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A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2 Positive Metastatic Breast Cancer.

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT00391092
Collaborator
(none)
424
Enrollment
90
Locations
2
Arms
95
Duration (Months)
4.7
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This 2 arm study will compare the efficacy and safety of Avastin plus Herceptin/docetaxel, versus Herceptin/docetaxel alone, in patients with HER2 positive locally recurrent or metastatic breast cancer who have not received prior chemotherapy for their metastatic disease. Patients will be randomized 1:1 to receive either Avastin (15mg/kg iv q3weeks) + Herceptin (8mg/kg iv loading dose and 6mg/kg iv q3weeks maintenance) + docetaxel (100mg/m2 iv q3weeks) or Herceptin + docetaxel alone. The anticipated time on study treatment is until disease progression, and the target sample size is 100-500 individuals.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
424 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open-label Study to Compare the Effect of First-line Treatment With Avastin in Combination With Herceptin/Docetaxel and Herceptin/Docetaxel Alone on Progression-free Survival in Patients With HER2 Positive Locally Recurrent or Metastatic Breast Cancer.
Study Start Date :
Sep 1, 2006
Actual Primary Completion Date :
Aug 1, 2014
Actual Study Completion Date :
Aug 1, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: 1

Drug: bevacizumab [Avastin]
15mg/kg iv every 3 weeks

Drug: Docetaxel
100mg/m2 iv every 3 weeks

Drug: Herceptin
8mg/kg iv loading dose, followed by 6mg/kg iv every 3 weeks
Active Comparator: 2

Drug: Docetaxel
100mg/m2 iv every 3 weeks

Drug: Herceptin
8mg/kg iv loading dose, followed by 6mg/kg iv every 3 weeks

Outcome Measures

Primary Outcome Measures

  1. Progression Free Survival (PFS) [Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)]

    PFS was defined as the time from randomization to time of first documented disease progression (unequivocal progression of existing non-target lesions) or death, whichever occurred first as assessed by Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0). Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started. Primary PFS variable was defined based on the investigators' assessments and the statistical conclusions on the primary efficacy endpoint were based on investigator assessed PFS. PFS was estimated using Kaplan-Meier methods.

Secondary Outcome Measures

  1. Overall Survival (OS) [Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)]

    OS was defined as the time from randomization to the date of death, regardless of the cause of death. OS was estimated using Kaplan-Meier methods.

  2. Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Partial Response (PR) in Participants With Measurable Disease at Baseline [Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)]

    Best OR was assessed using RECIST v1.0 criteria. Participants were classified as responders if their best OR was either confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of the longest diameter [LD] of target lesions, taking as reference the baseline sum LD). Participants without any post-baseline assessments were regarded as non-responders. The 95% CI for the one sample binomial using Pearson-Clopper method.

  3. Duration of Response (DR) [Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)]

    DR was defined as the time when response (CR or PR per RECIST v1.0) was first documented to the date of disease progression per RECIST v1.0 (unequivocal progression of existing non-target lesions) or death. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.

  4. Time to Treatment Failure (TTF) [Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)]

    TTF was defined as the time between randomization and date of disease progression (per RECIST v1.0; unequivocal progression of existing non-target lesions), death, or withdrawal of treatment due to adverse events, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.

  5. Functional Assessment of Cancer Therapy - Generic (FACT-G) and Functional Assessment of Cancer Therapy - Breast (FACT-B) Subscale Scores [Baseline, Cycles 3, 5, 11, and post progressive disease (PD; 14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])]

    FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.

  6. Change From Baseline for FACT-G and FACT-B [Baseline, Cycles 3, 5, 11, and post PD (14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])]

    FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.

Eligibility Criteria

Criteria

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

  • adult patients, >=18 years of age;

  • HER2 positive breast cancer with locally recurrent or metastatic lesions;

  • eligible for chemotherapy;

  • baseline LVEF >=50%.

Exclusion Criteria:

  • previous chemotherapy for metastatic or locally recurrent breast cancer;

  • previous radiotherapy for metastatic breast cancer (except for metastatic bone pain relief);

  • other primary tumor within last 5 years, with the exception of basal or squamous skin cancer, or in situ cancer of the cervix;

  • clinically significant cardiovascular disease;

  • chronic daily treatment with aspirin (>325mg/day) or clopidogrel (>75mg/day).

