Bevacizumab + Endocrine Treatment vs Endocrine Treatment as First Line in Postmenopausal Women
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Letrozole; Bevacizumab; Fulvestrant
Intervention MeSH terms: Bevacizumab; Letrozole; Fulvestrant
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 380.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: endocrine therapy; bevacizumab; breast cancer; first-line therapy

Summary:

      Locally advanced or metastatic breast cancer in postmenopausal women with negative Human
      Epidermal Growth Factor Receptor 2 (HER2), who are candidates for hormone treatment and who
      have not received previous chemotherapy or hormonotherapy for the metastatic disease.
    

Eligibility criteria:

        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 Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.

          5. Life expectancy ≥ 24 weeks.

          6. 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 Nuclear magnetic resonance (NMR) if
             there is any doubt after a single bone scan.

          7. Patients with HER2-negative disease evaluated by Immunohistochemistry (IHC) and
             Fluorescence in situ hybridization (FISH)/Chromogenic in situ hybridisation (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 be
             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:

               -  Not more than 30% of bone marrow has been irradiated.

               -  The patient has recovered from the reversible acute effects of the radiation.

               -  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 any kind of previous (neo)adjuvant hormone therapy
             provided that they are considered to be candidates for first-line hormonotherapy with
             either letrozole or fulvestrant.

         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 Left Ventricular
             Ejection Fraction (LVEF) must be determined by means of an echocardiogram or
             radionuclide ventriculography (MUGA), and it must t be > the lower limit of normal.

        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. 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
             neoadjuvant hormonotherapy the same premises than for the adjuvant hormonotherapy are
             valid.

          4. Previous therapy with anti-vascular endothelial growth factor (VEGF) or VEGF Receptor
             (VEGFR) tyrosine-kinase inhibitors.

          5. 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.

          6. Evidence of central nervous system (CNS) metastasis. A CT scan or brain NMR must be
             done within the 4 weeks before the randomization in case of suspecting brain
             metastasis.

          7. History or evidence in the physical or neurological examination of CNS pathology
             unrelated to cancer unless it is suitable treated with standard therapy (e.g.
             uncontrolled convulsions).

          8. History of peripheral neuropathy National Cancer Institute (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: absolute neutrophil count (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 upper limit of normal (ULN),
             aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) > 2.5 x ULN (> 5 x
             ULN in patients with liver metastases).

         13. Impaired kidney function:

               1. Serum creatinine > 2.0 mg/dL or 177 µmol/L.

               2. 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 acetylsalicylic acid (> 325 mg/day) or clopidogrel (> 75
             mg/day).

         16. Uncontrolled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg)
             or clinically significant cardiovascular disease: for example cerebrovascular accident
             (CVA) (in the 6 months prior to randomization), coronaropathy or history of acute
             mycardial infarction (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.

         17. History or evidence of hemorrhagic diathesis or coagulopathy with bleeding risk.

         18. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcess
             in the 6 months prior to randomization.

         19. Active infection requiring i.v. antibiotics at the time of randomization.

         20. Unhealed wounds, active peptic ulcer, esophageal varices.

         21. 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.

         22. 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.

         23. Known hypersensitivity to any of the study drugs or their components.

         24. Hypersensitivity to the products of Chinese hamster ovary cells or to other human or
             humanized recombinant antibodies.