Study Comparing Nanoparticle-based Paclitaxel With Solvent-based Paclitaxel as Part of Neoadjuvant Chemotherapy for Patients With Early Breast Cancer (GeparSepto)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Celgene Corporation
Roche Pharma AG
Information provided by (Responsible Party):
German Breast Group
ClinicalTrials.gov Identifier:
NCT01583426
First received: April 18, 2012
Last updated: February 10, 2014
Last verified: August 2013
  Purpose

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.


Condition Intervention Phase
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
Drug: nab-Paclitaxel
Drug: Paclitaxel
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by German Breast Group:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0, and regression grade [ Time Frame: 24 weeks (time window + 3 weeks) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: No ]
    To assess clinical response rate after taxane in both groups.

  • Breast conservation rate [ Time Frame: 24 weeks (time window + 3 weeks) ] [ Designated as safety issue: No ]
    To determine the breast conservation rate after each treatment.

  • Onset of grade 3 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ] [ Designated as safety issue: Yes ]
    To assess the time of onset of grade 3 neuropathy.

  • Resolution of grade 3/4 neuropathy [ Time Frame: 24 weeks (time window + 3 weeks) ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]

    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) ] [ Designated as safety issue: No ]
    To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.

  • Pharmacogenetic substudy [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 1200
Study Start Date: July 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: nab-Paclitaxel 125 mg/m² weekly, infusion
nab-Paclitaxel 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.
Drug: nab-Paclitaxel
nab-Paclitaxel 125 mg/m² weekly for 12 weeks
Other Name: Abraxane
Active Comparator: Paclitaxel 80 mg/m² weekly, infusion
Paclitaxel 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.
Drug: Paclitaxel
Paclitaxel 80 mg/m² weekly for 12 weeks

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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01583426

Locations
Germany
Helios-Klinikum Berlin-Buch
Berlin, Germany, 13125
Sponsors and Collaborators
German Breast Group
Celgene Corporation
Roche Pharma AG
Investigators
Principal Investigator: Michael Untch, Prof MD AGO, ASCO, DKG
  More Information

Additional Information:
No publications provided

Responsible Party: German Breast Group
ClinicalTrials.gov Identifier: NCT01583426     History of Changes
Other Study ID Numbers: GBG 69, 2011-004714-41
Study First Received: April 18, 2012
Last Updated: February 10, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by German Breast Group:
GeparSepto
GBG 69
GBG
German Breast Group
neo-adjuvant
GBG Forschungs GmbH
Tubular breast cancer stage II - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Mucinous breast cancer stage II
Invasive ductal breast cancer
Tubular breast cancer stage III
HER-2 positive breast cancer
Inflammatory breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Carcinoma, Ductal, Breast
Inflammatory Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carcinoma, Ductal
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms, Ductal, Lobular, and Medullary
Paclitaxel
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 22, 2014