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Trial record 57 of 104 for:    colon cancer | ( Map: Nebraska, United States )

Study of Bevacizumab + mFOLFOX6 Versus Bevacizumab + FOLFIRI With Biomarker Stratification in Participants With Previously Untreated Metastatic Colorectal Cancer (mCRC) (MAVERICC)

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ClinicalTrials.gov Identifier: NCT01374425
Recruitment Status : Completed
First Posted : June 16, 2011
Results First Posted : August 11, 2016
Last Update Posted : August 11, 2016
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Colorectal Cancer
Interventions Drug: 5-Fluorouracil
Drug: Bevacizumab
Drug: Irinotecan
Drug: Leucovorin
Drug: Oxaliplatin
Drug: Capecitabine
Enrollment 376
Recruitment Details  
Pre-assignment Details The trial included a 21-day Screening period during which participants provided information for demographics, medical history, and cancer/treatment history and completed urinalysis collection.
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description Participants with untreated metastatic colorectal cancer (mCRC) who were candidates for first-line therapy received bevacizumab plus leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) until disease progression or unacceptable toxicity. Bevacizumab was given as 5 milligrams per kilogram (mg/kg), leucovorin as 400 milligrams per meter-squared (mg/m^2), oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via intravenous (IV) infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI) until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Period Title: Overall Study
Started 188 188
Completed 0 0
Not Completed 188 188
Reason Not Completed
Radiographic Disease Progression             86             81
Clinical Disease Progression             9             6
Adverse Event             29             18
Death (Progression of Disease)             1             0
Death (Adverse Event)             2             4
Withdrawal by Subject             6             7
Refused Treatment             10             24
Protocol Violation             2             3
Sponsor Decision             0             1
Lost to Follow-up             2             1
Not Specified             41             43
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI Total
Hide Arm/Group Description Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Total of all reporting groups
Overall Number of Baseline Participants 188 188 376
Hide Baseline Analysis Population Description
Intent-to-Treat (ITT) Population: All randomized participants regardless of receiving any study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 188 participants 188 participants 376 participants
59.2  (10.88) 60.7  (10.66) 59.9  (10.78)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 188 participants 188 participants 376 participants
Female
66
  35.1%
71
  37.8%
137
  36.4%
Male
122
  64.9%
117
  62.2%
239
  63.6%
1.Primary Outcome
Title Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as greater than or equal to (≥) 20 percent (%) increase in sum of largest diameters (LD) of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 millimeters (mm). Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) Population
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 188 188
Median (95% Confidence Interval)
Unit of Measure: months
10.09
(8.80 to 11.56)
12.55
(10.48 to 14.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments Analysis stratified by high/low excision repair cross-complementing (ERCC)-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0555
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.61 to 1.01
Estimation Comments Hazard ratio (HR) (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
2.Primary Outcome
Title PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level greater than (>) 1.7 × 10^-3 ERCC-1/B-actin messenger ribonucleic acid (mRNA) at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 64 67
Median (95% Confidence Interval)
Unit of Measure: months
9.92
(8.51 to 12.48)
11.17
(9.10 to 17.84)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3944
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.56 to 1.26
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
3.Primary Outcome
Title PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level less than or equal to (≤) 1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Median (95% Confidence Interval)
Unit of Measure: months
10.97
(8.54 to 12.29)
12.68
(10.48 to 14.49)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0786
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.55 to 1.03
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
4.Primary Outcome
Title PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Median (95% Confidence Interval)
Unit of Measure: months
10.87
(9.10 to 12.68)
11.56
(9.95 to 12.98)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9576
Comments P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.99
Confidence Interval (2-Sided) 95%
0.77 to 1.28
Estimation Comments HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
5.Primary Outcome
Title PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 picograms per milliliter (pg/mL) at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Median (95% Confidence Interval)
Unit of Measure: months
10.02
(8.80 to 11.17)
12.68
(10.9 to 14.26)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments Analysis stratified by high/low ERCC-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1658
Comments P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.19
Confidence Interval (2-Sided) 95%
0.93 to 1.53
Estimation Comments HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
6.Secondary Outcome
Title PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High) Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 28 31
Median (95% Confidence Interval)
Unit of Measure: months
8.80
(5.91 to 10.02)
11.17
(8.11 to 18.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A High), Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A High)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3019
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.73
Confidence Interval (2-Sided) 95%
0.41 to 1.32
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
7.Secondary Outcome
Title PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low) Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 35 35
Median (95% Confidence Interval)
Unit of Measure: months
12.52
(9.43 to 15.64)
12.68
(8.18 to 20.83)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High, VEGF-A Low), Bevacizumab + FOLFIRI (ERCC-1 High, VEGF-A Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6035
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.48 to 1.53
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
8.Secondary Outcome
Title PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High) Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 66 59
Median (95% Confidence Interval)
Unit of Measure: months
9.76
(8.18 to 12.45)
11.07
(8.18 to 14.29)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A High), Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A High)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4032
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.54 to 1.28
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
9.Secondary Outcome
Title PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low) Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA and VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 55 60
Median (95% Confidence Interval)
Unit of Measure: months
11.10
(8.54 to 13.08)
14.32
(11.56 to 14.98)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low, VEGF-A Low), Bevacizumab + FOLFIRI (ERCC-1 Low, VEGF-A Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0647
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.65
Confidence Interval (2-Sided) 95%
0.41 to 1.03
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
10.Secondary Outcome
Title Overall Survival (OS)
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
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Hide Analysis Population Description
ITT Population
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 188 188
Median (95% Confidence Interval)
Unit of Measure: months
23.85
(20.40 to 26.05)
27.47
(24.64 to 36.73)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments Analysis stratified by high/low ERCC-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0861
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.56 to 1.04
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
11.Secondary Outcome
Title OS in Participants With High ERCC-1 Levels
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 64 67
Median (95% Confidence Interval)
Unit of Measure: months
22.54
(17.02 to 26.05)
26.51
(19.09 to 36.73)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3295
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval (2-Sided) 95%
0.51 to 1.26
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
12.Secondary Outcome
Title OS in Participants With Low ERCC-1 Levels
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Median (95% Confidence Interval)
Unit of Measure: months
25.53
(20.40 to 28.75)
27.93
(24.97 to 38.44)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1519
Comments P-value (relative to Bevacizumab + mFOLFOX6) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval (2-Sided) 95%
0.49 to 1.12
Estimation Comments HR (relative to Bevacizumab + mFOLFOX6) was estimated by Cox regression.
