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A Study of Avastin (Bevacizumab) in Combination Chemotherapy in Patients With Metastatic Cancer of the Colon or Rectum

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Completed
CT.gov ID
NCT01131078
Collaborator
(none)
306
Enrollment
44
Locations
3
Arms
89
Duration (Months)
7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A study of Avastin (bevacizumab) in combination chemotherapy in patients with metastatic cancer of the colon or rectum. The anticipated time on study treatment is until disease progression.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
306 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open-label Study Comparing the Effect of 3 Chemotherapy Regimens Containing Avastin on Time to Disease Progression in Patients With Metastatic Colorectal Cancer
Study Start Date :
Jun 1, 2005
Actual Primary Completion Date :
Nov 1, 2012
Actual Study Completion Date :
Nov 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Experimental: Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2)

Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal.

Drug: Bevacizumab [Avastin]
Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.
Other Names:
  • Avastin

    • Drug: Capecitabine
    Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.

    Drug: Irinotecan
    Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks.
    Experimental: Bevacizumab + Capecitabine (1250 mg/m^2)

    Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal.

    Drug: Bevacizumab [Avastin]
    Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.
    Other Names:
  • Avastin

    • Drug: Capecitabine
    Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.
    Experimental: Bevacizumab + Capecitabine (650 mg/m^2)

    Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 Week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of capecitabine treatment without interruptions. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.

    Drug: Bevacizumab [Avastin]
    Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle.
    Other Names:
  • Avastin

    • Drug: Capecitabine
    Capecitabine was administered orally at a doses of 1000 or 1250, mg/m^2 twice daily (Day 2 to 15) or as 650 mg/m^2 twice daily on Days 1 to 21.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With Disease Progression or Death [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Disease progression was defined according to National Cancer Institute (NCI) guidelines and best clinical practices.

    2. Time to Progression (TTP) [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      TTP is defined as the time from date of randomization until objective tumor progression or death due to any cause. It includes deaths and thus can be correlated to overall survival.

    Secondary Outcome Measures

    1. Percentage of Participants Who Died [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Overall survival is defined as the time from date of randomization until death from any cause

    2. Overall Survival [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Overall survival is defined as the time from date of randomization until death from any cause; Kaplan-Meier estimates were used for analysis.

    3. Percentage of Participants With Treatment Failure [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Treatment failure is defined as discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent.

    4. Time to Treatment Failure [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Time to treatment failure is defined as a composite endpoint measuring time from date of randomization to discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent. Analysis was performed using Kaplan-Meier estimates.

    5. Percentage of Participants With Progression Excluding Deaths [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      The failure event was defined as tumor progression excluding deaths due to any reason.

    6. Time to Progression Excluding Deaths [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      The failure event was defined as tumor progression excluding deaths due to any reason. Kaplan-Meier estimates were used for analysis.

    7. Percentage of Participants With Progression Excluding Deaths Not Related to Underlying Cancer [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      The failure event was defined as tumor progression excluding only deaths not related to underlying cancer.

    8. Time to Progression Excluding Deaths Not Related to Underlying Cancer [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      The failure event was defined as tumor progression excluding only deaths not related to underlying cancer. Kaplan-Meier estimates were used for analysis.

    9. Percentage of Participants by Best Overall Response [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Best overall response is defined as the best response recorded from the date of randomization until disease progression or recurrence. Complete response (CR): at least 2 determinations of CR at least 4 weeks apart before progression; Partial response (PR): at least 2 determinations of PR at least 4 weeks apart before progression; Stable disease (SD): at least one SD assessment; Progressive Disease (PD): Disease progression or death due to underlying cancer. CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions; PD: At least 20% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of longest diameter of all target lesions or the appearance of one or more new lesions; SD: Neither sufficient shrinkage to qualify for CR or PR or increase in lesions;

    10. Percentage of Participants With a Best Overall Response of CR or PR [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions;

    11. Percentage of Participants With Stable Disease [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Stable disease rate was the proportion of participants who achieved CR, PR, or SD.

    12. Percentage of Participants With Progressive Disease Within 12 Weeks From Start of Treatment [Randomization, Weeks 3, 6 and 9, and 12]

      Early progression was the proportion of participants with progressive disease within 12 weeks from the start of treatment.

    13. Duration of Overall Response [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Duration of overall response included participants who achieved a CR or PR.

    14. Duration of Stable Disease (SD) [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death]

      Duration of SD was calculated as the number of months the participants remained in CR, PR or SD. Kaplan-Meier estimates were used for analysis.

    15. Duration of Overall Complete Response [Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years]

      Duration of complete response was calculated as the time in months from the date of randomization to the date of first documentation of CR. Kaplan-Meier estimates were used for analysis.

    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;

    • colon or rectal cancer, with metastases;

    • =1 measurable lesion.

    Exclusion Criteria:

    • previous systemic treatment for advanced disease;

    • radiotherapy to any site within 4 weeks before study;

    • daily aspirin (>325 mg/day), anticoagulants, or other medications known to predispose to gastrointestinal ulceration;

    • co-existing malignancies or malignancies diagnosed within last 5 years (except basal cell cancer or cervical cancer in situ).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Paola Calabria Italy 87027
    2 Benevento Campania Italy 82100
    3 Napoli Campania Italy 80136
    4 Bologna Emilia-Romagna Italy 40138
    5 Carpi Emilia-Romagna Italy 41012
    6 Piacenza Emilia-Romagna Italy 29100
    7 Latisana Friuli-Venezia Giulia Italy 33053
    8 Udine Friuli-Venezia Giulia Italy 33100
    9 Latina Lazio Italy 04100
    10 Roma Lazio Italy 00168
    11 Roma Lazio Italy 00186
    12 Brescia Lombardia Italy 25123
    13 Busto Arsizio Lombardia Italy 21052
    14 Casalpusterlengo Lombardia Italy 20071
    15 Cremona Lombardia Italy 26100
    16 Gorgonzola Lombardia Italy 20064
    17 Lecco Lombardia Italy 23900
    18 Legnago Lombardia Italy 37045
    19 Mantova Lombardia Italy 46100
    20 Milano Lombardia Italy 20121
    21 Milano Lombardia Italy 20133
    22 Milano Lombardia Italy 20142
    23 Milano Lombardia Italy 20162
    24 Pavia Lombardia Italy 27100
    25 Saronno Lombardia Italy 21047
    26 Sondrio Lombardia Italy 23100
    27 Treviglio Lombardia Italy 24047
    28 Varese Lombardia Italy 21100
    29 Ancona Marche Italy 60121
    30 Novara Piemonte Italy 28100
    31 Torino Piemonte Italy 10153
    32 Cagliari Sardegna Italy 09100
    33 Catania Sicilia Italy 95100
    34 Palermo Sicilia Italy 90127
    35 Firenze Toscana Italy 50139
    36 Grosseto Toscana Italy 58100
    37 Pisa Toscana Italy 56100
    38 Prato Toscana Italy 59100
    39 Bolzano Trentino-Alto Adige Italy 39100
    40 Terni Umbria Italy 05100
    41 Camposampiero Veneto Italy 35012
    42 Este Veneto Italy 35042
    43 Montecchio Maggiore Veneto Italy 36075
    44 Negrar Veneto Italy 37024

    Sponsors and Collaborators

    • Hoffmann-La Roche

    Investigators

    • Study Chair: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01131078
    Other Study ID Numbers:
    • ML18524
    First Posted:
    May 26, 2010
    Last Update Posted:
    Jun 4, 2015
    Last Verified:
    Jun 1, 2015
    Additional relevant MeSH terms:
    Colorectal Neoplasms
    Bevacizumab
    Capecitabine
    Irinotecan

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 milligrams per kilogram (mg/kg) intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 milligrams per meter squared (mg/m^2) intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or stable disease (SD) were treated with bevacizumab alone until unacceptable toxicity, progressive disease (PD), or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 Week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of capecitabine treatment without interruptions. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Period Title: Overall Study
    STARTED 101 102 103
    COMPLETED 0 1 1
    NOT COMPLETED 101 101 102

    Baseline Characteristics

    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2) Total
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 Week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of capecitabine treatment without interruptions. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal. Total of all reporting groups
    Overall Participants 101 102 103 306
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    61.60
    (9.35)
    61.46
    (10.22)
    61.01
    (10.10)
    61.36
    (9.86)
    Sex: Female, Male (Count of Participants)
    Female
    58
    57.4%
    53
    52%
    63
    61.2%
    174
    56.9%
    Male
    43
    42.6%
    49
    48%
    40
    38.8%
    132
    43.1%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants With Disease Progression or Death
    Description Disease progression was defined according to National Cancer Institute (NCI) guidelines and best clinical practices.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population;
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 102 103
    Number [percentage of participants]
    86.14
    85.3%
    90.20
    88.4%
    88.35
    85.8%
    2. Secondary Outcome
    Title Percentage of Participants Who Died
    Description Overall survival is defined as the time from date of randomization until death from any cause
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 102 103
    Number [percentage of participants]
    67.33
    66.7%
    71.57
    70.2%
    73.79
    71.6%
    3. Secondary Outcome
    Title Overall Survival
    Description Overall survival is defined as the time from date of randomization until death from any cause; Kaplan-Meier estimates were used for analysis.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Only participants with an event (death) were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 68 73 76
    Median (95% Confidence Interval) [months]
    22.75
    19.76
    18.02
    4. Secondary Outcome
    Title Percentage of Participants With Treatment Failure
    Description Treatment failure is defined as discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 102 103
    Number [percentage of participants]
    100.0
    99%
    99.02
    97.1%
    99.03
    96.1%
    5. Secondary Outcome
    Title Time to Treatment Failure
    Description Time to treatment failure is defined as a composite endpoint measuring time from date of randomization to discontinuation of treatment for any reason, including disease progression, death, treatment toxicity, insufficient therapeutic response, failure to return, refusing treatment, being unwilling to cooperate and withdrawing consent. Analysis was performed using Kaplan-Meier estimates.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; only participants with a treatment failure event were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 101 102
    Median (95% Confidence Interval) [months]
    6.67
    6.87
    5.75
    6. Secondary Outcome
    Title Percentage of Participants With Progression Excluding Deaths
    Description The failure event was defined as tumor progression excluding deaths due to any reason.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 102 103
    Number [percentage of participants]
    71.29
    70.6%
    81.37
    79.8%
    75.73
    73.5%
    7. Secondary Outcome
    Title Time to Progression Excluding Deaths
    Description The failure event was defined as tumor progression excluding deaths due to any reason. Kaplan-Meier estimates were used for analysis.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Only participants with a time to progression event (excluding deaths) were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 72 83 78
    Median (95% Confidence Interval) [months]
    8.81
    8.48
    7.40
    8. Secondary Outcome
    Title Percentage of Participants With Progression Excluding Deaths Not Related to Underlying Cancer
    Description The failure event was defined as tumor progression excluding only deaths not related to underlying cancer.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal.. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 101 102 103
    Number [percentage of participants]
    81.19
    80.4%
    90.20
    88.4%
    85.44
    83%
    9. Secondary Outcome
    Title Time to Progression Excluding Deaths Not Related to Underlying Cancer
    Description The failure event was defined as tumor progression excluding only deaths not related to underlying cancer. Kaplan-Meier estimates were used for analysis.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; only participants with a time to progression event (excluding deaths not related to underlying cancer) were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 82 92 88
    Median (95% Confidence Interval) [months]
    8.68
    8.32
    7.27
    10. Primary Outcome
    Title Time to Progression (TTP)
    Description TTP is defined as the time from date of randomization until objective tumor progression or death due to any cause. It includes deaths and thus can be correlated to overall survival.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; only those participants with an event of disease progression or death were included in the analysis
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 87 92 91
    Median (95% Confidence Interval) [months]
    8.35
    8.15
    7.27
    11. Secondary Outcome
    Title Percentage of Participants by Best Overall Response
    Description Best overall response is defined as the best response recorded from the date of randomization until disease progression or recurrence. Complete response (CR): at least 2 determinations of CR at least 4 weeks apart before progression; Partial response (PR): at least 2 determinations of PR at least 4 weeks apart before progression; Stable disease (SD): at least one SD assessment; Progressive Disease (PD): Disease progression or death due to underlying cancer. CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions; PD: At least 20% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of longest diameter of all target lesions or the appearance of one or more new lesions; SD: Neither sufficient shrinkage to qualify for CR or PR or increase in lesions;
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; All participants with evaluable data were included in the analysis
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 91 92 94
    CR
    5.49
    5.4%
    1.09
    1.1%
    5.32
    5.2%
    PR
    46.15
    45.7%
    32.61
    32%
    28.72
    27.9%
    SD
    39.56
    39.2%
    52.17
    51.1%
    45.74
    44.4%
    PD
    8.79
    8.7%
    14.13
    13.9%
    20.21
    19.6%
    12. Secondary Outcome
    Title Percentage of Participants With a Best Overall Response of CR or PR
    Description CR: Complete disappearance of all target lesions; PR: At least 30% decrease in the sum of the longest diameter of all target lesions taking as reference the baseline sum of all target lesions;
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; All participants with evaluable data were included in the analysis
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 91 92 94
    Number (95% Confidence Interval) [percentage of participants]
    52.0
    51.5%
    34.0
    33.3%
    34.0
    33%
    13. Secondary Outcome
    Title Percentage of Participants With Stable Disease
    Description Stable disease rate was the proportion of participants who achieved CR, PR, or SD.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; All participants with evaluable data were included in the analysis
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 91 92 94
    Number (95% Confidence Interval) [percentage of participants]
    91.0
    90.1%
    86.0
    84.3%
    80.0
    77.7%
    14. Secondary Outcome
    Title Percentage of Participants With Progressive Disease Within 12 Weeks From Start of Treatment
    Description Early progression was the proportion of participants with progressive disease within 12 weeks from the start of treatment.
    Time Frame Randomization, Weeks 3, 6 and 9, and 12

    Outcome Measure Data

    Analysis Population Description
    ITT Population; All participants with evaluable data were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 91 92 94
    Number (95% Confidence Interval) [percentage of participants]
    9.0
    8.9%
    13.0
    12.7%
    18.0
    17.5%
    15. Secondary Outcome
    Title Duration of Overall Response
    Description Duration of overall response included participants who achieved a CR or PR.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; only participants with a best overall response of CR or PR were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 47 31 32
    Median (95% Confidence Interval) [months]
    6.51
    6.61
    9.12
    16. Secondary Outcome
    Title Duration of Stable Disease (SD)
    Description Duration of SD was calculated as the number of months the participants remained in CR, PR or SD. Kaplan-Meier estimates were used for analysis.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years or Death

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Only participants with a best overall response of CR, PR, or SD were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 83 79 75
    Median (95% Confidence Interval) [months]
    8.81
    8.65
    8.98
    17. Secondary Outcome
    Title Duration of Overall Complete Response
    Description Duration of complete response was calculated as the time in months from the date of randomization to the date of first documentation of CR. Kaplan-Meier estimates were used for analysis.
    Time Frame Randomization, Weeks 3, 6 and 9, and every 3 months up to 5 years

    Outcome Measure Data

    Analysis Population Description
    ITT Population; Only participants with a best overall response were included in the analysis.
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3-week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of continuous capecitabine treatment. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    Measure Participants 5 1 5
    Median (95% Confidence Interval) [months]
    8.35
    6.05
    12.89

    Adverse Events

    Time Frame Adverse events were recorded from the date of randomization until the End of Study or until death in safety population. Safety population included all participants who signed informed consent and took at least one dose of each drug of study combination.
    Adverse Event Reporting Description
    Arm/Group Title Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Arm/Group Description Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle. Irinotecan was administered as a 240 mg/m^2 intravenous infusion over 60 minutes (Day 1) every 3 weeks. Capecitabine was administered orally at a dose of 1000 mg/m^2 twice daily (Day 2 to 15). Cycle length was 3 weeks consisting of 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 week cycle in combination with capecitabine administered orally at 1250 mg/m^2 twice daily (Day 1 to 14). Cycle length was 3 weeks with 2 weeks of capecitabine treatment followed by 1 week without treatment up to 6 cycles. After 6 cycles, participants with objective response or SD were treated with bevacizumab alone until unacceptable toxicity, PD, or participant withdrawal. Bevacizumab was administered as a 7.5 mg/kg intravenous infusion over 30 to 90 minutes on Day 1 of each 3 Week cycle in combination with capecitabine administered orally at 650 mg/m^2 twice daily (Day 1 to 21). Cycle length was 3 weeks with 3 weeks of capecitabine treatment without interruptions. Participants received the same regimen until unacceptable toxicity, PD, or participant withdrawal.
    All Cause Mortality
    Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 38/100 (38%) 21/99 (21.2%) 20/102 (19.6%)
    Blood and lymphatic system disorders
    Febrile neutropenia 3/100 (3%) 0/99 (0%) 0/102 (0%)
    Neutropenia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Disseminated intravascular coagulation 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Leukopenia 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Pancytopenia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Thrombocytopenia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Cardiac disorders
    Arrhythmia 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Cardiac failure 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Myocardial infarction 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Myocardial ischemia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Supraventricular tachycardia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Gastrointestinal disorders
    Diarrhoea 7/100 (7%) 1/99 (1%) 1/102 (1%)
    Intestinal obstruction 6/100 (6%) 0/99 (0%) 2/102 (2%)
    Vomiting 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Abdominal haematoma 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Abdominal pain 1/100 (1%) 2/99 (2%) 2/102 (2%)
    Gastrointestinal disorder 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Intestinal haemorrhage 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Intestinal prolapse 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Nausea 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Pancreatitis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Rectal haemorrhage 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Subileus 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Swollen tongue 0/100 (0%) 1/99 (1%) 0/102 (0%)
    General disorders
    Chest pain 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Disease progression 0/100 (0%) 1/99 (1%) 2/102 (2%)
    General physical health deterioration 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Mucosal inflammation 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Pyrexia 3/100 (3%) 1/99 (1%) 1/102 (1%)
    Sudden death 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Hepatobiliary disorders
    Jaundice cholestatic 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Infections and infestations
    Central line infection 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Infection 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Septic shock 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Tuberculosis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Injury, poisoning and procedural complications
    Device migration 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Wound dehiscence 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Metabolism and nutrition disorders
    Anorexia 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Dehydration 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Musculoskeletal and connective tissue disorders
    Back pain 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung squamous cell carcinoma stage unspecified 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Nervous system disorders
    Cerebral ischaemia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Dizziness 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Spinal cord compression 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Syncope 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Renal and urinary disorders
