Trial Outcomes & Findings for A Study of Avastin (Bevacizumab) + Xeloda (Capecitabine)as Maintenance Therapy in Patients With HER2-Negative Metastatic Breast Cancer (NCT NCT00929240)

Last Updated: 2015-03-03

Results Overview

Progression Free Survival (PFS) was defined as the time from first study drug dosing (during the maintenance treatment phase) to the first documented disease progression or death, whichever occurred first. Progression was based on tumor assessment made by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST). Progressive Disease (PD) was defined as a 20 percent (%) or greater increase in the sum of the Longest Diameter (LD) of the target lesions taking as reference the smallest sum LD recorded or appearance of new lesions.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

287 participants

Primary outcome timeframe

Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years

Results posted on

2015-03-03

Participant Flow

Participant milestones

Participant milestones
Measure	Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel During the Initial Phase all participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 milligrams per square meter (mg/m\^2) IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.	Maintenance Phase: Bevacizumab During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (partial response \[PR\] or complete response \[CR\]) or disease stabilization (SD) received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Initial Treatment Phase STARTED	284	0	0
Initial Treatment Phase COMPLETED	185	0	0
Initial Treatment Phase NOT COMPLETED	99	0	0
Maintenance Phase STARTED	0	94	91
Maintenance Phase COMPLETED	0	0	0
Maintenance Phase NOT COMPLETED	0	94	91

Reasons for withdrawal

Reasons for withdrawal
Measure	Initial Treatment Phase: Bevacizumab Plus (+) Docetaxel During the Initial Phase all participants received bevacizumab 15 milligrams per kilogram (mg/kg) intravenously (IV) on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 milligrams per square meter (mg/m\^2) IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.	Maintenance Phase: Bevacizumab During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (partial response \[PR\] or complete response \[CR\]) or disease stabilization (SD) received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Initial Treatment Phase Adverse Event	31	0	0
Initial Treatment Phase Disease progression	41	0	0
Initial Treatment Phase Withdrawal by Subject	13	0	0
Initial Treatment Phase Protocol Violation	5	0	0
Initial Treatment Phase Death	2	0	0
Initial Treatment Phase Health authority/Study termination	3	0	0
Initial Treatment Phase Physician Decision	4	0	0
Maintenance Phase Disease progression	0	73	60
Maintenance Phase Adverse Event	0	9	12
Maintenance Phase Withdrawal by Subject	0	2	6
Maintenance Phase Protocol Violation	0	1	0
Maintenance Phase Health authority/Study termination	0	1	2
Maintenance Phase Physician Decision	0	2	1
Maintenance Phase Change of treatment	0	4	0
Maintenance Phase Treatment ongoing at study closure	0	0	10
Maintenance Phase Participant not treated	0	2	0

Baseline Characteristics

A Study of Avastin (Bevacizumab) + Xeloda (Capecitabine)as Maintenance Therapy in Patients With HER2-Negative Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intial Treatment Phase: Bevacizumab + Docetaxel n=287 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.
Age, Continuous	52.5 years STANDARD_DEVIATION 11.8 • n=93 Participants
Sex: Female, Male Female	287 Participants n=93 Participants
Sex: Female, Male Male	0 Participants n=93 Participants

PRIMARY outcome

Timeframe: Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013, up to 4 years

Population: Maintenance Phase ITT population: All randomized participants

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants With Disease Progression or Death (Maintenance Phase Data Cutoff October 4, 2013)	88.3 percentage of participants	75.8 percentage of participants

PRIMARY outcome

Population: Maintenance Phase ITT population

PFS was defined as the time from first study drug dosing to the first documented disease progression or death, whichever occurred first.Time to progression was defined as the time from randomization to the first documented disease progression defined per RECIST 1.0 criteria. Participants without an event at data cut-off or who were withdrawn from the study without documented progression were censored at the date of the last tumor assessment when the participant was known to be progression free. Participants who took other non-protocol anti-cancer drugs while being on study medication, and who were still event free were censored on the date of first dose of the anti-cancer drug. Participants without post-randomization tumor assessments but alive were censored at the time of randomization. Participants without post-randomization assessments, who died after randomization were considered to have the PFS event at date of death. Kaplan-Meier estimation was used for median time to PFS

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Progression Free Survival (Maintenance Phase Data Cutoff October 4, 2013)	4.3 months Interval 3.9 to 6.8	11.9 months Interval 9.8 to 15.4

SECONDARY outcome

Population: Maintenance Phase ITT Population

Objective Response was determined by the investigator using modified RECIST criteria, Version 1.0. An objective response was a complete or partial overall confirmed response as determined by investigators. CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as greater than or equal to (≥) 30 % decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. Progressive disease (PD) was defined as 20% increase in the sum of the longest diameter of target lesions and SD was defined as small changes that do not meet above criteria. Pearson-Clopper one-sample method was used for Confidence intervals (CIs).

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Maintenance Phase Data Cutoff October 4, 2013)	76.6 percentage of participants Interval 66.7 to 84.7	85.7 percentage of participants Interval 76.8 to 92.2

SECONDARY outcome

Population: Maintenance Phase ITT population

CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥ 30 % decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. SD was defined as small changes that do not meet above criteria.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Data Cutoff October 4, 2013)	97.9 percentage of participants Interval 92.5 to 99.7	98.9 percentage of participants Interval 94.0 to 100.0

SECONDARY outcome

Population: Maintenance Phase ITT population

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants Who Died (Maintenance Phase Data Cutoff October 4, 2013)	56.4 percentage of participants	36.3 percentage of participants

SECONDARY outcome

Population: Maintenance Phase ITT population

Duration of Overall Survival (OS) was defined as the time from randomization to death of any cause. The OS data for participants for whom no death was captured in the clinical database were censored at the last time they were known to be alive. Kaplan Meier estimation was used to determine OS.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Overall Survival (Maintenance Phase Data Cutoff October 4, 2013)	23.7 months Interval 18.5 to 31.7	39.0 months Interval 32.3 to Upper Confidence limit was not estimated because of the large number of censored events.

SECONDARY outcome

Timeframe: Years 1 and 2

Population: Maintenance Phase ITT Population

Probability of being alive after 1 and 2 years on treatment with 95% CIs was calculated using Kaplan Meier approach with LOGLOG transformation.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants Expected to Be Alive After 1 and 2 Years on Treatment (Maintenance Phase Data Cutoff October 4, 2013) 1 Year	71.6 percentage of participants Interval 61.1 to 79.7	90.4 percentage of participants Interval 81.8 to 95.1
Percentage of Participants Expected to Be Alive After 1 and 2 Years on Treatment (Maintenance Phase Data Cutoff October 4, 2013) 2 Years	49.4 percentage of participants Interval 38.5 to 59.3	69.0 percentage of participants Interval 57.6 to 77.9

SECONDARY outcome

Timeframe: Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013

Population: Maintenance Phase ITT population

PD was defined per RECIST 1.0 as 20% increase in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage Of Participants With PD or Death Due to PD (Maintenance Phase Data Cutoff October 4, 2013)	88.3 percentage of participants	74.7 percentage of participants

SECONDARY outcome

Timeframe: Randomization, at the end of every third cycle (every 9 weeks) until the end of maintenance phase and every 3 months until disease progression or death until data cutoff on October 4, 2013

Population: Maintenance Phase ITT population

Time to Progression was defined as the time from randomization to the first documented disease progression (using investigator assessments of disease progression by RECIST 1.0). PD was defined as 20% increase in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=94 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Time To Progression (Maintenance Phase Data Cutoff October 4, 2013)	4.3 months Interval 3.9 to 6.8	11.9 months Interval 9.8 to 15.4

SECONDARY outcome

Timeframe: Baseline, Randomization and Cycles 3, 6, 9 and 12

Population: Maintenance Phase ITT population; n (number) = number of participants analyzed at the specific visit. Only timepoints with more than 10 participants in each treatment arm are presented.

The EORTC QLQ-C30 incorporates 9 multi-item scales: 5 functional scales (physical, role, cognitive, emotional, and social); 9 symptom scales (fatigue, pain, nausea and vomiting, dyspnoea, insomnia, appetite loss, constipation, diarrhea and financial difficulties); and a global health and quality-of-life scale. Most questions used 4 point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. The change in global health status was determined to be the difference in values at baseline and each specific visit. The term ''baseline'' refers to the time of randomization to the maintenance phase.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=83 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=86 Participants During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013) Randomization (n= 83, 86)	-3.51 units on a scale Interval -9.63 to 2.6	-4.46 units on a scale Interval -9.4 to 0.48
Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013) Cycle 3 (n= 44, 52)	0.76 units on a scale Interval -6.65 to 8.17	-3.21 units on a scale Interval -9.99 to 3.58
Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013) Cycle 6 (n= 26, 54)	4.17 units on a scale Interval -6.49 to 14.82	-5.40 units on a scale Interval -11.67 to 0.87
Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013) Cycle 9 (n= 18, 37)	8.80 units on a scale Interval -4.57 to 22.17	-1.80 units on a scale Interval -8.92 to 5.32
Quality of Life Assessed As Change From Baseline in Global Health Status Using The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - 30 (EORTC QLQ - C30) (Maintenance Phase Data Cutoff October 4, 2013) Cycle 12 (n= 12, 31)	0.69 units on a scale Interval -17.99 to 19.37	0.00 units on a scale Interval -8.24 to 8.24

SECONDARY outcome

Timeframe: Screening and at the end of every third cycle until randomization for an average of 18 weeks

Population: Initial Phase ITT population; only participants who were not randomized at the end of the initial treatment phase were included in this analysis.

