NCT01583426 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2020-08-06

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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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

No posted result sections were captured. Registered plans do not establish that a treatment works.

Who could take part

eligibility 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: FEMALE
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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 Names
Drug: nab-Paclitaxel
label
nab-Paclitaxel
type
EXPERIMENTAL
description
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 Names
Drug: Paclitaxel
label
Paclitaxel
type
ACTIVE_COMPARATOR

interventions

arm Group Labels
nab-Paclitaxel
description
nab-Paclitaxel 125 mg/m² weekly for 12 weeks
name
nab-Paclitaxel
other Names
Abraxane
type
DRUG
arm Group Labels
Paclitaxel
description
Paclitaxel 80 mg/m² weekly for 12 weeks
name
Paclitaxel
type
DRUG

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 1229
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
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)

secondary Outcomes

description
Response (by physical examination, imaging response, breast conservation) will also be summarized as rates in each treatment group.
measure
Rates of ypT0/is ypN0; ypT0 ypN0/+; ypT0/is ypN0/+; ypT(any) ypN0, and regression grade
time Frame
24 weeks (time window + 3 weeks)
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.
measure
Clinical and imaging response
time Frame
24 weeks (time window + 3 weeks)
description
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.
measure
Tolerability and safety
time Frame
during treatment (24 weeks)
description
To assess clinical response rate after taxane in both groups.
measure
pCR rates per arm
time Frame
24 weeks (time window + 3 weeks)
description
To determine the breast conservation rate after each treatment.
measure
Breast conservation rate
time Frame
24 weeks (time window + 3 weeks)
description
To assess the time of onset of grade 3 neuropathy.
measure
Onset of grade 3 neuropathy
time Frame
24 weeks (time window + 3 weeks)
description
To assess the time of resolution of grade 3/4 neuropathy to at least grade 1.
measure
Resolution of grade 3/4 neuropathy
time Frame
24 weeks (time window + 3 weeks)
description
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.
measure
Regional recurrence free survival (RRFS) in patients with initial node-positive axilla
time Frame
until event occurs - no event for cured patients
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.
measure
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)
description
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.
measure
Examination and comparison of molecular markers
time Frame
Baseline, 12 weeks and 24 weeks (time frame + 3 weeks)
description
To assess, characterize, and correlate circulating tumor cells and proteins with the effect of treatment.
measure
CTC Substudy
time Frame
Baseline, 12 weeks and 24 weeks (time frame + 3 weeks)
description
To correlate Single Nucleotide Polymorphisms (SNPs) of genes with the associated toxicity and histologically assessed treatment effect.
measure
Pharmacogenetic substudy
time Frame
Baseline

Full study description

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.

Source references

references

citation
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