A Study of Avastin (Bevacizumab) in Combination With Chemotherapy in Patients With Breast Cancer Progressing After First-Line Therapy With Avastin and Chemotherapy (TANIA)

• ClinicalTrials.gov Identifier: NCT01250379
• Recruitment Status: Completed
• First Posted: November 30, 2010
• Results First Posted: June 30, 2015
• Last Update Posted: February 11, 2016
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: bevacizumab [Avastin]; Drug: Chemotherapy
• Enrollment: 494

Participant Flow

Recruitment Details	A total of 556 participants were screened and of these, 494 were randomized.
Pre-assignment Details

Arm/Group Title	Chemotherapy (CT) Arm	Chemotherapy Plus Bevacizumab (CT+BV) Arm
Arm/Group Description	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 milligrams per kilogram (mg/kg), intravenously (IV), every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Period Title: Overall Study
Started	247	247
Completed	45 [1]	54 [1]
Not Completed	202	193
Reason Not Completed
Death	141	148
Withdrawal by Subject	32	20
Physician Decision	11	3
Protocol Violation	2	8
Lost to Follow-up	9	6
Adverse Event	5	4
Other	0	4
Participant noncompliance	2	0
[1] Participants under study follow-up as of Data Cutoff 30 April 2015 were considered as completers.

Baseline Characteristics

Arm/Group Title		CT Arm	CT+BV Arm	Total
Arm/Group Description		Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Total of all reporting groups
Overall Number of Baseline Participants		247	247	494
Baseline Analysis Population Description		Intent-to-treat (ITT) population: all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	247 participants	247 participants	494 participants
		54.7 (10.83)	55.8 (11.17)	55.2 (11.01)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	247 participants	247 participants	494 participants
	Female	247 100.0%	247 100.0%	494 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Second-Line Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)
Description	Second-line PFS was defined as the time from randomization to progressive disease (PD) or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For target lesions (TLs), PD was defined at least a 20 percent (%) increase in the sum of the largest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For non-target lesions (NTLs), PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (less than or equal to [≤] 28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) population - all randomized participants.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Unit of Measure: percentage of participants
	88.7	93.9

2. Primary Outcome

Title	Second-Line PFS
Description	The median time, in months, from randomization to second-line PFS event. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Median (95% Confidence Interval); Unit of Measure: months
	4.2; (3.9 to 5.3)	6.3; (5.5 to 7.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0204
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.97
	Estimation Comments	The 95% confidence interval (CI) was estimated using Cox proportional hazards methodology. The stratification factors used in the analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and lactate dehydrogenase (LDH) level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0245
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.97
	Estimation Comments	Unstratified analysis.

3. Primary Outcome

Title	Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 6
Description	Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	40.7; (34.3 to 47.0)	54.2; (47.7 to 60.3)

4. Primary Outcome

Title	Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 12
Description	Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without secondline PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	16.9; (12.3 to 22.2)	24.2; (19.0 to 29.9)

5. Primary Outcome

Title	Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 18
Description	Second-line PFS was defined as the time from randomization to PD or death due to any cause during their secondline of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Month 18

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	9.9; (6.4 to 14.3)	11.0; (7.4 to 15.5)

6. Primary Outcome

Title	Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 24
Description	Second-line PFS was defined as the time from randomization to PD or death due to any cause during their second-line of treatment with bevacizumab and/or chemotherapy, whichever occurred first. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Month 24

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	6.4; (3.6 to 10.2)	6.5; (3.7 to 10.2)

7. Secondary Outcome

Title	Second-Line PFS by Baseline Risk Factor (Data Cutoff 20 December 2013)
Description	The median time, in months, from randomization to second-line PFS event according to the following baseline risk factors: hormone receptor negative, HER2 negative (triple negative), hormone receptor positive/HER-2 negative (HR-pos/HER-neg), first-line PFS less than (<) 6 months, first-line PFS greater than or equal to (≥) 6 months, taxane chemotherapy (chemo), non-taxane chemo, vinorelbine chemo, LDH ≤ 1.5 upper limit of normal (ULN), LDH greater than (>) 1.5 ULN, < 65 years of age, ≥ 65 years of age, < 70 years of age, ≥ 70 years of age, < 3 metastatic organ sites, ≥ 3 metastatic organ sites, bevacizumab-free (B-free) interval ≤ 6 weeks, B-free > 6 weeks, disease-free (D-free) interval ≤ 24 months, D-free > 24 months, D-free ≤ 12 months, and D-free > 12 months. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. PD: defined in Outcome measure 1. The 95% CI was estimated using Kaplan-Meier methodology.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed equals (=) participants evaluable for this outcome measure and number (n) = number of participants included in the analysis for the specified risk factor.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	226	219
Median (95% Confidence Interval); Unit of Measure: months
HR-neg (n=60,56)	2.1; (2.0 to 3.9)	4.9; (3.4 to 6.1)
HR-pos/HER-neg (n=187,191)	4.7; (4.2 to 6.2)	6.7; (6.0 to 7.8)
PFS <6 months (n=69,68)	3.9; (2.3 to 4.3)	5.1; (4.1 to 6.9)
PFS ≥6 months (n=178,179)	4.6; (3.9 to 6.1)	6.4; (5.8 to 7.6)
Taxane chemo (n=32,32)	3.2; (1.7 to 5.3)	6.9; (4.9 to 9.8)
Non-taxane chemo (n=191,188)	4.4; (3.9 to 5.8)	6.0; (4.9 to 6.8)
Vinorelbine chemo (n=24,27)	2.4; (1.8 to 4.3)	6.5; (4.2 to 11.1)
LDH ≤ 1.5 ULN (n=207,210)	4.4; (3.9 to 6.0)	6.3; (5.5 to 7.6)
LDH > 1.5 ULN (n=40,37)	2.1; (1.7 to 3.9)	5.8; (2.5 to 7.3)
< 65 years of age (n=196,183)	4.2; (3.9 to 4.7)	6.1; (4.7 to 6.9)
≥ 65 years of age (n=51,64)	4.2; (2.2 to 7.8)	6.7; (5.5 to 8.0)
< 70 years of age (n=226,219)	4.2; (3.7 to 4.6)	6.2; (5.3 to 7.3)
≥ 70 years of age (n=21,28)	7.8; (2.2 to 11.9)	6.7; (4.1 to 11.2)
< 3 metastatic organ sites (n=158,167)	4.2; (3.9 to 6.1)	6.9; (6.0 to 8.2)
≥ 3 metastatic organ sites (n=88,80)	4.0; (2.1 to 4.9)	4.7; (4.1 to 6.2)
B-free ≤ 6 weeks (n=165,149)	4.2; (3.6 to 4.6)	5.8; (4.4 to 6.6)
B-free > 6 weeks (n=81,98)	4.4; (3.3 to 6.3)	7.6; (6.0 to 9.5)
D-free ≤ 24 months (n=58,53)	2.8; (2.0 to 3.9)	5.8; (4.2 to 6.3)
D-free > 24 months (n=138,156)	4.9; (4.0 to 6.1)	6.5; (5.5 to 8.1)
D-free ≤ 12 months (n=24,18)	2.1; (1.3 to 5.8)	5.8; (3.9 to 9.7)
D-free > 12 months (n=172,191)	4.3; (3.9 to 5.7)	6.3; (5.3 to 7.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: HR-neg
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0088
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.88
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: HR-pos/HER-neg
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1196
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.05
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: PFS <6 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0110
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.90
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: PFS ≥6 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0816
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.03
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: taxane chemo
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0395
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.98
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: non-taxane chemo
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1385
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.06
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: vinorelbine chemo
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0029
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.75
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: LDH ≤ 1.5 ULN
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0171
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.96
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: LDH > 1.5 ULN
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1797
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.16
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: < 65 years of age
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0229
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.97
	Estimation Comments	[Not Specified]

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: ≥ 65 years of age
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2139
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.16
	Estimation Comments	[Not Specified]

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: < 70 years of age
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0021
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.89
	Estimation Comments	[Not Specified]

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: ≥ 70 years of age
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5216
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.64 to 2.39
	Estimation Comments	[Not Specified]

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: < 3 metastatic organ sites
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0148
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.94
	Estimation Comments	[Not Specified]

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: ≥ 3 metastatic organ sites
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3102
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.17
	Estimation Comments	[Not Specified]

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: B-free ≤ 6 weeks
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0967
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.04
	Estimation Comments	[Not Specified]

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: B-free > 6 weeks
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0489
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.00
	Estimation Comments	[Not Specified]

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: D-free ≤ 24 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0176
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.92
	Estimation Comments	[Not Specified]

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: D-free > 24 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2318
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.11
	Estimation Comments	[Not Specified]

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: D-free ≤ 12 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0568
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.26 to 1.03
	Estimation Comments	[Not Specified]

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	Subgroup analysis: D-free > 12 months
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1143
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.05
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Percentage of Participants With a Second-Line Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST v1.1 (Data Cutoff 20 December 2013)
Description	BOR was defined as a confirmed CR or PR during second-line treatment. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. The 95% Cl was determined using the Pearson-Clopper method.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population; only randomized participants with measurable disease at baseline were included in the analysis.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	185	182
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	16.8; (11.7 to 22.9)	20.9; (15.2 to 27.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3457
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; -4.2 to 12.4
	Estimation Comments	The 95% CI was estimated using Hauck-Anderson methodology.

9. Secondary Outcome

Title	Percentage of Participants With a Second-Line CR, PR, Stable Disease, and PD According to RECIST v1.1 (Data Cutoff 20 December 2013)
Description	For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; SD was defined as neither sufficient decrease in SLD to qualify for PR nor sufficient increase in SLD to qualify for PD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels; stable disease was defined as the persistence of 1 or more NTLs and/or maintenance of tumor marker levels above normal limits; and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. The 95% CI was determined using the Pearson-Clopper method.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population; only randomized participants with measurable disease at baseline were included in the analysis.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	185	182
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
CR	1.1; (0.1 to 3.9)	0.5; (0.0 to 3.0)
PR	15.7; (10.8 to 21.7)	20.3; (14.7 to 26.9)
Stable disease	33.5; (26.8 to 40.8)	48.9; (41.4 to 56.4)
PD	41.1; (33.9 to 48.5)	24.2; (18.1 to 31.1)
Unable to assess	8.6; (5.0 to 13.7)	6.0; (3.1 to 10.6)

10. Secondary Outcome

Title	Duration of Second-Line Objective Response (Data Cutoff 20 December 2013)
Description	The median time, in months, from the date of the first second-line documentation of CR or PR according to RECIST v1.1 to the date of the first second-line documentation of PD or death due to any cause. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels, and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants with CR or PR who had experienced neither disease progression nor died were censored at the date of the last available tumor assessment when the participant was known to be progression free.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years

Outcome Measure Data

Analysis Population Description

ITT population; only randomized participants with a CR or PR were included in the analysis.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	31	38
Median (95% Confidence Interval); Unit of Measure: months
	10.6; (4.4 to 16.7)	8.3; (6.1 to 10.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9825
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.99
	Estimation Comments	The 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in stratified analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and LDH level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3601
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.73 to 2.34
	Estimation Comments	Unstratified analysis.

11. Secondary Outcome

Title	Percentage of Participants With a Second-Line Documented CR or PR According to RECIST v1.1 Estimated to be Alive and Free of Disease Progression at Months 3, 6, and 9 (Data Cutoff 20 December 2013)
Description	Duration of objective response was defined as the median time, in months, from the date of the first second-line documentation of CR or PR to the date of the first second-line documentation of PD or death due to any cause. For TLs, CR was defined as the disappearance of all TLs; PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD; and PD was defined as at least a 20% increase in the SLD of TLs, taking as reference the smallest SLD recorded since the treatment started. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels, and PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants with CR or PR who had experienced neither disease progression nor died were censored at the date of the last available tumor assessment when the participant was known to be progression free.
Time Frame	Months 3, 6, and 9

Outcome Measure Data

Analysis Population Description

ITT population; only randomized participants with a CR or PR were included in the analysis.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	31	38
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Month 3	96.7; (78.6 to 99.5)	100.0 [1]; (NA to NA)
Month 6	69.0; (48.9 to 82.5)	72.8; (55.3 to 84.4)
Month 9	60.9; (40.4 to 76.3)	40.8; (24.6 to 56.3)

[1]

95% CI data was not applicable (NA) because all participants were estimated to be alive and free of disease progression at this time point.

12. Secondary Outcome

Title	Percentage of Participants With Third-Line PFS According to RECIST v1.1
Description	Third-line PFS was defined as the time from the date of first dose of third-line bevacizumab and/or chemotherapy to the date of third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without second-line PD or death were censored at the date of last tumor assessment where non-progression was documented. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	First dose of third-line treatment until PD or death due to any cause (assessed every 8-9 weeks, over a period of approximately 14 months)

Outcome Measure Data

Analysis Population Description

Third line ITT population: all randomized participants who received third-line treatment.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	105	129
Measure Type: Number; Unit of Measure: percentage of participants
	94.3	96.1

13. Secondary Outcome

Title	Third-Line PFS
Description	The median time, in months, from the first dose of third-line bevacizumab and/or chemotherapy to third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	First dose of third-line treatment until PD or death due to any cause (over a period of approximately 14 months)

Outcome Measure Data

Analysis Population Description

Third line ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	105	129
Median (95% Confidence Interval); Unit of Measure: months
	2.9; (2.2 to 3.9)	3.8; (2.4 to 5.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1080
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.06
	Estimation Comments	The 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in stratified analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and LDH level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0625
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.02
	Estimation Comments	Unstratified analysis.

14. Secondary Outcome

Title	Percentage of Participants With Second- and Third-Line PFS According to RECIST v1.1
Description	Second- and third-line PFS was defined as the time from the date randomization to the date of third-line PD or death due to any cause. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Unit of Measure: percentage of participants
	71.7	83.4

15. Secondary Outcome

Title	Second- and Third-Line PFS
Description	The median time, in months, from randomization to second-line and third-line PFS event. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Median (95% Confidence Interval); Unit of Measure: months
	10.7; (9.2 to 12.5)	12.8; (10.7 to 14.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1349
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.05
	Estimation Comments	The 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in stratified analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and LDH level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0863
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.03
	Estimation Comments	Unstratified analysis.

16. Secondary Outcome

Title	Percentage of Participants With Second- and Third-Line Tumor Progression
Description	Second- and third-line tumor progression was defined as occurrence of third-line PD according to RECIST v1.1 or death due to progression of disease. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death due to progression of disease were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Unit of Measure: percentage of participants
	67.2	75.3

17. Secondary Outcome

Title	Time to Second- and Third-Line Tumor Progression
Description	The median time, in months, from randomization to second- and third-line tumor progression. Second- and third-line tumor progression was defined as third-line PD according to RECIST v1.1 or death due to progression of disease. For TLs, PD was defined at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of one or more new lesions. For NTLs, PD was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing NTLs. Participants without third-line PD or death were censored at the date of last tumor assessment where non-progression was documented.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Median (95% Confidence Interval); Unit of Measure: months
	11.2; (9.4 to 12.7)	13.3; (12.0 to 15.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0744
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.02
	Estimation Comments	The 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in stratified analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and LDH level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0503
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.00
	Estimation Comments	Unstratified analysis.

18. Secondary Outcome

Title	Percentage of Participants Who Died
Description	Percentage of participants who died due to any reason were reported.
Time Frame	Baseline until death (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Unit of Measure: percentage of participants
	63.2	66.0

19. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the median time, in months, from the date of randomization to the date of death, due to any cause. Participants who had not died were censored at the date the patient was last known to be alive.
Time Frame	Baseline until death (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Median (95% Confidence Interval); Unit of Measure: months
	18.7; (15.4 to 21.2)	19.7; (17.6 to 21.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7253
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.21
	Estimation Comments	The 95% CI was estimated using Cox proportional hazards methodology. The stratification factors used in stratified analysis were hormone receptor status, first-line PFS, choice of chemotherapy, and LDH level.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5332
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.16
	Estimation Comments	Unstratified analysis.

20. Secondary Outcome

Title	Percentage of Participants Estimated to be Surviving at Months 6, 12, 18, and 24
Description	OS was defined as the median time, in months, from the date of randomization to the date of death, due to any cause.
Time Frame	Months 6, 12, 18, and 24

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	247	247
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Month 6	85.2; (79.9 to 89.2)	90.4; (85.9 to 93.5)
Month 12	68.6; (62.0 to 74.3)	72.4; (66.2 to 77.7)
Month 18	52.8; (46.0 to 59.3)	54.9; (48.2 to 61.0)
Month 24	38.4; (31.8 to 44.9)	37.6; (31.3 to 43.9)

21. Secondary Outcome

Title	Percentage of Participants Experiencing Problems by European Quality of Life Instrument (EQ-5D) Category (Data Cutoff 20 December 2013)
Description	The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either "no problems", "some problems", or "extreme problems" in the following categories: mobility (M) ("no problems"="I have no problems in walking about" to "extreme problems"="I am confined to bed"), self-care (SC) ("no problems"="I have no problems with self-care" to "extreme problems"="I am unable to wash or dress myself"), usual activities (UA) ("no problems"="I have no problems performing my usual activities" to "extreme problems"="I am unable to perform my usual activities"), pain/discomfort (P/D) ("no problems"="I have no pain or discomfort" to "extreme problems"="I have extreme pain or discomfort"), and anxiety/depression (A/D) ("no problems"="I am not anxious or depressed" to "extreme problems"='I am extremely anxious or depressed").
Time Frame	Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants completing the questionnaires at the corresponding timepoint.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	214	224
Measure Type: Number; Unit of Measure: percentage of participants
BL: M, no problems (n=214,224)	60.3	64.3
BL: M, some problems (n=214,224)	36.4	34.8
BL: M, extreme problems (n=214,224)	0.5	0.4
BL: SC, no problems (n=214,224)	82.7	85.7
BL: SC, some problems (n=214,224)	12.6	11.2
BL: SC, extreme problems (n=214,224)	0.5	1.8
BL: UA, no problems (n=214,224)	53.7	46.4
BL: UA, some problems (n=214,224)	40.2	48.7
BL: UA, extreme problems (n=214,224)	2.8	4.0
BL: P/D, no problems (n=214,224)	24.3	27.7
BL: P/D, some problems (n=214,224)	68.7	66.1
BL: P/D, extreme problems (n=214,224)	4.2	5.4
BL: A/D, no problems (n=214,224)	33.6	34.8
BL: A/D, some problems (n=214,224)	56.5	58.5
BL: A/D, extreme problems (n=214,224)	5.6	5.8
Week 8/9: M, no problems (n=133,141)	61.7	51.8
Week 8/9: M, some problems (n=133,141)	34.6	43.3
Week 8/9: M, extreme problems (n=133,141)	1.5	2.1
Week 8/9: SC, no problems (n=133,141)	82.0	75.9
Week 8/9: SC, some problems (n=133,141)	13.5	17.0
Week 8/9: SC, extreme problems (n=133,141)	1.5	3.5
Week 8/9: UA, no problems (n=133,141)	53.4	40.4
Week 8/9: UA, some problems (n=133,141)	40.6	51.8
Week 8/9: UA, extreme problems (n=133,141)	3.0	5.0
Week 8/9: P/D, no problems (n=133,141)	29.3	23.4
Week 8/9: P/D, some problems (n=133,141)	61.7	68.1
Week 8/9: P/D, extreme problems (n=133,141)	5.3	6.4
Week 8/9: A/D, no problems (n=133,141)	49.6	46.8
Week 8/9: A/D, some problems (n=133,141)	40.6	48.2
Week 8/9: A/D, extreme problems (n=133,141)	6.8	2.8
Week 16/18: M, no problems (n=84,123)	66.7	49.6
Week 16/18: M, some problems (n=84,123)	29.8	47.2
Week 16/18: M, extreme problems (n=84,123)	0.0	2.4
Week 16/18: SC, no problems (n=84,123)	81.0	78.9
Week 16/18: SC, some problems (n=84,123)	14.3	17.1
Week 16/18: SC, extreme problems (n=84,123)	0.0	3.3
Week 16/18: UA, no problems (n=84,123)	50.0	36.6
Week 16/18: UA, some problems (n=84,123)	42.9	56.1
Week 16/18: UA, extreme problems (n=84,123)	3.6	4.1
Week 16/18: P/D, no problems (n=84,123)	34.5	19.5
Week 16/18: P/D, some problems (n=84,123)	59.5	76.4
Week 16/18: P/D, extreme problems (n=84,123)	1.2	3.3
Week 16/18: A/D, no problems (n=84,123)	51.2	49.6
Week 16/18: A/D, some problems (n=84,123)	44.0	43.1
Week 16/18: A/D, extreme problems (n=84,123)	0.0	5.7
Second-line PD: M, no problems (n=82,76)	59.8	47.4
Second-line PD: M, some problems (n=82,76)	34.1	48.7
Second-line PD: M, extreme problems (n=82,76)	2.4	3.9
Second-line PD: SC, no problems (n=82,76)	76.8	75.0
Second-line PD: SC, some problems (n=82,76)	15.9	18.4
Second-line PD: SC, extreme problems (n=82,76)	1.2	6.6
Second-line PD: UA, no problems (n=82,76)	39.0	30.3
Second-line PD: UA, some problems (n=82,76)	50.0	59.2
Second-line PD: UA, extreme problems (n=82,76)	6.1	10.5
Second-line PD: P/D, no problems (n=82,76)	19.5	18.4
Second-line PD: P/D, some problems (n=82,76)	67.1	69.7
Second-line PD: P/D, extreme problems (n=82,76)	8.5	11.8
Second-line PD: A/D, no problems (n=82,76)	36.6	26.3
Second-line PD: A/D, some problems (n=82,76)	50.0	61.8
Second-line PD: A/D, extreme problems (n=82,76)	7.3	11.8

22. Secondary Outcome

Title	Quality of Life Assessed As an Index Score Using the EQ-5D (Data Cutoff 20 December 2013)
Description	The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either "no problems", "some problems", or "extreme problems" in the following categories: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Based on large population surveys, an algorithm was used to combine the responses to each of these 5 measures into 1 single EQ-5D index score ranging from -0.59 (extreme problems) to +1 (no problems).
Time Frame	Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants who completed the assessment at the specified timepoint

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	202	219
Mean (95% Confidence Interval); Unit of Measure: score on a scale
BL (n=202,219)	0.6806; (0.6489 to 0.7122)	0.6725; (0.6389 to 0.7061)
Week 8/9 (n=127,135)	0.6953; (0.6470 to 0.7437)	0.6515; (0.6057 to 0.6973)
Week 16/18 (n=80,118)	0.7496; (0.7114 to 0.7879)	0.6534; (0.6058 to 0.7010)
Second-line PD (n=77,76)	0.6290; (0.5642 to 0.6938)	0.5553; (0.4736 to 0.6370)

23. Secondary Outcome

Title	Change From Baseline in EQ-5D Index Scores (Data Cutoff 20 December 2013)
Description	The EQ-5D is composed of 5 single-item measures where participants responded to questions assessing health status by responding with either "no problems", "some problems", or "extreme problems" in the following categories: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Based on large population surveys, an algorithm was used to combine the responses to each of these 5 measures into 1 single EQ-5D index score ranging from -0.59 (extreme problems) to +1 (no problems) where a negative value indicated a worsening of perceived quality of life and a positive value indicated an improvement of perceived quality of life.
Time Frame	Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants who completed the assessment at the specified timepoint.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	107	122
Mean (95% Confidence Interval); Unit of Measure: score on a scale
Week 8/9 (n=107,122)	-0.0103; (-0.0482 to 0.0276)	-0.0370; (-0.0868 to 0.0127)
Week 16/18 (n=68,110)	0.0387; (-0.0025 to 0.0800)	-0.0508; (-0.1038 to 0.0021)
Second-line PD (n=69,71)	-0.0884; (-0.1398 to -0.0371)	-0.0878; (-0.1649 to -0.0107)

24. Secondary Outcome

Title	Quality of Life Assessed Using the EQ-5D Visual Analogue Scale (VAS) Scores (Data Cutoff 20 December 2013)
Description	The participant was asked to rate their overall health on a 0-100 millimeter (mm) vertical scale, where the lowest endpoint=0 (labeled as worst imaginable health state) and the highest endpoint =100 (labeled as the best imaginable health state). The participant marked the line corresponding to their assessment and the distance from the bottom was measured in millimeters. A higher value indicated a better health state.
Time Frame	Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population; n=number of participants who completed the assessment at the specified timepoint.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	200	212
Mean (95% Confidence Interval); Unit of Measure: mm
BL (n=200,212)	66.5; (64.1 to 69.0)	63.4; (60.8 to 65.9)
Week 8/9 (n=123,135)	69.3; (66.4 to 72.1)	66.5; (63.7 to 69.2)
Week 16/18 (n=75,119)	67.3; (63.3 to 71.3)	66.4; (63.2 to 69.5)
Second-line PD (n=78,75)	63.7; (59.5 to 68.0)	61.7; (57.0 to 66.5)

25. Secondary Outcome

Title	Change From Baseline in VAS Scores (Data Cutoff 20 December 2013)
Description	The participant was asked to rate their overall health on a 0-100 mm vertical scale, where the lowest endpoint = 0 (labeled as worst imaginable health state) and the highest endpoint =100 (labeled as the best imaginable health state). The participant marked the line corresponding to their assessment and the distance from the bottom was measured in millimeters. A negative value indicated a worsening of perceived quality of life and a positive value indicated an improvement of perceived quality of life.
Time Frame	Baseline, during second-line treatment at Weeks 8 and 16 (4-week cycles) or Weeks 9 and 18 (3-week cycles) and at second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants who completed the assessment at the specified timepoint.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	106	118
Mean (95% Confidence Interval); Unit of Measure: mm
Week 8/9 (n=106,118)	-2.0; (-4.8 to 0.9)	2.0; (-1.4 to 5.3)
Week 16/18 (n=66,107)	-0.2; (-4.7 to 4.3)	2.0; (-1.6 to 5.5)
Second-line PD (n=70,69)	-5.1; (-9.1 to -1.0)	-1.3; (-5.5 to 3.0)

26. Secondary Outcome

Title	Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores (Data Cutoff 20 December 2013)
Description	The Functional Assessment of Cancer Therapy-Breast (FACT-B) is composed of 5 multi-item sections where participants responded to questions assessing symptoms (scale: 0-4; 0="not at all" and 4="very much"), as follows: physical well-being (PWB) (7 items, total score 0-28), social/family well-being (SWB) (7 items, total score 0-28), emotional well-being (EWB) (6 items, total score 0-24), functional well-being (FWB) (7 items, total score 0-28); and breast cancer score based on the additional concerns section of FACT-B (10 items, total score 0-40). The FACT-B Trial Outcomes Index (TOI) score=sum of PWB, FWB, and breast cancer score subscale scores (total score 0-96). The Functional Assessment of Cancer Therapy-General (FACT-G) total score=sum of PWB, SWB, EWB, and FWB subscales scores (total score 0-108). The FACT-B total score=sum of PWB, SWB, EWB, FWB, and breast cancer score subscales scores (total score 0-148). In all cases a higher value indicated a better perceived quality of life.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants who completed the questionnaire at the specified timepoints.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	215	224
Mean (95% Confidence Interval); Unit of Measure: score on a scale
BL: PWB (n=215,222)	20.621; (19.900 to 21.342)	20.253; (19.500 to 21.006)
BL: SWB (n=214,223)	20.722; (20.028 to 21.416)	20.674; (19.923 to 21.425)
BL: EWB (n=215,224)	14.847; (14.176 to 15.519)	15.062; (14.419 to 15.704)
BL: FWB (n=215,224)	16.091; (15.289 to 16.894)	15.726; (14.951 to 16.502)
BL: Breast Cancer Score (n=210,224)	24.986; (24.103 to 25.869)	24.388; (23.578 to 25.198)
BL: FACT-B TOI (n=204,219)	61.677; (59.658 to 63.696)	60.277; (58.365 to 62.189)
BL: Total FACT-G Score (n=207,218)	72.169; (69.919 to 74.419)	71.864; (69.786 to 73.942)
BL: Total FACT-B Score (n=201,218)	96.908; (94.063 to 99.753)	96.115; (93.485 to 98.746)
Week 8/9: PWB (n=129,138)	20.413; (19.413 to 21.413)	19.156; (18.158 to 20.153)
Week 8/9: SWB (n=127,135)	20.833; (19.888 to 21.779)	21.116; (20.245 to 21.987)
Week 8/9: EWB (n=129,139)	15.943; (15.070 to 16.815)	16.671; (15.900 to 17.441)
Week 8/9: FWB (n=129,139)	16.662; (15.609 to 17.715)	16.169; (15.180 to 17.158)
Week 8/9: Breast Cancer Score (n=128,139)	26.276; (25.188 to 27.364)	25.884; (24.928 to 26.839)
Week 8/9: FACT-B TOI (n=126,136)	63.547; (60.975 to 66.118)	61.279; (58.811 to 63.747)
Week 8/9: Total FACT-G Score (n=122,134)	74.255; (71.212 to 77.299)	73.393; (70.603 to 76.184)
Week 8/9: Total FACT-B Score (n=123,134)	100.375; (96.582 to 104.169)	99.213; (95.667 to 102.760)
Week 16/18: PWB (n=83,107)	21.733; (20.721 to 22.744)	19.629; (18.571 to 20.688)
Week 16/18: SWB (n=80,105)	20.930; (19.855 to 22.006)	20.843; (19.829 to 21.857)
Week 16/18: EWB (n=80,107)	17.330; (16.260 to 18.400)	16.806; (15.961 to 17.650)
Week 16/18: FWB (n=81,106)	17.055; (15.818 to 18.291)	15.920; (14.787 to 17.053)
Week 16/18: Breast Cancer (n=81,106)	26.923; (25.493 to 28.354)	25.755; (24.630 to 26.880)
Week 16/18: FACT-B TOI (n=78,105)	65.628; (62.539 to 68.717)	61.107; (58.309 to 63.905)
Week 16/18: Total FACT-G (n=78,102)	76.794; (73.269 to 80.318)	73.269; (70.116 to 76.421)
Week 16/18: Total FACT-B (n=76,103)	103.503; (98.819 to 108.187)	98.906; (94.865 to 102.948)
Week 24/27: PWB (n=48,80)	21.940; (20.599 to 23.282)	18.965; (17.515 to 20.416)
Week 24/27: SWB (n=47,78)	20.840; (19.468 to 22.211)	21.399; (20.192 to 22.606)
Week 24/27: EWB (n=45,78)	17.098; (15.719 to 18.477)	16.438; (15.411 to 17.436)
Week 24/27: FWB (n=45,79)	18.244; (16.754 to 19.734)	16.051; (14.861 to 17.241)
Week 24/27: Breast Cancer (n=46,79)	26.067; (24.146 to 27.988)	24.632; (23.231 to 26.033)
Week 24/27: FACT-B TOI (n=44,77)	65.882; (61.991 to 69.653)	60.014; (56.548 to 63.480)
Week 24/27: Total FACT-G (n=44,77)	78.305; (74.166 to 82.443)	73.083; (69.365 to 76.801)
Week 24/27: Total FACT-B (n=43,77)	104.011; (98.433 to 109.588)	97.795; (92.995 to 102.595)
Week 32/36: PWB (n=26,44)	22.949; (21.427 to 24.471)	19.686; (18.121 to 21.250)
Week 32/36: SWB (n=25,43)	22.140; (20.433 to 23.847)	21.222; (19.645 to 22.798)
Week 32/36: EWB (n=26,44)	18.385; (16.690 to 20.079)	16.755; (15.481 to 18.028)
Week 32/36: FWB (n=26,44)	19.615; (17.875 to 21.356)	17.195; (15.585 to 18.805)
Week 32/36: Breast Cancer (n=26,43)	29.568; (27.722 to 31.415)	26.163; (24.457 to 27.869)
Week 32/36: FACT-B TOI (n=26,42)	72.132; (68.549 to 75.716)	63.017; (59.199 to 66.836)
Week 32/36: Total FACT-G (n=25,42)	83.087; (78.178 to 87.995)	74.879; (70.566 to 79.191)
Week 32/36: Total FACT-B (n=25,42)	112.904; (107.315 to 118.494)	100.904; (95.302 to 106.506)
Week 40/45: PWB (n=20,27)	22.215; (20.583 to 23.847)	20.630; (18.820 to 22.440)
Week 40/45: SWB (n=21,26)	19.658; (17.955 to 21.361)	20.915; (19.146 to 22.685)
Week 40/45: EWB (n=20,27)	17.560; (15.708 to 19.412)	16.067; (13.875 to 18.259)
Week 40/45: FWB (n=20,27)	18.450; (16.120 to 20.780)	16.519; (13.901 to 19.136)
Week 40/45: Breast Cancer (n=21,27)	29.386; (27.156 to 31.616)	23.819; (21.013 to 26.625)
Week 40/45: FACT-B TOI (n=19,27)	68.750; (63.981 to 73.518)	60.967; (55.065 to 66.870)
Week 40/45: Total FACT-G (n=19,26)	76.955; (71.480 to 82.430)	75.235; (68.901 to 81.568)
Week 40/45: Total FACT-B (n=19,26)	105.540; (98.512 to 112.568)	99.072; (90.613 to 107.531)
Week 48/54: PWB (n=13,24)	23.308; (21.283 to 25.333)	20.033; (18.124 to 21.943)
Week 48/54: SWB (n=13,23)	20.740; (18.953 to 22.527)	20.450; (18.310 to 22.590)
Week 48/54: EWB (n=13,23)	19.308; (17.522 to 21.093)	17.270; (15.494 to 19.045)
Week 48/54: FWB (n=13,23)	18.538; (16.586 to 20.491)	16.268; (13.949 to 18.587)
Week 48/54: Breast Cancer (n=13,23)	28.912; (26.879 to 30.945)	26.237; (22.842 to 29.632)
Week 48/54: Fact-B TOI (n=13,23)	70.758; (66.403 to 75.114)	62.679; (55.941 to 69.418)
