A Study Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy in Untreated Metastatic Breast Cancer (RIBBON 1)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Unknown status
• CT.gov ID: NCT00262067
• Collaborator: (none)
• Enrollment: 1,237
• Locations: 92
• Arms: 2
• Duration (Months): 96
• Patients Per Site: 13.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Bevacizumab; Drug: Placebo; Drug: Chemotherapy	Phase 3

Detailed Description

This study includes a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up phase. During the blinded treatment phase, patients receive chemotherapy and study drug (bevacizumab or placebo) every 3 weeks until disease progression, treatment-limiting toxicity, or death due to any cause. The optional open-label post-progression phase consists of chemotherapy treatment (per investigator discretion) and optional treatment with open-label bevacizumab. Patients who complete the study or who discontinue from treatment (regardless of participation in the optional open-label post-progression phase) will be followed for survival and subsequent anti-cancer therapies every 4 months until death, withdrawal of consent, loss to follow-up, or study termination. Patients who discontinue from treatment during the blinded treatment phase for reasons other than disease progression will have tumor assessments every 9 weeks until documented disease progression or death.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1237 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Phase III, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination With Chemotherapy Regimens in Subjects With Previously Untreated Metastatic Breast Cancer
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: Jul 1, 2008
• Anticipated Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab + chemotherapy Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle plus one of several standard chemotherapies (taxanes, anthracycline-based regimens, or capecitabine) for metastatic breast cancer.	Drug: Bevacizumab; 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.; Other Names: Avastin ; Drug: Chemotherapy; 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
Placebo Comparator: Placebo + chemotherapy Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + 1 of several standard chemotherapies (taxanes, anthracycline-based regimens, or capecitabine) for metastatic breast cancer.	Drug: Placebo; Placebo consisted of the vehicle for bevacizumab without the antibody.; Drug: Chemotherapy; 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

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)]

   PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.

Secondary Outcome Measures

1. Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)]

   An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.

2. Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)]

   Duration of objective response was defined as the time from the first tumor assessment that led to a determination of an objective response to the time of disease progression or death due to any cause, whichever occurred first.

3. Overall Survival [Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)]

   Overall survival was defined as the time from randomization until death from any cause.

4. 1-year Survival [Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)]

   1-year survival was defined as the percentage of patients who were alive 1 year after randomization. The percentage of patients alive at 1 year was determined using Kaplan-Meier analyses and the 95% confidence intervals were computed using the Brookmeyer-Crowley method.

5. Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST) [Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)]

   PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the Independent Review Committee using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Fullerton	California	United States	92835
2		Santa Barbara	California	United States	93105
3		Iowa City	Iowa	United States	52242
4		Sioux City	Iowa	United States	51101
5		Wichita	Kansas	United States	67214-3728
6		Geelong		Australia	3220
7		Malvern		Australia	3144
8		Melbourne		Australia	3002
9		Perth		Australia	6008
10		Southport		Australia	4215
11		Wahroonga		Australia	2076
12		Waratah		Australia	2298
13		Wollongong		Australia	2500
14		Porto Alegre		Brazil	91350-200
15		Rio de Janeiro		Brazil	22260-020
16		Salvador		Brazil	40170-110
17		Santo Andre		Brazil	09060-870
18		Sao Paulo		Brazil	03102-002
19		Winnipeg	Manitoba	Canada	R2H 2A6
20		Montreal	Quebec	Canada	H2L 4M1
21		Montreal	Quebec	Canada	H2W 1S6
22		Marseille		France	13273
23		Paris		France	75248
24		Reims		France	51100
25		Saint Herblain		France	44805
26		Strasbourg		France	67010
27		Athens		Greece	11521
28		Hania		Greece	73300
29		Heraklion		Greece	71110
30		Patras		Greece	26500
31		Thessaloniki		Greece	57001
32		Guatemala City		Guatemala	01015
33		Kyunggi-do		Korea, Republic of	411-769
34		Seoul		Korea, Republic of	110-744
35		Seoul		Korea, Republic of	120-752
36		Acapulco		Mexico	39670
37		Aguascalientes		Mexico	20230
38		Merida		Mexico	97500
39		Monterrey		Mexico	64020
40		Monterrey		Mexico	64380
41		Amstelveen		Netherlands	1186 AH
42		Apeldoorn		Netherlands	7334 DZ
43		Delft		Netherlands	2600 GA
44		Oslo		Norway	0310
45		Oslo		Norway	0407
46		Panama City		Panama
47		Callao		Peru
48		Quezon City		Philippines	1114
49		Chelyabinsk		Russian Federation	454 087
50		Ivanovo		Russian Federation	153040
51		Kazan		Russian Federation	420029
52		Kazan		Russian Federation	420111
53		Moscow		Russian Federation	115478
54		Moscow		Russian Federation	117837
55		Moscow		Russian Federation	129128
56		Novosibirsk		Russian Federation	630047
57		Obninsk		Russian Federation	249036
58		Ryazan		Russian Federation	390011
59		Samara		Russian Federation	443066
60		St Petersburg		Russian Federation	197758
61		UFA		Russian Federation	450054
62		Singapore		Singapore	119228
63		Singapore		Singapore	169610
64		Córdoba		Spain	14004
65		Elche		Spain	03203
66		Girona		Spain	17007
67		La Coruna		Spain	15006
68		La Laguna		Spain	38320
69		Madrid		Spain	28034
70		Santander		Spain	39008
71		Sevilla		Spain	41013
72		Valencia		Spain	46010
73		Zaragoza		Spain	50009
74		Gaevle		Sweden	80187
75		Uppsala		Sweden	751 85
76		Örebro		Sweden	701 85
77		Tainan		Taiwan	704
78		Taoyuan		Taiwan	333
79		Cherkassy		Ukraine	18009
80		Dnipropetrovsk		Ukraine	49102
81		Kiev		Ukraine	03115
82		Lvov		Ukraine	79031
83		Odessa		Ukraine	65055
84		Zaporozhye		Ukraine	69104
85		Chelsmford		United Kingdom	CM1 7ET
86		Cottingham		United Kingdom	HU16 5JQ
87		Epping		United Kingdom	CM16 6TN
88		Huddersfield		United Kingdom	HD3 3EA
89		Nottingham		United Kingdom	NG5 1PB
90		Sheffield		United Kingdom	S1O 2SJ
91		Swansea		United Kingdom	SA2 8QA
92		Montevideo		Uruguay	11200

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Leonardo Faoro, MD, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00262067
• Other Study ID Numbers: AVF3694g; BO20094
• First Posted: Dec 6, 2005
• Last Update Posted: Dec 13, 2013
• Last Verified: Nov 1, 2013

• Additional relevant MeSH terms: Breast Neoplasms; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Period Title: Overall Study
STARTED	415	207	409	206
COMPLETED	196	107	193	93
NOT COMPLETED	219	100	216	113

Baseline Characteristics

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine	Total
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Total of all reporting groups
Overall Participants	415	207	409	206	1237
Age, Customized (Number) [Number]
< 40 years	29 7%	14 6.8%	21 5.1%	15 7.3%	79 6.4%
40-64 years	295 71.1%	160 77.3%	289 70.7%	137 66.5%	881 71.2%
≥ 65 years	91 21.9%	33 15.9%	99 24.2%	54 26.2%	277 22.4%
Sex: Female, Male (Count of Participants)
Female	413 99.5%	207 100%	408 99.8%	204 99%	1232 99.6%
Male	2 0.5%	0 0%	1 0.2%	2 1%	5 0.4%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Description	PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first. For target lesions, PD was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started or the appearance of 1 or more new lesions. For non-target lesions, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-target lesions. Target lesions should be selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, should be identified as target lesions.
Time Frame	Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	415	207	409	206
Median (95% Confidence Interval) [Months]	9.2	8.0	8.6	5.7

2. Secondary Outcome

Title	Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Description	An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart as determined by the investigator using RECIST. For target lesions, a complete response was defined as the disappearance of all target lesions; a partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. For non-target lesions, a complete response was defined as the disappearance of all non-target lesions; a partial response was defined as the persistence of 1 or more non-target lesions.
Time Frame	Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment. Only patients with measurable disease at baseline were included in the analysis.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	345	177	325	161
Number (95% Confidence Interval) [Percentage of participants]	51.3 12.4%	37.9 18.3%	35.4 8.7%	23.6 11.5%

3. Secondary Outcome

Title	Duration of Objective Response as Determined by the Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Duration of objective response was defined as the time from the first tumor assessment that led to a determination of an objective response to the time of disease progression or death due to any cause, whichever occurred first.
Time Frame	Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment. Only patients with measurable disease at baseline and who had an objective response were included in the analysis.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	177	67	115	38
Median (95% Confidence Interval) [Months]	8.3	7.1	9.2	7.2

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from randomization until death from any cause.
Time Frame	Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	415	207	409	206
Median (95% Confidence Interval) [Months]	27.5	NA	25.7	22.8

5. Secondary Outcome

Title	1-year Survival
Description	1-year survival was defined as the percentage of patients who were alive 1 year after randomization. The percentage of patients alive at 1 year was determined using Kaplan-Meier analyses and the 95% confidence intervals were computed using the Brookmeyer-Crowley method.
Time Frame	Baseline to the data cut-off of 23 Feb 2009 (up to 3 years, 2 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	415	207	409	206
Number (95% Confidence Interval) [Percentage of participants]	80.7 19.4%	83.2 40.2%	81.0 19.8%	74.8 36.3%

6. Secondary Outcome

Title	Progression-free Survival (PFS) as Determined by the Independent Review Committee Using Response Evaluation Criteria in Solid Tumors (RECIST)
Description	PFS was defined as the time from randomization to first documented disease progression (PD) as determined by the Independent Review Committee using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, whichever occurred first.
Time Frame	Baseline to the data cut-off date of 31 Jul 2008 (up to 2 years, 7 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless of whether they received any study drug or completed the full course of treatment.

Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen	Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen	Bevacizumab 15 mg/kg + Capecitabine	Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.	Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
Measure Participants	415	207	409	206
Median (95% Confidence Interval) [Months]	10.7	8.3	9.8	6.2

Adverse Events

Time Frame	Adverse events were recorded from the first treatment until 30 days after the last treatment during the blinded treatment phase or the start date of the optional open-label treatment phase, whichever occurred first (up to 3 years 2 months).
Adverse Event Reporting Description	Safety population: All randomized patients who received any study treatment, defined as at least 1 full or partial dose of either study drug or chemotherapy. There were a total of 1220 patients in the safety population.
Arm/Group Title	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen		Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen		Bevacizumab 15 mg/kg + Capecitabine		Placebo to Bevacizumab + Capecitabine
Arm/Group Description	Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.		Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + either a taxane or anthracycline-based standard chemotherapy for metastatic breast cancer.		Patients received bevacizumab 15 mg/kg intravenously (IV) on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.		Patients received placebo to bevacizumab administered IV on Day 1 of every 21-day cycle + capecitabine standard chemotherapy for metastatic breast cancer.
All Cause Mortality
	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen		Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen		Bevacizumab 15 mg/kg + Capecitabine		Placebo to Bevacizumab + Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen		Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen		Bevacizumab 15 mg/kg + Capecitabine		Placebo to Bevacizumab + Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	156/413 (37.8%)		59/202 (29.2%)		140/404 (34.7%)		72/201 (35.8%)
Blood and lymphatic system disorders
Anaemia	3/413 (0.7%)		1/202 (0.5%)		3/404 (0.7%)		1/201 (0.5%)
Febrile bone marrow aplasia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Febrile neutropenia	26/413 (6.3%)		11/202 (5.4%)		3/404 (0.7%)		3/201 (1.5%)
Iron deficiency anaemia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Lymphadenopathy	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Neutropenia	10/413 (2.4%)		5/202 (2.5%)		3/404 (0.7%)		3/201 (1.5%)
Pancytopenia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cardiac disorders
Acute myocardial infarction	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Angina pectoris	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Atrial fibrillation	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Atrial tachycardia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cardiac arrest	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Cardiac failure	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Cardiac failure congestive	3/413 (0.7%)		1/202 (0.5%)		0/404 (0%)		1/201 (0.5%)
Cardiac valve disease	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cardio-respiratory arrest	1/413 (0.2%)		2/202 (1%)		0/404 (0%)		0/201 (0%)
Cardiogenic shock	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Cardiomyopathy	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Coronary artery disease	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Intracardiac thrombus	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Left ventricular dysfunction	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Left ventricular failure	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Myocardial infarction	2/413 (0.5%)		0/202 (0%)		7/404 (1.7%)		0/201 (0%)
Pericardial effusion	0/413 (0%)		1/202 (0.5%)		1/404 (0.2%)		2/201 (1%)
Pericarditis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Restrictive cardiomyopathy	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Sinus arrest	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Sinus tachycardia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Supraventricular tachycardia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Ventricular dysfunction	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Endocrine disorders
Hypercalcaemia of malignancy	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Eye disorders
Blindness	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Macular hole	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Gastrointestinal disorders
Abdominal pain	4/413 (1%)		1/202 (0.5%)		5/404 (1.2%)		2/201 (1%)
Abdominal pain upper	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Ascites	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Colitis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Constipation	0/413 (0%)		0/202 (0%)		2/404 (0.5%)		0/201 (0%)
Diarrhoea	8/413 (1.9%)		0/202 (0%)		6/404 (1.5%)		2/201 (1%)
Diverticular perforation	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Duodenal ulcer	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Duodenal ulcer haemorrhage	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Faecaloma	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Gastritis erosive	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Gastrointestinal haemorrhage	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		2/201 (1%)
Gastrointestinal perforation	5/413 (1.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Gastrointestinal toxicity	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Haemorrhoids	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Ileal ulcer perforation	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Ileus	0/413 (0%)		0/202 (0%)		2/404 (0.5%)		0/201 (0%)
Intestinal obstruction	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Intestinal perforation	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Jejunitis	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Large intestinal obstruction	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Lower gastrointestinal haemorrhage	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Nausea	6/413 (1.5%)		1/202 (0.5%)		2/404 (0.5%)		0/201 (0%)
Oesophagitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Pancreatitis	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Rectal haemorrhage	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Small intestinal haemorrhage	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Small intestinal obstruction	2/413 (0.5%)		0/202 (0%)		2/404 (0.5%)		1/201 (0.5%)
Stomatitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Upper gastrointestinal haemorrhage	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Vomiting	6/413 (1.5%)		3/202 (1.5%)		4/404 (1%)		3/201 (1.5%)
General disorders
Asthenia	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		2/201 (1%)
Chest pain	3/413 (0.7%)		1/202 (0.5%)		2/404 (0.5%)		3/201 (1.5%)
Death	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Fatigue	2/413 (0.5%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