Contacts and Locations

Locations

Site City State Country Postal Code
1 Buenos Aires Argentina 1417
2 Cordoba Argentina 5004
3 La Plata Argentina B1902CMK
4 Mar del Plata Argentina 7600
5 Mendoza Argentina 5500
6 Salta Argentina 4400
7 San Martin Argentina 1650
8 Santa Fe Argentina 03000
9 Santa Fe Argentina 2000
10 Lismore New South Wales Australia 2480
11 Newcastle New South Wales Australia 2298
12 Port Macquarie New South Wales Australia 2444
13 Wahroonga New South Wales Australia 2076
14 Wollongong New South Wales Australia 2500
15 Auchenflower Queensland Australia 4066
16 Nambour Queensland Australia 4560
17 Fitzroy Victoria Australia 3065
18 Geelong Victoria Australia 3220
19 Perth Western Australia Australia 6000
20 Graz Austria 8036
21 Salzburg Austria 5020
22 Vöcklabruck Austria 4840
23 Wien Austria 1090
24 Banja Luka Bosnia and Herzegovina 78000
25 Sarajevo Bosnia and Herzegovina 71000
26 Tuzla Bosnia and Herzegovina 75000
27 Goiania GO Brazil 74605-070
28 Porto Alegre RS Brazil 90610-000
29 Florianopolis SC Brazil 88034-000
30 Barretos SP Brazil 14784-400
31 Sao Paulo SP Brazil 01509-010
32 Calgary Alberta Canada T2N 4N2
33 Vancouver British Columbia Canada V5Z 4E6
34 Halifax Nova Scotia Canada B3H 1V7
35 Hamilton Ontario Canada L8V 5C2
36 Sudbury Ontario Canada P3E 5J1
37 Toronto Ontario Canada M4N 3M5
38 Montreal Quebec Canada H2W 1S6
39 Montreal Quebec Canada H3A 1A1
40 Montreal Quebec Canada H3T 1E2
41 Saskatoon Saskatchewan Canada S7N 4H4
42 Quebec Canada G1S 4L8
43 Praha 2 Czech Republic 128 08
44 Praha 5 Czech Republic 150 06
45 Avignon France 84918
46 Besancon France 25030
47 Bordeaux France 33076
48 Caen France 14076
49 Clermont Ferrand France 63011
50 Dijon France 21079
51 Lille France 59020
52 Montpellier France 34298
53 Villejuif France 94805
54 Parma Emilia-Romagna Italy 43100
55 Udine Friuli-Venezia Giulia Italy 33100
56 Milano Lombardia Italy 20133
57 Pavia Lombardia Italy 27100
58 Acapulco Mexico 39850
59 Guadalajara Mexico 45100
60 Merida Mexico 97500
61 Monterrey Mexico 66260
62 Torreon Mexico 27000
63 Bucharest Romania 050098
64 Bucuresti Romania 022328
65 Cluj Napoca Romania 400015
66 Cluj-Napoca Romania 400015
67 Iasi Romania 700106
68 Kazan Russian Federation 420029
69 Moscow Russian Federation 115478
70 Obninsk Russian Federation 249036
71 Ryazan Russian Federation 390011
72 Saint-Petersburg Russian Federation 197758
73 UFA Russian Federation 450054
74 Sabadell, Barcelona Barcelona Spain 08208
75 Barcelona Spain 08003
76 Cordoba Spain 14004
77 Madrid Spain 28046
78 Zaragoza Spain 50009
79 Izmir Turkey 35100
80 Sıhhiye, ANKARA Turkey 06100
81 Exeter United Kingdom EX2 5DW
82 London United Kingdom SE1 7EH
83 Manchester United Kingdom M20 4BX
84 Nottingham United Kingdom NG5 1PB
85 Preston United Kingdom PR2 9HT
86 Rhyl United Kingdom LL18 5UJ
87 Stoke-on-Trent United Kingdom ST4 6QG
88 Weston Super Mare United Kingdom BS23 4TQ
89 Montevideo Uruguay 11200
90 Montevideo Uruguay 11600

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:
NCT00391092
Other Study ID Numbers:
  • BO20231
First Posted:
Oct 23, 2006
Last Update Posted:
Aug 28, 2015
Last Verified:
Aug 1, 2015
Additional relevant MeSH terms:
Breast Neoplasms
Bevacizumab
Trastuzumab
Docetaxel

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail The participants were randomized 1:1 using a block design randomization procedure with stratification (for prior adjuvant/neo-adjuvant taxane, trastuzumab as part of adjuvant treatment versus no trastuzumab, estrogen/progesterone receptor hormone receptor status and measurable disease) to avoid an imbalance of important prognostic factors.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 milligrams per kilogram (mg/kg) loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 milligrams per square meter (mg/m^2) on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Period Title: Overall Study
STARTED 208 216
Received Treatment 206 215
COMPLETED 0 0
NOT COMPLETED 208 216

Baseline Characteristics

Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel Total
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent. Total of all reporting groups
Overall Participants 208 216 424
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
54.0
(11.71)
53.5
(10.90)
53.7
(11.29)
Sex: Female, Male (Count of Participants)
Female
208
100%
216
100%
424
100%
Male
0
0%
0
0%
0
0%

