A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1)
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Bevacizumab; Placebo; Chemotherapy
Intervention description: Patients received bevacizumab until disease progression, treatment limiting toxicity, or death due to any cause up to a maximum treatment duration of 48 months. The dose of bevacizumab was based on the patient's weight at either screening or baseline and remained the same throughout the blinded treatment phase of the study. The initial dose was delivered over 90±10 minutes. If there were no infusion related adverse events (fever and/or chills), the second infusion was delivered over 60±10 minutes. If the 60 minute infusion was well tolerated, all subsequent infusions were delivered over 30±10 minutes.; Placebo consisted of the vehicle for bevacizumab without the antibody.; The chemotherapy was selected by the investigator prior to randomization. Chemotherapy treatment continued until disease progression, unacceptable toxicity, investigator/patient decision, or death, whichever occurred first, except for the anthracycline-based regimens, which had a maximum treatment duration of 8 cycles.
Taxanes - 1 of the following 2 taxanes on Day 1 of every 21-day cycle
Docetaxel 75-100 mg/m^2 IV
Paclitaxel protein-bound particles (Abraxane®) 260 mg/m^2 IV
Anthracyclines - 1 of the following 4 anthracycline-based regimens on Day 1 of every 21-day cycle
5-fluorouracil 500 mg/m^2 IV + epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV
5-fluorouracil 500 mg/m^2 IV + doxorubicin 50 mg/m^2 IV + cyclophosphamide 500 mg/m^2 IV
Doxorubicin 50-60 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV
Epirubicin 90-100 mg/m^2 IV + cyclophosphamide 500-600 mg/m^2 IV
Capecitabine: 1000 mg/m^2 orally twice daily on Days 1-14 of each 21-day cycle
Intervention MeSH terms: Bevacizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1237.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase III, multicenter, randomized, placebo-controlled trial designed to evaluate
      the efficacy and safety of bevacizumab in combination with chemotherapy compared with
      chemotherapy alone in subjects with previously untreated metastatic breast cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed adenocarcinoma of the breast, with
             measurable or non-measurable locally recurrent or metastatic disease.

          -  Signed Informed Consent Form.

          -  Age ≥ 18 years.

          -  For women of childbearing potential, use of accepted and effective method of
             non-hormonal contraception.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Ability and capacity to comply with study and follow-up procedures.

          -  For anthracycline cohort only: Adequate left ventricular function at study entry,
             defined as a left ventricular ejection fraction (LVEF) ≥ 50% by either multigated
             acquisition (MUGA) scan scan or echocardiography (ECHO).

          -  For subjects who have received recent radiation therapy, recovery prior to baseline
             (Day 0) from any significant (Grade ≥ 3) acute toxicity.

        Exclusion Criteria:

          -  Unknown human epidermal growth factor receptor 2 (HER2) status or known HER2-positive
             status.

          -  Prior chemotherapy for locally recurrent or metastatic disease.

          -  Prior hormonal therapy less than 1 week prior to Day 0.

          -  Prior adjuvant or neoadjuvant chemotherapy within 12 months prior to Day 0.

          -  For anthracycline cohort only: Prior anthracycline as part of neoadjuvant or adjuvant
             therapy for localized breast cancer.

          -  Investigational therapy within 28 days of Day 0.

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to Day 0, or anticipation of need for major surgical procedure during the course
             of the study.

          -  Minor surgical procedures, such as fine needle aspirations or core biopsies, within 7
             days prior to Day 0.

          -  Prior therapy with bevacizumab, sorafenib, sunitinib, or other vascular endothelial
             growth factor (VEGF) pathway-targeted therapy.

          -  Known brain or other central nervous system (CNS) metastases.

          -  Blood pressure of > 150/100 mmHg.

          -  Unstable angina.

          -  New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF).

          -  History of myocardial infarction within 6 months prior to Day 0.

          -  History of stroke or transient ischemic attack within 6 months prior to Day 0.

          -  Clinically significant peripheral vascular disease.

          -  Evidence of bleeding diathesis or coagulopathy.

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months prior to Day 0.

          -  Serious non-healing wound, ulcer, or bone fracture.

          -  Pregnancy (positive serum pregnancy test) or lactation.

          -  Inadequate organ function, as evidenced by any of the following laboratory values:
             Absolute neutrophil count < 1500/uL; platelet count < 100,000/uL; total bilirubin >
             1.5 mg/dL; alkaline phosphatase, AST, and/or ALT > 2x upper limit of normal (ULN) (>
             5x ULN in subjects with known liver or, for alkaline phosphatase elevations, bone
             involvement); alkaline phosphatase > 2x ULN (> 7x ULN in subjects with known bone
             involvement); serum creatinine > 2.0 mg/dL; partial thromboplastin time (PTT) and/or
             either international normalized ratio (INR) or prothrombin time (PT) > 1.5x upper
             limit of normal (except for subjects receiving anti-coagulation therapy); urine
             protein/creatinine ratio > 1.0 at screening for U.S. subjects, or urine dipstick for
             proteinuria >/= 1+ at screening followed by 24-hour urine collection demonstrating > 1
             g protein/24 hr for ex-U.S. subjects.

          -  Uncontrolled serious medical or psychiatric illness.

          -  Active infection requiring intravenous (iv) antibiotics at Day 0.

          -  History of other malignancies within 5 years of Day 0 except for tumors with a
             negligible risk for metastasis or death, such as adequately controlled basal cell
             carcinoma or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix
             (subjects with a history of bilateral breast cancer will be eligible).