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A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer

Phase 3
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

A Phase III Trials Program Exploring the Integration of Bevacizumab, Everolimus (RAD001), and Lapatinib Into Current Neoadjuvant Chemotherapy Regimes for Primary Breast Cancer

Primary objectives:

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).

Secondary objectives:

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
determined separately.

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
treatment(CTC Substudy).

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
(SENTINA Substudy).

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).

Inclusion Criteria:

1. Written informed consent

2. Complete baseline documentation sent to GBG Forschungs GmbH;

3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by
core biopsy. Fine-needle aspiration is not sufficient. Incisional biopsy is not

4. Tumor lesion in the breast with a palpable size of ≥ 2 cm or a sonographically size
of at least 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;

5. Patients should have stages of disease in which adjuvant chemotherapy would be

- Locally advanced tumors with cT4 or cT3 or

- Estrogen (ER)- and progesterone (PgR)-receptor negative tumors or

- ER or PgR positive tumors which are cN+ (for cT2) or pNSLN+ (for cT1) * During
the Run-In-Safety phase only patients with cT4 or cT3 cN+ disease are eligible.

6. Known HER-2/neu status detected on core biopsy. HER-2/neu positive is defined as
HercepTest IHC 3+ or FISH+;

7. Age older than 18 years;

8. Karnofsky Performance status index at least 80%;

9. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or
shortening fraction) within 1 month prior to registration.

10. Laboratory requirements:

Hematology: Absolute neutrophil count (ANC) ≥ 2.0 x 10e9/L platelets ≥ 100 x 10e9/L,
Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L) Hepatic function: Total bilirubin < 1 x UNL ASAT
(SGOT) and ALAT (SGPT)≤ 2.5 x UNL Alkaline phosphatase ≤ 5 UNL. Patients with ASAT
and / or ALAT > 1.5 x UNL associated with alkaline phosphatase > 2.5 x UNL are not
eligible for the study; Renal function: Creatinine ≤ 175 µmol/L (2 mg/dL) < 1,25 UNL
(or the calculated creatinine clearance ≥ 60 mL/min) Urine dipstick for proteinuria <
2+. Patients discovered to have ≥2+ proteinuria on dipstick urinalysis should undergo
a 24 hour urine collection and must demonstrate ≤1 g of protein in 24 hours

11. Paraffin tumor tissue block and two serum samples centrally made available

12. Negative pregnancy test (urine or serum)

13. Complete staging work-up within 3 months prior to registration.

14. Patients must be available and compliant for treatment and follow-up.

Exclusion criteria:

1. Patients with low or moderate risk, which are only doubtful candidates for adjuvant

2. Evidence of distant metastasis;

3. Prior chemotherapy for any malignancy;

4. Prior radiation therapy for breast cancer;

5. Pregnant or lactating patients.

6. Inadequate general condition

7. Previous malignant disease

8. 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, un- or poorly controlled
arterial hypertension, rhythm abnormalities requiring permanent treatment, clinically
significant valvular heart disease

9. Previous thromboembolic event

10. Known hemorrhagic diathesis or increased bleeding risk

11. History of significant neurological or psychiatric disorders that would prohibit the
understanding and giving of informed consent;

12. Pre-existing motor or sensory neuropathy of a severity more than grade 2 by NCI

13. Currently active infection;incomplete wound healing

14. Active peptic ulcer

15. Disease significantly affecting gastrointestinal function

16. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 6 months of enrollment

17. Severe pulmonary condition/illness

18. Unstable diabetes mellitus; insulin dependent type II diabetes mellitus

19. Major surgery or incomplete wound healing within the last 28 days

20. Definite contraindications for the use of corticosteroids

21. Known hypersensitivity reaction to one of the investigational compounds or
incorporated substances; or known dihydropyrimidine dehydrogenase deficiency

22. Concurrent treatment with:chronic corticosteroids unless initiated > 6 months prior
to study entry and at low dose (20 mg methylprednisolone or equivalent); sex
hormones.Virostatic agents like sorivudine or analogs like brivudine, concurrent
treatment with aminoglycosides; anticoagulants: heparin, warfarin as well as acetic
acid (e.g. Aspirin®) at a dose of > 325mg/day or clopidogrel at a dose of > 75
mg/day)e.other experimental drugs or any other anti-cancer therapy; drugs recognized
as being strong inhibitors or inducers of the isoenzyme CYP3A (e.g. Rifabutin,
Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin,
Erythromycin, Verapamil, Dilitazem, within the last 5 days or the expected need for
these treatments during study participation.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To compare the pCR rates of neoadjuvant treatment in all 3 Settings

Outcome Time Frame:


Safety Issue:


Principal Investigator

Gunter von Minckwitz, MD, Prof.

Investigator Role:

Principal Investigator

Investigator Affiliation:

German Breast Group


Germany: Paul-Ehrlich-Institut

Study ID:

GBG 44



Start Date:

October 2007

Completion Date:

December 2015

Related Keywords:

  • Breast Cancer
  • breast cancer
  • primary systemic therapy
  • pCR Rates
  • Bevacizumab
  • Trastuzumab
  • Lapatinib
  • Everolimus
  • Breast Neoplasms