Outcome Measures

1. Primary Outcome
Title Progression Free Survival (PFS)
Description PFS was defined as the time from randomization to time of first documented disease progression (unequivocal progression of existing non-target lesions) or death, whichever occurred first as assessed by Response Evaluation Criteria in Solid Tumors version 1.0 (RECIST v1.0). Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started. Primary PFS variable was defined based on the investigators' assessments and the statistical conclusions on the primary efficacy endpoint were based on investigator assessed PFS. PFS was estimated using Kaplan-Meier methods.
Time Frame Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 208 216
Median (95% Confidence Interval) [months]
13.7
16.5
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Docetaxel, Trastuzumab + Bevacizumab + Docetaxel
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0775
Comments
Method Log Rank (unstratified)
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.82
Confidence Interval (2-Sided) 95%
0.65 to 1.02
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Survival (OS)
Description OS was defined as the time from randomization to the date of death, regardless of the cause of death. OS was estimated using Kaplan-Meier methods.
Time Frame Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 208 216
Median (95% Confidence Interval) [months]
38.3
38.5
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Docetaxel, Trastuzumab + Bevacizumab + Docetaxel
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.9543
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.74 to 1.38
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Percentage of Participants With a Best Overall Response (OR) of Confirmed Complete Response (CR) or Partial Response (PR) in Participants With Measurable Disease at Baseline
Description Best OR was assessed using RECIST v1.0 criteria. Participants were classified as responders if their best OR was either confirmed CR (disappearance of all target lesions) or confirmed PR (at least a 30% decrease in the sum of the longest diameter [LD] of target lesions, taking as reference the baseline sum LD). Participants without any post-baseline assessments were regarded as non-responders. The 95% CI for the one sample binomial using Pearson-Clopper method.
Time Frame Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Outcome Measure Data

Analysis Population Description
ITT Population; only participants with measurable disease at baseline were included in the analysis.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 176 183
Number (95% Confidence Interval) [percentage of participants]
69.9
33.6%
74.3
34.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Docetaxel, Trastuzumab + Bevacizumab + Docetaxel
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.3492
Comments
Method Chi-squared
Comments
Method of Estimation Estimation Parameter Difference in Response rates
Estimated Value 4.43
Confidence Interval (2-Sided) 95%
-5.2 to 14.0
Parameter Dispersion Type:
Value:
Estimation Comments 95% CI for the difference in response rates using Hauck-Anderson method.
4. Secondary Outcome
Title Duration of Response (DR)
Description DR was defined as the time when response (CR or PR per RECIST v1.0) was first documented to the date of disease progression per RECIST v1.0 (unequivocal progression of existing non-target lesions) or death. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.
Time Frame Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Outcome Measure Data

Analysis Population Description
ITT Population: only participants with a best OR of CR or PR were included in the analysis.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 123 136
Median (95% Confidence Interval) [months]
11.4
14.6
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Docetaxel, Trastuzumab + Bevacizumab + Docetaxel
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value
Comments
Method
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.56 to 0.98
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Time to Treatment Failure (TTF)
Description TTF was defined as the time between randomization and date of disease progression (per RECIST v1.0; unequivocal progression of existing non-target lesions), death, or withdrawal of treatment due to adverse events, withdrawal of informed consent, insufficient therapeutic response, refusal of treatment/failure to co-operate, or failure to return, whichever occurred first. Progressive disease is defined using RECIST v1.0 as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started.
Time Frame Every 9 weeks up to Week 36, thereafter every 12 weeks until disease progression (up to the clinical cutoff of 30 June 2011, up to 4.75 years)

Outcome Measure Data

Analysis Population Description
ITT Population
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 208 216
Median (95% Confidence Interval) [months]
7.7
9.8
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Trastuzumab + Docetaxel, Trastuzumab + Bevacizumab + Docetaxel
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.5392
Comments
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.94
Confidence Interval (2-Sided) 95%
0.76 to 1.15
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Functional Assessment of Cancer Therapy - Generic (FACT-G) and Functional Assessment of Cancer Therapy - Breast (FACT-B) Subscale Scores
Description FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.
Time Frame Baseline, Cycles 3, 5, 11, and post progressive disease (PD; 14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])

Outcome Measure Data

Analysis Population Description
ITT Population; n (number) = number of participants assessed for the given parameter at the specified visit.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 173 189
Physical Well-Being: Baseline (n=173,189)
21.20
(5.74)
21.47
(5.07)
Social Well-Being: Baseline (n=173,189)
20.59
(5.75)
20.88
(5.77)
Emotional Well-Being: Baseline (n=173,189)
14.95
(4.95)
15.54
(4.44)
Functional Well-Being: Baseline (n=173,189)
16.34
(5.83)
16.36
(5.57)
Total FACT-G Score: Baseline (n=173,189)
73.30
(16.60)
74.49
(14.50)
Breast Specific: Baseline (n=173,189)
21.67
(6.43)
22.84
(5.85)
Total FACT-B Score: Baseline (n=173,189)
94.97
(20.50)
97.46
(17.71)
Trial Outcome Index: Baseline (n=173,189)
59.54
(14.03)
60.85
(12.61)
Physical Well-Being: Cycle 3 (n=145,173)
20.19
(4.89)
19.96
(5.05)
Social Well-Being: Cycle 3 (n=145,173)
20.64
(5.32)
21.19
(5.44)
Emotional Well-Being: Cycle 3 (n=145,173)
16.47
(4.19)
16.70
(4.36)
Functional Well-Being: Cycle 3 (n=145, 173)
15.43
(5.33)
16.20
(5.22)
Total FACT-G Score: Cycle 3 (n=145,173)
72.94
(14.81)
74.05
(14.35)
Breast Specific: Cycle 3 (n=145,173)
22.29
(5.78)
23.17
(5.34)
Total FACT-B Score: Cycle 3 (n=145,173)
95.26
(18.52)
97.23
(17.81)
Trial Outcome Index: Cycle 3 (n=145,173)
58.04
(12.80)
59.33
(12.49)
Physical Well-Being: Cycle 5 (n=139, 166)
19.51
(4.83)
19.67
(4.56)
Social Well-Being: Cycle 5 (n=139, 166)
19.36
(5.26)
20.68
(4.92)
Emotional Well-Being: Cycle 5 (n=139, 166)
16.05
(4.44)
17.07
(4.30)
Functional Well-Being: Cycle 5 (n=139, 166)
14.81
(5.45)
15.78
(4.77)
Total FACT-G Score: Cycle 5 (n=139, 166)
69.78
(15.04)
73.21
(12.49)
Breast Specific: Cycle 5 (n=139, 166)
21.65
(5.83)
23.15
(4.90)
Total FACT-B Score: Cycle 5 (n=139, 166)
91.43
(18.81)
96.36
(15.63)
Trial Outcome Index: Cycle 5 (n=139, 166)
55.99
(13.09)
58.59
(11.01)
Physical Well-Being: Cycle 11 (n=100, 133)
21.71
(4.54)
21.56
(4.53)
Social Well-Being: Cycle 11 (n=100, 133)
19.71
(5.74)
20.78
(4.92)
Emotional Well-Being: Cycle 11 (n=100, 133)
15.96
(4.50)
17.46
(3.70)
Functional Well-Being: Cycle 11 (n=100, 133)
16.25
(5.16)
16.98
(4.92)
Total FACT-G Score: Cycle 11 (n=100, 133)
73.26
(15.24)
76.55
(13.56)
Breast Specific: Cycle 11 (n=100, 133)
21.29
(5.55)
23.80
(4.92)
Total FACT-B Score: Cycle 11 (n=100, 133)
94.57
(18.58)
100.43
(16.97)
Trial Outcome Index: Cycle 11 (n=100, 133)
59.19
(12.00)
62.34
(11.79)
Physical Well-Being: Post PD (n=33, 39)
19.94
(4.99)
20.35
(5.37)
Social Well-Being: Post PD (n=33, 39)
19.02
(5.61)
19.68
(4.77)
Emotional Well-Being: Post PD (n=33, 39)
14.76
(4.83)
14.77
(4.64)
Functional Well-Being: Post PD (n=33, 39)
14.13
(5.57)
15.08
(5.16)
Total FACT-G Score: Post PD (n=33, 39)
67.84
(14.21)
70.04
(15.08)
Breast Specific: Post PD (n=33, 39)
22.90
(4.48)
22.87
(5.14)
Total FACT-B Score: Post PD (n=33, 39)
90.74
(16.59)
92.92
(18.47)
Trial Outcome Index: Post PD (n=33, 39)
56.97
(11.16)
58.47
(12.43)
7. Secondary Outcome
Title Change From Baseline for FACT-G and FACT-B
Description FACT-G is core questionnaire of Functional Assessment of Chronic Illness Therapy (FACIT) measurement system to evaluate quality of life (QoL) in cancer population. FACT-G consisted of 27 questions grouped in 4 domains of general Health-Related QoL (HRQoL): Physical Well-being (PWB), Social/Family Well-Being (SWB), Emotional Well-Being (EWB) and Functional Well-Being (FWB); each ranged from 0 (not at all) to 4 (very much). FACT-G ranged between 0-108. Since questions could be reversed coded, as appropriate, before calculating FACT-G, 0 and 108 could be considered worst and best health states. FACT -B is used for assessment of HRQoL in participants with breast cancer. It consists of 36 items, summarized to 5 subscales: 7 items for each physical, functional, social/family; all 3 ranged from 0-28, emotional (6 items) ranged from 0-24, and breast cancer subscale (9 items) ranged from 0-36. All single-item measures ranges from 0-144. High scale score represents a better QoL.
Time Frame Baseline, Cycles 3, 5, 11, and post PD (14 to 28 days after disease progression [up to the clinical cutoff of 30 June 2011, up to 4.75 years])

Outcome Measure Data

Analysis Population Description
ITT Population; n (number) = number of participants assessed for the given parameter at the specified visit.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
Measure Participants 145 173
Physical Well-Being: Cycle 3 (n=145,173)
-1.01
(7.54)
-1.51
(7.16)
Social Well-Being: Cycle 3 (n=145,173)
0.05
(7.83)
0.32
(7.93)
Emotional Well-Being: Cycle 3 (n=145,173)
1.52
(6.49)
1.16
(6.22)
Functional Well-Being: Cycle 3 (n=145, 173)
-0.91
(7.90)
-0.16
(7.63)
Total FACT-G Score: Cycle 3 (n=145,173)
-0.36
(22.25)
-0.44
(20.40)
Breast Specific: Cycle 3 (n=145,173)
0.61
(8.65)
0.34
(7.92)
Total FACT-B Score: Cycle 3 (n=145,173)
0.29
(27.63)
-0.24
(25.12)
Trial Outcome Index: Cycle 3 (n=145,173)
-1.50
(18.99)
-1.52
(17.75)
Physical Well-Being: Cycle 5 (n=139, 166)
-1.69
(7.50)
-1.80
(6.82)
Social Well-Being: Cycle 5 (n=139, 166)
-1.23
(7.79)
-0.20
(7.58)
Emotional Well-Being: Cycle 5 (n=139, 166)
1.09
(6.65)
1.53
(6.18)
Functional Well-Being: Cycle 5 (n=139, 166)
-1.53
(7.98)
-0.58
(7.33)
Total FACT-G Score: Cycle 5 (n=139, 166)
-3.53
(22.40)
-1.28
(19.14)
Breast Specific: Cycle 5 (n=139, 166)
-0.03
(8.68)
0.31
(7.63)
Total FACT-B Score: Cycle 5 (n=139, 166)
-3.55
(27.82)
-1.10
(23.62)
Trial Outcome Index: Cycle 5 (n=139, 166)
-3.55
(19.19)
-2.26
(16.74)
Physical Well-Being: Cycle 11 (n=100, 133)
0.51
(7.32)
0.09
(6.80)
Social Well-Being: Cycle 11 (n=100, 133)
-0.89
(8.13)
-0.10
(7.58)
Emotional Well-Being: Cycle 11 (n=100, 133)
1.00
(6.69)
1.92
(5.78)
Functional Well-Being: Cycle 11 (n=100, 133)
-0.09
(7.79)
0.62
(7.43)
Total FACT-G Score: Cycle 11 (n=100, 133)
-0.05
(22.54)
2.06
(19.85)
Breast Specific: Cycle 11 (n=100, 133)
-0.38
(8.49)
0.96
(7.64)
Total FACT-B Score: Cycle 11 (n=100, 133)
-0.41
(27.67)
2.97
(24.53)
Trial Outcome Index: Cycle 11 (n=100, 133)
-0.35
(18.46)
1.49
(17.26)
Physical Well-Being: Post PD (n=33, 39)
-1.25
(7.61)
-1.12
(7.39)
Social Well-Being: Post PD (n=33, 39)
-1.58
(8.03)
-1.19
(7.48)
Emotional Well-Being: Post PD (n=33, 39)
-0.20
(6.92)
-0.78
(6.42)
Functional Well-Being: Post PD (n=33, 39)
-2.22
(8.06)
-1.28
(7.59)
Total FACT-G Score: Post PD (n=33, 39)
-5.46
(21.85)
-4.44
(20.92)
Breast Specific: Post PD (n=33, 39)
1.22
(7.84)
0.03
(7.79)
Total FACT-B Score: Post PD (n=33, 39)
-4.23
(26.37)
-4.55
(25.59)
Trial Outcome Index: Post PD (n=33, 39)
-2.57
(17.92)
-2.38
(17.70)

Adverse Events

Time Frame From time of first drug intake up to 28 days after last dose study treatment (up to 4.75 years).
Adverse Event Reporting Description Safety population included all participants who had received at least 1 dose of the trial medication, whether withdrawn prematurely or not.
Arm/Group Title Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Arm/Group Description Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent, and for a minimum of 6 cycles, respectively. Trastuzumab 8 mg/kg loading dose administered intravenously on Day 1 of Cycle 1, followed by bevacizumab 15 mg/kg and docetaxel 100 mg/m^2 on Day 2 of Cycle 1. Then a maintenance dose of trastuzumab at 6 mg/kg, bevacizumab 15 mg/kg and docetaxel at 100 mg/m^2 were administered intravenously on Day 1 of each 3-weekly cycle until disease progression, unacceptable toxicity (requiring discontinuation of study treatment), or withdrawal of participant's consent.
All Cause Mortality
Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 63/206 (30.6%) 72/215 (33.5%)
Blood and lymphatic system disorders
Febrile neutropenia 14/206 (6.8%) 18/215 (8.4%)
Neutropenia 9/206 (4.4%) 6/215 (2.8%)
Anaemia 1/206 (0.5%) 1/215 (0.5%)
Leukopenia 0/206 (0%) 1/215 (0.5%)
Thrombocytopenia 1/206 (0.5%) 0/215 (0%)
Cardiac disorders
Cardiac failure 0/206 (0%) 1/215 (0.5%)
Cardiac failure congestive 1/206 (0.5%) 0/215 (0%)
Cardiomyopathy 0/206 (0%) 1/215 (0.5%)
Coronary artery occlusion 1/206 (0.5%) 0/215 (0%)
Coronary artery thrombosis 0/206 (0%) 1/215 (0.5%)
Left ventricular dysfunction 0/206 (0%) 1/215 (0.5%)
Mitral vavle incompetence 0/206 (0%) 1/215 (0.5%)
Myocardial infarction 0/206 (0%) 2/215 (0.9%)
Arrhythmia 1/206 (0.5%) 0/215 (0%)
Cardio-respiratory arrest 0/206 (0%) 1/215 (0.5%)
Coronary artery stenosis 0/206 (0%) 1/215 (0.5%)
Gastrointestinal disorders
Diarrhoea 4/206 (1.9%) 6/215 (2.8%)
Vomiting 0/206 (0%) 3/215 (1.4%)
Abdominal pain 1/206 (0.5%) 0/215 (0%)
Anal Fistula 0/206 (0%) 1/215 (0.5%)
Aphthous stomatitus 0/206 (0%) 1/215 (0.5%)
Enteritis 0/206 (0%) 1/215 (0.5%)
Gastric haemorrhage 0/206 (0%) 1/215 (0.5%)
Gastrointestinal haemorrhage 0/206 (0%) 1/215 (0.5%)
Gastrointestinal perforation 1/206 (0.5%) 0/215 (0%)
Stomatitus 0/206 (0%) 1/215 (0.5%)
Abdominal wall haematoma 1/206 (0.5%) 0/215 (0%)
Duodenal ulcer perforation 1/206 (0.5%) 0/215 (0%)
Intestinal obstruction 1/206 (0.5%) 0/215 (0%)
Pancreatitis acute 1/206 (0.5%) 0/215 (0%)
Rectal Haemorrhage 0/206 (0%) 1/215 (0.5%)
General disorders
Asthenia 1/206 (0.5%) 1/215 (0.5%)
General physical health deterioration 0/206 (0%) 1/215 (0.5%)
Oedema peripheral 2/206 (1%) 0/215 (0%)
Performance status decreased 1/206 (0.5%) 0/215 (0%)
Pyrexia 2/206 (1%) 0/215 (0%)
Malaise 1/206 (0.5%) 0/215 (0%)
Hepatobiliary disorders
Cholecystitis 0/206 (0%) 1/215 (0.5%)
Hepatic vein thrombosis 1/206 (0.5%) 0/215 (0%)
Hepatocellular injury 1/206 (0.5%) 0/215 (0%)
Cholestasis 1/206 (0.5%) 0/215 (0%)
Immune system disorders
Anaphylactic reaction 0/206 (0%) 1/215 (0.5%)
Hypersensitivity 1/206 (0.5%) 0/215 (0%)
Infections and infestations
Neutropenic sepsis 3/206 (1.5%) 6/215 (2.8%)
Neutropenic infection 2/206 (1%) 4/215 (1.9%)
Urinary tract infection 1/206 (0.5%) 2/215 (0.9%)
Pneumonia 2/206 (1%) 1/215 (0.5%)
Anal abscess 0/206 (0%) 4/215 (1.9%)