General physical health deterioration	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Malaise	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Mucosal inflammation	1/413 (0.2%)		0/202 (0%)		6/404 (1.5%)		1/201 (0.5%)
Pain	3/413 (0.7%)		2/202 (1%)		1/404 (0.2%)		1/201 (0.5%)
Pyrexia	4/413 (1%)		1/202 (0.5%)		7/404 (1.7%)		2/201 (1%)
Sudden death	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Hepatobiliary disorders
Cholecystitis	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cholecystitis acute	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Cholelithiasis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Hepatic cirrhosis	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Hepatic failure	0/413 (0%)		0/202 (0%)		2/404 (0.5%)		1/201 (0.5%)
Hepatic function abnormal	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Hepatic pain	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Hepatorenal failure	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Hyperbilirubinaemia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Jaundice cholestatic	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Immune system disorders
Hypersensitivity	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Infections and infestations
Abdominal abscess	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Abscess intestinal	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Abscess jaw	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Arthritis bacterial	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Bacteraemia	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Bacterial sepsis	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Breast cellulitis	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Bronchitis	0/413 (0%)		1/202 (0.5%)		2/404 (0.5%)		0/201 (0%)
Bronchopneumonia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Bronchopulmonary aspergillosis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Catheter related infection	0/413 (0%)		0/202 (0%)		3/404 (0.7%)		0/201 (0%)
Catheter site infection	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Cellulitis	8/413 (1.9%)		1/202 (0.5%)		2/404 (0.5%)		2/201 (1%)
Central line infection	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Clostridial infection	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cystitis	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Diverticulitis	0/413 (0%)		0/202 (0%)		2/404 (0.5%)		0/201 (0%)
Erysipelas	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Gastroenteritis	0/413 (0%)		0/202 (0%)		2/404 (0.5%)		2/201 (1%)
Herpes oesophagitis	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Infection	4/413 (1%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Klebsiella bacteraemia	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Lobar pneumonia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Lower respiratory tract infection	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Nasopharyngitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Neutropenic sepsis	1/413 (0.2%)		2/202 (1%)		0/404 (0%)		0/201 (0%)
Osteomyelitis	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Pharyngitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Pneumonia	4/413 (1%)		5/202 (2.5%)		6/404 (1.5%)		5/201 (2.5%)
Pseudomonas infection	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Salpingo-oophoritis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Sepsis	6/413 (1.5%)		1/202 (0.5%)		4/404 (1%)		3/201 (1.5%)
Septic shock	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Sinusitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Staphylococcal bacteraemia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Sweat gland infection	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Upper respiratory tract infection	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Urinary tract infection	0/413 (0%)		2/202 (1%)		2/404 (0.5%)		0/201 (0%)
Urosepsis	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Wound infection	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Injury, poisoning and procedural complications
Ankle fracture	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Arthropod bite	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Cervical vertebral fracture	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Concussion	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Drug toxicity	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Fall	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Femoral neck fracture	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Femur fracture	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Fibula fracture	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Head injury	0/413 (0%)		0/202 (0%)		3/404 (0.7%)		0/201 (0%)
Hip fracture	0/413 (0%)		0/202 (0%)		3/404 (0.7%)		0/201 (0%)
Overdose	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Procedural pain	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Radiation oesophagitis	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Renal injury	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Spinal compression fracture	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Upper limb fracture	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Wound dehiscence	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Investigations
Blood potassiumiIncreased	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
General physical condition abnormal	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Haemoglobin decreased	0/413 (0%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Rotavirus test positive	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Metabolism and nutrition disorders
Cachexia	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Decreased appetite	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Dehydration	8/413 (1.9%)		1/202 (0.5%)		6/404 (1.5%)		2/201 (1%)
Fluid overload	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Hypercalcaemia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Hyperglycaemia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Hypoglycaemia	2/413 (0.5%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Back pain	1/413 (0.2%)		1/202 (0.5%)		5/404 (1.2%)		2/201 (1%)
Bone pain	1/413 (0.2%)		2/202 (1%)		0/404 (0%)		0/201 (0%)
Musculoskeletal pain	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Neck pain	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Osteonecrosis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Pathological fracture	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Spinal deformity	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Breast cancer	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Breast cancer metastatic	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Gastric cancer	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Malignant pleural effusion	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Metastases to central nervous system	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Metastases to meninges	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		2/201 (1%)
Metastatic neoplasm	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Myelodysplastic syndrome	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Ovarian cancer	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Tumour pain	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Tumour ulceration	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Nervous system disorders
Aphasia	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Ataxia	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Carotid sinus syndrome	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Cerebral ischaemia	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Cerebrovascular accident	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		1/201 (0.5%)
Coma hepatic	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Convulsion	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Encephalopathy	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Facial palsy	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Headache	3/413 (0.7%)		1/202 (0.5%)		2/404 (0.5%)		0/201 (0%)
Hypertensive encephalopathy	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Lethargy	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Nervous system disorder	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Neuralgia	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Neuropathy peripheral	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Peripheral motor neuropathy	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Peripheral sensory neuropathy	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Reversible posterior leukoencephalopathy syndrome	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Sciatica	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Somnolence	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Spinal cord compression	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Syncope	3/413 (0.7%)		1/202 (0.5%)		3/404 (0.7%)		0/201 (0%)
Transient ischaemic attack	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Psychiatric disorders
Anxiety	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Completed suicide	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Confusional state	2/413 (0.5%)		0/202 (0%)		3/404 (0.7%)		0/201 (0%)
Depression	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		0/201 (0%)
Mental status changes	1/413 (0.2%)		1/202 (0.5%)		3/404 (0.7%)		0/201 (0%)
Renal and urinary disorders
Calculus ureteric	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Hydronephrosis	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Nephrolithiasis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Nephrotic syndrome	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Renal failure	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Renal failure acute	3/413 (0.7%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Ureteric obstruction	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Urinary retention	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Reproductive system and breast disorders
Female genital tract fistula	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Metrorrhagia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Uterine haemorrhage	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/413 (0%)		1/202 (0.5%)		0/404 (0%)		1/201 (0.5%)
Asthma	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Chronic obstructive pulmonary disease	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Cough	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Diaphragmatic hernia	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Dyspnoea	8/413 (1.9%)		3/202 (1.5%)		7/404 (1.7%)		2/201 (1%)
Dyspnoea exertional	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Epistaxis	2/413 (0.5%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Haemoptysis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Haemothorax	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Hypoxia	1/413 (0.2%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Interstitial lung disease	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Lung disorder	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Lung infiltration	2/413 (0.5%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Pleural effusion	6/413 (1.5%)		3/202 (1.5%)		7/404 (1.7%)		5/201 (2.5%)
Pleuritic pain	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Pneumonia aspiration	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Pneumonitis	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Pneumothorax	2/413 (0.5%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Pulmonary embolism	4/413 (1%)		3/202 (1.5%)		9/404 (2.2%)		5/201 (2.5%)
Pulmonary haemorrhage	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Respiratory arrest	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Respiratory failure	2/413 (0.5%)		0/202 (0%)		2/404 (0.5%)		0/201 (0%)
Tracheomalacia	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Pain of skin	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Palmar-plantar erythrodysaesthesia syndrome	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Skin ulcer	1/413 (0.2%)		0/202 (0%)		0/404 (0%)		0/201 (0%)
Vascular disorders
Deep vein thrombosis	4/413 (1%)		1/202 (0.5%)		3/404 (0.7%)		2/201 (1%)
Hypertension	5/413 (1.2%)		0/202 (0%)		2/404 (0.5%)		0/201 (0%)
Hypotension	0/413 (0%)		1/202 (0.5%)		1/404 (0.2%)		0/201 (0%)
Jugular vein thrombosis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Peripheral arterial occlusive disease	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Thrombosis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Varicose vein	0/413 (0%)		0/202 (0%)		0/404 (0%)		1/201 (0.5%)
Venous thrombosis	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Venous thrombosis limb	0/413 (0%)		0/202 (0%)		1/404 (0.2%)		0/201 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab 15 mg/kg + Taxane or Anthracycline-based Regimen		Placebo to Bevacizumab + Taxane or Anthracycline-based Regimen		Bevacizumab 15 mg/kg + Capecitabine		Placebo to Bevacizumab + Capecitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/413 (22%)		19/202 (9.4%)		72/404 (17.8%)		15/201 (7.5%)
Blood and lymphatic system disorders
Neutropenia	21/413 (5.1%)		4/202 (2%)		16/404 (4%)		5/201 (2.5%)
Cardiac disorders
Left ventricular dysfunction	21/413 (5.1%)		8/202 (4%)		3/404 (0.7%)		2/201 (1%)
Renal and urinary disorders
Proteinuria	22/413 (5.3%)		1/202 (0.5%)		13/404 (3.2%)		0/201 (0%)
Vascular disorders
Hypertension	39/413 (9.4%)		8/202 (4%)		50/404 (12.4%)		8/201 (4%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.