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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01250379
• Collaborator: (none)
• Enrollment: 494
• Locations: 132
• Arms: 2
• Duration (Months): 48.9
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized, open-label, parallel-group study will assess the efficacy and s afety of Avastin (bevacizumab) in combination with chemotherapy versus chemother apy alone as second- and third-line therapy in patients with locally recurrent o r metastatic breast cancer progressing after first-line therapy with Avastin and chemotherapy. Patients will be randomized to receive either Avastin (15 mg/kg e very 3 weeks or 10 mg/kg every 2 weeks intravenously) plus standard chemotherapy or chemotherapy alone. Anticipated time on study treatment is until third-line disease progression or unacceptable toxicity occurs.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: bevacizumab [Avastin]; Drug: Chemotherapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 494 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Study Evaluating the Efficacy and Safety of Continued and Re-induced Bevacizumab in Combination With Chemotherapy for Patients With Locally Recurrent or Metastatic Breast Cancer After First-line Chemotherapy and Bevacizumab Treatment
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1	Drug: Chemotherapy; Standard chemotherapy (doublets not allowed)
Experimental: 2	Drug: bevacizumab [Avastin]; 10 mg/ kg iv every 2 weeks or 15 mg/kg iv every 3 weeks; Drug: Chemotherapy; Standard chemotherapy (doublets not allowed)

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Second-Line Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) [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]

   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.

2. Second-Line PFS [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years]

   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.

3. Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 6 [Month 6]

   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.

4. Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 12 [Month 12]

   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.

5. Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 18 [Month 18]

   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.

6. Percentage of Participants Estimated to be Alive and Free of Second-Line Disease Progression at Month 24 [Month 24]

   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.

Secondary Outcome Measures

1. Second-Line PFS by Baseline Risk Factor (Data Cutoff 20 December 2013) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years]

   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.

2. 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) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years]

   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.

3. Percentage of Participants With a Second-Line CR, PR, Stable Disease, and PD According to RECIST v1.1 (Data Cutoff 20 December 2013) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years]

   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.

4. Duration of Second-Line Objective Response (Data Cutoff 20 December 2013) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 3 years]

   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.

5. 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) [Months 3, 6, and 9]

   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.

6. Percentage of Participants With Third-Line PFS According to RECIST v1.1 [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)]

   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.

7. Third-Line PFS [First dose of third-line treatment until PD or death due to any cause (over a period of approximately 14 months)]

   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.

8. Percentage of Participants With Second- and Third-Line PFS According to RECIST v1.1 [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years]

   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.

9. Second- and Third-Line PFS [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years]

   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.

10. Percentage of Participants With Second- and Third-Line Tumor Progression [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years]

    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.

11. Time to Second- and Third-Line Tumor Progression [Baseline (≤28 days after randomization), every 8-9 weeks thereafter according to the standard of care of the treatment site until approximately 4 years]

    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.

12. Percentage of Participants Who Died [Baseline until death (up to approximately 4 years)]

    Percentage of participants who died due to any reason were reported.

13. Overall Survival (OS) [Baseline until death (up to approximately 4 years)]

    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.

14. Percentage of Participants Estimated to be Surviving at Months 6, 12, 18, and 24 [Months 6, 12, 18, and 24]

    OS was defined as the median time, in months, from the date of randomization to the date of death, due to any cause.

15. Percentage of Participants Experiencing Problems by European Quality of Life Instrument (EQ-5D) Category (Data Cutoff 20 December 2013) [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)]

    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").

16. Quality of Life Assessed As an Index Score Using the EQ-5D (Data Cutoff 20 December 2013) [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)]

    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).

17. Change From Baseline in EQ-5D Index Scores (Data Cutoff 20 December 2013) [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)]

    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.

18. Quality of Life Assessed Using the EQ-5D Visual Analogue Scale (VAS) Scores (Data Cutoff 20 December 2013) [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)]

    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.

19. Change From Baseline in VAS Scores (Data Cutoff 20 December 2013) [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)]

    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.

20. Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores (Data Cutoff 20 December 2013) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years)]

    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.

21. Change From Baseline in FACT-B Scores (Data Cutoff 20 December 2013) [Baseline (≤28 days after randomization), every 8-9 weeks thereafter until second-line PD (up to approximately 3 years)]

    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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Female patients, >/= 18 years of age

• Histologically confirmed HER2-negative breast cancer

• Disease progression during or following first-line treatment with Avastin and chemotherapy for locally recurrent or metastatic breast cancer

• Avastin treatment in first-line setting must have been a minimum of 4 cycles (15 mg/kg) or 6 cycles (10 mg/kg) in combination with chemotherapy

• ECOG performance status 0-2

• At least 28 days since prior radiation therapy or surgery and recovery from treatment

Exclusion Criteria:

• Anti-angiogenic therapy or anti-vascular endothelial growth factors other than Avastin for first-line treatment

• Active malignancy other than superficial basal cell and superficial squamous cell carcinoma of the skin, or in situ carcinoma of the cervix or breast within the last 5 years

• Inadequate renal function

• Clinically relevant cardio-vascular disease

• Known CNS disease except for treated brain metastases

• Chronic daily treatment with high-dose aspirin (>325 mg/day) or clopidogrel (>75 mg/day)

• Pregnant or lactating women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Buenos Aires		Argentina	C1199ACI
2		Buenos Aires		Argentina	C1280AEB
3		Buenos Aires		Argentina	C1426ANZ
4		San Miguel de Tucuman		Argentina	T4000IAK
5		Feldkirch		Austria	6807
6		Graz		Austria	8036
7		Innsbruck		Austria	6020
8		Krems		Austria	3500
9		Salzburg		Austria	5020
10		Steyr		Austria	4400
11		Villach		Austria	9500
12		Wien		Austria	1090
13		Goiania	GO	Brazil	74140-050
14		Porto Alegre	RS	Brazil	90430-090
15		Itajai	SC	Brazil	88301-220
16		Split		Croatia	21000
17		Amiens		France	80090
18		Angers		France	49933
19		Besancon		France	25030
20		Bordeaux		France	33000
21		Boulogne Sur Mer		France	62222
22		Brest		France	29609
23		Caen		France	14076
24		Clermont Ferrand		France	63011
25		Dijon		France	21079
26		Grenoble		France	38028
27		Limoges		France	87039
28		Marseille		France	13285
29		Montpellier		France	34298
30		Nancy		France	54100
31		Nantes		France	44202
32		Paris		France	75970
33		Pierre Benite		France	69495
34		Reims CEDEX		France	51056
35		Rouen		France	76038
36		Saint Gregoire		France	35768
37		Saint Jean		France	31240
38		St Cloud		France	92210
39		St Priest En Jarez		France	42271
40		St Quentin		France	02321
41		Strasbourg		France	67010
42		Toulouse		France	31076
43		Amberg		Germany	92224
44		Aschaffenburg		Germany	63739
45		Berlin		Germany	10367
46		Berlin		Germany	10719
47		Bielefeld		Germany	33604
48		Chemnitz		Germany	09116
49		Dresden		Germany	01307
50		Düsseldorf		Germany	40235
51		Essen		Germany	45122
52		Essen		Germany	45136
53		Freiburg		Germany	79110
54		Göttingen		Germany	37073
55		Hamburg		Germany	20249
56		Hannover		Germany	30177
57		Heidelberg		Germany	69115
58		Heidelberg		Germany	69120
59		Karlsruhe		Germany	76135
60		Koeln		Germany	50935
61		Mannheim		Germany	68161
62		Muenster		Germany	48149
63		München		Germany	80639
64		Naunhof		Germany	04683
65		Neuss		Germany	41462
66		Nordhausen		Germany	99734
67		Osnabrueck		Germany	49076
68		Ravensburg		Germany	88212
69		Stade		Germany	21680
70		Stralsund		Germany	18435
71		Wiesbaden		Germany	65199
72		Athens		Greece	11528
73		Ioannina		Greece	455 00
74		Patras		Greece	265 00
75		Thessaloniki		Greece	546 45
76		Budapest		Hungary	1122
77		Budapest		Hungary	1145
78		Szeged		Hungary	6720
79		Beer Sheva		Israel	8410101
80		Jerusalem		Israel	91120
81		Kfar-Saba		Israel	4428164
82		Petach Tikva		Israel	4941492
83		Ramat Gan		Israel	52620-00
84		Rehovot		Israel	7610001
85		Tel Aviv		Israel	6423906
86		Tel Aviv		Israel
87		Cosenza	Calabria	Italy	87100
88		Benevento	Campania	Italy	82100
89		Napoli	Campania	Italy	80131
90		Reggio Emilia	Emilia-Romagna	Italy	42100
91		Udine	Friuli-Venezia Giulia	Italy	33100
92		Roma	Lazio	Italy	00168
93		Monza	Lombardia	Italy	20052
94		Macerata	Marche	Italy	62100
95		Cagliari	Sardegna	Italy	09121
96		Sassari	Sardegna	Italy	07100
97		Catania	Sicilia	Italy	95100
98		Firenze	Toscana	Italy	50134
99		Pisa	Toscana	Italy	56100
100		Pontedera	Toscana	Italy	56025
101		Verona	Veneto	Italy	37126
102		Bardejov		Slovakia	085 01
103		Bratislava		Slovakia	812 50
104		Kosice		Slovakia	04001
105		Nove Zamky		Slovakia	940 34
106		Presov		Slovakia	080 01
107		Santander	Cantabria	Spain	39008
108		San Sebastian	Guipuzcoa	Spain	20080
109		Palma De Mallorca	Islas Baleares	Spain	07014
110		La Laguna	Tenerife	Spain	38320
111		Barcelona		Spain	08035
112		Barcelona		Spain	08036
113		Barcelona		Spain	08041
114		Castellon		Spain	12002
115		Cordoba		Spain	14004
116		Leon		Spain	24071
117		Lerida		Spain	25198
118		Madrid		Spain	28007
119		Madrid		Spain	28033
120		Madrid		Spain	28034
121		Madrid		Spain	28040
122		Madrid		Spain	28041
123		Madrid		Spain	28046
124		Madrid		Spain	28223
125		Malaga		Spain	29010
126		Murcia		Spain	30008
127		Sevilla		Spain	41014
128		Valencia		Spain	46009
129		Zaragoza		Spain	50009
130		Aarau		Switzerland	5000
131		Chur		Switzerland	7000
132		Zürich		Switzerland	8038

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01250379
• Other Study ID Numbers: MO22998; 2010-020998-16
• First Posted: Nov 30, 2010
• Last Update Posted: Feb 11, 2016
• Last Verified: Jan 1, 2016

• Additional relevant MeSH terms: Breast Neoplasms; Bevacizumab

Study Results

Participant Flow

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

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	54
NOT COMPLETED	202	193

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 Participants	247	247	494
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (10.83)	55.8 (11.17)	55.2 (11.01)
Sex: Female, Male (Count of Participants)
Female	247 100%	247 100%	494 100%
Male	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.
Measure Participants	247	247
Number [percentage of participants]	88.7 35.9%	93.9 38%

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.
Measure Participants	247	247
Median (95% Confidence Interval) [months]	4.2	6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0204
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.97
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0245
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

3. 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.
Measure Participants	226	219
HR-neg (n=60,56)	2.1	4.9
HR-pos/HER-neg (n=187,191)	4.7	6.7
PFS <6 months (n=69,68)	3.9	5.1
PFS ≥6 months (n=178,179)	4.6	6.4
Taxane chemo (n=32,32)	3.2	6.9
Non-taxane chemo (n=191,188)	4.4	6.0
Vinorelbine chemo (n=24,27)	2.4	6.5
LDH ≤ 1.5 ULN (n=207,210)	4.4	6.3
LDH > 1.5 ULN (n=40,37)	2.1	5.8
< 65 years of age (n=196,183)	4.2	6.1
≥ 65 years of age (n=51,64)	4.2	6.7
< 70 years of age (n=226,219)	4.2	6.2
≥ 70 years of age (n=21,28)	7.8	6.7
< 3 metastatic organ sites (n=158,167)	4.2	6.9
≥ 3 metastatic organ sites (n=88,80)	4.0	4.7
B-free ≤ 6 weeks (n=165,149)	4.2	5.8
B-free > 6 weeks (n=81,98)	4.4	7.6
D-free ≤ 24 months (n=58,53)	2.8	5.8
D-free > 24 months (n=138,156)	4.9	6.5
D-free ≤ 12 months (n=24,18)	2.1	5.8
D-free > 12 months (n=172,191)	4.3	6.3

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
Statistical Test of Hypothesis	p-Value	0.0088
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.40 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1196
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.67 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0110
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0816
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0395
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1385
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0029
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0171
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1797
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0229
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.2139
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.5216
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.64 to 2.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0148
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.3102
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0967
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.64 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0489
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0176
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; 0.41 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.2318
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.0568
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.26 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
Statistical Test of Hypothesis	p-Value	0.1143
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. 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.
Measure Participants	185	182
Number (95% Confidence Interval) [percentage of participants]	16.8 6.8%	20.9 8.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3457
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.1
	Confidence Interval	(2-Sided) 95%; -4.2 to 12.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 95% CI was estimated using Hauck-Anderson methodology.

5. 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.
Measure Participants	185	182
CR	1.1 0.4%	0.5 0.2%
PR	15.7 6.4%	20.3 8.2%
Stable disease	33.5 13.6%	48.9 19.8%
PD	41.1 16.6%	24.2 9.8%
Unable to assess	8.6 3.5%	6.0 2.4%

6. 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.
Measure Participants	31	38
Median (95% Confidence Interval) [months]	10.6	8.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9825
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.51 to 1.99
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3601
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.73 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

7. 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.
Measure Participants	31	38
Month 3	96.7 39.1%	100.0 40.5%
Month 6	69.0 27.9%	72.8 29.5%
Month 9	60.9 24.7%	40.8 16.5%

8. 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.
Measure Participants	105	129
Number [percentage of participants]	94.3 38.2%	96.1 38.9%

9. 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.
Measure Participants	105	129
Median (95% Confidence Interval) [months]	2.9	3.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1080
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.06
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0625
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

10. 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.
Measure Participants	247	247
Number [percentage of participants]	71.7 29%	83.4 33.8%

11. 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.
Measure Participants	247	247
Median (95% Confidence Interval) [months]	10.7	12.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1349
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.05
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0863
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

12. 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.
Measure Participants	247	247
Number [percentage of participants]	67.2 27.2%	75.3 30.5%

13. 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.
Measure Participants	247	247
Median (95% Confidence Interval) [months]	11.2	13.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0744
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.02
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0503
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

14. 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.
Measure Participants	247	247
Number (95% Confidence Interval) [percentage of participants]	40.7 16.5%	54.2 21.9%

15. 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.
Measure Participants	247	247
Number [percentage of participants]	63.2 25.6%	66.0 26.7%

16. 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.
Measure Participants	247	247
Median (95% Confidence Interval) [months]	18.7	19.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CT Arm, CT+BV Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7253
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.21
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5332
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.75 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified analysis.

17. 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.
Measure Participants	247	247
Month 6	85.2 34.5%	90.4 36.6%
Month 12	68.6 27.8%	72.4 29.3%
Month 18	52.8 21.4%	54.9 22.2%
Month 24	38.4 15.5%	37.6 15.2%

18. 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.
Measure Participants	214	224
BL: M, no problems (n=214,224)	60.3 24.4%	64.3 26%
BL: M, some problems (n=214,224)	36.4 14.7%	34.8 14.1%
BL: M, extreme problems (n=214,224)	0.5 0.2%	0.4 0.2%
BL: SC, no problems (n=214,224)	82.7 33.5%	85.7 34.7%
BL: SC, some problems (n=214,224)	12.6 5.1%	11.2 4.5%
BL: SC, extreme problems (n=214,224)	0.5 0.2%	1.8 0.7%
BL: UA, no problems (n=214,224)	53.7 21.7%	46.4 18.8%
BL: UA, some problems (n=214,224)	40.2 16.3%	48.7 19.7%
BL: UA, extreme problems (n=214,224)	2.8 1.1%	4.0 1.6%
BL: P/D, no problems (n=214,224)	24.3 9.8%	27.7 11.2%
BL: P/D, some problems (n=214,224)	68.7 27.8%	66.1 26.8%
BL: P/D, extreme problems (n=214,224)	4.2 1.7%	5.4 2.2%
BL: A/D, no problems (n=214,224)	33.6 13.6%	34.8 14.1%
BL: A/D, some problems (n=214,224)	56.5 22.9%	58.5 23.7%
BL: A/D, extreme problems (n=214,224)	5.6 2.3%	5.8 2.3%
Week 8/9: M, no problems (n=133,141)	61.7 25%	51.8 21%
Week 8/9: M, some problems (n=133,141)	34.6 14%	43.3 17.5%
Week 8/9: M, extreme problems (n=133,141)	1.5 0.6%	2.1 0.9%
Week 8/9: SC, no problems (n=133,141)	82.0 33.2%	75.9 30.7%
Week 8/9: SC, some problems (n=133,141)	13.5 5.5%	17.0 6.9%
Week 8/9: SC, extreme problems (n=133,141)	1.5 0.6%	3.5 1.4%
Week 8/9: UA, no problems (n=133,141)	53.4 21.6%	40.4 16.4%
Week 8/9: UA, some problems (n=133,141)	40.6 16.4%	51.8 21%
Week 8/9: UA, extreme problems (n=133,141)	3.0 1.2%	5.0 2%
Week 8/9: P/D, no problems (n=133,141)	29.3 11.9%	23.4 9.5%
Week 8/9: P/D, some problems (n=133,141)	61.7 25%	68.1 27.6%
Week 8/9: P/D, extreme problems (n=133,141)	5.3 2.1%	6.4 2.6%
Week 8/9: A/D, no problems (n=133,141)	49.6 20.1%	46.8 18.9%
Week 8/9: A/D, some problems (n=133,141)	40.6 16.4%	48.2 19.5%
Week 8/9: A/D, extreme problems (n=133,141)	6.8 2.8%	2.8 1.1%
Week 16/18: M, no problems (n=84,123)	66.7 27%	49.6 20.1%
Week 16/18: M, some problems (n=84,123)	29.8 12.1%	47.2 19.1%
Week 16/18: M, extreme problems (n=84,123)	0.0 0%	2.4 1%
Week 16/18: SC, no problems (n=84,123)	81.0 32.8%	78.9 31.9%
Week 16/18: SC, some problems (n=84,123)	14.3 5.8%	17.1 6.9%
Week 16/18: SC, extreme problems (n=84,123)	0.0 0%	3.3 1.3%
Week 16/18: UA, no problems (n=84,123)	50.0 20.2%	36.6 14.8%
Week 16/18: UA, some problems (n=84,123)	42.9 17.4%	56.1 22.7%
Week 16/18: UA, extreme problems (n=84,123)	3.6 1.5%	4.1 1.7%
Week 16/18: P/D, no problems (n=84,123)	34.5 14%	19.5 7.9%
Week 16/18: P/D, some problems (n=84,123)	59.5 24.1%	76.4 30.9%
Week 16/18: P/D, extreme problems (n=84,123)	1.2 0.5%	3.3 1.3%
Week 16/18: A/D, no problems (n=84,123)	51.2 20.7%	49.6 20.1%
Week 16/18: A/D, some problems (n=84,123)	44.0 17.8%	43.1 17.4%
Week 16/18: A/D, extreme problems (n=84,123)	0.0 0%	5.7 2.3%
Second-line PD: M, no problems (n=82,76)	59.8 24.2%	47.4 19.2%
Second-line PD: M, some problems (n=82,76)	34.1 13.8%	48.7 19.7%
Second-line PD: M, extreme problems (n=82,76)	2.4 1%	3.9 1.6%
Second-line PD: SC, no problems (n=82,76)	76.8 31.1%	75.0 30.4%
Second-line PD: SC, some problems (n=82,76)	15.9 6.4%	18.4 7.4%
Second-line PD: SC, extreme problems (n=82,76)	1.2 0.5%	6.6 2.7%
Second-line PD: UA, no problems (n=82,76)	39.0 15.8%	30.3 12.3%
Second-line PD: UA, some problems (n=82,76)	50.0 20.2%	59.2 24%
Second-line PD: UA, extreme problems (n=82,76)	6.1 2.5%	10.5 4.3%
Second-line PD: P/D, no problems (n=82,76)	19.5 7.9%	18.4 7.4%
Second-line PD: P/D, some problems (n=82,76)	67.1 27.2%	69.7 28.2%
Second-line PD: P/D, extreme problems (n=82,76)	8.5 3.4%	11.8 4.8%
Second-line PD: A/D, no problems (n=82,76)	36.6 14.8%	26.3 10.6%
Second-line PD: A/D, some problems (n=82,76)	50.0 20.2%	61.8 25%
Second-line PD: A/D, extreme problems (n=82,76)	7.3 3%	11.8 4.8%