    Calculus urinary 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Hydronephrosis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Nephrotic syndrome 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Renal failure 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Renal vein thrombosis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal oedema 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Pneumonitis 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Productive cough 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Pulmonary artery thrombosis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Pulmonary embolism 2/100 (2%) 2/99 (2%) 0/102 (0%)
    Pulmonary microemboll 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Respiratory failure 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Surgical and medical procedures
    Toe amputation 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Vascular disorders
    Deep vein thrombosis 2/100 (2%) 3/99 (3%) 0/102 (0%)
    Embolism 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Hypertension 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Other (Not Including Serious) Adverse Events
    Bevacizumab + Irinotecan + Capecitabine (1000 mg/m^2) Bevacizumab + Capecitabine (1250 mg/m^2) Bevacizumab + Capecitabine (650 mg/m^2)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 95/100 (95%) 88/99 (88.9%) 85/102 (83.3%)
    Blood and lymphatic system disorders
    Anaemia 18/100 (18%) 7/99 (7.1%) 6/102 (5.9%)
    Leukopenia 7/100 (7%) 2/99 (2%) 2/102 (2%)
    Neutropenia 33/100 (33%) 5/99 (5.1%) 6/102 (5.9%)
    Thrombocytopenia 5/100 (5%) 1/99 (1%) 2/102 (2%)
    Febrile neutropenia 3/100 (3%) 1/99 (1%) 0/102 (0%)
    Granulocytopenia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Leukocytosis 1/100 (1%) 1/99 (1%) 1/102 (1%)
    Pancytopenia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Cardiac disorders
    Arrhythmia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Atrial tachycardia 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Bradycardia 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Cyanosis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Extrasystoles 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Palpitations 0/100 (0%) 2/99 (2%) 1/102 (1%)
    Sinus tachycardia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Tachycardia 0/100 (0%) 2/99 (2%) 1/102 (1%)
    Ventricular extrasystoles 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Ear and labyrinth disorders
    Ear pain 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Vertigo 1/100 (1%) 2/99 (2%) 3/102 (2.9%)
    Endocrine disorders
    Hypothyroidism 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Eye disorders
    Conjunctivitis 1/100 (1%) 6/99 (6.1%) 2/102 (2%)
    Conjunctival haemorrhage 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Diplopia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Eye inflammation 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Glaucoma 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Ocular discomfort 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Ocular icterus 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Vision blurred 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Gastrointestinal disorders
    Abdominal pain 21/100 (21%) 11/99 (11.1%) 21/102 (20.6%)
    Abdominal pain upper 13/100 (13%) 8/99 (8.1%) 8/102 (7.8%)
    Constipation 12/100 (12%) 10/99 (10.1%) 8/102 (7.8%)
    Diarrhoea 56/100 (56%) 34/99 (34.3%) 28/102 (27.5%)
    Nausea 35/100 (35%) 16/99 (16.2%) 26/102 (25.5%)
    Stomatitis 6/100 (6%) 10/99 (10.1%) 2/102 (2%)
    Vomiting 23/100 (23%) 13/99 (13.1%) 6/102 (5.9%)
    Abdominal discomfort 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Anal discomfort 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Ano-rectal ulcer 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Ascites 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Cheilitis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Dry mouth 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Dyspepsia 4/100 (4%) 3/99 (3%) 4/102 (3.9%)
    Enteritis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Flatulence 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Gastritis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Gastrooesophageal reflux disease 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Gingival bleeding 0/100 (0%) 2/99 (2%) 0/102 (0%)
    Gingivitis 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Haematochezia 3/100 (3%) 1/99 (1%) 1/102 (1%)
    Haemorrhoids 3/100 (3%) 2/99 (2%) 2/102 (2%)
    Intestinal obstruction 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Mesenteric vein thrombosis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Mouth haemorrhage 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Mouth ulceration 0/100 (0%) 3/99 (3%) 0/102 (0%)
    Oral discomfort 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Oedema peripheral 2/100 (2%) 1/99 (1%) 1/102 (1%)
    Periodontitis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Polyp colorectal 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Proctalgia 0/100 (0%) 1/99 (1%) 2/102 (2%)
    Proctitis 2/100 (2%) 1/99 (1%) 1/102 (1%)
    Rectal haemorrhage 1/100 (1%) 2/99 (2%) 2/102 (2%)
    Toothache 1/100 (1%) 0/99 (0%) 2/102 (2%)
    General disorders
    Asthenia 16/100 (16%) 17/99 (17.2%) 20/102 (19.6%)
    Fatigue 14/100 (14%) 12/99 (12.1%) 16/102 (15.7%)
    Mucosal inflammation 13/100 (13%) 9/99 (9.1%) 7/102 (6.9%)