Objective Response was determined by the investigator using RECIST criteria, Version 1.0. An objective response was a complete or partial overall confirmed response as determined by investigators. CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥ 30% decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. Pearson-Clopper one-sample method was used for CI.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=102 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants With Best Overall Confirmed Objective Response of CR or PR Per RECIST 1.0 (Initial Treatment Phase)	8.8 percentage of participants Interval 4.1 to 16.1	—

SECONDARY outcome

Timeframe: Screening and at the end of every third cycle until randomization for an average of 18 weeks

Population: Initial Phase ITT population; only participants who were not randomized at the end of the initial treatment phase were included in this analysis.

CR was defined as complete disappearance of all target and non-target lesions and no new lesions. PR was defined as ≥30% decrease in the sum of appropriate diameters of all target measurable lesions, no progress in the non-measurable disease, and no new lesions. SD was defined as small changes that do not meet above criteria.

Outcome measures

Outcome measures
Measure	Maintenance Phase: Bevacizumab n=102 Participants During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Percentage of Participants With Clinical Benefit (CR, PR and SD) Per RECIST 1.0 (Initial Treatment Phase)	56.9 percentage of participants Interval 46.7 to 66.6	—

Adverse Events

Initial Treatment Phase:Bevacizumab + Docetaxel

Serious events: 78 serious events

Other events: 40 other events

Deaths: 0 deaths

Maintenance Phase:Bevacizumab

Serious events: 7 serious events

Other events: 4 other events

Deaths: 0 deaths

Maintenance Phase: Bevacizumab + Capecitabine

Serious events: 10 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Initial Treatment Phase:Bevacizumab + Docetaxel n=284 participants at risk During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first. Participants also received docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Treatment Phase, participants with an objective response (PR or CR) or SD following 3-6 cycles of bevacizumab + docetaxel were randomized to receive maintenance therapy with either bevacizumab alone or bevacizumab + capecitabine.	Maintenance Phase:Bevacizumab n=92 participants at risk During the Initial Phase all participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or participant request for withdrawal, whichever occurred first along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response (PR or CR) or SD received 15 mg/kg bevacizumab IV on Day 1 of each 3 week cycle until disease progression, unacceptable toxicity, participant request for withdrawal or end of study, whichever occurred first.	Maintenance Phase: Bevacizumab + Capecitabine n=91 participants at risk During the Initial Phase participants received bevacizumab 15 mg/kg IV on Day 1 of each 3 week cycle for a minimum of 3 cycles and a maximum of 6 cycles or until disease progression, unacceptable toxicity or withdrawal, whichever occurred first, along with docetaxel, a recommended dose of 100 mg/m\^2 IV administered on Day 1 of each cycle. Doses of 75 to 100 mg/m\^2 of docetaxel could be administered at investigator's discretion. At the end of the Initial Phase, participants with an objective response were randomized to receive bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle plus capecitabine 1000 mg/m\^2 twice daily on Days 1 to 14 of each 3 week cycle until disease progression, unacceptable toxicity, request for withdrawal or end of study, whichever occurred first. If one of the drugs was discontinued before disease progression, treatment was continued with the second drug until disease progression, unacceptable toxicity, withdrawal or end of study, whichever occurred first.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	2.1% 6/284 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	0.00% 0/92 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	31.9% 29/91 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.
Blood and lymphatic system disorders Neutropenia	10.2% 29/284 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	1.1% 1/92 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	2.2% 2/91 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.
Vascular disorders Hypertension	1.8% 5/284 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	3.3% 3/92 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.	7.7% 7/91 • Adverse Events (AEs) were recorded from the date of randomization until the end of study at the cutoff date of October 4, 2013. AEs were recorded for the Safety population (all participants who received at least one dose of study drug during the maintenance phase). Only Grade 3 and above AEs have been captured per protocol.

Additional Information

Medical Communications

Hoffmann- LaRoche

Phone: 1-800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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 after the first publication or presentation that involves the overall study. Sponsor may request that confidential information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER