Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00005204

Trial Description

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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)

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Trial Acronym

GeparSepto

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URL of the Trial

[---]*

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.

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Organizational Data

  •   DRKS00005204
  •   2013/09/03
  •   2012/04/18
  •   yes
  •   [---]*
  •   [---]*
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Secondary IDs

  •   2011-004714-41 
  •   NCT01583426  (ClinicalTrials.gov)
  •   GBG 69  (German Breast Group)
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Health Condition or Problem studied

  •   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
  •   C50 -  Malignant neoplasm of breast
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Interventions/Observational Groups

  •   Drug: nab-Paclitaxel
  •   Drug: Paclitaxel
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control
  •   Treatment
  •   Parallel
  •   III
  •   [---]*
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Primary Outcome

- 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.

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Secondary Outcome

- 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.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  •  
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Recruitment

  •   [---]*
  •   2012/07/31
  •   1200
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Female
  •   18   Years
  •   no maximum age
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Additional 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.

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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.

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Addresses

  • start of 1:1-Block address primary-sponsor
    • German Breast Group
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    • Celgene Corporation
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    •   [---]*
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    • Roche Pharma AG
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    • AGO, ASCO, DKG
    • Michael Untch, Prof MD 
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  • start of 1:1-Block address public-contact
    • Konstantin Reißmüller 
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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    •   [---]*
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Status

  •   Recruiting ongoing
  •   [---]*
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   5
  •   2013/10/20
* This entry means the parameter is not applicable or has not been set.