19. 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.
Measure Participants	202	219
BL (n=202,219)	0.6806	0.6725
Week 8/9 (n=127,135)	0.6953	0.6515
Week 16/18 (n=80,118)	0.7496	0.6534
Second-line PD (n=77,76)	0.6290	0.5553

20. 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.
Measure Participants	107	122
Week 8/9 (n=107,122)	-0.0103	-0.0370
Week 16/18 (n=68,110)	0.0387	-0.0508
Second-line PD (n=69,71)	-0.0884	-0.0878

21. 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.
Measure Participants	200	212
BL (n=200,212)	66.5	63.4
Week 8/9 (n=123,135)	69.3	66.5
Week 16/18 (n=75,119)	67.3	66.4
Second-line PD (n=78,75)	63.7	61.7

22. 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.
Measure Participants	106	118
Week 8/9 (n=106,118)	-2.0	2.0
Week 16/18 (n=66,107)	-0.2	2.0
Second-line PD (n=70,69)	-5.1	-1.3

23. 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.
Measure Participants	215	224
BL: PWB (n=215,222)	20.621	20.253
BL: SWB (n=214,223)	20.722	20.674
BL: EWB (n=215,224)	14.847	15.062
BL: FWB (n=215,224)	16.091	15.726
BL: Breast Cancer Score (n=210,224)	24.986	24.388
BL: FACT-B TOI (n=204,219)	61.677	60.277
BL: Total FACT-G Score (n=207,218)	72.169	71.864
BL: Total FACT-B Score (n=201,218)	96.908	96.115
Week 8/9: PWB (n=129,138)	20.413	19.156
Week 8/9: SWB (n=127,135)	20.833	21.116
Week 8/9: EWB (n=129,139)	15.943	16.671
Week 8/9: FWB (n=129,139)	16.662	16.169
Week 8/9: Breast Cancer Score (n=128,139)	26.276	25.884
Week 8/9: FACT-B TOI (n=126,136)	63.547	61.279
Week 8/9: Total FACT-G Score (n=122,134)	74.255	73.393
Week 8/9: Total FACT-B Score (n=123,134)	100.375	99.213
Week 16/18: PWB (n=83,107)	21.733	19.629
Week 16/18: SWB (n=80,105)	20.930	20.843
Week 16/18: EWB (n=80,107)	17.330	16.806
Week 16/18: FWB (n=81,106)	17.055	15.920
Week 16/18: Breast Cancer (n=81,106)	26.923	25.755
Week 16/18: FACT-B TOI (n=78,105)	65.628	61.107
Week 16/18: Total FACT-G (n=78,102)	76.794	73.269
Week 16/18: Total FACT-B (n=76,103)	103.503	98.906
Week 24/27: PWB (n=48,80)	21.940	18.965
Week 24/27: SWB (n=47,78)	20.840	21.399
Week 24/27: EWB (n=45,78)	17.098	16.438
Week 24/27: FWB (n=45,79)	18.244	16.051
Week 24/27: Breast Cancer (n=46,79)	26.067	24.632
Week 24/27: FACT-B TOI (n=44,77)	65.882	60.014
Week 24/27: Total FACT-G (n=44,77)	78.305	73.083
Week 24/27: Total FACT-B (n=43,77)	104.011	97.795
Week 32/36: PWB (n=26,44)	22.949	19.686
Week 32/36: SWB (n=25,43)	22.140	21.222
Week 32/36: EWB (n=26,44)	18.385	16.755
Week 32/36: FWB (n=26,44)	19.615	17.195
Week 32/36: Breast Cancer (n=26,43)	29.568	26.163
Week 32/36: FACT-B TOI (n=26,42)	72.132	63.017
Week 32/36: Total FACT-G (n=25,42)	83.087	74.879
Week 32/36: Total FACT-B (n=25,42)	112.904	100.904
Week 40/45: PWB (n=20,27)	22.215	20.630
Week 40/45: SWB (n=21,26)	19.658	20.915
Week 40/45: EWB (n=20,27)	17.560	16.067
Week 40/45: FWB (n=20,27)	18.450	16.519
Week 40/45: Breast Cancer (n=21,27)	29.386	23.819
Week 40/45: FACT-B TOI (n=19,27)	68.750	60.967
Week 40/45: Total FACT-G (n=19,26)	76.955	75.235
Week 40/45: Total FACT-B (n=19,26)	105.540	99.072
Week 48/54: PWB (n=13,24)	23.308	20.033
Week 48/54: SWB (n=13,23)	20.740	20.450
Week 48/54: EWB (n=13,23)	19.308	17.270
Week 48/54: FWB (n=13,23)	18.538	16.268
Week 48/54: Breast Cancer (n=13,23)	28.912	26.237
Week 48/54: Fact-B TOI (n=13,23)	70.758	62.679
Week 48/54: Total FACT-G (n=13,23)	81.894	74.162
Week 48/54: Total FACT-B (n=13,23)	110.806	100.399
Week 56/63: PWB (n=8,14)	21.792	20.298
Week 56/63: SWB (n=8,14)	19.583	20.817
Week 56/63: EWB (n=7,14)	17.143	15.714
Week 56/63: FWB (n=7,14)	17.143	16.476
Week 56/63: Breast Cancer (n=8,14)	28.240	25.459
Week 56/63: FACT-B TOI (n=7,14)	66.179	62.233
Week 56/63: Total FACT-G (n=6,14)	73.667	73.305
Week 56/63: Total FACT-B (n=6,14)	101.042	98.764
Week 64/72: PWB (n=7,9)	21.857	21.889
Week 64/72: SWB (n=7,9)	18.976	22.685
Week 64/72: EWB (n=7,9)	18.143	17.889
Week 64/72: FWB (n=7,9)	18.429	16.037
Week 64/72: Breast Cancer (n=7,9)	27.464	26.889
Week 64/72: FACT-B TOI (n=7,9)	67.750	64.815
Week 64/72: Total FACT-G (n=7,9)	77.405	78.500
Week 64/72: Total FACT-B (n=7,9)	104.869	105.389
Week 72/81: PWB (n=6,7)	23.083	21.000
Week 72/81: SWB (n=5,7)	19.667	20.043
Week 72/81: EWB (n=6,7)	17.500	18.114
Week 72/81: FWB (n=6,7)	17.333	16.429
Week 72/81: Breast Cancer (n=6,6)	28.597	25.333
Week 72/81: FACT-B TOI (n=6,6)	69.014	60.833
Week 72/81: Total FACT-G (n=5,7)	76.467	75.586
Week 72/81: Total FACT-B (n=5,6)	106.117	97.211
Week 80/90: PWB (n=2,3)	19.250	18.000
Week 80/90: SWB (n=2,3)	18.375	19.944
Week 80/90: EWB (n=2,3)	14.000	15.733
Week 80/90: FWB (n=2,3)	15.000	12.333
Week 80/90: Breast Cancer (n=2,3)	21.667	25.000
Week 80/90: FACT-B TOI (n=2,3)	55.917	55.333
Week 80/90: Total FACT-G (n=2,3)	66.625	66.011
Week 80/90: Total FACT-B (n=2,3)	88.292	91.011
Week 88/99: PWB (n=0,1)	NA	22.000
Week 88/99: SWB (n=0,1)	NA	23.333
Week 88/99: EWB (n=0,1)	NA	20.000
Week 88/99: FWB (n=0,1)	NA	21.000
Week 88/99: Breast Cancer (n=0,1)	NA	35.000
Week 88/99: FACT-B TOI (n=0,1)	NA	78.000
Week 88/99: Total FACT-G (n=0,1)	NA	86.333
Week 88/99: Total FACT-B (n=0,1)	NA	121.333
Week 96/108: PWB (n=2,1)	26.000	22.000
Week 96/108: SWB (n=2,1)	24.383	21.000
Week 96/108: EWB (n=2,2)	22.000	18.000
Week 96/108: FWB (n=2,2)	21.083	10.500
Week 96/108: Breast Cancer (n=2,2)	30.389	24.500
Week 96/108: FACT-B TOI (n=2,1)	77.472	59.000
Week 96/108: Total FACT-G (n=2,1)	93.467	74.000
Week 96/108: Total FACT-B (n=2,1)	123.856	96.000
Week 104/117: PWB (n=1,3)	27.000	21.333
Week 104/117: SWB (n=1,2)	26.600	20.5000
Week 104/117: EWB (n=1,3)	22.000	18.000
Week 104/117: FWB (n=1,3)	22.000	11.000
Week 104/117: Breast Cancer (n=1,3)	27.143	28.000
Week 104/117: FACT-B TOI (n=1,3)	76.143	60.333
Week 104/117: Total FACT-G (n=1,2)	97.600	70.500
Week 104/117: Total FACT-B (n=1,2)	124.743	100.500
Week 112/126: PWB (n=0,1)	NA	14.000
Week 112/126: SWB (n=0,1)	NA	15.400
Week 112/126: EWB (n=0,1)	NA	15.000
Week 112/126: FWB (n=0,1)	NA	11.000
Week 112/126: Breast Cancer (n=0,1)	NA	20.000
Week 112/126: FACT-B TOI (n=0,1)	NA	45.000
Week 112/126: Total FACT-G (n=0,1)	NA	55.400
Week 112/126: Total FACT-B (n=0,1)	NA	75.400
Second-Line PD: PWB (n=89,81)	19.086	17.412
Second-Line PD: SWB (n=88,79)	20.623	21.487
Second-Line PD: EWB (n=88,80)	15.111	14.175
Second-Line PD: FWB (n=88,80)	15.447	15.235
Second-Line PD: Breast Cancer (n=85,81)	24.978	24.445
Second-Line PD: FACT-B TOI (n=84,80)	59.230	57.002
Second-Line PD: Total FACT-G (n=86,78)	69.829	68.485
Second-Line PD: Total FACT-B (n=82,78)	94.930	92.983

24. 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.
Measure Participants	118	128
Week 8/9: PWB (n=118,125)	-1.281	-1.289
Week 8/9: SWB (n=116,125)	0.356	0.707
Week 8/9: EWB (n=116,128)	0.408	1.024
Week 8/9: FWB (n=117,128)	-0.226	-0.240
Week 8/9: Breast Cancer Score (n=113,128)	0.228	0.950
Week 8/9: FACT-B TOI (n=110,122)	-1.361	-0.357
Week 8/9: Total FACT-G Score (n=110,122)	-0.760	0.369
Week 8/9: Total FACT-B Score (n=108,120)	-0.728	1.342
Week 16/18: PWB (n=77,97)	0.294	-1.823
Week 16/18: SWB (n=74,97)	-0.443	0.359
Week 16/18: EWB (n=73,98)	1.197	0.921
Week 16/18: FWB (n=75,98)	-0.548	-0.517
Week 16/18: Breast Cancer (n=72,97)	0.578	0.546
Week 16/18: FACT-TOI (n=68,95)	-0.483	-1.732
Week 16/18: Total FACT-G (n=71,93)	-0.019	-0.836
Week 16/18: Total Fact-B (n=66,93)	-0.007	-0.127
Week 24/27: PWB (n=44,73)	0.181	-1.996
Week 24/27: SWB (n=44,72)	-0.193	1.375
Week 24/27: EWB (n=42,72)	0.867	1.217
Week 24/27: FWB (n=42,72)	0.119	0.056
Week 24/27: Breast Cancer (n=40,72)	-0.038	0.078
Week 24/27: FACT-B TOI (n=38,70)	0.221	-1.573
Week 24/27: Total FACT-G (n=40,70)	0.764	0.817
Week 24/27: Total FACT-B (n=37,70)	0.793	1.157
Week 32/36: PWB (n=25,39)	0.880	-1.235
Week 32/36: SWB (n=24,40)	-0.388	1.036
Week 32/36: EWB (n=25,40)	1.064	1.555
Week 32/36: FWB (n=25,40)	1.380	1.635
Week 32/36: Breast Cancer (n=23,40)	0.928	1.278
Week 32/36: FACT-B TOI (n=23,38)	3.123	1.471
Week 32/36: Total FACT-G (n=24,39)	2.617	3.197
Week 32/36: Total FACT-B (n=22,38)	3.529	3.896
Week 40/45: PWB (n=18,25)	0.137	-0.680
Week 40/45: SWB (n=19,24)	-0.589	0.951
Week 40/45: EWB (n=18,25)	0.200	1.048
Week 40/45: FWB (n=18,25)	1.417	0.857
Week 40/45: Breast Cancer (n=18,25)	1.395	0.444
Week 40/45: FACT-B TOI (n=16,25)	2.432	0.622
Week 40/45: Total FACT-G (n=17,24)	1.444	2.432
Week 40/45: Total FACT-B (n=16,24)	1.916	2.673
Week 48/54: PWB (n=13,20)	1.295	-1.833
Week 48/54: SWB (n=13,20)	1.529	2.008
Week 48/54: EWB (n=13,20)	1.492	1.710
Week 48/54: FWB (n=13,20)	2.269	1.592
Week 48/54: Breast Cancer (n=12,20)	0.599	1.897
Week 48/54: FACT-B TOI (n=12,20)	4.044	1.656
Week 48/54: Total FACT-G (n=13,20)	6.586	3.477
Week 48/54: Total FACT-B (n=12,20)	7.067	5.374
Week 56/63: PWB (n=8,13)	-2.063	-0.526
Week 56/63: SWB (n=8,13)	-1.500	3.033
Week 56/63: EWB (n=7,13)	0.857	0.954
Week 56/63: FWB (n=7,13)	0.000	5.654
Week 56/63: Breast Cancer (n=8,13)	-0.830	1.675
Week 56/63: FACT-B TOI (n=7,13)	-3.591	6.803
Week 56/63: Total FACT-G (n=6,13)	-4.083	9.115
Week 56/63: Total FACT-B (n=6,13)	-5.301	10.791
Week 64/72: PWB (n=7,9)	0.000	0.926
Week 64/72: SWB (n=7,9)	-2.014	3.570
Week 64/72: EWB (n=7,9)	-0.057	3.667
Week 64/72: FWB (n=7,9)	0.214	3.222
Week 64/72: Breast Cancer (n=7,9)	-2.298	3.086
Week 64/72: FACT-B TOI (n=7,9)	-2.083	7.235
Week 64/72: Total FACT-G (n=7,9)	-1.857	11.385
Week 64/72: Total FACT-B (n=7,9)	-4.155	14.472
Week 72/81: PWB (n=5,7)	2.133	-0.429
Week 72/81: SWB (n=4,7)	-1.208	6.829
Week 72/81: EWB (n=5,7)	-0.600	4.686
Week 72/81: FWB (n=5,7)	0.000	7.381
Week 72/81: Breast Cancer (n=5,6)	-0.461	3.667
Week 72/81: FACT-B TOI (n=5,6)	1.672	8.278
Week 72/81: Total FACT-G (n=4,7)	-0.167	18.467
Week 72/81: Total FACT-B (n=4,6)	1.174	16.906
Week 80/90: PWB (n=2,3)	-3.750	-3.000
Week 80/90: SWB (n=2,3)	-0.875	7.344
Week 80/90: EWB (n=2,3)	-4.000	4.733
Week 80/90: FWB (n=2,3)	-1.000	2.556
Week 80/90: Breast Cancer (n=2,3)	-5.833	3.667
Week 80/90: FACT-B TOI (n=2,3)	-10.583	3.222
Week 80/90: Total FACT-G (n=2,3)	-9.625	11.633
Week 80/90: Total FACT-B (n=2,3)	-15.458	15.300
Week 88/99: PWB (n=0,1)	NA	-6.000
Week 88/99: SWB (n=0,1)	NA	23.333
Week 88/99: EWB (n=0,1)	NA	0.000
Week 88/99: FWB (n=0,1)	NA	21.000
Week 88/99: Breast Cancer (n=0,1)	NA	3.000
Week 88/99: FACT TOI (n=0,1)	NA	18.000
Week 88/99: Total FACT-G (n=0,1)	NA	38.333
Week 88/99: Total FACT-B (n=0,1)	NA	41.333
Week 96/108: PWB (n=2,1)	7.333	-3.000
Week 96/108: SWB (n=2,1)	2.183	1.400
Week 96/108: EWB (n=2,1)	0.000	6.000
Week 96/108: FWB (n=2,1)	6.583	-1.333
Week 96/108: Breast Cancer (n=2,1)	3.167	-3.000
Week 96/108: FACT-B TOI (n=2,1)	17.083	-7.333
Week 96/108: Total FACT-G (n=2,1)	16.100	3.067
Week 96/108: Total FACT-B (n=2,1)	19.267	0.067
Week 104/117: PWB (n=1,2)	3.667	-2.000
Week 104/117: SWB (n=1,1)	4.200	8.800
Week 104/117: EWB (n=1,2)	0.000	10.000
Week 104/117: FWB (n=1,2)	8.000	2.333
Week 104/117: Breast Cancer (n=1,2)	6.032	4.000
Week 104/117: FACT-B TOI (n=1,2)	17.698	4.333
Week 104/117: Total FACT-G (n=1,1)	15.867	29.800
Week 104/117: Total GACT-B (n=1,1)	21.898	38.800
Week 112/126: PWB (n=0,1)	NA	-11.000
Week 112/126: SWB (n=0,1)	NA	-4.200
Week 112/126: EWB (n=0,1)	NA	5.000
Week 112/126: FWB (n=0,1)	NA	-5.333
Week 112/126: Breast Cancer (n=0,1)	NA	-5.000
Week 112/126: FACT-B TOI (n=0,1)	NA	-21.333
Week 112/126: Total FACT-G (n=0,1)	NA	-15.533
Week 112/126: Total FACT-B (n=0,1)	NA	-20.533
Second-Line PD: PWB (n=81,77)	-0.871	-2.507
Second-Line PD: SWB (n=80,75)	-0.106	-0.766
Second-Line PD: EWB (n=80,76)	-0.440	-0.508
Second-Line PD: FWB (n=80,76)	-1.415	-0.773
Second-Line PD: Breast Cancer (n=77,77)	0.120	0.241
Second-Line PD: FACT-B TOI (n=74,76)	-2.311	-3.003
Second-Line PD: Total FACT-G (n=76,74)	-2.771	-4.702
Second-Line PD: Total FACT-B (n=72,74)	-2.719	-4.440