Week 48/54: Total FACT-G (n=13,23)	81.894; (76.424 to 87.363)	74.162; (67.865 to 80.458)
Week 48/54: Total FACT-B (n=13,23)	110.806; (104.704 to 116.908)	100.399; (91.294 to 109.503)
Week 56/63: PWB (n=8,14)	21.792; (18.958 to 24.626)	20.298; (17.412 to 23.184)
Week 56/63: SWB (n=8,14)	19.583; (15.598 to 23.569)	20.817; (17.629 to 24.004)
Week 56/63: EWB (n=7,14)	17.143; (13.389 to 20.897)	15.714; (12.606 to 18.823)
Week 56/63: FWB (n=7,14)	17.143; (13.876 to 20.410)	16.476; (12.633 to 20.319)
Week 56/63: Breast Cancer (n=8,14)	28.240; (23.931 to 32.548)	25.459; (21.407 to 29.512)
Week 56/63: FACT-B TOI (n=7,14)	66.179; (55.888 to 76.469)	62.233; (53.524 to 70.942)
Week 56/63: Total FACT-G (n=6,14)	73.667; (58.381 to 88.952)	73.305; (62.863 to 83.746)
Week 56/63: Total FACT-B (n=6,14)	101.042; (81.841 to 120.242)	98.764; (85.368 to 112.160)
Week 64/72: PWB (n=7,9)	21.857; (17.376 to 26.338)	21.889; (19.569 to 24.209)
Week 64/72: SWB (n=7,9)	18.976; (16.352 to 21.600)	22.685; (19.417 to 25.953)
Week 64/72: EWB (n=7,9)	18.143; (13.758 to 22.527)	17.889; (14.274 to 21.503)
Week 64/72: FWB (n=7,9)	18.429; (14.658 to 22.199)	16.037; (12.890 to 19.184)
Week 64/72: Breast Cancer (n=7,9)	27.464; (22.941 to 31.988)	26.889; (22.584 to 31.194)
Week 64/72: FACT-B TOI (n=7,9)	67.750; (56.306 to 79.194)	64.815; (56.516 to 73.114)
Week 64/72: Total FACT-G (n=7,9)	77.405; (63.847 to 90.963)	78.500; (68.852 to 88.148)
Week 64/72: Total FACT-B (n=7,9)	104.869; (87.586 to 122.152)	105.389; (92.415 to 118.363)
Week 72/81: PWB (n=6,7)	23.083; (18.906 to 27.260)	21.000; (16.407 to 25.593)
Week 72/81: SWB (n=5,7)	19.667; (16.238 to 23.095)	20.043; (14.019 to 26.067)
Week 72/81: EWB (n=6,7)	17.500; (13.476 to 21.524)	18.114; (14.130 to 22.098)
Week 72/81: FWB (n=6,7)	17.333; (14.316 to 20.351)	16.429; (11.339 to 21.518)
Week 72/81: Breast Cancer (n=6,6)	28.597; (24.421 to 32.774)	25.333; (20.250 to 30.417)
Week 72/81: FACT-B TOI (n=6,6)	69.014; (59.566 to 78.462)	60.833; (47.031 to 74.635)
Week 72/81: Total FACT-G (n=5,7)	76.467; (62.045 to 90.889)	75.586; (57.141 to 94.030)
Week 72/81: Total FACT-B (n=5,6)	106.117; (88.146 to 124.087)	97.211; (73.196 to 121.226)
Week 80/90: PWB (n=2,3)	19.250; (-32.634 to 71.134)	18.000; (2.487 to 33.513)
Week 80/90: SWB (n=2,3)	18.375; (7.257 to 29.493)	19.944; (3.434 to 36.455)
Week 80/90: EWB (n=2,3)	14.000; (-49.531 to 77.531)	15.733; (-3.285 to 34.752)
Week 80/90: FWB (n=2,3)	15.000; (-35.825 to 65.825)	12.333; (-1.348 to 26.015)
Week 80/90: Breast Cancer (n=2,3)	21.667; (0.490 to 42.844)	25.000; (14.172 to 35.828)
Week 80/90: FACT-B TOI (n=2,3)	55.917; (-67.969 to 179.802)	55.333; (20.085 to 90.581)
Week 80/90: Total FACT-G (n=2,3)	66.625; (-110.732 to 243.982)	66.011; (2.191 to 129.831)
Week 80/90: Total FACT-B (n=2,3)	88.292; (-110.243 to 286.826)	91.011; (20.313 to 161.709)
Week 88/99: PWB (n=0,1)	NA [1]; (NA to NA)	22.000 [2]; (NA to NA)
Week 88/99: SWB (n=0,1)	NA [1]; (NA to NA)	23.333 [3]; (NA to NA)
Week 88/99: EWB (n=0,1)	NA [1]; (NA to NA)	20.000 [3]; (NA to NA)
Week 88/99: FWB (n=0,1)	NA [1]; (NA to NA)	21.000 [3]; (NA to NA)
Week 88/99: Breast Cancer (n=0,1)	NA [1]; (NA to NA)	35.000 [3]; (NA to NA)
Week 88/99: FACT-B TOI (n=0,1)	NA [1]; (NA to NA)	78.000 [3]; (NA to NA)
Week 88/99: Total FACT-G (n=0,1)	NA [1]; (NA to NA)	86.333 [3]; (NA to NA)
Week 88/99: Total FACT-B (n=0,1)	NA [1]; (NA to NA)	121.333 [3]; (NA to NA)
Week 96/108: PWB (n=2,1)	26.000 [3]; (NA to NA)	22.000 [3]; (NA to NA)
Week 96/108: SWB (n=2,1)	24.383; (-3.782 to 52.549)	21.000 [3]; (NA to NA)
Week 96/108: EWB (n=2,2)	22.000; (9.294 to 34.706)	18.000; (-7.412 to 43.412)
Week 96/108: FWB (n=2,2)	21.083; (7.318 to 34.848)	10.500; (-46.678 to 67.678)
Week 96/108: Breast Cancer (n=2,2)	30.389; (-2.788 to 63.566)	24.500; (-7.266 to 56.266)
Week 96/108: FACT-B TOI (n=2,1)	77.472; (58.060 to 96.884)	59.000 [3]; (NA to NA)
Week 96/108: Total FACT-G (n=2,1)	93.467; (38.830 to 148.103)	74.000 [3]; (NA to NA)
Week 96/108: Total FACT-B (n=2,1)	123.856; (102.396 to 145.315)	96.000 [3]; (NA to NA)
Week 104/117: PWB (n=1,3)	27.000 [3]; (NA to NA)	21.333; (17.539 to 25.128)
Week 104/117: SWB (n=1,2)	26.600 [3]; (NA to NA)	20.5000; (14.147 to 26.853)
Week 104/117: EWB (n=1,3)	22.000 [3]; (NA to NA)	18.000; (6.616 to 29.384)
Week 104/117: FWB (n=1,3)	22.000 [3]; (NA to NA)	11.000; (-1.908 to 23.908)
Week 104/117: Breast Cancer (n=1,3)	27.143 [3]; (NA to NA)	28.000; (19.395 to 36.605)
Week 104/117: FACT-B TOI (n=1,3)	76.143 [3]; (NA to NA)	60.333; (45.778 to 74.889)
Week 104/117: Total FACT-G (n=1,2)	97.600 [3]; (NA to NA)	70.500; (-50.209 to 191.209)
Week 104/117: Total FACT-B (n=1,2)	124.743 [3]; (NA to NA)	100.500; (-20.209 to 221.209)
Week 112/126: PWB (n=0,1)	NA [1]; (NA to NA)	14.000 [3]; (NA to NA)
Week 112/126: SWB (n=0,1)	NA [1]; (NA to NA)	15.400 [3]; (NA to NA)
Week 112/126: EWB (n=0,1)	NA [1]; (NA to NA)	15.000 [3]; (NA to NA)
Week 112/126: FWB (n=0,1)	NA [1]; (NA to NA)	11.000 [3]; (NA to NA)
Week 112/126: Breast Cancer (n=0,1)	NA [1]; (NA to NA)	20.000 [3]; (NA to NA)
Week 112/126: FACT-B TOI (n=0,1)	NA [1]; (NA to NA)	45.000 [3]; (NA to NA)
Week 112/126: Total FACT-G (n=0,1)	NA [1]; (NA to NA)	55.400 [3]; (NA to NA)
Week 112/126: Total FACT-B (n=0,1)	NA [1]; (NA to NA)	75.400 [3]; (NA to NA)
Second-Line PD: PWB (n=89,81)	19.086; (17.873 to 20.299)	17.412; (15.977 to 18.846)
Second-Line PD: SWB (n=88,79)	20.623; (19.456 to 21.790)	21.487; (20.335 to 22.639)
Second-Line PD: EWB (n=88,80)	15.111; (14.102 to 16.121)	14.175; (12.872 to 15.478)
Second-Line PD: FWB (n=88,80)	15.447; (14.122 to 16.772)	15.235; (13.877 to 16.593)
Second-Line PD: Breast Cancer (n=85,81)	24.978; (23.602 to 26.354)	24.445; (22.989 to 25.901)
Second-Line PD: FACT-B TOI (n=84,80)	59.230; (56.033 to 62.428)	57.002; (53.234 to 60.770)
Second-Line PD: Total FACT-G (n=86,78)	69.829; (66.264 to 73.393)	68.485; (64.384 to 72.586)
Second-Line PD: Total FACT-B (n=82,78)	94.930; (90.240 to 99.619)	92.983; (87.645 to 98.320)

[1]

Zero participants analyzed.

[2]

Standard deviation (SD) not calculated as only 1 participant was analyzed.

[3]

SD not calculated as only 1 participant was analyzed.

27. Secondary Outcome

Title	Change From Baseline in FACT-B Scores (Data Cutoff 20 December 2013)
Description	The FACT-B is composed of 5 multi-item sections where participants responded to questions assessing symptoms (scale: 0-4; 0="not at all" and 4="very much"), as follows: PWB (7 items, total score 0-28), SWB (7 items, total score 0-28), EWB (6 items, total score 0-24), FWB (7 items, total score 0-28); and breast cancer score based on the additional concerns section of FACT-B (10 items, total score 0-40). The FACT-B TOI score=sum of PWB, FWB, and breast cancer score subscale scores (total score 0-96). The FACT-G total score=sum of PWB, SWB, EWB, and FWB subscales scores (total score 0-108). The FACT-B total score=sum of PWB, SWB, EWB, FWB, and breast cancer score subscale scores (total score 0-148). In all cases a higher value indicated a better perceived quality of life.
Time Frame	Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, Number of participants analyzed = participants evaluable for this outcome measure and n=number of participants who completed the assessment at the specified timepoint.

Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description:	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
Overall Number of Participants Analyzed	118	128
Mean (95% Confidence Interval); Unit of Measure: score on a scale
Week 8/9: PWB (n=118,125)	-1.281; (-2.219 to -0.344)	-1.289; (-2.239 to -0.338)
Week 8/9: SWB (n=116,125)	0.356; (-0.283 to 0.994)	0.707; (-0.226 to 1.640)
Week 8/9: EWB (n=116,128)	0.408; (-0.274 to 1.089)	1.024; (0.314 to 1.734)
Week 8/9: FWB (n=117,128)	-0.226; (-1.043 to 0.591)	-0.240; (-1.027 to 0.548)
Week 8/9: Breast Cancer Score (n=113,128)	0.228; (-0.659 to 1.116)	0.950; (0.121 to 1.780)
Week 8/9: FACT-B TOI (n=110,122)	-1.361; (-3.295 to 0.573)	-0.357; (-2.407 to 1.693)
Week 8/9: Total FACT-G Score (n=110,122)	-0.760; (-2.920 to 1.399)	0.369; (-1.945 to 2.684)
Week 8/9: Total FACT-B Score (n=108,120)	-0.728; (-3.332 to 1.876)	1.342; (-1.544 to 4.229)
Week 16/18: PWB (n=77,97)	0.294; (-0,733 to 1.322)	-1.823; (-2.871 to -0.775)
Week 16/18: SWB (n=74,97)	-0.443; (-1.411 to 0.525)	0.359; (-0.678 to 1.397)
Week 16/18: EWB (n=73,98)	1.197; (0.415 to 1.979)	0.921; (0.186 to 1.657)
Week 16/18: FWB (n=75,98)	-0.548; (-1.666 to 0.570)	-0.517; (-1.422 to 0.389)
Week 16/18: Breast Cancer (n=72,97)	0.578; (-0.658 to 1.815)	0.546; (-0.423 to 1.514)
Week 16/18: FACT-TOI (n=68,95)	-0.483; (-3.149 to 2.183)	-1.732; (-4.049 to 0.586)
Week 16/18: Total FACT-G (n=71,93)	-0.019; (-2.970 to 2.931)	-0.836; (-3.494 to 1.821)
Week 16/18: Total Fact-B (n=66,93)	-0.007; (-3.744 to 3.730)	-0.127; (-3.421 to 3.167)
Week 24/27: PWB (n=44,73)	0.181; (-1.236 to 1.598)	-1.996; (-3.306 to -0.685)
Week 24/27: SWB (n=44,72)	-0.193; (-1.490 to 1.104)	1.375; (-0.001 to 2.750)
Week 24/27: EWB (n=42,72)	0.867; (-0.101 to 1.834)	1.217; (0.366 to 2.067)
Week 24/27: FWB (n=42,72)	0.119; (-1.405 to 1.643)	0.056; (-1.053 to 1.166)
Week 24/27: Breast Cancer (n=40,72)	-0.038; (-1.723 to 1.647)	0.078; (-1.106 to 1.262)
Week 24/27: FACT-B TOI (n=38,70)	0.221; (-3.411 to 3.853)	-1.573; (-4.383 to 1.238)
Week 24/27: Total FACT-G (n=40,70)	0.764; (-3.066 to 4.595)	0.817; (-2.497 to 4.131)
Week 24/27: Total FACT-B (n=37,70)	0.793; (-4.106 to 5.693)	1.157; (-2.828 to 5.142)
Week 32/36: PWB (n=25,39)	0.880; (-0.913 to 2.673)	-1.235; (-2.799 to 0.329)
Week 32/36: SWB (n=24,40)	-0.388; (-1.754 to 0.979)	1.036; (-1.209 to 3.281)
Week 32/36: EWB (n=25,40)	1.064; (-0.298 to 2.426)	1.555; (0.204 to 2.906)
Week 32/36: FWB (n=25,40)	1.380; (-0.103 to 2.863)	1.635; (-0.201 to 3.471)
Week 32/36: Breast Cancer (n=23,40)	0.928; (-1.916 to 3.771)	1.278; (-0.435 to 2.990)
Week 32/36: FACT-B TOI (n=23,38)	3.123; (-1.390 to 7.637)	1.471; (-2.522 to 5.464)
Week 32/36: Total FACT-G (n=24,39)	2.617; (-1.313 to 6.547)	3.197; (-1.346 to 7.740)
Week 32/36: Total FACT-B (n=22,38)	3.529; (-2.074 to 9.132)	3.896; (-1.579 to 9.370)
Week 40/45: PWB (n=18,25)	0.137; (-2.051 to 2.325)	-0.680; (-2.930 to 1.570)
Week 40/45: SWB (n=19,24)	-0.589; (-2.436 to 1.259)	0.951; (-1.590 to 3.492)
Week 40/45: EWB (n=18,25)	0.200; (-1.598 to 1.998)	1.048; (-0.658 to 2.754)
Week 40/45: FWB (n=18,25)	1.417; (-0.562 to 3.395)	0.857; (-0.893 to 2.608)
Week 40/45: Breast Cancer (n=18,25)	1.395; (-1.268 to 4.058)	0.444; (-2.358 to 3.247)
Week 40/45: FACT-B TOI (n=16,25)	2.432; (-2.496 to 7.360)	0.622; (-4.688 to 5.932)
Week 40/45: Total FACT-G (n=17,24)	1.444; (-3.342 to 6.231)	2.432; (-3.035 to 7.899)
Week 40/45: Total FACT-B (n=16,24)	1.916; (-3.950 to 7.782)	2.673; (-4.258 to 9.603)
Week 48/54: PWB (n=13,20)	1.295; (-2.037 to 4.627)	-1.833; (-3.721 to 0.055)
Week 48/54: SWB (n=13,20)	1.529; (-0.316 to 3.375)	2.008; (-1.083 to 5.099)
Week 48/54: EWB (n=13,20)	1.492; (0.492 to 2.492)	1.710; (-0.183 to 3.603)
Week 48/54: FWB (n=13,20)	2.269; (0.174 to 4.365)	1.592; (-0.872 to 4.055)
Week 48/54: Breast Cancer (n=12,20)	0.599; (-1.714 to 2.912)	1.897; (-0.463 to 4.258)
Week 48/54: FACT-B TOI (n=12,20)	4.044; (-2.832 to 10.919)	1.656; (-3.691 to 7.002)
Week 48/54: Total FACT-G (n=13,20)	6.586; (1.392 to 11.780)	3.477; (-2.596 to 9.550)
Week 48/54: Total FACT-B (n=12,20)	7.067; (0.241 to 13.894)	5.374; (-2.391 to 13.139)
Week 56/63: PWB (n=8,13)	-2.063; (-6.094 to 1.969)	-0.526; (-3.996 to 2.944)
Week 56/63: SWB (n=8,13)	-1.500; (-5.699 to 2.699)	3.033; (-1.729 to 7.796)
Week 56/63: EWB (n=7,13)	0.857; (-2.781 to 4.495)	0.954; (-2.190 to 4.097)
Week 56/63: FWB (n=7,13)	0.000; (-4.835 to 4.835)	5.654; (0.511 to 10.797)
Week 56/63: Breast Cancer (n=8,13)	-0.830; (-6.133 to 4.474)	1.675; (-1.291 to 4.641)
Week 56/63: FACT-B TOI (n=7,13)	-3.591; (-17.803 to 10.621)	6.803; (1.093 to 14.699)
Week 56/63: Total FACT-G (n=6,13)	-4.083; (-22.930 to 14.764)	9.115; (-3.820 to 22.050)
Week 56/63: Total FACT-B (n=6,13)	-5.301; (-29.740 to 19.138)	10.791; (-3.114 to 24.695)
Week 64/72: PWB (n=7,9)	0.000; (-6.733 to 6.733)	0.926; (-1.491 to 3.342)
Week 64/72: SWB (n=7,9)	-2.014; (-5.182 to 1.154)	3.570; (-1.034 to 8.174)
Week 64/72: EWB (n=7,9)	-0.057; (-3.537 to 3.423)	3.667; (-0.630 to 7.964)
Week 64/72: FWB (n=7,9)	0.214; (-4.531 to 4.959)	3.222; (-2.143 to 8.588)
Week 64/72: Breast Cancer (n=7,9)	-2.298; (-7.507 to 2.912)	3.086; (-1.361 to 7.534)
Week 64/72: FACT-B TOI (n=7,9)	-2.083; (-17.130 to 12.963)	7.235; (-3.624 to 18.093)
Week 64/72: Total FACT-G (n=7,9)	-1.857; (-17.855 to 14.140)	11.385; (-3.116 to 25.886)
Week 64/72: Total FACT-B (n=7,9)	-4.155; (-24.302 to 15.993)	14.472; (-4.192 to 33.135)
Week 72/81: PWB (n=5,7)	2.133; (-6.045 to 10.311)	-0.429; (-3.965 to 3.108)
Week 72/81: SWB (n=4,7)	-1.208; (-5.126 to 2.710)	6.829; (-3.189 to 16.846)
Week 72/81: EWB (n=5,7)	-0.600; (-5.042 to 3.842)	4.686; (-0.608 to 9.979)
Week 72/81: FWB (n=5,7)	0.000; (-5.341 to 5.341)	7.381; (-1.169 to 15.931)
Week 72/81: Breast Cancer (n=5,6)	-0.461; (-6.531 to 5.609)	3.667; (-3.410 to 10.743)
Week 72/81: FACT-B TOI (n=5,6)	1.672; (-12.563 to 15.907)	8.278; (-7.450 to 24.005)
Week 72/81: Total FACT-G (n=4,7)	-0.167; (-22.161 to 21.828)	18.467; (-1.867 to 38.801)
Week 72/81: Total FACT-B (n=4,6)	1.174; (-23.085 to 25.432)	16.906; (-9.207 to 43.018)
Week 80/90: PWB (n=2,3)	-3.750; (-30.221 to 22.721)	-3.000; (-11.605 to 5.605)
Week 80/90: SWB (n=2,3)	-0.875; (-34.229 to 32.479)	7.344; (-9.614 to 24.303)
Week 80/90: EWB (n=2,3)	-4.000; (-42.119 to 34.119)	4.733; (-18.466 to 27.932)
Week 80/90: FWB (n=2,3)	-1.000; (-64.531 to 62.531)	2.556; (-9.165 to 14.276)
Week 80/90: Breast Cancer (n=2,3)	-5.833; (-29.128 to 17.461)	3.667; (-11.512 to 18.845)
Week 80/90: FACT-B TOI (n=2,3)	-10.583; (-77.291 to 56.124)	3.222; (-30.212 to 36.657)
Week 80/90: Total FACT-G (n=2,3)	-9.625; (-171.100 to 151.850)	11.633; (-41.554 to 64.821)
Week 80/90: Total FACT-B (n=2,3)	-15.458; (-153.638 to 122.722)	15.300; (-48.177 to 78.777)
Week 88/99: PWB (n=0,1)	NA [1]; (NA to NA)	-6.000 [2]; (NA to NA)
Week 88/99: SWB (n=0,1)	NA [1]; (NA to NA)	23.333 [2]; (NA to NA)
Week 88/99: EWB (n=0,1)	NA [1]; (NA to NA)	0.000 [2]; (NA to NA)
Week 88/99: FWB (n=0,1)	NA [1]; (NA to NA)	21.000 [2]; (NA to NA)
Week 88/99: Breast Cancer (n=0,1)	NA [1]; (NA to NA)	3.000 [2]; (NA to NA)
Week 88/99: FACT TOI (n=0,1)	NA [1]; (NA to NA)	18.000 [2]; (NA to NA)
Week 88/99: Total FACT-G (n=0,1)	NA [1]; (NA to NA)	38.333 [2]; (NA to NA)
Week 88/99: Total FACT-B (n=0,1)	NA [1]; (NA to NA)	41.333 [2]; (NA to NA)
Week 96/108: PWB (n=2,1)	7.333; (-51.962 to 66.629)	-3.000 [2]; (NA to NA)
Week 96/108: SWB (n=2,1)	2.183; (-23.441 to 27.808)	1.400 [2]; (NA to NA)
Week 96/108: EWB (n=2,1)	0.000; (-12.706 to 12.706)	6.000 [2]; (NA to NA)
Week 96/108: FWB (n=2,1)	6.583; (-13.535 to 26.701)	-1.333 [2]; (NA to NA)
Week 96/108: Breast Cancer (n=2,1)	3.167; (-41.305 to 47.638)	-3.000 [2]; (NA to NA)
Week 96/108: FACT-B TOI (n=2,1)	17.083; (11.789 to 22.378)	-7.333 [2]; (NA to NA)
Week 96/108: Total FACT-G (n=2,1)	16.100; (15.253 to 16.947)	3.067 [2]; (NA to NA)
Week 96/108: Total FACT-B (n=2,1)	19.267; (-24.358 to 62.891)	0.067 [2]; (NA to NA)
Week 104/117: PWB (n=1,2)	3.667 [2]; (NA to NA)	-2.000; (-40.119 to 36.119)
Week 104/117: SWB (n=1,1)	4.200 [2]; (NA to NA)	8.800 [2]; (NA to NA)
Week 104/117: EWB (n=1,2)	0.000 [2]; (NA to NA)	10.000; (-28.119 to 48.119)
Week 104/117: FWB (n=1,2)	8.000 [2]; (NA to NA)	2.333; (-56.962 to 61.629)
Week 104/117: Breast Cancer (n=1,2)	6.032 [2]; (NA to NA)	4.000; (-59.531 to 67.531)
Week 104/117: FACT-B TOI (n=1,2)	17.698 [2]; (NA to NA)	4.333; (-156.612 to 165.279)
Week 104/117: Total FACT-G (n=1,1)	15.867 [2]; (NA to NA)	29.800 [2]; (NA to NA)
Week 104/117: Total GACT-B (n=1,1)	21.898 [2]; (NA to NA)	38.800 [2]; (NA to NA)
Week 112/126: PWB (n=0,1)	NA [1]; (NA to NA)	-11.000 [2]; (NA to NA)
Week 112/126: SWB (n=0,1)	NA [1]; (NA to NA)	-4.200 [2]; (NA to NA)
Week 112/126: EWB (n=0,1)	NA [1]; (NA to NA)	5.000 [2]; (NA to NA)
Week 112/126: FWB (n=0,1)	NA [1]; (NA to NA)	-5.333 [2]; (NA to NA)
Week 112/126: Breast Cancer (n=0,1)	NA [1]; (NA to NA)	-5.000 [2]; (NA to NA)
Week 112/126: FACT-B TOI (n=0,1)	NA [1]; (NA to NA)	-21.333 [2]; (NA to NA)
Week 112/126: Total FACT-G (n=0,1)	NA [1]; (NA to NA)	-15.533 [2]; (NA to NA)
Week 112/126: Total FACT-B (n=0,1)	NA [1]; (NA to NA)	-20.533 [2]; (NA to NA)
Second-Line PD: PWB (n=81,77)	-0.871; (-1.916 to 0.174)	-2.507; (-3.783 to -1.231)
Second-Line PD: SWB (n=80,75)	-0.106; (-0.902 to 0.690)	-0.766; (-1.788 to 0.256)
Second-Line PD: EWB (n=80,76)	-0.440; (-1.553 to 0.673)	-0.508; (-1.562 to 0.546)
Second-Line PD: FWB (n=80,76)	-1.415; (-2.590 to -0.239)	-0.773; (-1.809 to 0.263)
Second-Line PD: Breast Cancer (n=77,77)	0.120; (-1.182 to 1.421)	0.241; (-0.878 to 1.360)
Second-Line PD: FACT-B TOI (n=74,76)	-2.311; (-5.070 to 0.447)	-3.003; (-5.734 to -0.273)
Second-Line PD: Total FACT-G (n=76,74)	-2.771; (-5.902 to 0.361)	-4.702; (-7.941 to -1.462)
Second-Line PD: Total FACT-B (n=72,74)	-2.719; (-6.633 to 1.195)	-4.440; (-8.515 to -0.366)

[1]

Zero participants analyzed.

[2]

SD not calculated as only 1 participant was analyzed.

Adverse Events

Time Frame	Baseline up to approximately 4 years.
Adverse Event Reporting Description	All randomized participants who received at least 1 dose of bevacizumab and/or chemotherapy were included in the analysis.
Arm/Group Title	CT Arm	CT+BV Arm
Arm/Group Description	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.	Participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, until the maximum cumulative dose of anthracycline was reached, or end of study (24 months after randomization of the last participant). Upon second-line disease progression participants received a single-agent chemotherapy at the discretion of the investigator according to the standard of care at the investigator's site plus bevacizumab, 15 mg/kg, IV, every 3 weeks, or 10 mg/kg, IV, every 2 weeks until disease progression, unacceptable toxicity, participant request for withdrawal, or end of study. Upon subsequent disease progression participants received treatment according the standard of care of the treatment site until end of study.
All-Cause Mortality
	CT Arm	CT+BV Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	CT Arm	CT+BV Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	55/238 (23.11%)	89/245 (36.33%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	5/238 (2.10%)	12/245 (4.90%)
Neutropenia * 1	6/238 (2.52%)	10/245 (4.08%)
Leukopenia * 1	1/238 (0.42%)	2/245 (0.82%)
Thrombocytopenia * 1	0/238 (0.00%)	5/245 (2.04%)
Anaemia * 1	1/238 (0.42%)	1/245 (0.41%)
Pancytopenia * 1	0/238 (0.00%)	1/245 (0.41%)
Cardiac disorders
Cardiac failure * 1	1/238 (0.42%)	2/245 (0.82%)
Acute coronary syndrome * 1	0/238 (0.00%)	1/245 (0.41%)
Atrial fibrillation * 1	0/238 (0.00%)	1/245 (0.41%)
Cardiac failure congestive * 1	0/238 (0.00%)	2/245 (0.82%)
Cardiotoxicity * 1	0/238 (0.00%)	1/245 (0.41%)
Left ventricular failure * 1	0/238 (0.00%)	1/245 (0.41%)
Sinus tachycardia * 1	1/238 (0.42%)	0/245 (0.00%)
Tachycardia * 1	0/238 (0.00%)	1/245 (0.41%)
Angina pectoris * 1	1/238 (0.42%)	1/245 (0.41%)
Atrial tachycardia * 1	1/238 (0.42%)	0/245 (0.00%)
Congestive cardiomyopathy * 1	0/238 (0.00%)	1/245 (0.41%)
Left ventricular dysfunction * 1	0/238 (0.00%)	1/245 (0.41%)
Mitral valve incompetence * 1	1/238 (0.42%)	0/245 (0.00%)
Supraventricular tachycardia * 1	0/238 (0.00%)	1/245 (0.41%)
Ischaemic cardiomyopathy * 1	1/238 (0.42%)	0/245 (0.00%)
Gastrointestinal disorders
Diarrhoea * 1	2/238 (0.84%)	4/245 (1.63%)
Vomiting * 1	1/238 (0.42%)	2/245 (0.82%)
Abdominal pain * 1	1/238 (0.42%)	1/245 (0.41%)
Anal fissure * 1	0/238 (0.00%)	1/245 (0.41%)
Diverticular perforation * 1	0/238 (0.00%)	1/245 (0.41%)
Faecaloma * 1	0/238 (0.00%)	1/245 (0.41%)
Melaena * 1	0/238 (0.00%)	1/245 (0.41%)
Nausea * 1	1/238 (0.42%)	1/245 (0.41%)
Pancreatitis * 1	1/238 (0.42%)	0/245 (0.00%)
Ileus paralytic * 1	1/238 (0.42%)	0/245 (0.00%)
Subileus * 1	0/238 (0.00%)	1/245 (0.41%)
Gastrointestinal disorder * 1	0/238 (0.00%)	1/245 (0.41%)
General disorders
Pyrexia * 1	2/238 (0.84%)	4/245 (1.63%)
Fatigue * 1	2/238 (0.84%)	2/245 (0.82%)
General physical health deterioration * 1	1/238 (0.42%)	2/245 (0.82%)
Chest discomfort * 1	1/238 (0.42%)	0/245 (0.00%)
Chest pain * 1	1/238 (0.42%)	0/245 (0.00%)
Device failure * 1	0/238 (0.00%)	1/245 (0.41%)
Mucosal inflammation * 1	1/238 (0.42%)	3/245 (1.22%)
Pain * 1	1/238 (0.42%)	0/245 (0.00%)
Sudden death * 1	0/238 (0.00%)	1/245 (0.41%)
Device dislocation * 1	1/238 (0.42%)	0/245 (0.00%)
Device occlusion * 1	1/238 (0.42%)	0/245 (0.00%)
Impaired healing * 1	0/238 (0.00%)	1/245 (0.41%)
Multi-organ failure * 1	0/238 (0.00%)	1/245 (0.41%)
Patient-device incompatibility * 1	0/238 (0.00%)	1/245 (0.41%)
Hepatobiliary disorders
Cholelithiasis * 1	0/238 (0.00%)	2/245 (0.82%)
Cholecystitis * 1	0/238 (0.00%)	1/245 (0.41%)
Cholangitis * 1	1/238 (0.42%)	0/245 (0.00%)
Hepatitis toxic * 1	0/238 (0.00%)	1/245 (0.41%)
Infections and infestations
Infection * 1	2/238 (0.84%)	3/245 (1.22%)
Bronchitis * 1	0/238 (0.00%)	3/245 (1.22%)
Pneumonia * 1	0/238 (0.00%)	2/245 (0.82%)
Device related infection * 1	1/238 (0.42%)	0/245 (0.00%)
Device related sepsis * 1	1/238 (0.42%)	0/245 (0.00%)
Ear infection * 1	1/238 (0.42%)	0/245 (0.00%)
Enterocolitis infectious * 1	1/238 (0.42%)	0/245 (0.00%)
Erysipelas * 1	1/238 (0.42%)	0/245 (0.00%)
Herpes zoster * 1	1/238 (0.42%)	0/245 (0.00%)
Injection site infection * 1	1/238 (0.42%)	0/245 (0.00%)
Osteomyelitis * 1	0/238 (0.00%)	1/245 (0.41%)
Sepsis * 1	0/238 (0.00%)	2/245 (0.82%)
Tooth infection * 1	0/238 (0.00%)	1/245 (0.41%)
Urinary tract infection * 1	0/238 (0.00%)	1/245 (0.41%)
Wound infection * 1	0/238 (0.00%)	1/245 (0.41%)
Anal abscess * 1	0/238 (0.00%)	1/245 (0.41%)
Peritonitis bacterial * 1	0/238 (0.00%)	1/245 (0.41%)
Pseudomembranous colitis * 1	0/238 (0.00%)	1/245 (0.41%)
Urosepsis * 1	0/238 (0.00%)	1/245 (0.41%)
Injury, poisoning and procedural complications
Foot fracture * 1	1/238 (0.42%)	0/245 (0.00%)
Femoral neck fracture * 1	1/238 (0.42%)	1/245 (0.41%)
Head injury * 1	0/238 (0.00%)	1/245 (0.41%)
Subdural haematoma * 1	0/238 (0.00%)	1/245 (0.41%)
Investigations
Gamma-glutamyltransferase increased * 1	1/238 (0.42%)	1/245 (0.41%)
Alanine aminotransferase increased * 1	0/238 (0.00%)	1/245 (0.41%)
Aspartate aminotransferase increased * 1	0/238 (0.00%)	1/245 (0.41%)
Blood bilirubin increased * 1	0/238 (0.00%)	1/245 (0.41%)
Blood potassium increased * 1	1/238 (0.42%)	0/245 (0.00%)
Biopsy liver * 1	1/238 (0.42%)	0/245 (0.00%)
Metabolism and nutrition disorders
Hyponatraemia * 1	1/238 (0.42%)	2/245 (0.82%)
Hypercalcaemia * 1	1/238 (0.42%)	1/245 (0.41%)
Hypocalcaemia * 1	0/238 (0.00%)	1/245 (0.41%)
Hypoglycaemia * 1	0/238 (0.00%)	1/245 (0.41%)
Musculoskeletal and connective tissue disorders
Bone pain * 1	1/238 (0.42%)	2/245 (0.82%)
Osteonecrosis of jaw * 1	0/238 (0.00%)	2/245 (0.82%)
Musculoskeletal pain * 1	0/238 (0.00%)	1/245 (0.41%)
Pathological fracture * 1	1/238 (0.42%)	0/245 (0.00%)
Osteolysis * 1	0/238 (0.00%)	1/245 (0.41%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma * 1	0/238 (0.00%)	1/245 (0.41%)
Metastases to liver * 1	0/238 (0.00%)	1/245 (0.41%)
Nervous system disorders
Ischaemic stoke * 1	2/238 (0.84%)	0/245 (0.00%)
Cerebrovascular accident * 1	1/238 (0.42%)	0/245 (0.00%)
Cerebrovascular disorder * 1	1/238 (0.42%)	0/245 (0.00%)
Convulsion * 1	0/238 (0.00%)	2/245 (0.82%)
Headache * 1	1/238 (0.42%)	0/245 (0.00%)
Motor dysfunction * 1	1/238 (0.42%)	0/245 (0.00%)
Partial seizures * 1	1/238 (0.42%)	0/245 (0.00%)
Polyneuropathy * 1	1/238 (0.42%)	0/245 (0.00%)
Spinal cord compression * 1	1/238 (0.42%)	0/245 (0.00%)
Facial paresis * 1	0/238 (0.00%)	1/245 (0.41%)
Ruptured cerebral aneurysm * 1	0/238 (0.00%)	1/245 (0.41%)
Psychiatric disorders
Depression * 1	1/238 (0.42%)	1/245 (0.41%)
Confusional state * 1	1/238 (0.42%)	0/245 (0.00%)
Renal and urinary disorders
Obstructive uropathy * 1	1/238 (0.42%)	0/245 (0.00%)
Postrenal failure * 1	0/238 (0.00%)	1/245 (0.41%)
Reproductive system and breast disorders
Menstrual disorder * 1	1/238 (0.42%)	0/245 (0.00%)
Metrorrhagia * 1	1/238 (0.42%)	0/245 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism * 1	2/238 (0.84%)	6/245 (2.45%)
Pleural effusion * 1	1/238 (0.42%)	2/245 (0.82%)
Dyspnoea * 1	1/238 (0.42%)	3/245 (1.22%)
Pneumothorax * 1	0/238 (0.00%)	1/245 (0.41%)
Pneumonia aspiration * 1	1/238 (0.42%)	0/245 (0.00%)
Skin and subcutaneous tissue disorders
Skin ulcer * 1	0/238 (0.00%)	1/245 (0.41%)
Surgical and medical procedures
Salpingo-oophorectomy * 1	0/238 (0.00%)	1/245 (0.41%)
Tooth extraction * 1	1/238 (0.42%)	0/245 (0.00%)
Large intestine anastomosis * 1	1/238 (0.42%)	0/245 (0.00%)
Vascular disorders
Embolism venous * 1	1/238 (0.42%)	3/245 (1.22%)
Haemorrhage * 1	1/238 (0.42%)	1/245 (0.41%)
Embolism arterial * 1	0/238 (0.00%)	1/245 (0.41%)
Infarction * 1	0/238 (0.00%)	1/245 (0.41%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.1)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	CT Arm	CT+BV Arm
	Affected / at Risk (%)	Affected / at Risk (%)
Total	181/238 (76.05%)	218/245 (88.98%)
Blood and lymphatic system disorders
Neutropenia * 1	55/238 (23.11%)	64/245 (26.12%)
Leukopenia * 1	18/238 (7.56%)	30/245 (12.24%)
Anaemia * 1	13/238 (5.46%)	22/245 (8.98%)
Thrombocytopenia * 1	4/238 (1.68%)	16/245 (6.53%)
Gastrointestinal disorders
Diarrhoea * 1	27/238 (11.34%)	35/245 (14.29%)
Nausea * 1	31/238 (13.03%)	33/245 (13.47%)
Vomiting * 1	22/238 (9.24%)	16/245 (6.53%)
Abdominal pain * 1	3/238 (1.26%)	15/245 (6.12%)
Constipation * 1	9/238 (3.78%)	13/245 (5.31%)
General disorders
Fatigue * 1	33/238 (13.87%)	49/245 (20.00%)
Mucosal inflammation * 1	9/238 (3.78%)	26/245 (10.61%)
Asthenia * 1	5/238 (2.10%)	14/245 (5.71%)
Pyrexia * 1	11/238 (4.62%)	14/245 (5.71%)
Infections and infestations
Urinary tract infection * 1	2/238 (0.84%)	16/245 (6.53%)
Metabolism and nutrition disorders
Decreased appetite * 1	4/238 (1.68%)	21/245 (8.57%)
Nervous system disorders
Peripheral sensory neuropathy * 1	10/238 (4.20%)	15/245 (6.12%)
Renal and urinary disorders
Proteinuria * 1	70/238 (29.41%)	133/245 (54.29%)
Respiratory, thoracic and mediastinal disorders
Epistaxis * 1	3/238 (1.26%)	18/245 (7.35%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome * 1	58/238 (24.37%)	72/245 (29.39%)
Vascular disorders
Hypertension * 1	55/238 (23.11%)	90/245 (36.73%)
Haemorrhage * 1	7/238 (2.94%)	29/245 (11.84%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (17.1)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffman-LaRoche
• Phone: 800-821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Levy C, Brain E, Pivot X, Putzu C, Gonzalez Martin A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. doi: 10.1093/annonc/mdw316. Epub 2016 Aug 8.

von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. doi: 10.1016/S1470-2045(14)70439-5. Epub 2014 Sep 28.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01250379
• Other Study ID Numbers: MO22998; 2010-020998-16
• First Submitted: November 25, 2010
• First Posted: November 30, 2010
• Results First Submitted: June 5, 2015
• Results First Posted: June 30, 2015
• Last Update Posted: February 11, 2016