    Pyrexia 30/100 (30%) 17/99 (17.2%) 15/102 (14.7%)
    Catheter site related reaction 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Chest discomfort 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Chest pain 1/100 (1%) 3/99 (3%) 4/102 (3.9%)
    Facial pain 1/100 (1%) 0/99 (0%) 0/102 (0%)
    General physical health deterioration 1/100 (1%) 1/99 (1%) 2/102 (2%)
    Influenza-like illness 1/100 (1%) 3/99 (3%) 1/102 (1%)
    Local swelling 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Malaise 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Oedema peripheral 2/100 (2%) 1/99 (1%) 1/102 (1%)
    Pain 0/100 (0%) 2/99 (2%) 1/102 (1%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 10/100 (10%) 22/99 (22.2%) 26/102 (25.5%)
    Hepatic failure 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Hepatic pain 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Hepatotoxicity 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Jaundice 3/100 (3%) 0/99 (0%) 2/102 (2%)
    Infections and infestations
    Abdominal wall infection 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Bacteriuria 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Bronchitis 0/100 (0%) 2/99 (2%) 2/102 (2%)
    Cellulitis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Cystitis 1/100 (1%) 4/99 (4%) 1/102 (1%)
    Dental caries 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Ear infection 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Erysipelas 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Folliculitis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Gastroenteritis viral 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Herpes zoster 2/100 (2%) 0/99 (0%) 1/102 (1%)
    Influenza 3/100 (3%) 4/99 (4%) 5/102 (4.9%)
    Nail infection 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Paronychia 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Perianal abscess 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Pharyngitis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Relapsing fever 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Rhinitis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Subcutaneous abscess 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Tooth abscess 3/100 (3%) 1/99 (1%) 2/102 (2%)
    Urinary tract infection 0/100 (0%) 0/99 (0%) 3/102 (2.9%)
    Vaginal infection 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Injury, poisoning and procedural complications
    Intestinal stoma complication 1/100 (1%) 1/99 (1%) 1/102 (1%)
    Radius fracture 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Wound 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Wound dehiscence 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Investigations
    Alanine aminotransferase increased 7/100 (7%) 9/99 (9.1%) 12/102 (11.8%)
    Aspartate aminotransferase increased 6/100 (6%) 8/99 (8.1%) 11/102 (10.8%)
    Blood alkaline phosphatase increased 6/100 (6%) 4/99 (4%) 4/102 (3.9%)
    Blood alkaline phosphatase 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Blood bilirubin 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Blood calcium decreased 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Blood calcium increased 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Blood creatine increased 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Blood creatinine increased 1/100 (1%) 4/99 (4%) 2/102 (2%)
    Blood glucose increased 2/100 (2%) 1/99 (1%) 1/102 (1%)
    Blood lactate dehydrogenase increased 2/100 (2%) 2/99 (2%) 1/102 (1%)
    Blood sodium increased 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Coagulation test abnormal 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Gamma-glutamyltransferase increased 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Haematocrit decreased 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Hepatic enzyme increased 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Platelet count increased 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Prothrombin time shortened 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Transaminases increased 0/100 (0%) 3/99 (3%) 0/102 (0%)
    Weight decreased 1/100 (1%) 0/99 (0%) 2/102 (2%)
    Metabolism and nutrition disorders
    Anorexia 9/100 (9%) 5/99 (5.1%) 5/102 (4.9%)
    Dehydration 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Diabetes mellitus 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Gout 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Hypercalcaemia 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Hyperglycaemia 2/100 (2%) 1/99 (1%) 0/102 (0%)
    Hyperkalaemia 2/100 (2%) 0/99 (0%) 1/102 (1%)
    Hypertriglyceridaemia 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Hyperuricaemia 2/100 (2%) 1/99 (1%) 3/102 (2.9%)
    Hypoalbuminaemia 1/100 (1%) 0/99 (0%) 2/102 (2%)
    Hypocalcaemia 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Hypokalaemia 3/100 (3%) 1/99 (1%) 2/102 (2%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 5/100 (5%) 4/99 (4%) 4/102 (3.9%)
    Back pain 5/100 (5%) 2/99 (2%) 4/102 (3.9%)
    Arthritis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Bone pain 3/100 (3%) 0/99 (0%) 1/102 (1%)
    Buttock pain 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Chest wall pain 0/100 (0%) 2/99 (2%) 1/102 (1%)
    Muscle spasms 0/100 (0%) 0/99 (0%) 2/102 (2%)
    Musculoskeletal pain 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Myalgia 1/100 (1%) 2/99 (2%) 1/102 (1%)
    Neck pain 0/100 (0%) 2/99 (2%) 3/102 (2.9%)
    Pain in extremity 2/100 (2%) 2/99 (2%) 5/102 (4.9%)
    Periarthritis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Sacral pain 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Shoulder pain 3/100 (3%) 2/99 (2%) 2/102 (2%)
    Tendonitis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Nervous system disorders
    Headache 4/100 (4%) 7/99 (7.1%) 5/102 (4.9%)
    Cholinergic syndrome 5/100 (5%) 0/99 (0%) 0/102 (0%)
    Carpal tunnel syndrome 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Coordination abnormal 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Dizziness 3/100 (3%) 0/99 (0%) 1/102 (1%)
    Dysaesthesia 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Dysguesia 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Migraine without aura 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Neuropathy 3/100 (3%) 0/99 (0%) 1/102 (1%)
    Paraesthesia 4/100 (4%) 3/99 (3%) 5/102 (4.9%)
    Sciatica 1/100 (1%) 3/99 (3%) 2/102 (2%)
    Somnolence 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Syncope 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Psychiatric disorders
    Anxiety 0/100 (0%) 3/99 (3%) 1/102 (1%)
    Confusional state 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Depression 1/100 (1%) 1/99 (1%) 3/102 (2.9%)
    Insomnia 2/100 (2%) 2/99 (2%) 1/102 (1%)
    Mood altered 0/100 (0%) 1/99 (1%) 1/102 (1%)
    Panic attack 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Restlessness 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Renal and urinary disorders
    Bladder spasm 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Dysuria 2/100 (2%) 0/99 (0%) 0/102 (0%)
    Nocturia 1/100 (1%) 0/99 (0%) 1/102 (1%)
    Pollakiuria 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Proteinuria 4/100 (4%) 4/99 (4%) 4/102 (3.9%)
    Renal colic 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Renal failure acute 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Ureteric obstruction 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Ureteric stenosis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Reproductive system and breast disorders
    Female genital-digestive tract fistula 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Pelvic pain 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Penis disorder 0/100 (0%) 3/99 (3%) 1/102 (1%)
    Vaginal haemorrhage 0/100 (0%) 0/99 (0%) 2/102 (2%)
    Rhinorrhoea 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 5/100 (5%) 3/99 (3%) 6/102 (5.9%)
    Dyspnoea 4/100 (4%) 5/99 (5.1%) 6/102 (5.9%)
    Epistaxis 14/100 (14%) 6/99 (6.1%) 7/102 (6.9%)
    Dysphonia 1/100 (1%) 0/99 (0%) 2/102 (2%)
    Haemoptysis 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Pharyngolaryngeal pain 4/100 (4%) 3/99 (3%) 1/102 (1%)
    Pleural effusion 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Productive cough 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Sleep apnoea syndrome 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Skin and subcutaneous tissue disorders
    Alopecia 22/100 (22%) 2/99 (2%) 3/102 (2.9%)
    Erythema 5/100 (5%) 0/99 (0%) 1/102 (1%)
    Palmar-plantar erythrodysaesthesia syndrome 16/100 (16%) 40/99 (40.4%) 39/102 (38.2%)
    Dry skin 0/100 (0%) 2/99 (2%) 0/102 (0%)
    Hyperhidrosis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Nail disorder 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Nail dystrophy 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Onycholysis 0/100 (0%) 2/99 (2%) 0/102 (0%)
    Photosensitivity reaction 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Pruritus 0/100 (0%) 1/99 (1%) 2/102 (2%)
    Rash 3/100 (3%) 1/99 (1%) 3/102 (2.9%)
    Rash papular 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Skin exfoliation 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Skin fissures 0/100 (0%) 2/99 (2%) 0/102 (0%)
    Urticaria 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Surgical and medical procedures
    Cataract operation 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Inguinal hernia repair 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Stent placement 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Tooth extraction 0/100 (0%) 1/99 (1%) 0/102 (0%)
    Vascular disorders
    Hypertension 28/100 (28%) 29/99 (29.3%) 19/102 (18.6%)
    Axillary vein thrombosis 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Deep vein thrombosis 3/100 (3%) 1/99 (1%) 1/102 (1%)
    Haemorrhage 0/100 (0%) 0/99 (0%) 1/102 (1%)
    Hypotension 1/100 (1%) 1/99 (1%) 0/102 (0%)
    Phlebitis 1/100 (1%) 0/99 (0%) 0/102 (0%)
    Thrombosis 2/100 (2%) 0/99 (0%) 1/102 (1%)

    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 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.

    Results Point of Contact

    Name/Title Medical Communications
    Organization Hoffmann- LaRoche
    Phone 1-800-821-8590
    Email genentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT01131078
    Other Study ID Numbers:
    • ML18524
    First Posted:
    May 26, 2010
    Last Update Posted:
    Jun 4, 2015
    Last Verified:
    Jun 1, 2015