Angina gangrenous 1/206 (0.5%) 0/215 (0%)
Arthritis bacterial 0/206 (0%) 1/215 (0.5%)
Cellulitis 1/206 (0.5%) 2/215 (0.9%)
Erysipelas 3/206 (1.5%) 0/215 (0%)
Lower respiratory tract infection 1/206 (0.5%) 1/215 (0.5%)
Sepsis 0/206 (0%) 1/215 (0.5%)
Viral infection 0/206 (0%) 1/215 (0.5%)
Device related infection 1/206 (0.5%) 1/215 (0.5%)
Abscess soft tissue 1/206 (0.5%) 0/215 (0%)
Endocarditis 0/206 (0%) 1/215 (0.5%)
Hepatitis C 1/206 (0.5%) 0/215 (0%)
Lymphangitis 1/206 (0.5%) 0/215 (0%)
Mastitis 0/206 (0%) 1/215 (0.5%)
Wound infection 0/206 (0%) 1/215 (0.5%)
Injury, poisoning and procedural complications
Infusion related reaction 1/206 (0.5%) 0/215 (0%)
Comminuted fracture 1/206 (0.5%) 0/215 (0%)
Fracture 0/206 (0%) 1/215 (0.5%)
Vascular access complication 0/206 (0%) 1/215 (0.5%)
Wrist fracture 1/206 (0.5%) 0/215 (0%)
Investigations
General physical condition 1/206 (0.5%) 0/215 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain 0/206 (0%) 1/215 (0.5%)
Pathological fracture 1/206 (0.5%) 0/215 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Thyroid cancer 1/206 (0.5%) 0/215 (0%)
Nervous system disorders
Convulsion 0/206 (0%) 1/215 (0.5%)
Syncope 0/206 (0%) 1/215 (0.5%)
Psychiatric disorders
Bipolar I Disorder 1/206 (0.5%) 0/215 (0%)
Psychotic disorder 0/206 (0%) 1/215 (0.5%)
Reproductive system and breast disorders
Bartholinitis 0/206 (0%) 1/215 (0.5%)
Female genital tract fistula 0/206 (0%) 1/215 (0.5%)
Breast discharge 1/206 (0.5%) 0/215 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion 2/206 (1%) 0/215 (0%)
Acute pulmonary oedema 0/206 (0%) 1/215 (0.5%)
Epistaxis 0/206 (0%) 1/215 (0.5%)
Pulmonary embolism 2/206 (1%) 0/215 (0%)
Dyspnoea 1/206 (0.5%) 3/215 (1.4%)
Cough 0/206 (0%) 1/215 (0.5%)
Dysphonia 0/206 (0%) 1/215 (0.5%)
Pneumothorax 0/206 (0%) 1/215 (0.5%)
Respiratory failure 1/206 (0.5%) 0/215 (0%)
Skin and subcutaneous tissue disorders
Exfoliative rash 1/206 (0.5%) 0/215 (0%)
Vascular disorders
Hypertension 0/206 (0%) 2/215 (0.9%)
Hypertensive crisis 0/206 (0%) 1/215 (0.5%)
Vena cava thrombosis 1/206 (0.5%) 0/215 (0%)
Circulatory collapse 0/206 (0%) 1/215 (0.5%)
Deep vein thrombosis 0/206 (0%) 1/215 (0.5%)
Jugular vein thrombosis 0/206 (0%) 1/215 (0.5%)
Other (Not Including Serious) Adverse Events
Trastuzumab + Docetaxel Trastuzumab + Bevacizumab + Docetaxel
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 198/206 (96.1%) 202/215 (94%)
Blood and lymphatic system disorders
Neutropenia 51/206 (24.8%) 44/215 (20.5%)
Anaemia 24/206 (11.7%) 16/215 (7.4%)
Cardiac disorders
Left ventricular dysfunction 17/206 (8.3%) 24/215 (11.2%)
Ear and labyrinth disorders
Vertigo 13/206 (6.3%) 3/215 (1.4%)
Eye disorders
Lacrimation increased 59/206 (28.6%) 75/215 (34.9%)
Conjuctivitis 9/206 (4.4%) 22/215 (10.2%)
Dry eye 6/206 (2.9%) 12/215 (5.6%)
Gastrointestinal disorders
Diarrhoea 85/206 (41.3%) 107/215 (49.8%)
Nausea 76/206 (36.9%) 82/215 (38.1%)
Stomatitis 61/206 (29.6%) 95/215 (44.2%)
Constipation 47/206 (22.8%) 54/215 (25.1%)
Vomiting 37/206 (18%) 42/215 (19.5%)
Dyspepsia 18/206 (8.7%) 34/215 (15.8%)
Abdominal pain upper 24/206 (11.7%) 23/215 (10.7%)
Abdominal pain 15/206 (7.3%) 27/215 (12.6%)
Haemorrhoids 8/206 (3.9%) 22/215 (10.2%)
Gastrooesophageal reflux disease 11/206 (5.3%) 8/215 (3.7%)
