A randomized, open-label, 2-arm, multicentre, phase III study to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab / docetaxel compared with trastuzumab / docetaxel alone as first line treatment for patients with HER2 positive locally recurrent or metastatic breast cancer

Conditions: First line treatment for patients with HER2 positive locally recurrent or metastatic breast cancer
MedDRA version: 8.1Level: LLTClassification code 10027475Term: Metastatic breast cancer

Registration Number: EUCTR2006-001365-42-DE

Lead Sponsor: F. Hoffmann-La Roche Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 320

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, candidate 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 (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.
8. Patients who received trastuzumab in the adjuvant setting are eligible as long as their treatment with trastuzumab lasted for at least 10 months and who have not relapsed within 9 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
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Previous chemotherapy for metastatic or locally recurrent breast cancer. Prior hormonal therapy for locally recurrent or metastatic disease is allowed but must have been discontinued at least 3 weeks prior to randomization.
2. Previous radiotherapy for treatment of metastatic breast cancer is not allowed. However, prior adjuvant radiotherapy for breast cancer is allowed, provided it has stopped at least 6 months prior to randomization. Radiotherapy administered for the relief of metastatic bone pain is allowed prior to study entry, but
- No more than 30% of marrow-bearing bone should have been irradiated
- The last fraction of radiotherapy should not have been administered within 3
weeks 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 109/L, Platelet count < 100 x 109/L and Hb <9 g/dL
9. Inadequate liver function:
- serum (total) bilirubin > ULN
- AST and ALT > 2.5 x ULN ( > 5 x ULN in patients with liver metastasis)
- AST and 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 com

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To compare Progression Free Survival (PFS) in patients randomized to bevacizumab in combination with trastuzumab / docetaxel versus patients randomized to trastuzumab / docetaxel alone;Secondary Objective: To evaluate:<br>- Overall Survival (OS)<br>- Best Overall Response (OR)<br>- Duration of Response (DR)<br>- Time to Treatment Failure (TTF)<br>- Safety and tolerability of combining bevacizumab with trastuzumab and docetaxel<br>- Quality of Life;Primary end point(s): The primary endpoint of this study is progression-free survival (PFS), which is defined as the time from randomization to time of first documented disease progression or death, whichever occurs first. Patients without an event will be censored at the last tumor assessment or last follow-up for disease progression at which they were known to be progression free. Patients without any post-baseline tumor assessment will be censored at randomization.

Secondary Outcome Measures