13.Secondary Outcome
Title OS in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Median (95% Confidence Interval)
Unit of Measure: months
23.23
(19.09 to 26.94)
27.27
(24.34 to 31.28)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments Analysis stratified by region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2774
Comments P-value (relative to ERCC-1 Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.19
Confidence Interval (2-Sided) 95%
0.87 to 1.62
Estimation Comments HR (relative to ERCC-1 Low subgroup) was estimated by Cox regression.
14.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1
Hide Description Objective response was defined as complete response (CR) or partial response (PR) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 188 188
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
61.2
(54.2 to 68.1)
65.4
(58.6 to 72.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value 4.3
Confidence Interval (2-Sided) 95%
-5.5 to 14.0
Estimation Comments The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
15.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
Hide Description Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 64 67
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
56.3
(44.1 to 68.4)
65.7
(54.3 to 77.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value 9.4
Confidence Interval (2-Sided) 95%
7.2 to 26.1
Estimation Comments The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
16.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
Hide Description Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
63.7
(55.2 to 72.2)
65.8
(57.3 to 74.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
-9.9 to 14.1
Estimation Comments The difference was calculated as the percentage of participants with objective response in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
17.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
61.1
(52.7 to 69.4)
64.8
(58.8 to 70.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value -3.7
Confidence Interval (2-Sided) 95%
-14.0 to 6.6
Estimation Comments The difference was calculated as the percentage of participants with objective response in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
18.Secondary Outcome
Title Percentage of Participants With Disease Control According to RECIST Version 1.1
Hide Description Disease control was defined as CR, PR, or stable disease (SD) according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 188 188
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
93.1
(89.5 to 96.7)
91.0
(86.9 to 95.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Disease Control Rates
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
-7.6 to 3.3
Estimation Comments The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
19.Secondary Outcome
Title Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels
Hide Description Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 64 67
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
93.8
(87.8 to 99.7)
85.1
(76.5 to 93.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Disease Control Rates
Estimated Value -8.7
Confidence Interval (2-Sided) 95%
-19.1 to 1.7
Estimation Comments The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
20.Secondary Outcome
Title Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels
Hide Description Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
92.7
(88.2 to 97.3)
95.0
(91.1 to 98.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Disease Control Rates
Estimated Value 2.3
Confidence Interval (2-Sided) 95%
-3.7 to 8.3
Estimation Comments The difference was calculated as the percentage of participants with disease control in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
21.Secondary Outcome
Title Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
89.3
(84.0 to 94.6)
93.9
(90.8 to 96.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Disease Control Rates
Estimated Value -4.5
Confidence Interval (2-Sided) 95%
-10.6 to 1.5
Estimation Comments The difference was calculated as the percentage of participants with disease control in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
22.Secondary Outcome
Title Percentage of Participants With Liver Metastasis Resection
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 67 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
14.9
(6.4 to 23.5)
10.9
(2.7 to 19.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Resection Rates
Estimated Value -4.0
Confidence Interval (2-Sided) 95%
-15.9 to 7.8
Estimation Comments The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
23.Secondary Outcome
Title Percentage of Participants With Complete Liver Metastasis Resection
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis.
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
Overall Number of Participants Analyzed 67 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
11.9
(4.2 to 19.7)
5.5
(0.0 to 11.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6, Bevacizumab + FOLFIRI
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Complete Resection Rates
Estimated Value -6.5
Confidence Interval (2-Sided) 95%
-16.3 to 3.3
Estimation Comments The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
24.Secondary Outcome
Title Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 17 15
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
17.6
(0.0 to 35.8)
6.7
(0.0 to 19.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Resection Rates
Estimated Value -11.0
Confidence Interval (2-Sided) 95%
-33.1 to 11.1
Estimation Comments The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
25.Secondary Outcome
Title Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 High) Bevacizumab + FOLFIRI (ERCC-1 High)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 17 15
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
17.6
(0.0 to 35.8)
6.7
(0.0 to 19.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 High), Bevacizumab + FOLFIRI (ERCC-1 High)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Complete Resection Rates
Estimated Value -11.0
Confidence Interval (2-Sided) 95%
-33.1 to 11.1
Estimation Comments The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
26.Secondary Outcome
Title Percentage of Participants With Liver Metastasis Resection in Participants With Low ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
10.5
(5.1 to 15.9)
7.5
(2.8 to 12.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Resection Rates
Estimated Value -3.0
Confidence Interval (2-Sided) 95%
-10.1 to 4.2
Estimation Comments The difference was calculated as the percentage of participants with resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
27.Secondary Outcome
Title Percentage of Participants With Complete Liver Metastasis Resection in Participants With Low ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX6 (ERCC-1 Low) Bevacizumab + FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 124 120
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
8.9
(3.9 to 13.9)
3.3
(0.1 to 6.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX6 (ERCC-1 Low), Bevacizumab + FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Complete Resection Rates
Estimated Value -5.5
Confidence Interval (2-Sided) 95%
-11.5 to 0.4
Estimation Comments The difference was calculated as the percentage of participants with complete resection in the Bevacizumab + FOLFIRI arm minus the Bevacizumab + mFOLFOX6 arm. The 95% CI was computed using normal approximation to the binomial distribution.
28.Secondary Outcome
Title Percentage of Participants With Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
4.6
(1.0 to 8.2)
9.0
(5.4 to 12.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Resection Rates
Estimated Value -4.4
Confidence Interval (2-Sided) 95%
-9.5 to 0.6
Estimation Comments The difference was calculated as the percentage of participants with resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
29.Secondary Outcome
Title Percentage of Participants With Complete Liver Metastasis Resection in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High) Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level >1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with ERCC-1 level ≤1.7 × 10^-3 ERCC-1/B-actin mRNA at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 131 244
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
4.6
(1.0 to 8.2)
6.1
(3.1 to 9.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 High), Bevacizumab + mFOLFOX/FOLFIRI (ERCC-1 Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Complete Resection Rates
Estimated Value -1.6
Confidence Interval (2-Sided) 95%
-6.2 to 3.1
Estimation Comments The difference was calculated as the percentage of participants with complete resection in the ERCC-1 High subgroup minus the ERCC-1 Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
30.Secondary Outcome
Title PFS According to RECIST Version 1.1 in Participants With Wild-Type V-Ki-ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Versus Participants With Mutant KRAS
Hide Description Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with wild-type KRAS at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with mutant KRAS at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 208 128
Median (95% Confidence Interval)
Unit of Measure: months
12.45
(10.48 to 14.06)
10.94
(8.77 to 12.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type), Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Comments Analysis stratified by high/low ERCC-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0593
Comments P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.29
Confidence Interval (2-Sided) 95%
0.99 to 1.69
Estimation Comments HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
31.Secondary Outcome
Title OS in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Median (95% Confidence Interval)
Unit of Measure: months
22.83
(18.76 to 27.27)
27.93
(24.97 to 36.01)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments Analysis stratified by high/low ERCC-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0020
Comments P-value (relative to VEGF-A Low subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.64
Confidence Interval (2-Sided) 95%
1.20 to 2.24
Estimation Comments HR (relative to VEGF-A Low subgroup) was estimated by Cox regression.
32.Secondary Outcome
Title OS in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
Hide Description Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. OS was defined as the time from randomization to death. The median duration of OS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.
Time Frame From Baseline until death (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with wild-type KRAS at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with mutant KRAS at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 208 128
Median (95% Confidence Interval)
Unit of Measure: months
28.75
(24.77 to 36.73)
24.64
(19.98 to 26.94)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type), Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Comments Analysis stratified by high/low ERCC-1 level and region of enrollment.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0955
Comments P-value (relative to KRAS Wild-Type subgroup) based on two-sided stratified log rank test and not adjusted for multiple comparisons.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.34
Confidence Interval (2-Sided) 95%
0.95 to 1.88
Estimation Comments HR (relative to KRAS Wild-Type subgroup) was estimated by Cox regression.
33.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
Hide Description Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
60.5
(53.5 to 67.6)
66.5
(59.7 to 73.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value -5.9
Confidence Interval (2-Sided) 95%
-15.7 to 3.8
Estimation Comments The difference was calculated as the percentage of participants with objective response in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
34.Secondary Outcome
Title Percentage of Participants With Objective Response According to RECIST Version 1.1 in Participants With Wild-Type KRAS Versus Participants With Mutant KRAS
Hide Description Objective response was defined as CR or PR according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. The percentage of participants with CR or PR was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type) Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with wild-type KRAS at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with mutant KRAS at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 208 128
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
66.3
(59.9 to 72.8)
60.9
(52.5 to 69.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (KRAS Wild-Type), Bevacizumab + mFOLFOX/FOLFIRI (KRAS Mutant)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Objective Response Rates
Estimated Value -5.4
Confidence Interval (2-Sided) 95%
-16.0 to 5.2
Estimation Comments The difference was calculated as the percentage of participants with objective response in the KRAS Mutant subgroup minus the KRAS Wild-Type subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
35.Secondary Outcome
Title Percentage of Participants With Disease Control According to RECIST Version 1.1 in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
Hide Description Disease control was defined as CR, PR, or SD according to RECIST Version 1.1. CR was defined as disappearance of all target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as ≥30% decrease in sum of LD of target lesions in reference to sum of LD at Baseline. Confirmation of response at a consecutive assessment was not required. SD was defined as neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for disease progression (≥20% increase in sum of LD of target lesions plus absolute increase ≥5 mm) in reference to the smallest sum of LD on study. The percentage of participants with CR, PR, or SD was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame From Baseline until disease progression; assessed every 6 weeks (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
91.9
(88.0 to 95.8)
93.0
(89.3 to 96.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Disease Control Rates
Estimated Value -1.1
Confidence Interval (2-Sided) 95%
-6.5 to 4.3
Estimation Comments The difference was calculated as the percentage of participants with disease control in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
36.Secondary Outcome
Title Percentage of Participants With Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. R1 was defined as the presence of exposed tumor or histologically detected tumor cells at the line of transection, or <1 mm microscopic margins. In the case of use of radiofrequency ablation or cryotherapy, the resection was considered as R1. R2 was defined as macroscopic positive margins or incomplete resection at time of surgery. The percentage of participants with resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
5.9
(2.5 to 9.4)
9.2
(5.0 to 13.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Resection Rates
Estimated Value -3.2
Confidence Interval (2-Sided) 95%
-8.6 to 2.1
Estimation Comments The difference was calculated as the percentage of participants with resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
37.Secondary Outcome
Title Percentage of Participants With Complete Liver Metastasis Resection in Participants With High VEGF-A Levels Versus Participants With Low VEGF-A Levels
Hide Description The timing of resective surgery was not defined in the protocol and was left at the discretion of the Investigator. Resection was classified as R0, R1, or R2 following surgery. R0 was defined as complete resection with clear margins ≥1 mm. The percentage of participants with R0 resection of liver or liver plus lymph node metastases was reported. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame At time of resective surgery during study (maximum up to 45 months overall)
Hide Outcome Measure Data
Hide Analysis Population Description
ITT Population; only those participants with liver or liver plus lymph node metastases were included in the analysis. The "Number of Participants Analyzed" reflects the number of evaluable participants for the outcome measure.
Arm/Group Title Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High) Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Hide Arm/Group Description:
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level >5 pg/mL at Baseline were included in separate analyses.
Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 or bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Depending on the regimen to which the participant was randomized, bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin or irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with VEGF-A level ≤5 pg/mL at Baseline were included in separate analyses.
Overall Number of Participants Analyzed 185 185
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
3.2
(0.7 to 5.8)
8.1
(4.2 to 12.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A High), Bevacizumab + mFOLFOX/FOLFIRI (VEGF-A Low)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in Complete Resection Rates
Estimated Value -4.9
Confidence Interval (2-Sided) 95%
-9.6 to -0.2
Estimation Comments The difference was calculated as the percentage of participants with complete resection in the VEGF-A High subgroup minus the VEGF-A Low subgroup. The 95% CI was computed using normal approximation to the binomial distribution.
Time Frame Serious Adverse Events (AEs): Baseline until 3 months after last dose or study discontinuation/termination (up to 45 months overall); Other AEs: Baseline until 28 days after last dose or study discontinuation/termination (up to 45 months overall).
Adverse Event Reporting Description Safety Population: All randomized participants who received at least one partial or complete dose of study drug.
 
Arm/Group Title Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Hide Arm/Group Description Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus mFOLFOX6 until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, oxaliplatin as 85 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles. Participants with untreated mCRC who were candidates for first-line therapy received bevacizumab plus FOLFIRI until disease progression or unacceptable toxicity. Bevacizumab was given as 5 mg/kg, leucovorin as 400 mg/m^2, irinotecan as 180 mg/m^2, and 5-fluorouracil as 400 mg/m^2 bolus followed by 2400 mg/m^2 continuous 46-hour infusion. All treatments were administered via IV infusion and started on Day 1 of each 2-week cycle. Participants could be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan and given as 850 or 1000 mg/m^2 twice a day on Days 1 to 14, with bevacizumab continued in 3-week cycles.
All-Cause Mortality
Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Affected / at Risk (%) Affected / at Risk (%)
Total   79/185 (42.70%)   87/183 (47.54%) 
Blood and lymphatic system disorders     
Thrombocytopenia * 1  3/185 (1.62%)  0/183 (0.00%) 
Febrile neutropenia * 1  2/185 (1.08%)  4/183 (2.19%) 
Anaemia * 1  1/185 (0.54%)  1/183 (0.55%) 
Immune thrombocytopenic purpura * 1  1/185 (0.54%)  0/183 (0.00%) 
Neutropenia * 1  1/185 (0.54%)  2/183 (1.09%) 
Pancytopenia * 1  1/185 (0.54%)  1/183 (0.55%) 
Cardiac disorders     
Atrial flutter * 1  1/185 (0.54%)  0/183 (0.00%) 
Cardio-respiratory arrest * 1  1/185 (0.54%)  0/183 (0.00%) 
Left ventricular dysfunction * 1  1/185 (0.54%)  0/183 (0.00%) 
Myocardial infarction * 1  1/185 (0.54%)  1/183 (0.55%) 
Supraventricular tachycardia * 1  1/185 (0.54%)  0/183 (0.00%) 
Atrial fibrillation * 1  0/185 (0.00%)  3/183 (1.64%) 
Atrial thrombosis * 1  0/185 (0.00%)  1/183 (0.55%) 
Gastrointestinal disorders     
Diarrhoea * 1  6/185 (3.24%)  2/183 (1.09%) 
Small intestinal obstruction * 1  5/185 (2.70%)  6/183 (3.28%) 
Rectal haemorrhage * 1  4/185 (2.16%)  0/183 (0.00%) 
Abdominal pain * 1  3/185 (1.62%)  7/183 (3.83%) 
Intestinal obstruction * 1  3/185 (1.62%)  3/183 (1.64%) 
Vomiting * 1  3/185 (1.62%)  4/183 (2.19%) 
Constipation * 1  2/185 (1.08%)  0/183 (0.00%) 
Dysphagia * 1  2/185 (1.08%)  0/183 (0.00%) 
Large intestine perforation * 1  2/185 (1.08%)  1/183 (0.55%) 
Nausea * 1  2/185 (1.08%)  1/183 (0.55%) 
Oesophagitis * 1  2/185 (1.08%)  0/183 (0.00%) 
Upper gastrointestinal haemorrhage * 1  2/185 (1.08%)  0/183 (0.00%) 
Abdominal pain lower * 1  1/185 (0.54%)  0/183 (0.00%) 
Ascites * 1  1/185 (0.54%)  0/183 (0.00%) 
Duodenal ulcer haemorrhage * 1  1/185 (0.54%)  0/183 (0.00%) 
Enteritis * 1  1/185 (0.54%)  0/183 (0.00%) 
Gastrooesophageal reflux disease * 1  1/185 (0.54%)  0/183 (0.00%) 
Ileal perforation * 1  1/185 (0.54%)  0/183 (0.00%) 
Large intestinal haemorrhage * 1  1/185 (0.54%)  0/183 (0.00%) 
Neutropenic colitis * 1  1/185 (0.54%)  0/183 (0.00%) 
Oesophageal motility disorder * 1  1/185 (0.54%)  0/183 (0.00%) 
Oesophageal varices haemorrhage * 1  1/185 (0.54%)  0/183 (0.00%) 
Pneumoperitoneum * 1  1/185 (0.54%)  0/183 (0.00%) 
Small intestinal perforation * 1  1/185 (0.54%)  0/183 (0.00%) 
Abdominal distension * 1  0/185 (0.00%)  1/183 (0.55%) 
Abdominal pain upper * 1  0/185 (0.00%)  2/183 (1.09%) 
Anal fistula * 1  0/185 (0.00%)  1/183 (0.55%) 
Colitis * 1  0/185 (0.00%)  2/183 (1.09%) 
Duodenitis * 1  0/185 (0.00%)  1/183 (0.55%) 
Enterovesical fistula * 1  0/185 (0.00%)  1/183 (0.55%) 
Gastric haemorrhage * 1  0/185 (0.00%)  1/183 (0.55%) 
Gastrointestinal haemorrhage * 1  0/185 (0.00%)  1/183 (0.55%) 
Haemorrhoidal haemorrhage * 1  0/185 (0.00%)  1/183 (0.55%) 
Ileus * 1  0/185 (0.00%)  2/183 (1.09%) 
Large intestinal obstruction * 1  0/185 (0.00%)  2/183 (1.09%) 
Pancreatitis * 1  0/185 (0.00%)  1/183 (0.55%) 
Reflux gastritis * 1  0/185 (0.00%)  1/183 (0.55%) 
General disorders     
Chest pain * 1  3/185 (1.62%)  4/183 (2.19%) 
Pyrexia * 1  3/185 (1.62%)  4/183 (2.19%) 
Device dislocation * 1  2/185 (1.08%)  1/183 (0.55%) 
Asthenia * 1  1/185 (0.54%)  1/183 (0.55%) 
Chills * 1  1/185 (0.54%)  0/183 (0.00%) 
Mucosal inflammation * 1  1/185 (0.54%)  0/183 (0.00%) 
Multi-organ failure * 1  1/185 (0.54%)  0/183 (0.00%) 
Peripheral swelling * 1  1/185 (0.54%)  0/183 (0.00%) 
Systemic inflammatory response syndrome * 1  1/185 (0.54%)  0/183 (0.00%) 
Device malfunction * 1  0/185 (0.00%)  1/183 (0.55%) 
Fatigue * 1  0/185 (0.00%)  3/183 (1.64%) 
Gait disturbance * 1  0/185 (0.00%)  1/183 (0.55%) 
Localised oedema * 1  0/185 (0.00%)  1/183 (0.55%) 
Hepatobiliary disorders     
Cholecystitis * 1  1/185 (0.54%)  1/183 (0.55%) 
Cholecystitis acute * 1  1/185 (0.54%)  0/183 (0.00%) 
Hyperbilirubinaemia * 1  1/185 (0.54%)  0/183 (0.00%) 
Ischaemic hepatitis * 1  1/185 (0.54%)  0/183 (0.00%) 
Biloma * 1  0/185 (0.00%)  1/183 (0.55%) 
Cholangitis * 1  0/185 (0.00%)  1/183 (0.55%) 
Cholecystitis chronic * 1  0/185 (0.00%)  1/183 (0.55%) 
Cholelithiasis * 1  0/185 (0.00%)  1/183 (0.55%) 
Hepatic steatosis * 1  0/185 (0.00%)  1/183 (0.55%) 
Hepatitis * 1  0/185 (0.00%)  1/183 (0.55%) 
Jaundice * 1  0/185 (0.00%)  1/183 (0.55%) 
Infections and infestations     
Sepsis * 1  4/185 (2.16%)  3/183 (1.64%) 
Pneumonia * 1  3/185 (1.62%)  7/183 (3.83%) 
Cellulitis * 1  2/185 (1.08%)  0/183 (0.00%) 
Septic shock * 1  2/185 (1.08%)  1/183 (0.55%) 
Upper respiratory tract infection * 1  2/185 (1.08%)  0/183 (0.00%) 
Abdominal abscess * 1  1/185 (0.54%)  0/183 (0.00%) 
Abdominal infection * 1  1/185 (0.54%)  0/183 (0.00%) 
Appendicitis * 1  1/185 (0.54%)  0/183 (0.00%) 
Bronchitis * 1  1/185 (0.54%)  0/183 (0.00%) 
Candida sepsis * 1  1/185 (0.54%)  0/183 (0.00%) 
Diverticulitis * 1  1/185 (0.54%)  0/183 (0.00%) 
Endocarditis * 1  1/185 (0.54%)  0/183 (0.00%) 
Infection * 1  1/185 (0.54%)  1/183 (0.55%) 
Lung infection * 1  1/185 (0.54%)  0/183 (0.00%) 
Respiratory tract infection * 1  1/185 (0.54%)  0/183 (0.00%) 
Subcutaneous abscess * 1  1/185 (0.54%)  0/183 (0.00%) 
Urinary tract infection * 1  1/185 (0.54%)  0/183 (0.00%) 
Urosepsis * 1  1/185 (0.54%)  1/183 (0.55%) 
Device related infection * 1  0/185 (0.00%)  2/183 (1.09%) 
Gastroenteritis * 1  0/185 (0.00%)  1/183 (0.55%) 
Gastroenteritis viral * 1  0/185 (0.00%)  1/183 (0.55%) 
Kidney infection * 1  0/185 (0.00%)  1/183 (0.55%) 
Lower respiratory tract infection * 1  0/185 (0.00%)  1/183 (0.55%) 
Neutropenic sepsis * 1  0/185 (0.00%)  1/183 (0.55%) 
Perineal abscess * 1  0/185 (0.00%)  1/183 (0.55%) 
Pneumonia bacterial * 1  0/185 (0.00%)  1/183 (0.55%) 
Pneumonia parainfluenzae viral * 1  0/185 (0.00%)  1/183 (0.55%) 
Injury, poisoning and procedural complications     
Infusion related reaction * 1  1/185 (0.54%)  0/183 (0.00%) 
Laceration * 1  1/185 (0.54%)  0/183 (0.00%) 
Stoma site haemorrhage * 1  1/185 (0.54%)  0/183 (0.00%) 
Toxicity to various agents * 1  1/185 (0.54%)  0/183 (0.00%) 
Wound dehiscence * 1  1/185 (0.54%)  0/183 (0.00%) 
Abdominal wound dehiscence * 1  0/185 (0.00%)  1/183 (0.55%) 
Intestinal anastomosis complication * 1  0/185 (0.00%)  1/183 (0.55%) 
Spinal compression fracture * 1  0/185 (0.00%)  1/183 (0.55%) 
Investigations     
Platelet count decreased * 1  2/185 (1.08%)  0/183 (0.00%) 
Weight decreased * 1  1/185 (0.54%)  0/183 (0.00%) 
Blood bilirubin increased * 1  0/185 (0.00%)  2/183 (1.09%) 
Metabolism and nutrition disorders     
Dehydration * 1  8/185 (4.32%)  5/183 (2.73%) 
Decreased appetite * 1  1/185 (0.54%)  0/183 (0.00%) 
Diabetes mellitus * 1  1/185 (0.54%)  0/183 (0.00%) 
Failure to thrive * 1  1/185 (0.54%)  1/183 (0.55%) 
Hyperglycaemia * 1  1/185 (0.54%)  0/183 (0.00%) 
Hypokalaemia * 1  1/185 (0.54%)  1/183 (0.55%) 
Hyponatraemia * 1  1/185 (0.54%)  2/183 (1.09%) 
Malnutrition * 1  1/185 (0.54%)  0/183 (0.00%) 
Hypoalbuminaemia * 1  0/185 (0.00%)  1/183 (0.55%) 
Hypophosphataemia * 1  0/185 (0.00%)  1/183 (0.55%) 
Metabolic alkalosis * 1  0/185 (0.00%)  1/183 (0.55%) 
Musculoskeletal and connective tissue disorders     
Muscular weakness * 1  1/185 (0.54%)  1/183 (0.55%) 
Polyarthritis * 1  1/185 (0.54%)  0/183 (0.00%) 
Rhabdomyolysis * 1  1/185 (0.54%)  0/183 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Meningioma * 1  0/185 (0.00%)  1/183 (0.55%) 
Nervous system disorders     
Aphonia * 1  1/185 (0.54%)  0/183 (0.00%) 
Ataxia * 1  1/185 (0.54%)  0/183 (0.00%) 
Cerebrovascular accident * 1  1/185 (0.54%)  1/183 (0.55%) 
Seizure * 1  1/185 (0.54%)  0/183 (0.00%) 
Syncope * 1  1/185 (0.54%)  2/183 (1.09%) 
Haemorrhage intracranial * 1  0/185 (0.00%)  1/183 (0.55%) 
Ischaemic stroke * 1  0/185 (0.00%)  1/183 (0.55%) 
Thrombotic stroke * 1  0/185 (0.00%)  1/183 (0.55%) 
Psychiatric disorders     
Confusional state * 1  1/185 (0.54%)  1/183 (0.55%) 
Mental status changes * 1  0/185 (0.00%)  2/183 (1.09%) 
Renal and urinary disorders     
Acute kidney injury * 1  1/185 (0.54%)  2/183 (1.09%) 
Proteinuria * 1  1/185 (0.54%)  1/183 (0.55%) 
Renal failure * 1  0/185 (0.00%)  1/183 (0.55%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary embolism * 1  9/185 (4.86%)  9/183 (4.92%) 
Acute respiratory failure * 1  2/185 (1.08%)  1/183 (0.55%) 
Respiratory distress * 1  2/185 (1.08%)  0/183 (0.00%) 
Chronic obstructive pulmonary disease * 1  1/185 (0.54%)  0/183 (0.00%) 
Dyspnoea * 1  1/185 (0.54%)  1/183 (0.55%) 
Epistaxis * 1  1/185 (0.54%)  1/183 (0.55%) 
Hiccups * 1  1/185 (0.54%)  0/183 (0.00%) 
Pulmonary thrombosis * 1  1/185 (0.54%)  0/183 (0.00%) 
Asthma * 1  0/185 (0.00%)  1/183 (0.55%) 
Cough * 1  0/185 (0.00%)  1/183 (0.55%) 
Interstitial lung disease * 1  0/185 (0.00%)  1/183 (0.55%) 
Pulmonary artery thrombosis * 1  0/185 (0.00%)  1/183 (0.55%) 
Surgical and medical procedures     
Colostomy * 1  0/185 (0.00%)  1/183 (0.55%) 
Vascular disorders     
Hypotension * 1  5/185 (2.70%)  1/183 (0.55%) 
Hypertension * 1  3/185 (1.62%)  6/183 (3.28%) 
Arterial thrombosis * 1  1/185 (0.54%)  0/183 (0.00%) 
Deep vein thrombosis * 1  1/185 (0.54%)  4/183 (2.19%) 
Embolism venous * 1  1/185 (0.54%)  1/183 (0.55%) 
Venous thrombosis * 1  1/185 (0.54%)  1/183 (0.55%) 
Jugular vein thrombosis * 1  0/185 (0.00%)  1/183 (0.55%) 
Thrombosis * 1  0/185 (0.00%)  1/183 (0.55%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (18.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bevacizumab + mFOLFOX6 Bevacizumab + FOLFIRI
Affected / at Risk (%) Affected / at Risk (%)
Total   185/185 (100.00%)   181/183 (98.91%) 
Blood and lymphatic system disorders     
Neutropenia * 1  65/185 (35.14%)  86/183 (46.99%) 
Anaemia * 1  25/185 (13.51%)  34/183 (18.58%) 
Thrombocytopenia * 1  44/185 (23.78%)  13/183 (7.10%) 
Eye disorders     
Vision blurred * 1  13/185 (7.03%)  12/183 (6.56%) 
Lacrimation increased * 1  4/185 (2.16%)  10/183 (5.46%) 
Gastrointestinal disorders     
Diarrhoea * 1  99/185 (53.51%)  123/183 (67.21%) 
Nausea * 1  106/185 (57.30%)  109/183 (59.56%) 
Constipation * 1  63/185 (34.05%)  65/183 (35.52%) 
Vomiting * 1  58/185 (31.35%)  57/183 (31.15%) 
Abdominal pain * 1  39/185 (21.08%)  54/183 (29.51%) 
Stomatitis * 1  35/185 (18.92%)  38/183 (20.77%) 
Gastrooesophageal reflux disease * 1  17/185 (9.19%)  18/183 (9.84%) 
Dyspepsia * 1  19/185 (10.27%)  14/183 (7.65%) 
Rectal haemorrhage * 1  11/185 (5.95%)  18/183 (9.84%) 
Abdominal pain upper * 1  8/185 (4.32%)  15/183 (8.20%) 
Oral pain * 1  8/185 (4.32%)  14/183 (7.65%) 
Haemorrhoids * 1  6/185 (3.24%)  16/183 (8.74%) 
Proctalgia * 1  7/185 (3.78%)  13/183 (7.10%) 
Dry mouth * 1  7/185 (3.78%)  11/183 (6.01%) 
Abdominal distension * 1  5/185 (2.70%)  12/183 (6.56%) 
Dysphagia * 1  10/185 (5.41%)  2/183 (1.09%) 
General disorders     
Fatigue * 1  105/185 (56.76%)  104/183 (56.83%) 
Mucosal inflammation * 1  37/185 (20.00%)  51/183 (27.87%) 
Pyrexia * 1  18/185 (9.73%)  29/183 (15.85%) 
Asthenia * 1  21/185 (11.35%)  18/183 (9.84%) 
Oedema peripheral * 1  18/185 (9.73%)  18/183 (9.84%) 
Temperature intolerance * 1  34/185 (18.38%)  1/183 (0.55%) 
Chest pain * 1  15/185 (8.11%)  10/183 (5.46%) 
Chills * 1  10/185 (5.41%)  10/183 (5.46%) 
Influenza like illness * 1  10/185 (5.41%)  6/183 (3.28%) 
Immune system disorders     
Hypersensitivity * 1  10/185 (5.41%)  0/183 (0.00%) 
Infections and infestations     
Urinary tract infection * 1  18/185 (9.73%)  20/183 (10.93%) 
Upper respiratory tract infection * 1  15/185 (8.11%)  18/183 (9.84%) 
Sinusitis * 1  9/185 (4.86%)  13/183 (7.10%) 
Injury, poisoning and procedural complications     
Infusion related reaction * 1  15/185 (8.11%)  8/183 (4.37%) 
Investigations     
Weight decreased * 1  33/185 (17.84%)  29/183 (15.85%) 
Neutrophil count decreased * 1  33/185 (17.84%)  23/183 (12.57%) 
Platelet count decreased * 1  24/185 (12.97%)  3/183 (1.64%) 
White blood cell count decreased * 1  15/185 (8.11%)  9/183 (4.92%) 
Metabolism and nutrition disorders     
Decreased appetite * 1  56/185 (30.27%)  55/183 (30.05%) 
Hypokalaemia * 1  36/185 (19.46%)  33/183 (18.03%) 
Dehydration * 1  28/185 (15.14%)  27/183 (14.75%) 
Hyperglycaemia * 1  9/185 (4.86%)  23/183 (12.57%) 
Hyponatraemia * 1  8/185 (4.32%)  15/183 (8.20%) 
Musculoskeletal and connective tissue disorders     
Arthralgia * 1  22/185 (11.89%)  25/183 (13.66%) 
Back pain * 1  21/185 (11.35%)  23/183 (12.57%) 
Pain in extremity * 1  22/185 (11.89%)  19/183 (10.38%) 
Musculoskeletal pain * 1  17/185 (9.19%)  11/183 (6.01%) 
Muscle spasms * 1  7/185 (3.78%)  11/183 (6.01%) 
Nervous system disorders     
Neuropathy peripheral * 1  85/185 (45.95%)  23/183 (12.57%) 
Headache * 1  31/185 (16.76%)  38/183 (20.77%) 
Dysgeusia * 1  33/185 (17.84%)  31/183 (16.94%) 
Paraesthesia * 1  35/185 (18.92%)  15/183 (8.20%) 
Peripheral sensory neuropathy * 1  35/185 (18.92%)  12/183 (6.56%) 
Dizziness * 1  15/185 (8.11%)  28/183 (15.30%) 
Psychiatric disorders     
Insomnia * 1  29/185 (15.68%)  35/183 (19.13%) 
Depression * 1  24/185 (12.97%)  18/183 (9.84%) 
Anxiety * 1  19/185 (10.27%)  20/183 (10.93%) 
Renal and urinary disorders     
Proteinuria * 1  38/185 (20.54%)  39/183 (21.31%) 
Respiratory, thoracic and mediastinal disorders     
Epistaxis * 1  41/185 (22.16%)  59/183 (32.24%) 
Cough * 1  31/185 (16.76%)  29/183 (15.85%) 
Dyspnoea * 1  28/185 (15.14%)  26/183 (14.21%) 
Rhinorrhoea * 1  12/185 (6.49%)  21/183 (11.48%) 
Dysphonia * 1  14/185 (7.57%)  18/183 (9.84%) 
Hiccups * 1  8/185 (4.32%)  14/183 (7.65%) 
Oropharyngeal pain * 1  11/185 (5.95%)  8/183 (4.37%) 
Skin and subcutaneous tissue disorders     
Alopecia * 1  26/185 (14.05%)  61/183 (33.33%) 
Dry skin * 1  27/185 (14.59%)  26/183 (14.21%) 
Rash * 1  19/185 (10.27%)  26/183 (14.21%) 
Palmar-plantar erythrodysaesthesia syndrome * 1  24/185 (12.97%)  18/183 (9.84%) 
Skin hyperpigmentation * 1  18/185 (9.73%)  13/183 (7.10%) 
Pruritus * 1  11/185 (5.95%)  9/183 (4.92%) 
Hyperhidrosis * 1  2/185 (1.08%)  10/183 (5.46%) 
Vascular disorders     
Hypertension * 1  61/185 (32.97%)  54/183 (29.51%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (18.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800-821-8590
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT01374425     History of Changes
Other Study ID Numbers: ML25710
2011-004755-39 ( EudraCT Number )
First Submitted: June 14, 2011
First Posted: June 16, 2011
Results First Submitted: June 30, 2016
Results First Posted: August 11, 2016
Last Update Posted: August 11, 2016