A study to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab/docetaxel in patients with breast cancer that spread to other tissues.

Conditions: First-line treatment of patients with HER2 negative metastatic breast cancer.
MedDRA version: 14.1Level: LLTClassification code 10027475Term: Metastatic breast cancerSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2006-001365-42-AT

Lead Sponsor: F. Hoffmann-La Roche Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 424

Inclusion Criteria

1. Patients age = 18 years
2. Able to comply with the protocol
3. ECOG PS of = 1
4. Life expectancy of = 12 weeks
5. Written informed consent [Informed Consent document to be approved by the institution’s Independent Ethics Committee (IEC)] obtained prior to any study specific screening activities.
6. Pre- or postmenopausal patients with histologically or cytologically confirmed breast cancer (adenocarcinoma) with measurable or non-measurable, locally recurrent or metastatic lesions (excluding primary tumor-T4d-Inflammatory carcinoma) who are candidates for chemotherapy. Locally recurrent disease must not be amenable to resection with curative intent ER/PgR and HER2 status must be documented.
7. Patients must have HER2 protein overexpression (3+) as determined by immunohistochemistry (IHC); or amplification of HER2/c-erbB2 as determined by fluorescent in situ hybridization (FISH) or chromogenic in situ hybridization (CISH), of the primary tumor or a metastasis confirmed by the central laboratory prior to randomization. Confirmation of HER2 positivity of the primary tumor by the central laboratory is not required in this trial for the patients who previously participated in Roche or Genentech sponsored trials of adjuvant Trastuzumab where HER2 status has been centrally confirmed (e.g. the HERA, BCIRG 006, NSABP B31, or Intergroup/NCCTG/H2061s trials).
8. Patients who received trastuzumab in the adjuvant setting are eligible as long as they have not relapsed within 6 months after the last dose of trastuzumab.
9. Patients who were treated with anthracyclines in adjuvant or neo-adjuvant setting are only eligible if they received their last dose = 6 months prior to randomization. The maximum cumulative dose must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin
10. Patients who were treated with a taxane are only eligible if they received their last adjuvant or neo-adjuvant chemotherapy = 12 months prior to randomization.
11. Baseline Left Ventricular Ejection Fraction (LVEF) not below 50% measured by either echocardiography or MUGA
12. The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization:
– Patients on heparin treatment should have a baseline aPTT between 1.5 - 2.5 times ULN or patients value before starting heparin treatment
– Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5 - 2 mg/kg (of enoxaparin) or appropriate doses of the correspondent anticoagulant, according to package insert
– Patients on coumarin derivatives should have an INR between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1-4 days apart
Patients not receiving anticoagulant medication must have an INR = 1.5 and aPTT = 1.5 times ULN within 7 days prior to randomization.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 347
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 77

Exclusion Criteria

1. Previous chemotherapy for metastatic or locally recurrent breast cancer. Prior hormonal therapy is allowed but must have been discontinued at least 2 weeks prior randomization.
2. Previous radiotherapy for treatment of metastatic breast cancer is not allowed in case:
- More than 30% of marrow-bearing bone have been irradiated
- The last fraction of radiotherapy has been administered within 3 weeks prior to randomization
Prior adjuvant radiotherapy for breast cancer is allowed, provided it has stopped at least 6 months prior to randomization.
3. Other primary tumor (including primary brain tumors) within the last 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer
4. Evidence of spinal cord compression or current evidence of CNS metastasis. CT or MRI scan of the brain is mandatory (within 4 weeks prior to randomization) in case of clinical suspicion of brain metastasis.
5. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures
6. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgery during the course of the study treatment
7. Existing peripheral neuropathy > CTC Grade 2 at randomization.
8. Inadequate bone marrow function: ANC < 1.5 x 1'000'000'000/L, Platelet count <100 x 1'000'000'000/L and Hb <9 g/dL
9. Inadequate liver function:
- serum (total) bilirubin > ULN
- AST and ALT > 2.5 x ULN
- AST or ALT > 1.5 x ULN concurrent with serum alkaline phosphatase levels > 2.5 x ULN at baseline
10. Inadequate renal function:
i. Serum Creatinine > 2.0 mg/dL or 177 µmol/L
ii. Urine dipstick for proteinuria > 2+. Patients with = 2+ proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate = 1 g of protein/24 hr.
11. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
12. Chronic daily treatment with aspirin (> 325 mg / day) or clopidogrel (> 75 mg /day).
13. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: CVA/stroke (= 6 months prior to randomization), myocardial infarction (= 6 months prior to
randomization), unstable angina, New York Heart Association (NYHA) Class 2 or greater Congestive Heart Failure, or serious cardiac arrhythmia requiring medication
14. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
15. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of randomization.
16. Active infection requiring i.v. antibiotics at randomization.
17. Serious non-healing wound, peptic ulcer, or bone fracture.
18. 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, or that may affect patient compliance with study routines, or place the patient at high risk from treatment complications.
19. Pregnant or lactating females.