Toothache 7/206 (3.4%) 12/215 (5.6%)
Gingival bleeding 1/206 (0.5%) 15/215 (7%)
Rectal Haemorrhage 1/206 (0.5%) 10/215 (4.7%)
General disorders
Asthenia 76/206 (36.9%) 75/215 (34.9%)
Fatigue 48/206 (23.3%) 69/215 (32.1%)
Oedema peripheral 72/206 (35%) 37/215 (17.2%)
Pyrexia 41/206 (19.9%) 51/215 (23.7%)
Influenza like illness 18/206 (8.7%) 17/215 (7.9%)
Chills 11/206 (5.3%) 15/215 (7%)
Spinal pain 4/206 (1.9%) 11/215 (5.1%)
Immune system disorders
Hypersensitivity 14/206 (6.8%) 10/215 (4.7%)
Infections and infestations
Urinary tract infection 33/206 (16%) 27/215 (12.6%)
Nasopharyngitis 20/206 (9.7%) 18/215 (8.4%)
Cystitis 17/206 (8.3%) 19/215 (8.8%)
Rhinitis 16/206 (7.8%) 17/215 (7.9%)
Upper respiratory tract infection 11/206 (5.3%) 21/215 (9.8%)
Bronchitis 15/206 (7.3%) 9/215 (4.2%)
Investigations
Weight decreased 6/206 (2.9%) 20/215 (9.3%)
Weight increased 13/206 (6.3%) 8/215 (3.7%)
Metabolism and nutrition disorders
Decreased appetite 25/206 (12.1%) 39/215 (18.1%)
Musculoskeletal and connective tissue disorders
Myalgia 60/206 (29.1%) 59/215 (27.4%)
Arthralgia 41/206 (19.9%) 63/215 (29.3%)
Pain in extremity 37/206 (18%) 35/215 (16.3%)
Musculoskeletal pain 32/206 (15.5%) 39/215 (18.1%)
Back pain 26/206 (12.6%) 32/215 (14.9%)
Bone pain 25/206 (12.1%) 23/215 (10.7%)
Neck pain 10/206 (4.9%) 17/215 (7.9%)
Muscle spasms 8/206 (3.9%) 18/215 (8.4%)
Musculoskeletal chest pain 7/206 (3.4%) 14/215 (6.5%)
Nervous system disorders
Headache 40/206 (19.4%) 66/215 (30.7%)
Peripheral sensory neuropathy 52/206 (25.2%) 46/215 (21.4%)
Dysgeusia 32/206 (15.5%) 37/215 (17.2%)
Paraesthesia 28/206 (13.6%) 37/215 (17.2%)
Neuropathy peripheral 18/206 (8.7%) 22/215 (10.2%)
Dizziness 16/206 (7.8%) 14/215 (6.5%)
Psychiatric disorders
Insomnia 21/206 (10.2%) 19/215 (8.8%)
Anxiety 16/206 (7.8%) 12/215 (5.6%)
Depression 15/206 (7.3%) 13/215 (6%)
Renal and urinary disorders
Proteinuria 1/206 (0.5%) 22/215 (10.2%)
Dysuria 7/206 (3.4%) 13/215 (6%)
Respiratory, thoracic and mediastinal disorders
Epistaxis 35/206 (17%) 109/215 (50.7%)
Cough 43/206 (20.9%) 43/215 (20%)
Dyspnoea 46/206 (22.3%) 36/215 (16.7%)
Rhinorrhoea 18/206 (8.7%) 26/215 (12.1%)
Oropharyngeal pain 13/206 (6.3%) 26/215 (12.1%)
Dysphonia 8/206 (3.9%) 21/215 (9.8%)
Respiratory disorder 8/206 (3.9%) 11/215 (5.1%)
Skin and subcutaneous tissue disorders
Alopecia 141/206 (68.4%) 135/215 (62.8%)
Nail disorder 59/206 (28.6%) 68/215 (31.6%)
Rash 41/206 (19.9%) 37/215 (17.2%)
Dry skin 25/206 (12.1%) 28/215 (13%)
Palmar-plantar erythrodysaesthesia syndrome 26/206 (12.6%) 27/215 (12.6%)
Pruritus 24/206 (11.7%) 19/215 (8.8%)
Nail toxicity 24/206 (11.7%) 15/215 (7%)
Erythema 12/206 (5.8%) 16/215 (7.4%)
Onycholysis 5/206 (2.4%) 16/215 (7.4%)
Vascular disorders
Hypertension 27/206 (13.1%) 79/215 (36.7%)
Hot flush 16/206 (7.8%) 12/215 (5.6%)
Lymphoedema 17/206 (8.3%) 8/215 (3.7%)
Flushing 10/206 (4.9%) 12/215 (5.6%)

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 the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

Name/Title Medical Communications
Organization Hoffmann-LaRoche
Phone 800-821-8590
Email genentech@druginfo.com
Responsible Party:
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00391092
Other Study ID Numbers:
  • BO20231
First Posted:
Oct 23, 2006
Last Update Posted:
Aug 28, 2015
Last Verified:
Aug 1, 2015