25. 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.
Measure Participants	247	247
Number (95% Confidence Interval) [percentage of participants]	16.9 6.8%	24.2 9.8%

26. 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.
Measure Participants	247	247
Number (95% Confidence Interval) [percentage of participants]	9.9 4%	11.0 4.5%

27. 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.
Measure Participants	247	247
Number (95% Confidence Interval) [percentage of participants]	6.4 2.6%	6.5 2.6%

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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	CT Arm		CT+BV Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/238 (23.1%)		89/245 (36.3%)
Blood and lymphatic system disorders
Febrile neutropenia	5/238 (2.1%)		12/245 (4.9%)
Neutropenia	6/238 (2.5%)		10/245 (4.1%)
Leukopenia	1/238 (0.4%)		2/245 (0.8%)
Thrombocytopenia	0/238 (0%)		5/245 (2%)
Anaemia	1/238 (0.4%)		1/245 (0.4%)
Pancytopenia	0/238 (0%)		1/245 (0.4%)
Cardiac disorders
Cardiac failure	1/238 (0.4%)		2/245 (0.8%)
Acute coronary syndrome	0/238 (0%)		1/245 (0.4%)
Atrial fibrillation	0/238 (0%)		1/245 (0.4%)
Cardiac failure congestive	0/238 (0%)		2/245 (0.8%)
Cardiotoxicity	0/238 (0%)		1/245 (0.4%)
Left ventricular failure	0/238 (0%)		1/245 (0.4%)
Sinus tachycardia	1/238 (0.4%)		0/245 (0%)
Tachycardia	0/238 (0%)		1/245 (0.4%)
Angina pectoris	1/238 (0.4%)		1/245 (0.4%)
Atrial tachycardia	1/238 (0.4%)		0/245 (0%)
Congestive cardiomyopathy	0/238 (0%)		1/245 (0.4%)
Left ventricular dysfunction	0/238 (0%)		1/245 (0.4%)
Mitral valve incompetence	1/238 (0.4%)		0/245 (0%)
Supraventricular tachycardia	0/238 (0%)		1/245 (0.4%)
Ischaemic cardiomyopathy	1/238 (0.4%)		0/245 (0%)
Gastrointestinal disorders
Diarrhoea	2/238 (0.8%)		4/245 (1.6%)
Vomiting	1/238 (0.4%)		2/245 (0.8%)
Abdominal pain	1/238 (0.4%)		1/245 (0.4%)
Anal fissure	0/238 (0%)		1/245 (0.4%)
Diverticular perforation	0/238 (0%)		1/245 (0.4%)
Faecaloma	0/238 (0%)		1/245 (0.4%)
Melaena	0/238 (0%)		1/245 (0.4%)
Nausea	1/238 (0.4%)		1/245 (0.4%)
Pancreatitis	1/238 (0.4%)		0/245 (0%)
Ileus paralytic	1/238 (0.4%)		0/245 (0%)
Subileus	0/238 (0%)		1/245 (0.4%)
Gastrointestinal disorder	0/238 (0%)		1/245 (0.4%)
General disorders
Pyrexia	2/238 (0.8%)		4/245 (1.6%)
Fatigue	2/238 (0.8%)		2/245 (0.8%)
General physical health deterioration	1/238 (0.4%)		2/245 (0.8%)
Chest discomfort	1/238 (0.4%)		0/245 (0%)
Chest pain	1/238 (0.4%)		0/245 (0%)
Device failure	0/238 (0%)		1/245 (0.4%)
Mucosal inflammation	1/238 (0.4%)		3/245 (1.2%)
Pain	1/238 (0.4%)		0/245 (0%)
Sudden death	0/238 (0%)		1/245 (0.4%)
Device dislocation	1/238 (0.4%)		0/245 (0%)
Device occlusion	1/238 (0.4%)		0/245 (0%)
Impaired healing	0/238 (0%)		1/245 (0.4%)
Multi-organ failure	0/238 (0%)		1/245 (0.4%)
Patient-device incompatibility	0/238 (0%)		1/245 (0.4%)
Hepatobiliary disorders
Cholelithiasis	0/238 (0%)		2/245 (0.8%)
Cholecystitis	0/238 (0%)		1/245 (0.4%)
Cholangitis	1/238 (0.4%)		0/245 (0%)
Hepatitis toxic	0/238 (0%)		1/245 (0.4%)
Infections and infestations
Infection	2/238 (0.8%)		3/245 (1.2%)
Bronchitis	0/238 (0%)		3/245 (1.2%)
Pneumonia	0/238 (0%)		2/245 (0.8%)
Device related infection	1/238 (0.4%)		0/245 (0%)
Device related sepsis	1/238 (0.4%)		0/245 (0%)
Ear infection	1/238 (0.4%)		0/245 (0%)
Enterocolitis infectious	1/238 (0.4%)		0/245 (0%)
Erysipelas	1/238 (0.4%)		0/245 (0%)
Herpes zoster	1/238 (0.4%)		0/245 (0%)
Injection site infection	1/238 (0.4%)		0/245 (0%)
Osteomyelitis	0/238 (0%)		1/245 (0.4%)
Sepsis	0/238 (0%)		2/245 (0.8%)
Tooth infection	0/238 (0%)		1/245 (0.4%)
Urinary tract infection	0/238 (0%)		1/245 (0.4%)
Wound infection	0/238 (0%)		1/245 (0.4%)
Anal abscess	0/238 (0%)		1/245 (0.4%)
Peritonitis bacterial	0/238 (0%)		1/245 (0.4%)
Pseudomembranous colitis	0/238 (0%)		1/245 (0.4%)
Urosepsis	0/238 (0%)		1/245 (0.4%)
Injury, poisoning and procedural complications
Foot fracture	1/238 (0.4%)		0/245 (0%)
Femoral neck fracture	1/238 (0.4%)		1/245 (0.4%)
Head injury	0/238 (0%)		1/245 (0.4%)
Subdural haematoma	0/238 (0%)		1/245 (0.4%)
Investigations
Gamma-glutamyltransferase increased	1/238 (0.4%)		1/245 (0.4%)
Alanine aminotransferase increased	0/238 (0%)		1/245 (0.4%)
Aspartate aminotransferase increased	0/238 (0%)		1/245 (0.4%)
Blood bilirubin increased	0/238 (0%)		1/245 (0.4%)
Blood potassium increased	1/238 (0.4%)		0/245 (0%)
Biopsy liver	1/238 (0.4%)		0/245 (0%)
Metabolism and nutrition disorders
Hyponatraemia	1/238 (0.4%)		2/245 (0.8%)
Hypercalcaemia	1/238 (0.4%)		1/245 (0.4%)
Hypocalcaemia	0/238 (0%)		1/245 (0.4%)
Hypoglycaemia	0/238 (0%)		1/245 (0.4%)
Musculoskeletal and connective tissue disorders
Bone pain	1/238 (0.4%)		2/245 (0.8%)
Osteonecrosis of jaw	0/238 (0%)		2/245 (0.8%)
Musculoskeletal pain	0/238 (0%)		1/245 (0.4%)
Pathological fracture	1/238 (0.4%)		0/245 (0%)
Osteolysis	0/238 (0%)		1/245 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial adenocarcinoma	0/238 (0%)		1/245 (0.4%)
Metastases to liver	0/238 (0%)		1/245 (0.4%)
Nervous system disorders
Ischaemic stoke	2/238 (0.8%)		0/245 (0%)
Cerebrovascular accident	1/238 (0.4%)		0/245 (0%)
Cerebrovascular disorder	1/238 (0.4%)		0/245 (0%)
Convulsion	0/238 (0%)		2/245 (0.8%)
Headache	1/238 (0.4%)		0/245 (0%)
Motor dysfunction	1/238 (0.4%)		0/245 (0%)
Partial seizures	1/238 (0.4%)		0/245 (0%)
Polyneuropathy	1/238 (0.4%)		0/245 (0%)
Spinal cord compression	1/238 (0.4%)		0/245 (0%)
Facial paresis	0/238 (0%)		1/245 (0.4%)
Ruptured cerebral aneurysm	0/238 (0%)		1/245 (0.4%)
Psychiatric disorders
Depression	1/238 (0.4%)		1/245 (0.4%)
Confusional state	1/238 (0.4%)		0/245 (0%)
Renal and urinary disorders
Obstructive uropathy	1/238 (0.4%)		0/245 (0%)
Postrenal failure	0/238 (0%)		1/245 (0.4%)
Reproductive system and breast disorders
Menstrual disorder	1/238 (0.4%)		0/245 (0%)
Metrorrhagia	1/238 (0.4%)		0/245 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	2/238 (0.8%)		6/245 (2.4%)
Pleural effusion	1/238 (0.4%)		2/245 (0.8%)
Dyspnoea	1/238 (0.4%)		3/245 (1.2%)
Pneumothorax	0/238 (0%)		1/245 (0.4%)
Pneumonia aspiration	1/238 (0.4%)		0/245 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/238 (0%)		1/245 (0.4%)
Surgical and medical procedures
Salpingo-oophorectomy	0/238 (0%)		1/245 (0.4%)
Tooth extraction	1/238 (0.4%)		0/245 (0%)
Large intestine anastomosis	1/238 (0.4%)		0/245 (0%)
Vascular disorders
Embolism venous	1/238 (0.4%)		3/245 (1.2%)
Haemorrhage	1/238 (0.4%)		1/245 (0.4%)
Embolism arterial	0/238 (0%)		1/245 (0.4%)
Infarction	0/238 (0%)		1/245 (0.4%)
Other (Not Including Serious) Adverse Events
	CT Arm		CT+BV Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	181/238 (76.1%)		218/245 (89%)
Blood and lymphatic system disorders
Neutropenia	55/238 (23.1%)		64/245 (26.1%)
Leukopenia	18/238 (7.6%)		30/245 (12.2%)
Anaemia	13/238 (5.5%)		22/245 (9%)
Thrombocytopenia	4/238 (1.7%)		16/245 (6.5%)
Gastrointestinal disorders
Diarrhoea	27/238 (11.3%)		35/245 (14.3%)
Nausea	31/238 (13%)		33/245 (13.5%)
Vomiting	22/238 (9.2%)		16/245 (6.5%)
Abdominal pain	3/238 (1.3%)		15/245 (6.1%)
Constipation	9/238 (3.8%)		13/245 (5.3%)
General disorders
Fatigue	33/238 (13.9%)		49/245 (20%)
Mucosal inflammation	9/238 (3.8%)		26/245 (10.6%)
Asthenia	5/238 (2.1%)		14/245 (5.7%)
Pyrexia	11/238 (4.6%)		14/245 (5.7%)
Infections and infestations
Urinary tract infection	2/238 (0.8%)		16/245 (6.5%)
Metabolism and nutrition disorders
Decreased appetite	4/238 (1.7%)		21/245 (8.6%)
Nervous system disorders
Peripheral sensory neuropathy	10/238 (4.2%)		15/245 (6.1%)
Renal and urinary disorders
Proteinuria	70/238 (29.4%)		133/245 (54.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	3/238 (1.3%)		18/245 (7.3%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	58/238 (24.4%)		72/245 (29.4%)
Vascular disorders
Hypertension	55/238 (23.1%)		90/245 (36.7%)
Haemorrhage	7/238 (2.9%)		29/245 (11.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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