E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of patients with locally recurrent or metastatic HER2 positive breast cancer who have not received prior chemotherapy for their metastatic disease, both ER/PgR negative or positive. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 6.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10055113 |
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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 o Overall Survival OS o Best Overall Response OR o Duration of Response DR o Time to Treatment Failure TTF o Safety and tolerability of combining bevacizumab with trastuzumab and docetaxel o Quality of Life |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
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, 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 8804; 1.5 and aPTT 8804; 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 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 - Serum Creatinine 2.0 mg/dL or 177 mol/L - Urine dipstick for proteinuria 2 . Patients with 8805; 2 proteinuria on dipstick urinalysis at baseline should undergo 24 hours urine collection and must demonstrate 8804; 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 8804; 6 months prior to randomization , myocardial infarction 8804; 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival PFS , defined as the time from randomization to time of first documented disease progression or death, whichever occurs first. |
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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 | No |
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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |