Time Frame: Baseline, 12 weeks and 24 weeks (time frame + 3 weeks) ]
To examine and compare pre-specified molecular markers such as SPARC, gp60, calveoline 1 and other markers potentially differentially predicting efficacy of nab-paclitaxel and solvent-based paclitaxel on core biopsies before, during and after chemotherapy. The aim is to identify potential predictive short and long term parameters.
CTC Substudy [ Time Frame: Baseline, 12 weeks and 24 weeks (time frame + 3 weeks) ]
To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.
Pharmacogenetic substudy [ Time Frame: Baseline ]
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
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, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.
Loco-regional invasive recurrence free survival (LRRFS) in both arms and according to stratified subpopulations. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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.
Surgical substudy in patients with high probability for pCR [ Time Frame: Baseline, after 4 cycles and before surgery (time frame + 3 weeks) ]
If it can be shown at an interim analysis that the positive predictive value for a pCR of a negative (>=3) core biopsies before surgery in patients with complete clinical response is >90%, these patients might opt for having no further breast surgery.

Original Secondary Outcome Measures ^ICMJE

Rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0, and regression grade [ Time Frame: 24 weeks (time window + 3 weeks) ]
Response (by physical examination, imaging response, breast conservation) will also be summarized as rates in each treatment group.
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.
Tolerability and safety [ Time Frame: during treatment (24 weeks) ]
Descriptive statistics for the 4 treatments (each taxane +/- anti-HER2-treatment) will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.
pCR rates per arm [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess clinical response rate after taxane in both groups.
Breast conservation rate [ Time Frame: 24 weeks (time window + 3 weeks) ]
To determine the breast conservation rate after each treatment.
Onset of grade 3 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess the time of onset of grade 3 neuropathy.
Resolution of grade 3/4 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ]
To assess the time of resolution of grade 3/4 neuropathy to at least grade 1.
Regional recurrence free survival (RRFS) in patients with initial node-positive axilla [ Time Frame: until event occurs - no event 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.
pCR rate and local recurrence free survival (LRFS) in patients with a clinical complete response (cCR) and a negative core biopsy [ Time Frame: 24 weeks (time frame + 3 weeks) ]
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.
Examination and comparison of molecular markers [ Time Frame: Baseline, 12 weeks and 24 weeks (time frame + 3 weeks) ]
To examine and compare pre-specified molecular markers such as SPARC, gp60, calveoline 1 and other markers potentially differentially predicting efficacy of nab-paclitaxel and solvent-based paclitaxel on core biopsies before, during and after chemotherapy. The aim is to identify potential predictive short and long term parameters.
CTC Substudy [ Time Frame: Baseline, 12 weeks and 24 weeks (time frame + 3 weeks) ]
To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.
Pharmacogenetic substudy [ Time Frame: Baseline ]
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
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, LH , Anti-Müller Hormone, ultrasound-follicle count in patients aged <45 years.
Loco-regional invasive recurrence free survival (LRRFS) in both arms and according to stratified subpopulations. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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. [ Time Frame: 5 years ]
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.

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

Nanoparticle-based Paclitaxel vs Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Early Breast Cancer (GeparSepto)

Official Title ^ICMJE

A Randomized Phase III Trial Comparing Nanoparticle-based Paclitaxel With Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (GeparSepto)

Brief Summary

Current guidelines as those from the AGO-Breast commission recommend for neoadjuvant breast cancer patients either a sequence of 4 cycles EC followed by 4 cycles of a taxane or 6 cycles of TAC based on previous large scale studies.

Treatment of patients with HER2-positive disease should include also simultaneous application of trastuzumab.

Solvent-based taxanes (paclitaxel, docetaxel) cause severe toxicities not only by the active agents itself but also by the solvents like cremophor. Nab-paclitaxel (Abraxane®) is a solvent-free formulation of paclitaxel encapsulated in albumin. It does not require premedication with corticosteroids or antihistamines to prevent the risk of solvent-mediated hypersensitivity reactions. This new formulation improves safety profile, allows higher dosing with shorter infusion duration, and produces higher tumor drug concentration.

As neoadjuvant treatment does not only allow to compare competing treatment approaches with a very high quality (homogenous treatment population, precise assessment of response by histological assessment), but also to identify predictive markers, this trial will compare weekly nab-paclitaxel with solvent-based paclitaxel at their currently optimal doses.

In case of HER2-positive tumor status patients receive Pertuzumab and Trastuzumab additionally.

Detailed Description

Primary Objectives:

To compare the pathological complete response (pCR=ypT0 ypN0) rates of neoadjuvant treatment of nab-paclitaxel with solvent-based paclitaxel as part of neoadjuvant treatment of operable or locally advanced primary breast cancer

Secondary Objectives:

To assess the pCR rates per arm separately for the stratified subpopulations.
To determine the rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0; and regression grades.
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.
To assess clinical response rate after taxane in both groups
To determine the breast conservation rate after each treatment.
To assess the toxicity and compliance.
To assess the time of onset of grade 3 neuropathy
To assess the time of resolution of grade 3/4 neuropathy to at least grade 1
To determine loco-regional invasive recurrence free survival (LRRFS), distant-disease-free survival (DDFS), invasive disease-free survival (IDFS), and overall survival (OS) in both arms and according to stratified subpopulations.
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.
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.
To examine and compare pre-specified molecular markers such as SPARC, gp60, calveoline 1 and other markers potentially differentially predicting efficacy of nab-paclitaxel and solvent-based paclitaxel on core biopsies before, during and after chemotherapy.

Objectives of Substudies:

To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment (CTC Substudy).
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect (Pharmacogenetic substudy)
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.

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 3

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment

Condition ^ICMJE

Tubular Breast Cancer Stage II
Mucinous Breast Cancer Stage II
Breast Cancer Female NOS
Invasive Ductal Breast Cancer
Tubular Breast Cancer Stage III
HER-2 Positive Breast Cancer
Inflammatory Breast Cancer Stage IV
Inflammatory Breast Cancer

Intervention ^ICMJE

Drug: nab-Paclitaxel
nab-Paclitaxel 125 mg/m² weekly for 12 weeks

Other Name: Abraxane
Drug: Paclitaxel
Paclitaxel 80 mg/m² weekly for 12 weeks

Study Arms ^ICMJE

Experimental: nab-Paclitaxel
nab-Paclitaxel (125 mg/m² weekly, infusion) is applicated for 12 weeks, followed by epirubicin and cyclophosphamide, applicated 4 cycles 3-weekly . In case of HER2-positive tumor patients receive tarstuzumab and pertuzumab 3-weekly during all cycles.

Intervention: Drug: nab-Paclitaxel
Active Comparator: Paclitaxel
Paclitaxel (80 mg/m² weekly, infusion) is applicated for 12 weeks, followed by epirubicin and cyclophosphamide, applicated 4 cycles 3-weekly . In case of HER2-positive tumor patients receive tarstuzumab and pertuzumab 3-weekly during all cycles.

Intervention: Drug: Paclitaxel

Publications *

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Completed

Actual Enrollment ^ICMJE

1229

Original Estimated Enrollment ^ICMJE

1200

Actual Study Completion Date ^ICMJE

December 2018

Actual Primary Completion Date

December 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria:

Patients will be eligible for study participation only if they comply with the following 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 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 be in the following stages of disease:
- - cT2 - cT4a-d or
- cT1c and cN+ or
- - cT1c and pNSLN+ or
- - cT1c and ER-neg and PR-neg or
- - cT1c and Ki67 > 20%
- - cT1c and HER2-pos
- In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
Centrally confirmed ER/PR/HER-2, Ki-67 and SPARC status detected on core biopsy. ER/PR positive is defined as >1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridisation (ISH) ratio >2.0. 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.
Age >= 18 years.
Karnofsky Performance status index >= 80%.
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. For patients with HER2-positive tumors LVEF must be >= 55%.
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.
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 done. 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.

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 without 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.
History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
Persons who have been admitted to an institution by order of jurisdictional or governmental grounds.
Pre-existing motor or sensory neuropathy of grade 2 or more by NCI-CTC criteria v 4.0.
Currently active infection.
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.

Sex/Gender ^ICMJE

Sexes Eligible for Study:

Female

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ^ICMJE

Germany

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT01583426

Other Study ID Numbers ^ICMJE

GBG 69
2011-004714-41 ( EudraCT Number )

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Not Provided

IPD Sharing Statement ^ICMJE

Not Provided

Current Responsible Party

German Breast Group

Original Responsible Party

Same as current

Current Study Sponsor ^ICMJE

German Breast Group

Original Study Sponsor ^ICMJE

Same as current

Collaborators ^ICMJE

Celgene Corporation
Roche Pharma AG

Investigators ^ICMJE

Principal Investigator:

Michael Untch, Prof MD

AGO, ASCO, DKG

PRS Account

German Breast Group

Verification Date

August 2020

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

To Top