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Multicentre Randomized Phase II Study of Neoadjuvant Trastuzumab Plus Docetaxel With and Without Bevacizumab and Trastuzumab Plus Docetaxel Plus Non-pegylated Liposome-encapsulated Doxorubicin (NPLD) With and Without Bevacizumab in HER2-positive Early Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Multicentre Randomized Phase II Study of Neoadjuvant Trastuzumab Plus Docetaxel With and Without Bevacizumab and Trastuzumab Plus Docetaxel Plus Non-pegylated Liposome-encapsulated Doxorubicin (NPLD) With and Without Bevacizumab in HER2-positive Early Breast Cancer

The target study population consists of male and female pre- and postmenopausal patients
with HER2-positive, adenocarcinoma of the breast (except inflammatory breast cancer, T4d)
scheduled to receive neoadjuvant cytotoxic treatment.

Patients must have pathologically confirmed breast cancer with histologically confirmed HER2
over-expression. At screening, patients must have an adequate left ventricular ejection
fraction (LVEF); an ECOG performance status of 0 or 1; adequate liver, renal and bone marrow
function; and be free of other serious diseases that could affect protocol compliance or
interpretation of results.

Patients should not be at increased risk of GI perforation, hypertension, proteinuria, wound
healing complications, thromboembolism or hemorrhage. Patients must not have had another
primary malignancy that could affect compliance with the protocol or interpretation of
results. Patients with central nervous system (CNS) metastases are excluded. Pregnant or
lactating females are excluded. Patients with hypertension (>150 mmHG systolic or >100 mmHG
diastolic) and patients with a history of GI perforation, abdominal fistula or
intra-abdominal abscess within 6 months of study entry are excluded.

Full anticoagulation therapy at study entry is allowed as long as the patient has been on a
stable level of anticoagulants for at least 2 weeks at the time of study treatment start.

Inclusion Criteria:

- Female or male, age ≥ 18 years

- Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory
breast cancer, T4d) scheduled for taxane containing neoadjuvant systemic treatment
with/without palpable lymph nodes.

- Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+
or by demonstrated HER2/c-erbB2 gene amplification of the primary tumor by a local

- LVEF ≥ 55% measured by echocardiography or MUGA within 4 weeks before randomization

- ECOG Performance Status ≤ 1

- Able and willing to comply with scheduled visits, treatment plans, laboratory tests,
and other study procedures.

- Written Informed Consent

Exclusion Criteria:

Current Treatment

- Requirement for concurrent use of the antiviral agent sorivudine or chemically
related analogues, such as brivudine.

- Chronic daily treatment with corticosteroids excl. inhaled steroids.

- Chronic daily treatment with aspirin and aspirin analogs or clopidogrel

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to randomization or anticipation of need for major surgery during the course of
study treatment

- Current or recent (within 30 days prior to randomization) treatment with another
investigational drug or participation in another investigational study.


- Inadequate bone marrow function

- Inadequate liver function

- Inadequate renal function

- Patients not receiving anticoagulant medication who have activated partial
thromboplastin time (aPTT) within 7 days prior to Day1 of the cycle 1.

Concomitant Conditions

- Other malignancy within the last 5 years before randomization except for curatively
treated carcinoma in situ of the cervix or non-melanomatous skin cancer

- Evidence of distant metastasis judged clinically and at least by chest-X-ray,
liver-sonography and bone scan. If there is any clinical suspicion of brain
metastasis, a CT-scan or MRI of the brain must be conducted within 4 weeks prior to

- Serious concurrent disease which could affect compliance with the protocol or
interpretation of results, including, but not limited to:

- Active infection requiring i.v. antibiotics

- Uncontrolled hypertension

- Clinically significant history of cardiovascular disease as indicated by:
cerebrovascular accident or stroke; myocardial infarction; unstable angina; NYHA
Grade II or greater CHF; cardiac arrhythmia requiring medication; clinically
significant valvular heart disease.

- Dyspnea at rest necessitating supportive oxygen therapy or with significant
pleural effusions

- Poorly controlled diabetes mellitus

- History or evidence upon physical/neurological examination of CNS disease
unrelated to cancer (e.g. uncontrolled seizures) unless adequately treated with
standard medical therapy

- History or evidence of inherited bleeding diathesis or coagulopathy with the
risk of bleeding

- History of abdominal fistula, GI perforation, or intra-abdominal abscess within
6 months of randomization

- Serious non-healing wound, peptic ulcer, or bone fracture

- Clinically significant malabsorption syndrome, ulcerative colitis, disease
affecting GI function, resection of the stomach or small bowel, or inability to
take oral medication

- Uncorrected hypokalemia or hypomagnesemia

- Organ allografts requiring immunosuppressive therapy

- Evidence of any other disease, metabolic or psychological dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of an investigational drug, may
affect patient compliance with study routines, or place the patient at high risk from
treatment related complications.

- Known hypersensitivity to any of the study drugs/excipients.

- Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or
humanized antibodies.


- Pregnant, lactating females or women of childbearing potential without a negative
pregnancy test

- Fertile males or females of childbearing potential

- Patients not accessible for treatment or follow-up

Type of Study:


Study Design:

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

Outcome Measure:

Cardiac toxicity

Outcome Description:

to evaluate the cardiac toxicity of the combination trastuzumab+docetaxel+bevacizumab and trastuzumab+docetaxel+NPLD +/- bevacizumab in comparison to the standard therapy, trastuzumab+docetaxel using a composite endpoint appearing between day 1 of cycle 1 and day 28 after the day of final surgery.

Outcome Time Frame:

between day 1 of cycle 1 and day 28 after the day of final surgery

Safety Issue:


Principal Investigator

Guenther Steger, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Austrian Breast & Colorectal Cancer Study Group


Austria: Federal Office for Safety in Health Care

Study ID:




Start Date:

June 2011

Completion Date:

September 2014

Related Keywords:

  • Breast Cancer
  • HER2-positive early breast cancer
  • Breast Neoplasms