E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
First-line treatment of patients with HER2 negative metastatic breast cancer. |
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E.1.1.1 | Medical condition in easily understood language |
Breast cancer that spread to other tissues. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare Progression Free Survival (PFS) in patients randomized to bevacizumab in combination with trastuzumab/docetaxel versus patients randomized to trastuzumab/docetaxel alone |
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E.2.2 | Secondary objectives of the trial |
To evaluate:
- Overall Survival (OS)
- Best Overall Response (OR)
- Duration of Response (DR)
- Time to Treatment Failure (TTF)
- Safety and tolerability of combining bevacizumab with trastuzumab and docetaxel
- Quality of Life |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.
20. Patients of childbearing potential (women < 2 years after last menstruation) not using effective non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile).
21. Current or recent (within 30 days prior to starting study treatment) treatment with another investigational drug or participation in another investigational study.
22. Known hypersensitivity to any of the study drugs or excipients.
23. Hypersensitivity to Chinese hamster ovary cell products or other recombinant
human or humanized antibodies. |
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The Primary endpoint (Final PFS) analysis was performed in 2011 (Database lock : 30/09/2011) PFS pre-specified after 310 events. Data cut-off June-30-2011. |
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E.5.2 | Secondary end point(s) |
1) Overall survival
2) Best overall response
3) Duration of response
4) Time to treatment failure |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary endpoints analyses were performed in 2011 (Database lock : 30/09/2011) PFS pre-specified after 310 events. Data cut-off June-30-2011. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
France |
Italy |
Austria |
Mexico |
Romania |
Russian Federation |
Czech Republic |
Spain |
Turkey |
United Kingdom |
Bosnia and Herzegovina |
Uruguay |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
This is an event driven trial. The analysis of the primary endpoint will be performed when 310 events have been confirmed in the 410 patients randomized. The study will end when the last patient has discontinued study medication and completed his/her final safety follow-up visit.
Amendment E defines that the study will be closed as soon as the protocol amendment is approved by regulatory authority and Ethics Committees. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |