Breast Cancer
Conditions
Keywords
breast, cancer, unilateral, non metastatic, HER2 negative
Brief summary
The purpose of this study is to assess the efficacy of neoadjuvant weekly nab-paclitaxel followed by Adriamycin, Cyclophosphamide (AC) or Epirubicin, Cyclophosphamide (EC) or Fluorouracil,Epirubicin,Cyclophosphamide (FEC)compared with neoadjuvant weekly solvent-based paclitaxel followed by AC or EC or FEC in terms of rate of pathological complete remissions at surgery.
Detailed description
In this study, eligible and consenting patients will be randomized to receive either 4 cycles of weekly abraxane (nab-paclitaxel) followed by 4 cycles of an anthracycline-containing regimen or 4 cycles of weekly paclitaxel followed by 4 cycles of an anthracycline-containing regimen.The anthracycline regimen (AC, EC or FEC) will be chosen by the investigator at the participating sites. Before randomization patients will be stratified according to Disease stage \[operable (tumor stage: T2N0-1; T3N0) and locally advanced (T3N1;T4, any N2-3)\] and Tumor subtype \[luminal B intermediate (HER2 negative, ER or PGR positive, Ki67 from 14% to 20%) vs luminal B high (HER2 negative, ER or PGR positive, Ki67 \>20%) vs triple negative tumors (HER2 negative, ER negative and PgR negative, Ki67 any value)\]. Tumor subtype will be confirmed at two selected referral laboratories. Neoadjuvant chemotherapy will be followed by definite surgery and irradiation as per international and local guidelines. During neoadjuvant chemotherapy patients will be assessed for safety and efficacy as detailed in the protocol. After definite surgery patients will be followed for approximately 10 years according to local procedures
Interventions
DRUGAbraxane
Abraxane at the dosage of 125 mg/m2 will be delivered over 30 minutes on week 1, 2 and 3 followed by 1 week rest. week rest and will be repeated for 4 cycles followed by AC or EC (adriamycin or epirubicin and cyclophosphamide) on day 1 every 3 weeks for 4 cycles or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles
DRUGPaclitaxel
Paclitaxel at the dosage of 90 mg/m2 diluted in 250 mL of water for injection (WFI) over 1 hour given week 1, 2 and 3 followed by 1 week rest and will be repeated for 4 cycles followed by AC or EC (adriamycin or epirubicin and cyclophosphamide) on day 1 every 3 weeks for 4 cycles or FEC (fluorouracil, epirubicin, and cyclophosphamide) on day 1 every three weeks for 4 cycles
Sponsors
Fondazione Michelangelo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients aged 18 years or older * Histologically confirmed invasive unilateral breast cancer * HER2-negative disease * Known hormone receptor status (estrogen receptor \[ER\], progesterone receptor \[PgR\]), tumor grade and, if institutional standard permits, known Ki67 value * Available paraffin-embedded tumor block taken at diagnostic biopsy for central confirmation of HER2 eligibility, hormone receptor status, Ki67 value and biomarker evaluation is mandatory * One of the following clinical stages: * T2, T3, T4 disease, triple negative (HER2, ER, PgR) * T2, T3, T4 disease, ER or PgR positive and moderately differentiated or poorly differentiated tumor grade (G II-III) * ECOG performance status 0 or 1 * Written informed consent to participate in the trial (approved by the Institutional Review Board \[IRB\]/ Independent Ethics Committee \[IEC\]) obtained prior to any study specific screening procedures * Willing and able to comply with the protocol
Exclusion criteria
* Synchronous contralateral breast cancer or presence of metastatic disease (M1). Exception: contralateral insitu ductal cancer * Surgical axillary staging procedure prior to study entry. Exceptions: 1) Fine needle aspiration (FNA) of an axillary node is permitted for any patient, and 2) although not recommended, a pre-neoadjuvant therapy sentinel lymph node biopsy for patients with clinically negative axillary nodes is permitted * Pregnant or lactating women. * Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception, for example abstinence, an intra-uterine device, or double barrier method of contraception * Treatment including radiation therapy, chemotherapy, biotherapy, and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry * Previous investigational treatment for any condition within 4 weeks of randomization date * Patients on therapy with a strong CYP3A4 inhibitor and on therapy with Warfarin (Coumadin) * Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results. Patients with curatively treated basal cell carcinoma of the skin or in situ cervix cancer are generally eligible. * Pre-existing motor or sensory neuropathy of grade \> 1 for any reason * Patients with a history of hypersensitivity due to drugs containing polyoxyethylene castor oil (Cremophor EL) (e.g., ciclosporin), or hardened castor oil (e.g., vitamin preparations for injection, etc.) * Other serious illness or medical condition including: history of documented congestive cardiac failure; angina pectoris requiring anti-anginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension (e.g. systolic \>180 mm Hg or diastolic \>100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias * Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs * Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus * Hematology and biochemistry tests within normla limits * Baseline left ventricular ejection fraction (LVEF) \< 50% by echocardiography or multi-gated scintigraphic scan (MUGA)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| pathologic Complete Response (pCR) | At the time of surgery: 40 months after the randomization of the first patient | To compare the rate of pathologic Complete Response (pCR, absence of invasive disease in breast and nodes (ypT0/ypTis, ypN0)) for abraxane (Abraxane®, abraxane) vs paclitaxel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| clinical Overall Response (cOR) | At the time of surgery: 40 months after the randomization of the first patient | To compare the rate of clinical overall response (cOR) after the first 4 cycles of abraxane vs paclitaxel and to compare the rate of cOR after the entire preoperative chemotherapy (i.e. before surgery) in the study arms of abraxane vs paclitaxel |
| Event Free Survival (EFS) | 5 years after the first patient in and 10 years after randomization of last patient in | To compare the Event Free Survival (EFS, i.e. disease progression while on primary therapy or disease recurrence after surgery) in the study arms of abraxane vs paclitaxel |
| Distant Event Free Survival (DEFS) | 5 years after the first patient in and 10 years after randomization of last patient in | The distant event free survival (DEFS) is defined as the time from randomization to the first date of distant metastasis while on primary therapy or distant recurrence after surgery or death due to any cause. Patients who terminate the study without evidence of any of the above events will be censored at the date of their last follow-up tumor assessment |
| Local Event Free Survival | 5 years after the first patient in and 10 years after randomization of last patient in | The local event free survival (LEFS) is defined as the time from randomization to the first date of local progression while on primary therapy or local recurrence after surgery. Rules for censoring and methods of analysis will be the same as defined for EFS |
| Regional Event Free Survival | 5 years after the first patient in and 10 years after randomization of last patient in | The regional event free survival (REFS) is defined as the time from randomization to the first date of regional progression while on primary therapy or regional recurrence after surgery. Rules for censoring and methods of analysis will be the same as defined for EFS. |
| Overall Survival (OS) | 13 years from the date of first patient in | The overall survival (OS) is defined as the time from randomization to the date of death. Patients alive at the end of study will be censored at their last contact date. |
| Safety and Tolerability | Each participant will be followed for the duration of treatment period, approximately 9 months | Patients will be assessed for adverse events by clinical examination, questioning for symptoms of toxicity, laboratory assessments, vital signs, ECG and LVEF. Neurological toxicity and other toxicities will be assessed throughout the study according the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. |
Countries
Australia, Germany, Italy, Russia, Singapore, Spain
Outcome results
None listed