A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer
To compare the pCR rates of neoadjuvant treatment of epirubicin / cyclophosphamide followed
by docetaxel (EC-T) with or without bevacizumab (EC-T vs. ECB-TB) in patients with Her-2
negative primary breast cancer (Setting I).
To compare the pCR rates of neoadjuvant treatment with weekly paclitaxel with or without
Everolimus (RAD001) (Pw vs. PwR) in patients with Her-2 negative primary breast cancer
showing no sonographic response to 4 cycles of EC +/-B (Setting II).
To compare the pCR rates of neoadjuvant treatment with epirubicin / cyclophosphamide
followed by docetaxel with either trastuzumab or lapatinib (ECH-TH vs. ECL-TL) in patients
with Her-2 positive primary breast cancer (Setting III).
1. To assess the toxicity of and compliance to all six treatments.
2. To determine the response rates of the breast tumor and axillary nodes by physical
examination and imaging tests (sonography, mammography, or MRI) after treatment in all
3. To determine the breast conservation rate after each treatment.
4. To determine the (loco-regional and distant) disease-free and overall survival after
each treatment. In Her-2 positive disease, the cerebral disease-free survival will be
5. To assess treatment efficacies in subgroups defined according to tumor stage (T2-3 vs.
T4), receptor status (ER and / or PgR positive vs. ER and PgR negative) and response by
best appropriate imaging method to the first four cycles of treatment (complete vs.
partial vs. no change).
6. To examine and compare pre-specified molecular markers such as Ki-67, phospho-mTOR,
YB-1, COX-2, HuR, phospho-p70 S6K, p65 NF kappa B, PTEN, PI3-K, Akt, and a marker for
stem cell like breast cancers (SOX-10) on core biopsy before and after end of
Objectives of Substudies:
1. To assess and correlate circulating tumor cells and proteins with the effect of
2. To compare the pathologic complete response (pCR), breast conservation, clinical and
imaging response rate (after four cycles and before surgery) in patients where the
tumor shows a favorable profile of a predetermined combined biomarker set to those
where the tumor does not show it (PREDICT Substudy).
3. To determine the percentage of patients in which conventional axillary clearance can be
substituted by sentinel node biopsy when a predetermined clinical algorithm is used
4. To assess the surgical outcome according to patient's and surgeon's perspectives in
correlation with clinical and pathological response to systemic treatment (SOS -
Surgical Outcome Substudy).
5. To correlate Single Nucleotide Polymorphisms (SNPs) of genes which are either involved
in the metabolism or in the effectiveness of the distinct therapies with the associated
toxicity and histologically assessed treatment effect (Pharmacogenomic Substudy).
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
To compare the pCR rates of neoadjuvant treatment in all 3 Settings
Gunter von Minckwitz, MD, Prof.
German Breast Group