| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal women with advanced or metastatic cancer with indication of hormonotherapy as first-line treatment. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006275 |
| E.1.2 | Term | Breast metastases |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006212 |
| E.1.2 | Term | Breast carcinoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 the progression-free survival (PFS) between both treatment arms. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following parameters between both treatment arms:
• Overall survival (OS)
• Time to treatment failure (TTF)
• Better response to treatment (RR)
• Response duration (RD)
• Clinical benefit proportion (CBP = CR + PR + SD > 6 months)
• Safety and tolerance
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy with Biomarkers and tumor samples. Version 2007-04-20
Biomarkers to investigate the efficacy, safety and action mechanism of bevacizumab, and potential interactions between the tumor expression of VEGF-A/VEGFR (KDR-1) and hormone receptor processes will be studied. |
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| E.3 | Principal inclusion criteria |
1 Before starting the specific protocol procedures, the written informed consent must be obtained and documented.
2. Women ≥ 18 years.
3. Capacity to comply with all the protocol requirements.
4. Functional ECOG status of 0 or 1.
5. Life expectancy ≥ 24 weeks.
6. Postmenopausal women with histologically confirmed breast adenocarcinoma, with measurable or non-measurable, locally advanced or metastatic (stage IV) disease. In the event that the patient only has locally advanced disease, she will not be able to undergo curative local treatment. Patients with metastasis confined to the bone can be chosen, but the disease must be confirmed by radiology, CT scan or NMR if there is any doubt after a single bone scan.
7. Patients with HER2-negative disease evaluated by IHC and FISH/CISH (IHC 0 or 1+, or 2+ and negative FISH). Patients with 3+ by IHC cannot be chosen regardless of the FISH/CISH status and those with positive FISH/CISH (> 2 amplifications) cannot be chosen either, regardless of the IHC findings.
8. Positive hormone receptors (estrogen receptor [ER] and/or progesterone receptor [PgR]) evaluated by a local or central laboratory, according to the criteria of the participating institution.
9. Patients who are candidates for receiving first-line treatment with letrozole.
10. Patients may have received (neo)adjuvant chemotherapy, provided that the last dose of the latter was received at least 12 months before randomization . Patients must have recovered from toxicity.
11. The patients are allowed to have received adjuvant radiotherapy, provided that it was completed at least 6 weeks before randomization and the patient has recovered from the reversible acute effects of the radiation. The previous administration of radiotherapy to palliate the pain of bone metastases is authorized, provided that:
a. Not more than 30% of bone marrow has been irradiated.
b. The patient has recovered from the reversible acute effects of the radiation.
c. The patient has at least one metastatic location which has not been irradiated and which may be evaluated for progression, or a clear progression of the bone disease has been objectified after the end of the palliative radiotherapy.
12. The patients may have received previous (neo)adjuvant hormonotherapy provided that they are considered to be candidates to first-line hormonotherapy with letrozole. They may also have received previous adjuvant treatment with an aromatase inhibitor provided that it ended at least 12 months before randomization.
13. The treatment with bisphosphonates is allowed and recommended for patients with bone metastases. Whenever it is possible, the treatment should be started before or within the 4 weeks of starting the study therapy. The patients starting treatment with bisphosphonates must be carefully evaluated so that they do not mask the progression of the disease.
14. In the patients with heart failure risk (e.g. previously treated with > 360mg/m2 of doxorubicin or equivalent doses of other anthracyclines), the LVEF must be determined by means of an echocardiogram or radionuclide ventriculography (MUGA), and it must t be > the lower limit of normal.
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|
| E.4 | Principal exclusion criteria |
1. Evolutionary disease requiring an immediate treatment with cytotoxic chemotherapy according to the investigator’s judgment.
2. Patients with locally advanced breast cancer who are expected to undergo surgery or curative radiotherapy.
3. Patient in treatment with anticoagulant therapy.
4. Previous chemotherapy or hormonotherapy for the metastatic disease. Patients may have received neoadjuvant chemotherapy or neoadjuvant hormonotherapy with curative intention as a part or as an alternative to an adjuvant treatment. For the previous neoadjunvant hormonotherapy the same premises than for the adjunvant hormonotherapy are valid.
5. Previous therapy with anti-VEGF or VEGFR tyrosine-kinase inhibitors.
6. History of another pathology that may affect the development of the protocol or the interpretation of results. It is considered that patients who have suffered from a skin carcinoma that is not melanoma, cervical carcinoma in situ or another neoplasia treated with a curative intention and with a disease-free interval exceeding 5 years can be chosen.
7. Evidence of CNS metastasis. A CT scan or brain NMR must be done within the 4 weeks before the randomization in case of suspecting brain metastasis.
8. History of peripheral neurophaty NCI CTCAE grade >2 at the time of randomization.
9. Patients subjected to major surgical procedures, open biopsies or those having significant trauma injuries within the 28 days prior to randomization, or patients who are expected to undergo a major surgical procedure that must necessarily be performed within the course of the study.
10. Minor surgical procedures in the 7 days prior to randomization.
11. Unsuitable bone marrow supply: ANC < 1.5 x 109/L, platelets < 100 x 109/L or Hb < 10 g/dL.
12. Impaired liver function: total bilirubin total > 1.5 x ULN, AST and ALT > 2.5 x ULN (> 5 x ULN in patients with liver metastases).
13. Impaired kidney function:
a. Serum creatinine > 2.0 mg/dL or 177 µmol/L.
b. Proteinuria determined by reactive strip > 2+. A 24h determination of proteins in urine will be requested for the patients with > 2+ in the baseline analysis and must have a protein figure > 1 g/24 h.
14. Chronic treatment with oral corticoids (dose > 10 mg/day of methylprednisolone or equivalent): the use of inhaled corticoids is allowed.
15. Chronic Treatment with heparin and oral anticoagulants (coumarin derivates)
16. Chronic treatment with acetylsalicylic acid (> 325 mg/day) or clopidogrel (> 75 mg/day).
17. Uncontrolled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant cardiovascular disease: for example CVA (in the 6 months prior to randomization), coronaropathy or history of AMI in the last 6 months, unstable angina, congestive heart failure of grade > II of the New York Heart Association (NYHA) or severe heart arrhythmias which are not controlled with medication or which can potentially interfere with the study treatment.
18. History or evidence of hemorrhagic diathesis or coagulopathy with bleeding risk.
19. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcess in the 6 months prior to randomization.
20. Active infection requiring i.v. antibiotics at the time of randomization.
21. Unhealed wounds, active peptic ulcer, esophageal varices.
22. Any other disease, psychological or metabolic alteration, found in the physical or laboratory examination, providing reasonable indications for suspecting a disease or complaint for which the use of any of the study drugs are contraindicated, or which may affect the patient’s compliance with the routine procedures of the study or which places the patient at a high risk of experiencing complications related to the treatment.
23. Current or recent (within 30 days prior to that start of the study treatment) treatment with another drug under investigation or participation in another investigation study.
24. Known hypersensitivity to any of the study drugs or their components.
25. Hypersensitivity to the products of Chinese hamster ovary cells or to other human or humanized recombinant antibodies.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The patients will receive the study treatment until:
1. The progression of the disease
2. Occurrence of unacceptable toxicity
3. Until the investigators decision to stop study treatment
4. Until the patient refuses to continue the proposed treatment
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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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 50 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
| The patients will be subjected to a follow-up up to 24 months after the inclusion of the last patient, to verify the date of the progression of the disease (if such progression has still not occurred) and/or exitus. This will be considered as the study end. |
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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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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